Branched 3-phenylpropionic acid derivatives and their use

Abstract

The present application relates to novel 3-phenylpropionic acid derivatives which carry a branched or cyclic alkyl substituent in the 3-position, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular diseases.

Claims

1. A compound having a formula selected from the group consisting of: ##STR00219## and hydrolysable ester derivatives thereof.

2. The compound of claim 1 having the formula ##STR00220## and hydrolysable ester derivatives thereof.

3. The compound of claim 1 having the formula ##STR00221## and hydrolysable ester derivatives thereof.

4. The hydrolysable ester derivative of the compound as defined in claim 1.

5. A medicament comprising the compound as defined in claim 1 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

6. A medicament comprising the compound as defined in claim 1 in combination with one or more further active compounds selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents having antithrombotic activity, agents lowering blood pressure, and agents altering lipid metabolisms.

Description

A. EXAMPLES

(1) Abbreviations and acronyms:

(2) abs. absolute Ac acetyl AIBN 2,2′-azobis-(2-methylpropionitrile) aq. aqueous, aqueous solution ATP adenosine 5′-triphosphate Bn benzyl Brij® polyethylene glycol dodecyl ether BSA bovine serum albumin Ex. example Bu butyl c concentration cat. catalytic CI chemical ionization (in MS) d day(s) DAST diethylaminosulphur trifluoride DC thin-layer chromatography DCI direct chemical ionization (in MS) DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess DMF dimethylformamide DMSO dimethyl sulphoxide DTT dithiothreitol EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride cc enantiomeric excess EI electron impact ionization (in MS) ent enantiomerically pure, enantiomer eq. equivalent(s) ESI electrospray ionization (in MS) Et ethyl GC gas chromatography sat. saturated GTP guanosine 5′-triphosphate h hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt 1-hydroxy-1H-benzotriazole hydrate HPLC high pressure, high performance liquid chromatography iPr isopropyl conc. concentrated LC-MS liquid chromatography-coupled mass spectroscopy LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide [lithium bis(trimethylsilyl)amide] Me methyl min minute(s) MS mass spectroscopy NB S N-bromosuccinimide NMP N-methylpyrrolidin-2-one NMR nuclear magnetic resonance spectroscopy p para Pd/C palladium on activated carbon Ph phenyl PMB p-methoxybenzyl Pr propyl Pt/c platinum on activated carbon rac racemic, racemate R.sub.f retention index (in TLC) RP reverse phase (in HPLC) RT room temperature R.sub.t retention time (in HPLC or GC) tBu tert-butyl TEA triethanolamine TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet spectroscopy v/v ratio by volume (of a solution)
GC-MS and LC-MS Methods:
Method 1 (GC-MS):

(3) Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min.fwdarw.310° C. (maintained for 3 min).

(4) Method 2 (LC-MS):

(5) MS instrument type: Waters Micromass Quattro Micro; HPLC instrument type: Agilent 1100 Series; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A.fwdarw.3.0 min 10% A.fwdarw.4.0 min 10% A.fwdarw.4.01 min 100% A (flow rate 2.5 ml/min).fwdarw.5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UV detection: 210 nm.

(6) Method 3 (LC-MS):

(7) MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.2.5 min 30% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; flow rate: 0.0 min 1 ml/min.fwdarw.2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

(8) Method 4 (LC-MS):

(9) Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min 10% A.fwdarw.2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.

(10) Method 5 (LC-MS):

(11) Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8μ, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; flow rate: 0.40 ml/min; oven: 50° C.; UV detection: 210-400 nm.

(12) Method 6 (GC-MS):

(13) Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintained for 3.33 min).

(14) Method 7 (LC-MS):

(15) Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8μ, 30 mm×2 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; flow rate: 0.60 ml/min; oven: 50° C.; UV detection: 208-400 nm.

(16) Method 8 (LC-MS):

(17) Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97% A.fwdarw.3.2 min 5% A.fwdarw.4.0 min 5% A; flow rate: 0.3 ml/min; oven: 50° C.; UV detection: 210 nm.

(18) Starting Materials and Intermediates:

Example 1A

(19) tert-Butyl (2E/Z)-4-methoxy-4-methylpent-2-enoate

(20) ##STR00056##

(21) At −70° C. and under argon, 6.8 ml (96 mmol) of DMSO in 10 ml of dichloromethane were added dropwise to a mixture of 24 ml (48 mmol) of a 2 M solution of oxalyl chloride in dichloromethane and a further 100 ml of dichloromethane, and the mixture was stirred for 15 minutes. 5.2 ml (48 mmol) of 2-methoxy-2-methylpropan-1-ol [H. Garcia el al., Chem. Eur. J. 16 (28), 8530-8536 (2010)], dissolved in 15 ml of dichloromethane, were then added dropwise, and the mixture was stirred at −70° C. for another 15 min. 22.1 ml (158 mmol) of triethylamine were added slowly, and the reaction mixture was then stirred for another 15 min and subsequently slowly warmed to room temperature. 22 g (58 mmol) of tert-butyl (triphenyl-λ.sup.5-phosphanylidene)acetate were then added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was then slowly added to 100 ml of ice-water, and the phases obtained were separated. The organic phase was washed twice with in each case 100 ml of water, dried over magnesium sulphate and concentrated under reduced pressure on a rotary evaporator (water bath temperature 40° C., pressure not below 150 mbar). The residue obtained was taken up in about 100 ml of diethyl ether and allowed to stand in a fridge at +3° C. for 2 days. The precipitated triphenylphosphine oxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1.fwdarw.50:1). This gave 7.06 g (73% of theory) of the title compound as a colourless liquid.

(22) GC-MS (method 6): R.sub.t=3.32 min, m/z=218 (M+NH.sub.4).sup.+.

(23) The two compounds below were obtained analogously to synthesis Example 1A:

(24) TABLE-US-00001 Example Name/Structure/Starting materials Analytical data 2A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.42 (s, 9H), 2.48- 2.64 (m, 2H, partially obscured by DMSO signal), 2.70-2.84 (m, 2H), 2.90-3.04 (m, 1H), 5.84 (d, 1H, .sup.3J = 16.38 Hz), 6.88 (dd, 1H). 3A GC-MS (Method 6): R.sub.t = 3.42 nun, m/z = 200 (M + NH.sub.4).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = -0.04-0.02 (m, 2H), 0.33-0.40 (m, 2H), 0.63-0.75 (m, 1H), 1.34 (s, 9H), 1.94-2.00 (m, 2H), 5.69-5.76 (m, 1H), 6.69- 6.79 (m, 1H).

Example 4A and Example 5A

(25) Methyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate and methyl 3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate

(26) Under argon, a mixture of 3.22 g (15.6 mmol) of 5-bromo-2-chloroaniline, 3.0 g (23.4 mmol) of methyl-(2E)-4-methylpent-2-enoate, 143 mg (0.16 mmol) of tris(dibenzylideneacetone)-dipalladium, 63 mg (0.31 mmol) of tri-tert-butylphosphine and 3.64 ml (17.2 mmol) of N,N-dicyclohexylmethylamine in 30 ml of dioxane were heated to 120° C. and stirred at this temperature for three days. Both after the first and after the second day of the reaction, the same amount of palladium catalyst and phosphine ligand was added to the reaction mixture. The reaction mixture was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was separated into its components by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 1.52 g of methyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate (38% of theory) and 906 mg of methyl 3-(3-amino-4-chlorophenyl)-4-methyl-pent-3-enoate (22% of theory).

(27) Example 4A

(28) Methyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate

(29) ##STR00059##

(30) LC-MS (Method 2): R.sub.t=2.46 min, m/z=254 (M+H).sup.+.

(31) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.03 (d, 6H), 3.65 (s, 3H), 3.90-4.03 (m, 1H), 5.42 (br. s, 2H), 5.63 (s, 1H), 6.40 (dd, 1H), 6.69 (d, 1H), 7.16 (d, 1H).

(32) Example 5A

(33) Methyl 3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate

(34) ##STR00060##

(35) LC-MS (Method 2): R.sub.t=2.28 min, m/z=254 (M+H).sup.+.

(36) The following compound was obtained analogously to Synthesis Example 4A/5A:

(37) TABLE-US-00002 Example Name/Structure/Starting materials Analytical data 6A LC-MS (Method 5): R.sub.t = 1.25 min, m/z, = 326/328 (M + H).sup.+.

Example 7A

(38) tert-Butyl (2E)-3-cyclobutylacrylate

(39) ##STR00062##
Step 1:

(40) A solution of 11.1 ml (116.1 mmol) of oxalyl chloride in 50 ml of abs. dichloromethane was cooled to −78° C., and a solution of 16.5 ml (232.2 mmol) of DMSO in 50 ml of abs. dichloromethane was added dropwise, keeping the temperature below −50° C. After 5 min, a solution of 10.0 g (116.1 mmol) of cyclobutanemethanol in 20 ml of abs. dichloromethane was added dropwise. After a further 15 min of stirring at −78° C., 80.9 ml (580.5 mmol) of triethylamine were added. After 5 min, cooling was removed and the mixture was slowly warmed to RT, and the reaction mixture was then added to water. The mixture was saturated with sodium chloride and the separated organic phase was washed twice with saturated sodium chloride solution, three times with 1 N hydrochloric acid and three times with pH buffer solution, dried over sodium sulphate and concentrated under reduced pressure (500 mbar). This gave 6.28 g of cyclobutanecarbaldehyde as a crude product which was directly reacted further.

(41) Step 2:

(42) 6.4 ml (27.3 mmol) of tert-butyl (diethoxyphosphoryl)acetate were added dropwise to a suspension, cooled to 0° C., of 1.05 g (60% in mineral oil, 26.2 mmol) of sodium hydride in a mixture of 22 ml of THF and 22 ml of DMF. After 30 min, the mixture was cooled to −10° C., and 2.0 g (crude, about 23.8 mmol) of cyclobutanecarbaldehyde were added in several portions. The reaction mixture was stirred at 0° C. for 5 h and then slowly warmed to RT overnight, subsequently added to water and extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 1.21 g of the target product (about 28% of theory).

(43) GC-MS (Method 1): R.sub.t=3.26 min; m/z=126 (M-C.sub.4H.sub.8).sup.+.

(44) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.42 (s, 9H), 1.74-1.96 (m, 4H), 2.05-2.17 (m, 2H), 3.03-3.16 (m, 1H), 5.66 (dd, 1H), 6.86 (dd, 1H).

Example 8A and Example 9A

(45) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate and tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate

(46) 0.78 ml (5.60 mmol) of triethylamine was added to a mixture of 385.2 mg (1.87 mmol) of 5-bromo-2-chloroaniline and 510 mg (2.80 mmol) of tert-butyl (2E)-3-cyclobutylacrylate in 2.8 ml of DMF. The mixture was evacuated three times and in each case vented with argon. After the addition of 41.9 mg (0.187 mmol) of palladium(II) acetate and 113.6 mg (0.373 mmol) of tri-2-tolylphosphine, the reaction mixture was evacuated two more times and in each case vented with argon and then stirred at 150° C. for 3 h. A further 193 mg of 5-bromo-2-chloroaniline were then added, and the reaction mixture was stirred at 150° C. for another 1 h. After cooling, the reaction mixture was filtered through Celite and the filter residue was washed twice with DMF. The combined filtrate was concentrated under high vacuum, and by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 60:1) the two isomeric target products were isolated from the residue. This gave 203 mg of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate (35.4% of theory) and 137 mg of tort-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate (23.8% of theory).

(47) Example 8A

(48) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate

(49) ##STR00063##

(50) LC-MS (Method 5): R.sub.t=1.36 min, m/z=308 (M+H).sup.+.

(51) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.45 (s, 9H), 1.52-1.63 (m, 1H), 1.74-1.85 (m, 3H), 2.09-2.18 (m, 2H), 4.10 (quin, 1H), 5.35-5.41 (m, 2H), 5.55 (d, 1H), 6.38 (dd, 1H), 6.66 (d, 1H), 7.16 (d, 1H).

(52) Example 9A

(53) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate

(54) ##STR00064##

(55) LC-MS (Method 5): R.sub.t=1.27 min, m/z=252 (M+H-C.sub.4H.sub.8).sup.+.

(56) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.31 (s, 9H), 1.93 (quin, 2H), 2.72-2.86 (m, 4H), 3.12 (s, 2H), 5.18-5.24 (m, 2H), 6.42 (dd, 1H), 6.69 (d, 1H), 7.06-7.11 (m, 1H).

(57) The following compounds were obtained analogously to Synthesis Example 8A/9A:

(58) TABLE-US-00003 Example Name/Structure/Starting materials Analytical data 10A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.46 (s, 9H), 2.23- 2.41 (m, 2H), 2.77-2.90 (m, 2H), 3.88-4.01 (m, 1H), 5.45 (br. s, 2H), 5.73 (d, 1H), 6.41 (dd, 1H), 6.66 (d, 1H), 7 19 (d, 1H). LC-MS (Method 7): R.sub.t = 1.37 min, m/z = 344 (M + H).sup.+. 11A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] =1.31 (s, 9H), 3.24 (s, 2H), 3.32-3.47 (m, 4H, partially obscured by H.sub.2Q signal), 5.30 (br. s, 2H), 6.46 (dd, 1H), 6.74 (d, 1H), 7.13 (d, 1H). LC-MS (Method 7): R.sub.t = 1.28 min, m/z = 344 (M + H).sup.+. 12A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.05-0.11 (m, 2H), 0.27-0.34 (m, 2H), 0.64-0.75 (m, 1H), 1.45 (s, 9H), 2.91 (d, 2H), 5.42 (br. s, 2H), 5.84 (s, 1H), 6.70 (dd, 1H), 6.96 (d, 1H), 7 19 (d, 1H). LC-MS (Method 5): R.sub.t= 1.35 min, m/z = 308 (M + H).sup.+.

Example 13A

(59) Methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate

(60) ##STR00068##

(61) At RT, a solution of 6.77 g (26.7 mmol) of methyl 2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate in 130 ml of methanol was added to 2.2 g (90.7 mmol) of magnesium turnings and a few grains of iodine. After about 30 min, the internal temperature increased to about 60° C. After the reaction solution had cooled to room temperature, stirring at room temperature was continued for another 2 h. 50 ml of saturated aqueous ammonium chloride solution were then added slowly to the dark reaction mixture, and the mixture was extracted repeatedly with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.95 g (40% of theory) of the title compound as an oil.

(62) LC-MS (Method 5): R.sub.t=1.06 min; m/z=256 (M+H).sup.+.

(63) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80 (m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H), 2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br. s, 2H), 6.35 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H).

(64) The following compounds were obtained analogously to Synthesis Example 13A:

(65) TABLE-US-00004 Example Name/Structure/Starting materials Analytical data 14A LC-MS (Method 7): R.sub.t = 1.26 min, m/z = 328/330 (M + H).sup.+. 15A 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.24 (s, 9H), 1.99- 2.17 (m, 1H), 2.19-2.40 (m, 4H), 2.46-2.57 (m, 1H, partially obscured by DMSO signal), 2.59-2.72 (m, 1H), 2.72-2.83 (m, 1H), 5.24 (br s, 2H), 6.42 (dd, 1H), 6.63 (d, 1H), 7.07 (d, 1H). LC-MS (Method 7): R.sub.t = 1.28 min, m/z = 346 (M + H).sup.+. 16A LC-MS (Method 5): R.sub.t = 1.32 min, m/z = 310 (M + H).sup.+.

Example 17A and Example 18A

(66) Methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate (Enantiomers 1 and 2)

(67) ##STR00072##

(68) By preparative HPLC on a chiral phase, 960 mg (3.75 mmol) of the racemate of methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate (Example 13A) were separated into the enantiomers [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/isopropanol 90:10 (v/v); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25° C.]:

(69) Example 17A (Enantiomer 1):

(70) Yield: 315 mg

(71) R.sub.t=6.90 min; chemical purity >99%; >99% ee

(72) [Column: Daicel AD-H, 5 μm, 250 mm×4 mm; mobile phase: isohexane/(isopropanol+0.2% diethylamine) 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 25° C.].

(73) LC-MS (Method 8): R.sub.t=2.34 min; m/z=256 (M+H).sup.+.

(74) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80 (m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H), 2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br. s, 2H), 6.35 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H).

(75) Example 18A (Enantiomer 2):

(76) Yield: 247 mg

(77) R.sub.t=7.76 min; chemical purity >99%; >99% ee

(78) [Column: Daicel AD-H, 5 μm, 250 mm×4 mm; mobile phase: isohexane/(isopropanol+0.2% diethylamine) 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 25° C.].

(79) LC-MS (Method 8): R.sub.t=2.34 min; m/z=256 (M+H).sup.+.

(80) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80 (m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H), 2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br. s, 2H), 6.35 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H).

Example 19A

2-Chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline

(81) ##STR00073##

(82) Under argon, 12.62 g (316.16 mmol, 60% in mineral oil) of sodium hydride were suspended in 250 ml of abs. DMF and cooled to 0° C. 32 g (126.3 mmol) of 2-chloro-5-iodoaniline, dissolved in 80 ml of abs. DMF, were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 41 ml (303 mmol) of 1-(chloromethyl)-4-methoxybenzene were then slowly added to the reaction mixture, and the mixture was subsequently warmed to room temperature. The mixture was stirred at RT overnight and then carefully poured into 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was then extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 59 g of the title compound (94% of theory).

(83) LC-MS (Method 4): R.sub.t=1.77 min; m/z=494/496 (M+H).sup.+.

(84) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=3.71 (s, 6H), 4.08 (s, 4H), 6.86 (d, 4H), 7.22 (d, 5H), 7.29-7.35 (m, 2H).

Example 20A

(85) {3-[Bis(4-methoxybenzyl)amino]-4-chlorophenyl}(1-methylcyclopropyl)methanone

(86) ##STR00074##

(87) Under argon, 7.587 g (15.37 mmol) of 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml of THF and cooled to −78° C. 7.65 ml (15.27 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 30 min. 2 g (13.97 mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF, were then slowly added dropwise to the reaction solution. The reaction mixture obtained was then slowly warmed to room temperature and stirred at this temperature overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of theory) of the title compound.

(88) LC-MS (Method 5): R.sub.t=1.50 min; m/z=450/452 (M+H).sup.+.

(89) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.72-0.76 (m, 2H), 0.93-0.98 (m, 2H), 1.09 (s, 3H), 3.69 (s, 6H), 4.15 (s, 4H), 6.85 (d, 4H), 7.23 (d, 4H), 7.25-7.29 (m, 2H), 7.52-7.57 (m, 1H).

Example 21A

(90) tert-Butyl (2E/Z)-3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)-acrylate

(91) ##STR00075##

(92) 0.84 ml (3.57 mmol) of tert-butyl (diethoxyphosphoryl)acetate was added dropwise to a suspension, cooled to 0° C., of 143 mg (60% in mineral oil, 3.57 mmol) of sodium hydride in 15 ml of THF. After 30 min, 1070 mg (2.38 mmol) of {3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}(1-methylcyclopropyl)methanone, dissolved in 10 nil of THF, were added. The cooling bath was removed, and the reaction mixture was stirred at RT overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 960 mg of the target product as an E/Z isomer mixture (74% of theory).

(93) LC-MS (Method 7): R.sub.t=1.67 min (isomer 1), m/z=548/550 (M+H).sup.+; R.sub.t=1.70 min (isomer 2), m/z=548/550 (M+H)+.

Example 22A

(94) tert-Butyl 3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)-propanoate

(95) ##STR00076##

(96) 130 mg (1.58 mmol) of magnesium turnings and a few grains of iodine were initially charged, 865 mg (1.58 mmol) of tort-butyl (2E/Z)-3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)acrylate in 10 ml of methanol were added and the mixture was stirred at room temperature. After about 10 min, there was a weak evolution of gas combined with a temperature increase. Using an ice bath, the temperature was kept at 35°−40° C. After the reaction had ended, 10 ml of a saturated aqueous ammonium chloride solution and 20 ml of dichloromethane were added to the reaction mixture. The organic phase was then separated off and the aqueous phase was extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water 9:1 isocratic). This gave 159 mg of the target product (18% of theory).

(97) LC-MS (Method 4): R.sub.t=1.91 min; m/z=550/552 (M+H).sup.+.

Example 23A

(98) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-(1-methylcyclopropyl)propanoate

(99) ##STR00077##

(100) 159 mg (0.29 mmol) of tert-butyl 3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)propanoate were taken up in 7 ml of dichloromethane and 1.2 ml of water. 145 mg (0.64 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then added, and the reaction solution was stirred at room temperature for 2 h. The reaction mixture was then added to 10 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, and the aqueous phase was then extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 31 mg of the target product (34% of theory).

(101) LC-MS (Method 7): R.sub.t=1.35 min; m/z=310 (M+H).sup.+.

Example 24A

(102) (4-Chloro-3-nitrophenyl)(cyclopropyl)methanone

(103) ##STR00078##

(104) Under argon and at −10° C., 20 g (110.7 mmol) of (4-chlorophenyl)(cyclopropyl)methanone were added slowly to 60 ml of concentrated nitric acid. The reaction mixture was then slowly warmed to 5° C. and stirred at this temperature for 6 h. Carefully, the reaction solution was then added with stirring to about 100 ml of ice-water. This resulted in the precipitation of a white solid which was filtered off with suction and washed repeatedly with water. The solid obtained in this manner was then dried under high vacuum. This gave 24.3 g (97% of theory) of the desired product.

(105) LC-MS (Method 7): R.sub.t=1.06 min; m/z=224/226 (M−H).sup.−.

(106) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.05-1.18 (m, 4H), 2.92-3.02 (m, 1H), 7.97 (d, 1H), 8.32 (dd, 1H), 8.66 (d, 1H).

(107) The following compound was obtained analogously to Synthesis Example 24A:

(108) TABLE-US-00005 Ex- Analytical ample Name/Structure/Starting materials data 25A LC-MS (Method 7): R.sub.t = 1.11 min, m/z = 242 (M − H).sup.−.

Example 26A

(109) tert-Butyl (2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropylacrylate

(110) ##STR00080##

(111) 13.5 ml (57.6 mmol) of tert-butyl (diethoxyphosphoryl)acetate were added dropwise to a suspension, cooled to 0° C., of 2.3 g (60% in mineral oil, 57.6 mmol) of sodium hydride in 50 ml of THF and 50 ml of DMF. After 30 min, 10 g (44.3 mmol) of (4-chloro-3-nitrophenyl)-(cyclopropyl)methanone were added a little at a time, the cooling bath was removed and the reaction mixture was stirred at RT overnight. 50 ml of an ice-cooled saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate and the combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (mobile phase cyclohexane.fwdarw.cyclohexane/ethyl acetate 40:1). This gave 13.4 g of the target product as an E/Z isomer mixture (93% of theory).

(112) MS (DCI): m/z=324 (M+H).sup.+, 341 (M+NH.sub.4).sup.+.

(113) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.32-0.39 (m, 0.5H), 0.51-0.58 (m, 1.5H), 0.79-0.87 (m, 1.5H), 0.88-0.96 (m, 0.5H), 1.17 (s, 6.75H), 1.47 (s, 2.25H), 1.73-1.82 (m, 0.75H), 2.81-2.90 (m, 0.25H), 5.84 (s, 0.25H), 5.88 (s, 0.75H), 7.43 (dd, 0.75H), 7.59 (dd, 0.25H), 7.72-7.78 (m, 1H), 7.81 (d, 0.75H), 7.95 (d, 0.25H).

(114) The following compounds were obtained analogously to Synthesis Example 26A:

(115) TABLE-US-00006 Example Name/Structure/Starting materials Analytical data 27A MS (DCI): m/z = 359 (M + NH.sub.4).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.01-1.10 (m, 2H), 1.19 (s, 7.74H), 1.31-1.41 (m, 2H), 1.51 (s, 1.26H), 6.13 (s, 0.86H), 6.77 (s, 0.14H), 7.55 (dd, 1H), 7.81 (d, 0.86H), 7.84 (d, 0.14H), 7.95 (d, 0.86H), 8.29 (d, 0.14H). 28A MS (DCI): m/z = 327 (M + NH.sub.4).sup.+. LC-MS (Method 7): R.sub.t = 1.26 min: m/z = 310 (M + H).sup.+.

Example 29A

(116) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate

(117) ##STR00083##

(118) 200 mg (0.62 mmol) of tert-butyl (2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropylacrylate were dissolved in 12 ml of ethyl acetate, and 20 mg (0.06 mmol) of platinum (10% on carbon) were added. The reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for 12 hours. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 96 mg (52.1% of theory) of the target compound.

(119) LC-MS (Method 5): R.sub.t=1.24 min; m/z=296 (M+H).sup.+.

Example 30A and Example 31A

(120) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomers 1 and 2)

(121) ##STR00084##

(122) By preparative HPLC on a chiral phase, 500 mg (1.69 mmol) of the racemate of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (Example 29A) were separated into the enantiomers [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm×20 mm; mobile phase: iso-hexane/ethanol 90:10 (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 30° C.]:

(123) Example 30A (Enantiomer 1):

(124) Yield: 237 mg

(125) R.sub.t=4.91 min; chemical purity >99%; >99% ee

(126) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(127) LC-MS (Method 5): R.sub.t=1.23 min; m/z=296 (M+H).sup.+.

(128) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.02-0.10 (m, 1H), 0.16-0.25 (m, 1H), 0.27-0.36 (m, 1H), 0.45-0.54 (m, 1H), 0.85-0.98 (m, 1H), 1.28 (s, 9H), 2.02-2.11 (m, 1H), 2.43-2.62 (m, 2H, partially obscured by DMSO signal), 5.21 (br. s, 2H), 6.43 (dd, 1H), 6.64 (d, 1H), 7.06 (d, 1H).

(129) [α].sub.D.sup.20=−22.3°, c=0.465, Methanol.

(130) Example 31A (Enantiomer 2):

(131) Yield: 207 mg

(132) R.sub.t=5.25 min; chemical purity >99%; >99% ee

(133) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(134) LC-MS (Method 5): R.sub.t=1.23 min; m/z=296 (M+H).sup.+.

(135) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.02-0.10 (m, 1H), 0.16-0.25 (m, 1H), 0.27-0.36 (m, 1H), 0.45-0.54 (m, 1H), 0.85-0.98 (m, 1H), 1.28 (s, 9H), 2.02-2.11 (m, 1H), 2.43-2.62 (m, 2H, partially obscured by DMSO signal), 5.21 (br. s, 2H), 6.43 (dd, 1H), 6.64 (d, 1H), 7.06 (d, 1H).

(136) [α].sub.D.sup.20=+24.1°, c=0.330, methanol.

Example 32A

(137) tert-Butyl 3-(3-amino-4-chlorophenyl)-3-(1-fluorocyclopropyl)propanoate

(138) ##STR00085##

(139) 384 mg (1.12 mmol) of tert-butyl (2E/Z)-3-(4-chloro-3-nitrophenyl)-3-(1-fluorocyclopropyl)-acrylate were dissolved in 12 ml of ethyl acetate, and 38 mg (0.17 mmol) of platinum(IV) oxide were added. The reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr and the filtrate was concentrated. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 68 mg (19% of theory) of the target compound.

(140) LC-MS (Method 7): R.sub.t=1.24 min; m/z=314 (M+H).sup.+.

Example 33A

(141) (+/−)-tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylpropanoate

(142) ##STR00086##
Method A:

(143) 133 mg (9.432 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate were dissolved in 20 ml of ethyl acetate. The solution was deoxygenated with argon, and 30 mg of 10% palladium on carbon were added. At RT, the reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure overnight. The mixture was then filtered off through Celite, and the filtrate was concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 67 mg of the target compound (50% of theory).

(144) LC-MS (Method 5): R.sub.t=1.31 min; m/z=310 (M+H).sup.+.

(145) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.24 (s, 9H), 1.47-1.57 (m, 1H), 1.57-1.77 (m, 4H), 1.94-2.05 (m, 1H), 2.19 (dd, 1H), 2.31-2.40 (m, 1H), 2.43 (dd, 1H), 2.71 (td, 1H), 5.13-5.22 (m, 2H), 6.36 (dd, 1H), 6.59 (d, 1H), 7.04 (d, 1H).

(146) Method B:

(147) At RT, a solution of 189 mg (0.614 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate in 0.9 ml of methanol was added to 39 mg (1.60 mmol) of magnesium turnings and a few grains of iodine. The dark reaction mixture was stirred at RT overnight and then added to water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC. This gave 57.7 mg of the target compound (30.3% of theory).

Example 34A

(148) Ethyl (2E/Z)-3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylacrylate

(149) ##STR00087##

(150) Under argon, 2.53 g (8.17 mmol) of ethyl (2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropyl-2-methylacrylate were dissolved in 10 ml of dioxane, and 9.22 g (40.84 mmol) of tin(II) chloride dihydrate were added. The reaction mixture was then heated to 70° C. and stirred at this temperature overnight. After cooling to room temperature, about 20 ml of ethyl acetate were added and the reaction mixture was then added to about 20 ml of a 10% strength aqueous potassium fluoride solution. The resulting mixture was stirred vigorously for 10 min. The phases were separated, and the aqueous phase was then extracted two more times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with about 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. This gave 2.2 g (96% of theory) of the target compound which was used without further purification for the next step.

(151) LC-MS (Method 7): R.sub.t=1.19 min; m/z=280/282 (M+H).sup.+.

Example 35A

(152) Ethyl 3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylpropanoate (Diastereomer Mixture)

(153) ##STR00088##

(154) Under argon and at RT, a solution of 2.2 g (7.86 mmol) of ethyl (2E/Z)-3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylacrylate in 20 ml of methanol was added to 497 mg (20.45 mmol) of magnesium turnings and a few grains of iodine. The dark reaction mixture was stirred at RT overnight and then allowed to stand under argon for two days. The reaction solution was then diluted with ethyl acetate, and 1 M hydrochloric acid was added. The mixture was stirred for 5 min and then adjusted to pH 8-9 using saturated sodium bicarbonate solution. The organic phase was separated off, and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1.fwdarw.50:1.fwdarw.20:1). This gave 1.38 g (62% of theory) of the target compound.

(155) LC-MS (Method 5): R.sub.t=1.13 min; m/z=282/284 (M+H).sup.+.

Example 36A

(156) Dimethyl (3-methylbutan-2-ylidene)malonate

(157) ##STR00089##

(158) Under argon and at 0° C., 10 g (75.7 mmol) of dimethyl malonate in 20 ml of chloroform were slowly added dropwise to a solution of 16.6 ml (151.4 mmol) of titanium tetrachloride in 60 ml of chloroform. After the addition had ended, the reaction solution was stirred at 0° C. for another 30 min. At 0° C., 6.52 g (75.7 mmol) of 3-methyl-2-butanone in 20 ml of chloroform were then added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 4 h. The reaction solution was then once more cooled to 0° C., and 30.6 ml (378.5 mmol) of pyridine in 20 ml of chloroform were added. After the addition had ended, the solution was warmed to room temperature and stirred at this temperature overnight. The reaction solution was then once more cooled to 0° C., and 50 ml of water were added slowly. The resulting phases were separated, and the aqueous phase was extracted two more times with in each case about 50 ml of dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 9.4 g (62% of theory) of the target compound.

(159) GC-MS (Method 1): R.sub.t=3.57 min; m/z=185 (M-CH.sub.3).sup.+.

(160) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.00 (d, 6H), 1.92 (s, 3H), 2.86-2.98 (m, 1H), 3.67 (s, 3H), 3.69 (s, 3H).

(161) The following compounds were obtained analogously to Synthesis Example 36A:

(162) TABLE-US-00007 Ex- Analytical ample Name/Structure/Starting materials data 37A 0 MS (DCI): m/z = 213 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.64-1.77 (m, 1H), 1.79-1.93 (m, 1H), 1.94-2.09 (m, 4H), 2.03 (s, 3H), 3.43-3.55 (m, 1H), 3.66 (s, 3H), 3.68 (s, 3H). 38A GC-MS (Method 1): R.sub.t = 4.36 min; m/z = 198 (M).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.83-0.89 (m, 4H), 1.62 (s, 311), 2.10- 2.20 (m, 1H), 3.67 (s, 3H), 3.70 (s, 3H).

Example 39A

(163) Dimethyl [2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate

(164) ##STR00092##

(165) Under argon, 6.2 g (26 mmol) of 1-chloro-4-iodobenzene were dissolved in 50 ml of THF and cooled to −78° C. 24 ml (31.2 mmol) of a 1.3 M solution of isopropylmagnesium chloride x lithium chloride in THF were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 2 h. The reaction solution was then warmed to −10° C., and 495 mg (2.6 mmol) of copper(I) iodide were added. 5 g (24.97 mmol) of dimethyl (3-methylbutan-2-ylidene)malonate, dissolved in 30 ml of THF, were then slowly added dropwise to the reaction solution. The resulting reaction mixture was slowly warmed to room temperature and stirred at this temperature for 1 h. The mixture was then cooled to 0° C., and ice-cold 1 M hydrochloric acid (pH ˜2) was added carefully. The phases were separated, the aqueous phase was then extracted three more times with ethyl acetate and the combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. The resulting crude product was initially pre-purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). The product was then re-purified by preparative RP-HPLC (mobile phase methanol/water). This gave 3.38 g (42% of theory) of the target compound.

(166) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.63-0.71 (m, 6H), 1.52 (s, 3H), 2.11-2.24 (m, 1H), 3.43 (s, 3H), 3.63 (s, 3H), 4.31 (s, 1H), 7.29-7.38 (m, 4H).

(167) The following compounds were obtained analogously to Synthesis Example 39A:

(168) TABLE-US-00008 Example Name/Structure/Starting materials Analytical data 40A .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.34-1.49 (m, 3H), 1.53 (s, 3H), 1.55-1.65 (m, 2H), 1.66-1.76 (m, 1H), 2.79-2.91 (m, 1H), 3.38 (s, 3H), 3.66 (s, 3H), 4.07 (s, 1H), 7.35 (q, 4H). 41A LC-MS (Method 5): R.sub.t = 1.53 min; m/z = 566/568 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = -0.16-0.07 (m, 1H), 0.01-0.09 (m, 1H), 0.16-0.24 (m, 1H), 0.24-0.32 (m, 1H), 1.04 (s, 3H), 1.35-1 44 (m, 1H), 3.46 (s, 3H), 3.50 (s, 3H), 3.69 (s, 6H), 4.06 (s, 4H), 4.15 (s, 1H), 6.83 (d, 4H), 7.05 (dd, 1H), 7.10 (d, 1H), 7.21 (d, 411), 7.28 (d, 1H).

Example 42A

(169) Dimethyl [1-(3-amino-4-chlorophenyl)-1-cyclopropylethyl]malonate

(170) ##STR00095##

(171) 627 mg (1.11 mmol) of dimethyl (1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-1-cyclo-propylethyl)malonate were taken up in 60 ml of dichloromethane and 15 ml of water. 553 mg (2.44 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then added to about 50 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, and the aqueous phase was extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 283 mg of the target product (78% of theory).

(172) LC-MS (Method 5): R.sub.t=1.03 min; m/z=326/328 (M+H).sup.+.

(173) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.11-0.18 (m, 2H), 0.31-0.39 (m, 2H), 1.12 (s, 3H), 1.40-1.49 (m, 1H), 3.53 (s, 3H), 3.57 (s, 3H), 4.10 (s, 1H), 5.20 (s, 2H), 6.61 (dd, 1H), 6.91 (d, 1H), 7.05 (d, 1H).

Example 43A

(174) Methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoate

(175) ##STR00096##

(176) 3.38 g (10.81 mmol) of dimethyl [2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate, 0.92 g (21.61 mmol) of lithium chloride and 0.2 ml of water in 10 ml of DMSO were heated under reflux for 4 h. After cooling, about 50 ml of diethyl ether were added to the reaction solution, and the phases were separated. The organic phase was washed twice with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.3 g (84% of theory) of the target compound.

(177) GC-MS (Method 1): R.sub.t=5.43 min; m/z=254 (M).sup.+.

(178) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.54 (d, 3H), 0.83 (d, 3H), 1.33 (s, 3H), 1.86-1.98 (m, 1H), 2.62 (d, 1H), 2.87 (d, 1H), 3.35 (s, 3H), 7.32 (s, 4H).

(179) The following compounds were obtained analogously to Synthesis Example 43A:

(180) TABLE-US-00009 Example Name/Structure/Starting material Analytical data 44A MS (DCI): m/z = 284 (M + NH.sub.4).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.36 (s, 3H), 1.46- 1.58 (m, 2H), 1.58-1.67 (m, 2H), 1.67-1.78 (m, 2H), 2.45-2.55 (m, 1H, partially obscured by DMSO signal), 2.55-2.64 (m, 1H), 2.81 (d, 1H), 3.41 (s, 3H), 7.28-7.35 (m, 4H). 45A LC-MS (Method 7): R.sub.t = 1.12 min; m/z = 268/270 (M + H).sup.+.

Example 46A

(181) Methyl 3-(4-chloro-3-nitrophenyl)-3,4-dimethylpentanoate

(182) ##STR00099##

(183) 2.3 g (9.03 mmol) of methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoate were dissolved in 50 ml of dichloromethane and cooled to 0° C. 1.44 g (10.8 mmol) of nitronium tetrafluoroborate were then added a little at a time. After the addition had ended, the reaction solution was initially stirred at 0°−10° C. for 1 h. The mixture was then slowly warmed to room temperature and stirred at this temperature for another 2 h. The reaction mixture was then added to about 50 ml of water, the phases were separated and the organic phase was dried over magnesium sulphate. The solution was concentrated by evaporation and the residue obtained was then purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 2.3 g (85% of theory) of the target compound.

(184) MS (DCI): m/z=317 (M+NH.sub.4).sup.+.

(185) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.56 (d, 3H), 0.84 (d, 3H), 1.35 (s, 3H), 1.89-2.02 (m, 1H), 2.66 (d, 1H), 3.02 (d, 1H), 3.39 (s, 3H), 7.63-7.71 (m, 2H), 7.96 (s, 1H).

(186) The following compound was obtained analogously to Synthesis Example 46A:

(187) TABLE-US-00010 Example Name/Structure/Starting material Analytical data 47A 00 GC-MS (Method 6): R.sub.t = 7.62 min; m/z = 329 (M + NH.sub.4).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.38 (s, 3H), 1.50- 1.58 (m, 2H), 1.58-1.70 (m, 2H), 1.70-1.81 (m, 2H), 2.54 (d, 1H, partially obscured by DMSO signal), 2.57-2.66 (m, 1H), 2.95 (d, 1H), 3.44 (s, 3H), 7.62-7.70 (m, 2H), 7.94 (d, 1H).

Example 48A

(188) Methyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylbutanoate

(189) ##STR00101##

(190) 1.79 g (5.74 mmol) of methyl 3-(4-chloro-3-nitrophenyl)-3-cyclobutylbutanoate were dissolved in 50 ml of ethyl acetate, and about 150 mg of 10% palladium on carbon were added. At RT, the reaction mixture was stirred vigorously under an atmosphere of hydrogen at atmospheric pressure overnight. The mixture was then filtered through Celite, and the filtrate obtained was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 1.36 g of the target product (84% of theory).

(191) LC-MS (Method 7): R.sub.t=1.22 min; m/z=282 (M+H).sup.+.

(192) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.31 (s, 3H), 1.45-1.67 (m, 4H), 1.68-1.77 (m, 2H), 2.43 (d, 1H), 2.48-2.60 (m, 1H, partially obscured by DMSO signal), 2.66 (d, 1H), 3.43 (s, 3H), 5.16 (br. s, 2H), 6.47 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

(193) The following compound was obtained analogously to Synthesis Example 48A:

(194) TABLE-US-00011 Example Name/Structure/Starting material Analytical data 49A 02 LC-MS (Method 5): R.sub.t = 1.11 min; m/z = 270/272 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s, 3H), 1.80-1.92 (m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15 (br. s, 2H), 6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

Example 50A and Example 51A

(195) Methyl 3-(3-amino-4-chlorophenyl)-3,4-dimethylpentanoate (Enantiomers 1 and 2)

(196) ##STR00103##

(197) 1700 mg (6.30 mmol) of the racemate of methyl 3-(3-amino-4-chlorophenyl)-3,4-dimethylpentanoate (Example 49A) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/isopropanol 95:5 (v/v); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25° C.]. The material obtained in each case was re-purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1).

(198) Example 50A (Enantiomer 1):

(199) Yield: 588 mg

(200) R.sub.t=7.21 min; chemical purity >99%; >99% ee

(201) [Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 30° C.].

(202) LC-MS (Method 5): R.sub.t=1.15 min; m/z=270 (M+H).sup.+.

(203) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s, 3H), 1.80-1.92 (m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15 (br. s, 2H), 6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

(204) [α].sub.D.sup.20−30°, c=0.275, methanol.

(205) Example 51A (Enantiomer 2):

(206) Yield: 499 mg

(207) R.sub.t=8.59 min; chemical purity >99%; >96.7% ee

(208) [Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 30° C.].

(209) LC-MS (Method 5): R.sub.t=1.15 min; m/z=270 (M+H).sup.+.

(210) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s, 3H), 1.80-1.92 (m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15 (br. s, 2H), 6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

(211) [α].sub.D.sup.20=+29°, c=0.270, methanol.

Example 52A and Example 53A

(212) Methyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylbutanoate (Enantiomers 1 and 2)

(213) ##STR00104##

(214) 1075 mg (3.82 mmol) of the racemate of methyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylbutanoate (Example 48A) were separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/ethanol 95:5 (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 25° C.]:

(215) Example 52A (Enantiomer 1):

(216) Yield: 472 mg

(217) R.sub.t=6.40 min; chemical purity >99%; >99% ee

(218) [Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 40° C.].

(219) LC-MS (Method 5): R.sub.t=1.15 min; m/z=282/284 (M+H).sup.+.

(220) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.31 (s, 3H), 1.45-1.67 (m, 4H), 1.68-1.78 (m, 2H), 2.43 (d, 1H), 2.48-2.60 (m, 1H, partially obscured by DMSO signal), 2.66 (d, 1H), 3.43 (s, 3H), 5.16 (br. s, 2H), 6.47 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

(221) [α].sub.D.sup.20=−2.3°, c=0.450, methanol.

(222) Example 53A (Enantiomer 2):

(223) Yield: 489 mg

(224) R.sub.t=7.85 min; chemical purity >99%; >99% ee

(225) [Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 40° C.].

(226) [α].sub.D.sup.20=+2.5°, c=0.330, methanol.

Example 54A

(227) 1-(4-Chlorophenyl)prop-2-en-1-one

(228) ##STR00105##

(229) 60 g (295.5 mmol) of 3-chloro-1-(4-chlorophenyl)propan-1-one were dissolved in 900 ml of acetonitrile. With ice bath cooling, 41.2 ml (295.5 mmol) of triethylamine were then slowly added dropwise to the solution (exothermal reaction). After the addition had ended, the reaction solution was stirred at room temperature for 4 h. About one litre of water, one litre of ethyl acetate and about 250 ml of saturated sodium chloride solution were then added to the reaction mixture. The phases were separated, the organic phase was then dried over magnesium sulphate and filtered and the filtrate was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel (about 1.3 kg) (mobile phase cyclohexane/ethyl acetate 6:1). This gave 45 g of the target product (91% of theory).

(230) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=6.02 (d, 1H), 6.36 (dd, 1H), 7.34-7.44 (m, 1H), 7.63 (d, 1H), 8.03 (d, 2H).

Example 55A

(231) (4-Chlorophenyl)(2,2-difluorocyclopropyl)methanone

(232) ##STR00106##

(233) Under argon, 91 g (546 mmol) of 1-(4-chlorophenyl)prop-2-en-1-one, 2.293 g (54.6 mmol) of sodium fluoride and 2.41 g (10.92 mmol) of 2,6-di-ten-butyl 4-methylphenol were heated in a 3 litre three-necked flask to 110° C. and stirred at this temperature for 5 min. At an internal temperature of 110°−125° C., 183 ml (928.5 mmol) of trimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetate were then slowly added dropwise over a period of 30-35 min to the solution (careful: evolution of gas). After the addition and the evolution of gas had ended, the reaction solution was stirred for another 20 min. After cooling, the reaction mixture was taken up in several litres of ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution. The phases were separated, the organic phase was then dried over magnesium sulphate and filtered and the filtrate was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel (about 2 kg) (mobile phase cyclohexane/ethyl acetate 10:1). This gave 63 g of the target product (53% of theory).

(234) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.04-2.14 (m, 1H), 2.21-2.31 (m, 1H), 3.98-4.09 (m, 1H), 7.65-7.70 (m, 2H), 8.06-8.11 (m, 2H).

Example 56A

(235) Methyl (2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate and methyl (2E)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate

(236) ##STR00107##

(237) 2.2 g (60% in mineral oil, 55 mmol) of sodium hydride were stirred with 20 ml of THF and then filtered off with suction, and the filtercake was washed with 20 ml of THF. Under argon, the sodium hydride purified in this manner was introduced into 200 ml of THF. The mixture was then cooled to 0° C., and 10.1 g (55 mmol) of methyl (diethoxyphosphoryl)acetate, dissolved in 10 ml of THF, were added. After warming to room temperature, the solution was stirred for another 1 h. 5.15 g (19.73 mmol) of (4-chlorophenyl)(2,2-difluorocyclopropyl)methanone in 50 ml of THF were then added dropwise. After the addition had ended, the solution was heated to reflux and stirred for 2 h. The solution was then cooled to 5° C., and the mixture was poured into 400 ml of ice-water. The phases were separated, and the aqueous phase was then extracted three more times with tert-butyl methyl ether. The combined organic phases were washed successively with 1 M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1.fwdarw.8:1). The E/Z isomers were isolated in separated form. This gave 2.23 g (37% of theory) of methyl (2E)-3-(4-chlorophenyl)-3-(2,2-difluoro-cyclopropyl)acrylate and 1.6 g (24.4% of theory) of methyl (2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate.

(238) Methyl (2E)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate:

(239) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.00-1.12 (m, 1H), 1.92-2.06 (m, 1H), 3.21-3.37 (m, 1H, partially obscured by H.sub.2O signal), 3.71 (s, 3H), 6.42 (d, 1H), 7.49 (d, 2H), 7.55 (d, 2H).

(240) Methyl (2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate:

(241) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.83-1.96 (m, 1H), 1.97-2.09 (m, 1H), 2.76-2.88 (m, 1H), 3.51 (s, 3H), 6.10 (s, 1H), 7.23 (d, 2H), 7.46 (d, 2H).

Example 57A

(242) Methyl 3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(4-chlorophenyl)-5,5-difluorohexanoate

(243) ##STR00108##

(244) 1000 mg (3.67 mmol) of methyl (2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate were dissolved in 75 ml of ethyl acetate and hydrogenated in a continuous-flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest) fitted with a catalyst cartridge (10% palladium on carbon) at a flow rate of 1 ml/min and at room temperature and atmospheric pressure using hydrogen. After the reaction had gone to completion, the reaction mixture was concentrated under reduced pressure. This gave 980 mg of a product mixture consisting of methyl 3-(4-chlorophenyl)-3-(2,2-difluoro-cyclopropyl)propanoate and methyl 3-(4-chlorophenyl)-5,5-difluorohexanoate as a colourless oil.

(245) GC-MS (Method 6): R.sub.t=5.38 min; m/z=292/294/296 (M+NH.sub.4).sup.+.

Example 58A

(246) Methyl 3-(4-chloro-3-nitrophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(4-chloro-3-nitrophenyl)-5,5-difluorohexanoate

(247) ##STR00109##

(248) 610 mg of the mixture consisting of methyl 3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)-propanoate and methyl 3-(4-chlorophenyl)-5,5-difluorohexanoate (Example 57A) were dissolved in 12 ml of dichloromethane and cooled to 0° C. 351 mg (2.65 mmol) of nitroniumtetrafluoroborate were then added a little at a time. After the addition had ended, the reaction solution was stirred at 0°−10° C. for 1 h. The mixture was then slowly warmed to room temperature and stirred at this temperature for a further 2 h. The reaction mixture was then added to about 20 ml of water, the phases were separated and the organic phase was dried over magnesium sulphate. The solution was concentrated by evaporation and the residue obtained was then purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 637 mg of the mixture of the two target compounds.

(249) GC-MS (Method 6): R.sub.t=6.74 min; m/z=337/339/341 (M+NH.sub.4).sup.+.

Example 59A

(250) Methyl 3-(3-amino-4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(3-amino-4-chlorophenyl)-5,5-difluorohexanoate

(251) ##STR00110##

(252) 640 mg of the mixture consisting of methyl 3-(4-chloro-3-nitrophenyl)-3-(2,2-difluorocyclo-propyl)propanoate and methyl 3-(4-chloro-3-nitrophenyl)-5,5-difluorohexanoate (Example 58A) were dissolved in 40 ml of ethyl acetate, and 106 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously under an atmosphere of hydrogen at atmospheric pressure overnight. The mixture was then filtered through Celite, and the filtrate obtained was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 361 mg of the mixture of the two target compounds.

(253) LC-MS (Method 5): R.sub.t=0.98 min; m/z=290/292 (M+H).sup.+.

Example 60A

(254) (+)-Ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate

(255) ##STR00111##

(256) At room temperature, 133 ml (1.82 mol) of thionyl chloride were added slowly to 287 g (1.65 mol) of (3R)-4,4,4-trifluoro-3-methylbutanoic acid [A. Gerlach and U. Schulz, Speciality Chemicals Magazine 24 (4), 37-38 (2004); CAS Acc.-No. 142:179196] in 580 ml of ethanol. The reaction solution was then heated to 80° C. and stirred at this temperature for 2 h. The mixture was then cooled to room temperature, 250 ml of water were added slowly and the mixture was extracted three times with in each case 150 ml of tert-butyl methyl ether. The combined organic phases were dried over sodium sulphate. After filtration the solvent was removed under reduced pressure at 30° C. and a pressure of 300 mbar. The crude product was then distilled at 100 mbar and a head temperature of 65° C. This gave 225.8 g (113 mol, 74% of theory) of the title compound as a colourless liquid.

(257) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 4.10 (2H, q), 2.88-2.72 (1H, m), 2.66-2.57 (1H, m), 2.46-2.36 (1H, m), 1.19 (3H, t), 1.11 (3H, d).

(258) GC-MS (Method 1): R.sub.t=1.19 min; m/z=184 (M).sup.+.

(259) [α].sub.D.sup.20=+16.1°, c=0.41, methanol.

Example 61A

(260) Ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate (Diastereomer Mixture)

(261) ##STR00112##

(262) Under argon 196.9 mg (0.88 mmol) of palladium(II) acetate and 724.8 mg (1.84 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were initially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8 mmol) of a 1 M solution of lithium hexamethyldisilazide in THF were added slowly, and the reaction solution was then stirred at RT for 10 min. The reaction solution was then cooled to −10° C., 7 g (38.0 mmol) of (+/−)-ethyl 4,4,4-trifluoro-3-methylbutanoate were added slowly and the mixture was stirred at −10° C. for 10 min. 5 g (29.2 mmol) of 4-bromotoluene, dissolved in 50 ml of toluene, were then added dropwise, and the reaction solution was warmed first to RT and then heated to 80° C. The mixture was stirred at this temperature for 2 h and then cooled to RT and stirred overnight. After the reaction had ended (monitored by TLC; mobile phase cyclohexane/dichloromethane 2:1), the reaction mixture was filtered through kieselguhr, the residue was washed repeatedly with ethyl acetate and dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1.fwdarw.3:1). This gave 3.91 g (14.3 mmol, 48.8% of theory) of the title compound as a colourless liquid.

(263) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.26 (2H, d), 7.20-7.12 (2H, m), 4.17-3.95 (2H, m), 3.74 (0.25H, d), 3.66 (0.75H, d), 3.35-3.07 (1H, m), 2.29 (2.25H, s), 2.28 (0.75H, s), 1.17 (0.75H, d), 1.11 (3H, t), 0.76 (2.25H, d).

(264) GC-MS (Method 1): R.sub.t=4.20 min, m/z=275 (M+H).sup.+ (diastereomer 1); R.sub.t=4.23 min, m/z=275 (M+H).sup.+ (diastereomer 2).

Example 62A

(265) Ethyl (3R)-4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate (Diastereomer Mixture)

(266) ##STR00113##

(267) Preparation of solution A: Under argon, 16.3 ml of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −10° C. to −20° C. (cooling with acetone/dry ice), and 2 g (10.86 mmol) of (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 10 ml of toluene, were added slowly; during the addition, it was made sure that a temperature of −10° C. was not exceeded. The solution was then stirred for another 10 min at at most −10° C.

(268) Preparation of solution B: Under argon, 2.415 g (14.12 mmol) of 4-bromotoluene were dissolved at RT in 10 ml of toluene, and 73 mg (0.33 mmol) of palladium(II) acetate and 269 mg (0.68 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were added. The solution was stirred at RT for 10 min.

(269) First, the cooling bath was removed from solution A. Solution B was then slowly added dropwise to solution A, which was still cold. The combined solutions were then slowly warmed to RT and stirred at this temperature for 1 h. The reaction solution was then heated to 80° C. (internal temperature) and stirred at this temperature for 3 h. The reaction solution was then slowly cooled to RT and stirred for another 12 h. Finally, the reaction mixture was filtered through kieselguhr, the residue was washed repeatedly with toluene and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/dichloromethane 10:1.fwdarw.4:1). This gave 2.35 g (79% of theory) of the title compound.

(270) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.76 (d, 2.13H), 1.11 (t, 3H), 1.17 (d, 0.87H), 3.07-3.30 (m, 1H), 3.66 (d, 0.7H), 3.75 (d, 0.3H), 3.94-4.15 (m, 2H), 7.12-7.20 (m, 2H), 7.23-7.29 (m, 2H).

(271) GC-MS (Method 1): R.sub.t=3.88 min, m/z=275 (M+H).sup.+ (diastereomer 1); R.sub.t=3.90 min, m/z=275 (M+1-1).sup.+ (diastereomer 2).

Example 63A

(272) Ethyl (3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (Diastereomer Mixture)

(273) ##STR00114##

(274) Preparation of solution A: Under argon, 163.9 ml of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −10° C. to −20° C. (cooling using acetone/dry ice), and 20 g (108.6 mmol) of (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 150 ml of toluene, were added slowly; during the addition care was taken that a temperature of −10° C. was not exceeded. The solution was then stirred for another 10 min at at most −10° C.

(275) Preparation of solution B: Under argon, 27.03 g (141.2 mmol) of 1-bromo-4-chlorobenzene were dissolved at RT in 100 ml of toluene, and 731 mg (3.26 mmol) of palladium(II) acetate and 2.693 g (6.84 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were added. The solution was stirred at RT for 10 min.

(276) First, the cooling bath was removed from solution A. Solution B was then slowly added dropwise to solution A, which was still cold. The combined solutions were then slowly warmed to RT and stirred at this temperature for 1 h. The reaction solution was then heated to 80° C. (internal temperature) and stirred at this temperature for 3 h. The reaction solution was then slowly cooled to RT and stirred for another 12 h. The reaction mixture was finally filtered through kieselguhr, the residue was washed repeatedly with toluene and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 27.4 g (92.98 mmol, 86% of theory) of the title compound as a yellow oil in a diastereomer ratio of 3:1.

(277) GC-MS (Method 1): R.sub.t=4.45 min, m/z=294 (M).sup.+ (diastereomer 1); R.sub.t=4.48 min, m/z=294 (M).sup.+ (diastereomer 2).

(278) The following compounds were obtained analogously to Synthesis Examples 61A and 63A:

(279) TABLE-US-00012 Example Name/Structure/Starting materials Analytical data 64A GC-MS (Method 1): R.sub.t = 4.61 min, m/z = 302 (M).sup.+ (diastereomer 1); R.sub.t = 4.64 min, m/z = 302 (M).sup.+ (diastereomer 2). 65A GC-MS (Method 1): R.sub.t = 4.83 min, m/z = 317 (M + H).sup.+ (diastereomer 1); R.sub.t = 4.85 min, m/z = 317 (M + H).sup.+ (diastereomer 2). MS (DCI): m/z = 334 (M + NH.sub.4).sup.+. 66A GC-MS (Method 1): R.sub.t = 5.34 min; m/z = 324/326 (M).sup.+. 67A GC-MS (Method 1): R.sub.t = 4.81 min/m/z = 308/310 (M).sup.+ (diastereomer 1); R.sub.t = 4.84 min, m/z = 308/310 (M).sup.+ (diastereomer 2).

Example 68A

(280) Ethyl (3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (Diastereomer Mixture)

(281) ##STR00119##

(282) 24.4 ml (24.4 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −10° C., and a solution of 3.0 g (16.29 mmol) of (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 15 ml of abs. toluene was added dropwise. The mixture was stirred for 10 min. At −10° C., a solution, prepared beforehand, of 3.92 g (21.18 mmol) of 1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of palladium(II) acetate and 404 mg (1.03 mmol) of 2′-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs. toluene was then added dropwise. The resulting reaction mixture was then stirred first at RT for 1 h and then at 80° C. for 3 h. The mixture was then concentrated under reduced pressure and the residue was taken up in ethyl acetate and added to water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic phases were washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue gave, after chromatography on silica gel (mobile phase first cyclohexane, then gradient cyclohexane/ethyl acetate 200:1.fwdarw.50:1), 3.051 g of the title compound (64.9% of theory, diastereomer ratio about 3:1).

(283) LC-MS (Method 4): R.sub.t=1.52 min, m/z=289 (M+H).sup.+ (minor diastereomer); R.sub.t=1.54 min, m/z=289 (M+H).sup.+ (major diastereomer).

(284) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.76 (d, 3H), 1.13 (t, 3H), 1.17 (t, 3H), 2.55-2.63 (m, 2H), 3.21-3.31 (m, 1H), 3.67 (d, 1H), 3.95-4.16 (m, 2H), 7.15-7.23 (m, 2H), 7.25-7.31 (m, 2H).

(285) The following compounds were prepared in a similar manner from (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate and the appropriate phenyl bromides:

Example 69A

(286) Ethyl (3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate (Diastereomer Mixture)

(287) ##STR00120##

(288) GC-MS (Method 1): R.sub.t=4.64 min and 4.66 min; in each case m/z=286 (M).sup.+.

(289) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.79 (d, 3H), 1.12 (t, 3H), 3.22-3.32 (m, 1H), 3.73 (d, 1H), 3.99-4.17 (m, 2H), 5.28 (d, 1H), 5.84 (d, 1H), 6.72 (dd, 1H), 7.34-7.40 (m, 2H), 7.45-7.51 (m, 2H).

Example 70A

(290) Ethyl (3R)-4,4,4-trifluoro-2-(4-fluorophenyl)-3-methylbutanoate (Diastereomer Mixture)

(291) ##STR00121##

(292) GC-MS (Method 1): R.sub.t=3.63 min, m/z=278 (M).sup.+ (minor diastereomer); R.sub.t=3.66 min, m/z=278 (M).sup.+ (major diastereomer).

(293) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.77 (d, 3H), 1.12 (t, 3H), 3.23-3.30 (m, 1H), 3.79 (d, 1H), 4.01-4.14 (m, 2H), 7.19-7.24 (m, 2H), 7.43-7.47 (m, 2H).

Example 71A

(294) Ethyl (3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate (Diastereomer Mixture)

(295) ##STR00122##

(296) GC-MS (Method 1): R.sub.t=4.33 min and 4.36 min; in each case m/z=312 (M).sup.+.

(297) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.80 (d, 3H), 1.08-1.19 (m, 3H), 3.34-3.41 (m, 1H), 3.88 (d, 1H), 4.01-4.18 (m, 2H), 7.28-7.34 (m, 1H), 7.51-7.64 (m, 2H).

Example 72A

(298) Ethyl (3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate

(299) ##STR00123##

(300) 1.58 g (5.52 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate, 23 mg (0.55 mmol) of sodium fluoride and 24 mg (0.11 mmol) of 2,6-di-tert-butyl 4-methylphenol were heated to 110° C. and stirred for 5 minutes. 1.9 ml (9.38 mmol) of trimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetate were then slowly added dropwise, and the mixture was stirred at 110° C. for 60 min (careful: evolution of gas after about 30 min). After cooling to room temperature and addition of ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase was separated off, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/-dichloromethane 4:1). This gave 1.5 g of the title compound (81% of theory).

(301) GC-MS (Method 1): R.sub.t=4.99 min, m/z=336 (M).sup.+ (diastereomer 1); R.sub.t=5.01 min, m/z=336 (M).sup.+ (diastereomer 2).

(302) MS (DCI): m/z=354 (M+NH.sub.4).sup.+.

Example 73A

(303) Ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate

(304) ##STR00124##

(305) 2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-(2-methylpropanenitrile) in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.

(306) GC-MS (Method 1): R.sub.t=5.72 min, m/z=373 (M-Br).sup.+ (diastereomer 1); R.sub.t=5.74 min, m/z=373 (M-Br).sup.+ (diastereomer 2).

Example 74A

(307) Ethyl 4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate

(308) ##STR00125##

(309) 529 mg (2.78 mmol) of copper(I) iodide and 4 g (20.82 mmol) of methyl 2,2-difluoro-2-(fluorosulphonyl)acetate were added to 3.77 g (10.67 mmol) of ethyl 2-[4-(bromo-methyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate in 40 ml of 1-methylpyrrolidin-2-one, and the mixture was stirred at 80° C. overnight. After the reaction had ended, the reaction solution was slowly poured into 100 ml of ice-water. The mixture obtained was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 1.48 g (4.32 mmol, 41% of theory) of the title compound as a yellowish oil.

(310) GC-MS (Method 1): R.sub.t=4.06 min, m/z=342 (M).sup.+ (diastereomer 1); R.sub.t=4.09 min, m/z=342 (M).sup.+ (diastereomer 2).

(311) MS (DCI): m/z=360 (M+NH.sub.4).sup.+.

Example 75A

(312) Methyl (4-chlorophenyl)(3-oxocyclopentyl)acetate

(313) ##STR00126##

(314) Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initially charged in 150 ml of THF, the mixture was cooled to −30° C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to −20° C., 15 g (81.25 mmol) of methyl (4-chlorophenyl)acetate, dissolved in 90 ml of THF, were added slowly and the mixture was stirred at this temperature for 2 h. The reaction solution then cooled to −78° C., and 7.2 ml (86.1 mmol) of 2-cyclopenten-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at −78° C. for another hour. After TLC (mobile phase cyclohexane/ethyl acetate 9:1), saturated aqueous ammonium chloride solution was added and the product was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate.

(315) The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of theory) of the title compound as a yellowish oil.

(316) GC-MS (Method 1): R.sub.t=7.02 min, m/z=266 (M).sup.+ (diastereomer 1); R.sub.t=7.04 min, m/z=266 (M).sup.+ (diastereomer 2).

(317) MS (DCI): m/z=284 (M+NH.sub.4).sup.+.

Example 76A

(318) Methyl (4-chlorophenyl)(3,3-difluorocyclopentyl)acetate

(319) ##STR00127##

(320) Under argon, 82.5 ml (82.14 mmol) of a 50% strength solution of 1,1′-[(trifluoro-λ.sup.4-sulphonyl)-imino]bis(2-methoxyethane) (Desoxofluor) in THF, diluted with 200 ml of toluene, were initially charged and cooled to 5° C., and 744 μl (5.87 mmol) of a 1 M solution of boron trifluoride/diethyl ether complex were added slowly. The mixture was stirred at 5° C. for 2 h. 15.65 g (58.67 mmol) of methyl (4-chlorophenyl)(3-oxocyclopentyl)acetate, dissolved in 200 ml of toluene, were then added slowly, and the reaction solution was subsequently warmed to 55° C. and stirred at this temperature for 60 h. The reaction mixture was then added to a mixture, cooled to 0° C., consisting of 100 ml of toluene and 100 ml of 2 M aqueous sodium hydroxide solution. The organic phase was separated off, and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 7:1). This gave 13.24 g (45.86 mmol, 78% of theory) of the title compound as a colourless oil.

(321) MS (DCI): m/z=306 (M+NH.sub.4).sup.+.

(322) GC-MS (Method 1): R.sub.t=5.83 min, m/z=288 (M).sup.+ (diastereomer 1); R.sub.t=5.86 min, m/z=288 (M).sup.+ (diastereomer 2).

Example 77A

(323) (+)-(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid

(324) ##STR00128##
Method A:

(325) 5.086 g (17.26 mmol) of ethyl (3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were dissolved in 68 ml of dioxane, and 34 ml of 1 N aqueous sodium hydroxide solution were added. The reaction was stirred at 50° C. for 2 h. The reaction mixture was then acidified with 1 N hydrochloric acid to pH 1 and repeatedly extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.9 g (14.63 mmol, 85% of theory, 83% de) of the target compound.

(326) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 12.95-12.73 (1H, br. s), 7.49-7.34 (4H, m), 3.68 (1H, d), 3.31-3.18 (1H, m), 1.20 (0.25H, d), 0.78 (2.75H, d).

(327) GC-MS (Method 1): R.sub.t=4.85 min; m/z=266 (M).sup.+.

(328) [α].sub.D.sup.20=+57.2°, c=0.41, methanol.

(329) Method B:

(330) 16.28 g (55.24 mmol) of ethyl (3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were dissolved in 220 ml of dioxane, and 110.5 ml of 1 N aqueous sodium hydroxide solution were added. The reaction was stirred at 50° C. for 3 h. The dioxane was then removed on a rotary evaporator, and the aqueous solution that remained was, with ice-cooling, neutralized with 1 N hydrochloric acid (˜pH 7). The precipitated solid was filtered off with suction and dried under high vacuum at 40° C. overnight. This gave 9.2 g of the target compound as a slightly beige solid (fraction 1; 62.5% of theory, 94% de). The filtrate was acidified by further addition of 1 N hydrochloric acid (˜pH 1) and stirred overnight. Once more, the precipitated solid was filtered off with suction and dried under high vacuum at 40° C. overnight. This gave a further 3.46 g of the target compound as a white solid (fraction 2; contaminated with 10% of the second diastereomer). The aqueous filtrate that remained was repeatedly extracted with dichloromethane, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave another 2.44 g of the target compound as a colourless oil (fraction 3; contaminated with 15% of the second diastereomer). Fractions 2 and 3 were finally combined and re-purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.7 g of the target compound as a white solid (fraction 4; 25% of theory, >95% de).

(331) Fraction 1 (=Sodium Salt of the Title Compound):

(332) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 7.44-7.33 (4H, m), 3.61 (1H, d), 3.30-3.15 (1H, m), 1.17 (0.09H, d, minor diastereomer), 0.76 (2.91H, d, major diastereomer).

(333) Fraction 4:

(334) .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 13.03-12.69 (br. s, 1H), 7.47-7.39 (4H, m), 3.68 (1H, d), 3.39-3.17 (1H, m, partially obscured by H.sub.2O signal), 0.77 (3H, d).

(335) Compounds listed in the table below were prepared in an analogous manner:

(336) TABLE-US-00013 Example Name/Structure/Starting material Analytical data 78A GC-MS (Method 1): R.sub.t = 4.17 min; m/z = 246 (M).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75 (d, 2.75H, major diastereomer), 1.19 (d, 0.25H, minor diastereomer), 2.29 (s, 3H), 3.15-3.28 (m, 1H), 3.55 (d, 0.915H, major diastereomer), 3.60 (d, 0.085H, minor diastereomer), 7.17 (d, 2H), 7.24 (d, 2H), 12.68 (br. s. 1H) (83% de). 79A 0 LC-MS (Method 5): R.sub.t = 1.06 min; m/z = 259 (M − H).sup.−. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.75 (d, 3H), 1.17 (t, 3H), 2.59 (q, 2H), 3.14-3.29 (m, 1H), 3.56 (d, 1H), 7.20 (d, 2H), 7.27 (d, 2H), 12.53-12.86 (br. s, 1H). 80A LC-MS (Method 5): R.sub.t = 1.06 min; m/z = 259 (M − H).sup.−. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 0.80 (d, 2.75H, major diastereomer), 1.19 (d, 0.25H, minor diastereomer), 3.21-3.37 (m, 1H, partially obscured by H.sub.2O signal), 3.75 (d, 1H), 7.29 (dd, 1H), 7.51 (dd, 1H), 7.60 (t, 1H), 12.97 (br. s, 1H) (83% de). 81A LC-MS (Method 5): R.sub.t = 0.97 min; m/z = 249 (M − H).sup.−. .sup.1H-NMR (from sodium salt; 400 MHz, DMSO-d.sub.6, δ/ppm): 0.76 (d, 2.73H, major diastereomer), 1.19 (d, 0.27H, minor diastereomer), 3.16-3.31 (m, 1H), 3.66 (d, 1H), 7.15-7.23 (m, 2H), 7.37-7.46 (m, 2H) (82% de). 82A .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 12.56 (1H, br. s), 7.25 (4H, q), 3.56 (1H, d), 3.28-3.16 (1H, m), 2.94-2.81 (1H, m), 1.19 (6H, d), 0.75 (3H, d). GC-MS (Method 1): R.sub.t = 4.93 min; m/z = 274 (M).sup.+. 83A GC-MS (Method 1): R.sub.t = 5.15 min; m/z = 288 (M).sup.+. 84A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 12.95-12.59 (1H, br. s), 7.37 (4H, q), 3.70-3.57 (3H, m), 3.30-3.18 (1H, m), 0.76 (3H, d). GC-MS (Method 1): R.sub.t = 4.45 min; m/z = 315 (M + H).sup.+. 85A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 12.59 (1H, br. s), 7.38 (4H, q), 3.51 (0.5H, d), 3.48 (0.5H, d), 2.77-2.60 (1H, m), 2.42- 2.27 (0.5H, m), 2.26-1.20 (5.5H, m). GC-MS (Method 1): R.sub.t = 6.33 min, m/z = 274 (M).sup.+ (diastereomer 1); R.sub.t = 6.38 min, m/z = 274 (M).sup.+ (diastereomer 2). 86A .sup.1H-NMR (400 MHz, DMSO-d.sub.6, δ/ppm): 12.91-12.71 (1H, br. s), 7.41 (1H, d), 7.18 (1H, d), 6.98 (1H, dd), 3.86 (3H, s), 3.66 (1H, d), 3.40-3.19 (1H, m), 0.79 (3H, d). LC-MS (Method 2): R.sub.t = 2.20 min; m/z = 295/297 (M − H).sup.−. 87A GC-MS (Method 1): R.sub.t = 5.20 min; m/z = 280/282 (M).sup.+ (diastereomer 1); R.sub.t = 5.23 min; m/z = 280/282 (M).sup.+ (diastereomer 2). 88A LC-MS (Method 5): R.sub.t = 1.09 min; m/z = 307 (M − H).sup.−. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.76 (d, 3H), 1.86-2.04 (m, 2H), 2.92-3.06 (m, 1H), 3.18- 3.29 (m, 1H), 3.61 (d, 1H), 7.27 (d, 2H), 7.34 (d, 2H), 12.72 (br. s, 1H).

Example 89A

(337) (3R)-2-(4-Ethylphenyl)-4,4,4-trifluoro-3-methylbutanoic acid (Diastereomer Mixture)

(338) ##STR00140##

(339) 3.0 g of ethyl (3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (purity about 88%, about 9.16 mmol; diastereomer mixture) were dissolved in the mixture of in each case 12.4 ml of methanol, THF and water, and 5.49 g (137.35 mmol) of sodium hydroxide were added a little at a time. The reaction mixture was stirred at 40° C. for 9 h. After cooling, the volatile solvents were substantially removed under reduced pressure and the residue was diluted with water. The mixture was acidified by addition of hydrochloric acid, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, and concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 2.61 g of the title compound as a crude product which was not purified any further (diastereomer ratio about 9:1).

(340) LC-MS (Method 5): R.sub.t=1.08 min, m/z=259 (M−H).sup.− (minor diastereomer); R.sub.t=1.11 min, m/z=259 (M−H).sup.− (major diastereomer).

(341) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.76 (d, 3H), 1.17 (t, 3H), 2.54-2.66 (m, 4H), 3.10-3.29 (m, 1H), 3.56 (d, 1H), 7.14-7.22 (m, 2H), 7.22-7.32 (m, 2H), 12.58 (br. s, 1H).

(342) In a comparable manner (reaction temperature: RT to +40° C.; reaction time: 9-12 h), the following carboxylic acids were prepared from the corresponding esters:

Example 90A

(343) (3R)-4,4,4-Trifluoro-2-(4-fluorophenyl)-3-methylbutanoic acid (Diastereomer Mixture)

(344) ##STR00141##

(345) Diastereomer ratio about 9:1.

(346) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): major diastereomer: δ [ppm]=0.77 (d, 3H), 3.18-3.30 (m, 1H), 3.67 (d, 1H), 7.17-7.24 (m, 2H), 7.39-7.47 (m, 2H), 12.78 (br. s, 1H).

Example 91A

(347) (3R)-2-(4-Chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (Diastereomer Mixture)

(348) ##STR00142##

(349) Diastereomer ratio about 1:1.

(350) GC-MS (Method 1): R.sub.t=4.79 min; m/z=284 (M).sup.+.

(351) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): both diastereomers: δ [ppm]=0.80/1.19 (each d, 3H), 3.18-3.29 (m, 1H), 3.74/3.77 (each dd, 1H), 7.28 (d, 1H), 7.43-7.65 (m, 2H), 12.91/13.24 (each br. s, 1H).

Examples 92A-95A

(352) (4-Chlorophenyl)(3,3-difluorocyclopentyl)acetic acid (Isomers 1-4)

(353) ##STR00143##

(354) By preparative HPLC on a chiral phase, 4 g (14.56 mmol) of the diastereomer mixture of (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid (Example 85A) were separated into the four enantiomerically pure diastereomers [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25° C.]:

(355) Example 92A (Isomer 1):

(356) Yield: 682 mg

(357) R.sub.t=8.12 min; chemical purity >94%

(358) [Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

(359) LC-MS (Method 5): R.sub.t=1.03 min; m/z=273 (M−H).sup.−.

(360) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.46-1.82 (m, 3H), 1.96-2.27 (m, 3H), 2.62-2.77 (m, 1H), 3.50 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.60 (br. s, 1H).

(361) [α].sub.D.sup.20=−54.2°, c=0.490, methanol.

(362) Example 93A (Isomer 2):

(363) Yield: 543 mg

(364) R.sub.t=9.53 min; chemical purity >97%

(365) [Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

(366) LC-MS (Method 5): R.sub.t=1.03 min; m/z=273 (M−H).sup.−.

(367) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.46-1.82 (m, 3H), 1.96-2.27 (m, 3H), 2.63-2.77 (m, 1H), 3.50 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.61 (br. s, 1H).

(368) [α].sub.D.sup.20=+53.0°, c=0.375, methanol.

(369) Example 94A (Isomer 3):

(370) Yield: 530 mg

(371) R.sub.t=10.36 min; chemical purity >92%

(372) [Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

(373) LC-MS (Method 5): R.sub.t=1.04 min; m/z=273 (M−H).sup.−.

(374) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.21-1.34 (m, 1H), 1.34-1.45 (m, 1H), 1.76-2.17 (m, 3H), 2.27-2.42 (m, 1H), 2.60-2.75 (m, 1H), 3.49 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.60 (br. s, 1H).

(375) [α].sub.D.sup.20=−61.0°, c=0.340, methanol.

(376) Example 95A (Isomer 4):

(377) Yield: 560 mg

(378) R.sub.t=11.35 min; chemical purity >91%

(379) [Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

(380) LC-MS (Method 5): R.sub.t=1.04 min; m/z=273 (M−H).sup.−.

(381) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.21-1.34 (m, 1H), 1.34-1.45 (m, 1H), 1.77-2.17 (m, 3H), 2.27-2.42 (m, 1H), 2.60-2.75 (m, 1H), 3.49 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.59 (br. s, 1H).

(382) [α].sub.D.sup.20=+56.4°, c=0.485, methanol.

Example 96A

(383) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4-methylpentanoate (Diastereomer 1)

(384) ##STR00144##

(385) 328 mg (1.23 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 17.5 ml of dichloromethane, 263 mg (1.97 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 299 μl (3.7 mmol) of pyridine and 315 mg (1.23 mmol) of methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomer 1; Example 17A) were then added, and the reaction mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was purified directly by preparative RP-HPLC (mobile phase methanol/water 80:20). This gave 237 mg of the target compound (38% of theory).

(386) LC-MS (Method 5): R.sub.t=1.43 min; m/z=504/506 (M+H).sup.+.

(387) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.68 (d, 3H), 0.80 (d, 3H), 0.85 (d, 3H), 1.70-1.85 (m, 1H), 2.48-2.58 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m, 2H), 3.30-3.41 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.31-7.37 (m, 2H), 7.43-7.50 (m, 4H), 9.83 (s, 1H).

(388) [α].sub.D.sup.20=+111°, c=0.25, methanol.

Example 97A

(389) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4-methylpentanoate (Diastereomer 2)

(390) ##STR00145##

(391) 255 mg (0.96 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 14 ml of dichloromethane, 205 mg (1.53 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 232 μl (2.87 mmol) of pyridine and 245 mg (0.96 mmol) of methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomer 2; Example 18A) were then added, and the reaction mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was purified directly by preparative RP-HPLC (mobile phase methanol/water 80:20). This gave 228 mg of the target compound (47% of theory).

(392) LC-MS (Method 5): R.sub.t=1.43 min; m/z=504/506 (M+H).sup.+.

(393) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.67 (d, 3H), 0.80 (d, 3H), 0.85 (d, 3H), 1.71-1.82 (m, 1H), 2.47-2.58 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m, 2H), 3.29-3.41 (m, 1H, partially obscured by H.sub.2O signal), 3.43 (s, 3H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.33 (d, 1H), 7.35 (d, 1H), 7.43-7.50 (m, 4H), 9.82 (s, 1H).

(394) [α].sub.D.sup.20=+84.7°, c=0.325, methanol.

Example 98A

(395) tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-cyclopropylpropanoate (Diastereomer 1)

(396) ##STR00146##

(397) 45 mg (0.17 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 1 ml of dichloromethane, 36 mg (0.27 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 41 μl (0.51 mmol) of pyridine and 50 mg (0.17 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 1; Example 30A), dissolved in 1 ml of dichloromethane, were then added, and the reaction mixture was stirred for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was directly purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 78 mg of the target compound (85% of theory).

(398) LC-MS (Method 7): R.sub.t=1.52 min; m/z=542/544 (M−H).sup.−.

Example 99A

(399) tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-cyclopropylpropanoate (diastereomer 2)

(400) ##STR00147##

(401) 119 mg (0.45 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 2 nil of dichloromethane, 95 mg (0.71 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 108 (1.34 mmol) of pyridine and 132 mg (0.45 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 2; Example 31A), dissolved in 2 ml of dichloromethane, were then added, and the reaction mixture was stirred for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was directly purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 206 mg of the target compound as a colourless oil (85% of theory).

(402) LC-MS (Method 7): R.sub.t=1.53 min; m/z=542/544 (M−H).sup.−.

(403) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.03-0.11 (m, 1H), 0.17-0.34 (m, 2H), 0.45-0.55 (m, 1H), 0.80 (d, 3H), 0.88-1.00 (m, 1H), 1.21 (s, 9H), 2.14-2.24 (m, 1H), 2.47-2.57 (m, 1H, obscured by DMSO signal), 2.58-2.66 (m, 1H), 3.29-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.14 (d, 1H), 7.11 (dd, 1H), 7.37 (d, 1H), 7.40-7.51 (m, 5H), 9.82 (s, 1H).

(404) The compounds listed in the table below were prepared in an analogous manner:

(405) TABLE-US-00014 Example Name/Structure/Starting materials Analytical data 100A LC-MS (Method 7): R.sub.t = 1.56 min; m/z = 556/558 (M − H).sup.−. 101A LC-MS (Method 5): R.sub.t = 1.48 min; m/z = 574/576 (M − H).sup.−. 102A 0 LC-MS (Method 5): R.sub.t = 1.46 min; m/z = 560/562 (M − H).sup.−. 103A LC-MS (Method 7): R.sub.t = 1.48 min; m/z = 518/520 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.56 (d, 3H), 0.81 (dd, 6H), 1.29 (s, 3H), 1.82-1.93 (m, 1H), 2.58 (d, 1H), 2.77 (d, 1H), 3.30-3.44 (m, 1H), 3.33 (s, 3H), 4.12 (d, 1H), 7.12 (dd, 1H), 7.33 (d, 1H), 7.43-7.50 (m, 5H), 9.81 (s, 1H). 104A LC-MS (Method 5): R.sub.t = 1.48 min; m/z = 518/520 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.57 (d, 3H), 0.81 (dd, 6H), 1.29 (s, 3H), 1.80-1.92 (m, 1H), 2.58 (d, 1H), 2.77 (d, 1H), 3.29-3.46 (m, 1H), 3.35 (s, 3H), 4.12 (d, 1H), 7.12 (dd, 1H), 7.33 (d, 1H), 7.42-7.50 (m, 5H), 9.81 (s, 1H). 105A LC-MS (Method 5): R.sub.t = 1.51 min; m/z = 530/532 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.80 (d, 3H), 1.31 (s, 3H), 1.44-1.53 (m, 1H), 1.53-1.67 (m, 3H), 1.67-1.78 (m, 2H), 2.46 (d, 1H), 2.47-2.60 (m, 1H, partially obscured by DMSO signal), 2.70 (d, 1H), 3.36-3.46 (m, 1H), 3.38 (s, 3H), 4.12 (d, 1H), 7.10 (dd, 1H), 7.34 (d, 1H), 7.42-7.51 (m, 5H), 9.81 (s, 1H). 106A LC-MS (Method 5): R.sub.t = 1.51 min; m/z = 530/532 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.81 (d, 3H), 1.31 (s, 3H), 1.43-1.53 (m, 1H), 1.53-1.67 (m, 3H), 1.67-1.78 (m, 2H), 2.46 (d, 1H), 2.46-2.59 (m, 1H, partially obscured by DMSO signal), 2.70 (d, 1H), 3.36-3.46 (m, 1H), 3.40 (s, 3H), 4.12 (d, 1H), 7.10 (dd, 1H), 7.34 (d, 1H), 7.43-7.50 (m, 5H), 9.81 (s, 1H). 107A LC-MS (Method 5): R.sub.t = 1.48 min; m/z = 498 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.17 (t, 3H), 1.70-1.84 (m, 1H), 2.45- 2.64 (m, 3H, partially obscured by DMSO signal), 2.70-2.82 (m, 2H), 3.28-3.39 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.06 (d, 1H), 6.98 (dd, 1H), 7.21 (d, 2H), 7.30-7.39 (m, 4H), 9.73 (s, 1H). 108A LC-MS (Method 5): R.sub.t = 1.43 min; m/z = 522/524 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 2.77H, major diastereomer), 0.84 (t, 6H), 1.25 (d, 0.23H, minor diastereomer), 1.71-1.84 (m, 1H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.81 (m, 2H), 3.36-3.49 (m, 1H), 3.43 (s, 3H), 4.15 (d, 1H), 7.02 (dd, 1H), 7.29-7.38 (m, 3H), 7.50 (dd, 1H), 7.63 (t, 1H), 9.87 (s, 0.925H, major diastereomer), 10.01 (s, 0.075H, minor diastereomer) (85% de). 109A LC-MS (Method 5): R.sub.t = 1.54 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.19 (d, 6H), 1.71-1.83 (m, 1H), 2.45- 2.58 (m, 1H, obscured by DMSO signal), 2.70-2.80 (m, 2H), 2.81-2.93 (m, 1H), 3.28- 3.39 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.07 (d, 1H), 6.98 (dd, 1H), 7.24 (d, 2H), 7.31-7.41 (m, 4H), 9.73 (s, 1H). 110A LC-MS (Method 5): R.sub.t = 1.36 min; m/z = 488/490 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 2.77H, major diastereomer), 0.80 (d, 3H), 0.85 (d, 3H), 1.25 (d, 0.23H, minor diastereomer), 1.71-1.83 (m, 1H), 2.45 (m, 1H, obscured by DMSO signal), 2.70-2.81 (m, 2H), 3.28-3.40 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.11 (d, 1H), 7.00 (dd, 1H), 7.22 (t, 2H), 7.31-7.37 (m, 2H), 7.44- 7.54 (m, 2H), 9.80 (s, 0.925H, major diastereomer), 9.93 (s, 0.075H, minor diastereomer) (85% de). 111A LC-MS (Method 5): R.sub.t = 1.40 min; m/z = 522/554 (M + H).sup.+. 112A 0 LC-MS (Method 5): R.sub.t = 1.39 min; m/z = 546/548 (M + H).sup.+. 113A LC-MS (Method 5): R.sub.t = 1.52 min; m/z = 526/528 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.27 (s, 9H), 1.70-1.84 (m, 1H), 2.46- 2.58 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m, 2H), 3.28-3.39 (m, 1H, partially obscured by H2O signal), 3.42 (s, 3H), 4.08 (d, 1H), 6.98 (dd, 1H), 7.31-7.43 (m, 6H), 9.72 (s, 0.96H, major diastereomer), 9.86 (s, 0.04H, minor diastereomer) (92% de). 114A LC-MS (Method 4): R.sub.t = 2.91 min; m/z = 534-536 (M + H).sup.+. 115A LC-MS (Method 5): R.sub.t = 1.40 min; m/z = 484/486 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.70-1.84 (m, 1H), 2.29 (s, 3H), 2.48-2.57 (m, 1H, obscured by DMSO signal), 2.70-2.80 (m, 2H), 3.29- 3.40 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.05 (d, 1H), 6.99 (dd, 1H), 7.18 (d, 2H), 7.29-7.38 (m, 4H), 9.73 (s, 0.94H, major diastereomer), 9.87 (s, 0.06H, minor diastereomer) (88% de). 116A LC-MS (Method 5): R.sub.t = 1.51 min; m/z = 518/520 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.81 (d, 3H), 0.85 (d, 3H), 1.70-1.83 (m, 1H), 2.23 (s, 3H), 2.45-2.59 (m, 1H, partially obscured by DMSO signal), 2.70-2.81 (m, 2H), 3.28-3.41 (m, 1H, partially obscured by H.sub.2O signal), 3.42 (s, 3H), 4.07 (d, 1H), 7.00 (dd, 1H), 7.27-7.45 (m, 5H), 9.81 (s, 0.94H, major diastereomer), 9.89 (s, 0.06H, minor diastereomer) (88% de). 117A LC-MS (Method 5): R.sub.t = 1.41 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H), 1.52-1.70 (m, 2H), 1.72-1.82 (m, 1H), 1.82-1.95 (m, 1H), 1.98-2.30 (m, 3H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m, 2H), 2.80-2.93 (m, 1H), 3.43 (s, 3H), 3.78 (d, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.37 (d, 1H), 7.44 (q, 4H), 9.78 (s, 1H). 118A LC-MS (Method 5): R.sub.t = 1.41 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H), 1.52-1.69 (m, 2H), 1.72-1.81 (m, 1H), 1.81-1.96 (m, 1H), 1.98-2.30 (m, 3H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m, 2H), 2.80-2.93 (m, 1H), 3.43 (s, 3H), 3.78 (d, 1H), 7.02 (dd, 1H), 7.34 (d, 1H), 7.36 (d, 1H), 7.44 (q, 4H), 9.78 (s, 1H). 119A LC-MS (Method 5): R.sub.t = 1.42 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H), 1.21-1.35 (m, 1H), 1.45-1.58 (m, 1H), 1.72-1.83 (m, 1H), 1.85-2.20 (m, 3H), 2.28-2.43 (m, 1H), 2.47-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.90 (m, 3H), 3.44 (s, 3H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.37 (d, 1H), 7.44 (q, 4H), 9.74 (s, 1H). 120A LC-MS (Method 5): R.sub.t = 1.42 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.86 (d, 3H), 1.21-1.35 (m, 1H), 1.45-1.58 (m, 1H), 1.71-1.83 (m, 1H), 1.85-2.20 (m, 3H), 2.29-2.44 (m, 1H), 2.46-2.61 (m, 1H, partially obscured by DMSO signal), 2.70-2.90 (m, 3H), 3.43 (s, 3H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.34 (d, 1H), 7.36 (d, 1H), 7.44 (q, 4H), 9.74 (s, 1H).

Example 121A

(406) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate

(407) ##STR00169##

(408) 330 mg (1.24 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 10 ml of dichloromethane, 264 mg (1.98 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 300 (3.71 mmol) of pyridine and 360 mg of the mixture consisting of methyl 3-(3-amino-4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(3-amino-4-chlorophenyl)-5,5-difluorohexanoate (Example 59A), dissolved in 1 ml of dichloromethane, were then added, and the reaction mixture was stirred for a further 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was directly purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 479 mg of the mixture of the two target compounds.

(409) LC-MS (Method 5): R.sub.t=1.33 min; m/z=538/540/542 (MA-1).sup.+.

Examples 122A-125A

(410) 476 mg of the mixture of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-5,5-difluorohexanoate (Example 121A) were separated further by preparative HPLC on a chiral phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/isopropanol 95:5 (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 30° C.]. The material initially obtained for peak 2 and peak 3 was combined and then separated by another preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/isopropanol 95:5 (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 30° C.].

Example 122A

(411) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate (diastereomer 1)

(412) ##STR00170##

(413) Yield: 100 mg

(414) R.sub.t=8.42 min; chemical purity >99%, >99% de

(415) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(416) LC-MS (Method 5): R.sub.t=1.33 min; m/z=540/542 (M+H).sup.+.

(417) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.46 (t, 3H), 2.19-2.32 (m, 2H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.69-2.78 (m, 1H), 3.20-3.30 (m, 1H), 3.30-3.43 (m, 1H, obscured by H.sub.2O signal), 3.48 (s, 3H), 4.12 (d, 1H), 7.14 (dd, 1H), 7.37 (d, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H).

Example 123A

(418) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate (Diastereomer 2)

(419) ##STR00171##

(420) Yield: 96 mg

(421) R.sub.t=10.14 min; chemical purity >94%, >99% de

(422) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(423) LC-MS (Method 5): R.sub.t=1.33 min; m/z=540/542 (M+H).sup.+.

(424) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.47 (t, 3H), 2.19-2.32 (m, 2H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.69-2.78 (m, 1H), 3.20-3.30 (m, 1H), 3.30-3.43 (m, 1H, obscured by H.sub.2O signal), 3.46 (s, 3H), 4.12 (d, 1H), 7.14 (dd, 1H), 7.37 (d, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H).

Example 124A

(425) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(2,2-difluorocyclopropyl)propanoate (Isomer 1)

(426) ##STR00172##

(427) Yield: 124 mg

(428) R.sub.t=9.00 min; chemical purity >96%

(429) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(430) LC-MS (Method 5): R.sub.t=1.34 min; m/z=538/540 (M+H).sup.+.

(431) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.06-1.18 (m, 1H), 1.38-1.51 (m, 1H), 2.01-2.16 (m, 1H), 2.64-2.82 (m, 3H), 3.28-3.54 (m, 1H, partially obscured by H.sub.2O signal), 3.50 (s, 3H), 4.12 (d, 1H), 7.22 (dd, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 5H), 9.88 (s, 1H).

Example 125A

(432) Methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(2,2-difluorocyclopropyl)propanoate (Isomer 2)

(433) ##STR00173##

(434) Yield: 118 mg

(435) R.sub.t=9.47 min; chemical purity >99%

(436) [Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(437) LC-MS (Method 5): R.sub.t=1.33 min; m/z=538/540 (M+H).sup.+.

(438) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.06-1.18 (m, 1H), 1.38-1.52 (m, 1H), 2.01-2.15 (m, 1H), 2.63-2.83 (m, 3H), 3.28-3.58 (m, 1H, partially obscured by H.sub.2O signal), 3.49 (s, 3H), 4.12 (d, 1H), 7.21 (dd, 1H), 7.40 (d, 1H), 7.42-7.50 (m, 5H), 9.87 (s, 1H).

Example 126A

(439) tert-Butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(3,3-difluorocyclobutyl)propanoate (Diastereomer Mixture)

(440) ##STR00174##

(441) A solution of 76 mg (0.29 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 45 mg (0.13 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg (0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was directly, without further work-up, separated into its components by preparative HPLC. This gave 19 mg (25% of theory) of the title compound as a colourless oil.

(442) LC-MS (Method 5): R.sub.t=1.47 min; m/z=592/594 (M−H).sup.−.

(443) The compounds listed in the table below were prepared in an analogous manner:

(444) TABLE-US-00015 Example Name/Structure/Starting materials Analytical data 127A LC-MS (Method 5): R.sub.t = 1.57 min; m/z = 556 (M − H).sup.−. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): both diastereomers: δ [ppm] = 0.80 (d, 3H), 1.15/1.18 (2s, together 9H), 1.46-1.62 (m, 2H), 1.62-1.76 (m, 3H), 1.96- 2.06 (m, 1H), 2.16-2.28 (m, 1H), 2.32-2.48 (m, 2H), 2.76- 2.87 (m, 1H), 3.35-3.45 (m, 1H), 4.13-4.14 (2d, together 1H), 7.00 (dt, 1H), 7.34 (d, 1H), 7.36-7.53 (m, 5H), 9.79/9.80 (2s, together 1H). 128A LC-MS (Method 5): R.sub.t = 1.62 min; m/z = 556/558 (M − H).sup.−. 129A LC-MS (Method 7): R.sub.t = 1.49 min; m/z = 530/532 (M + H).sup.+. 130A LC-MS (Method 5): R.sub.t = 1.41 min; m/z = 516/518 (M + H).sup.+.

Example 131A

(445) 2-(1-Methylcyclopropyl)ethanol

(446) ##STR00179##

(447) 11.23 g (87.1 mmol) of zinc/copper pair were taken up in 50 ml of diethyl ether, and 6.76 ml (92.9 mmol) of chloroiodomethane were added at room temperature. 5.84 ml (58.1 mmol) of 3-methylbut-3-en-1-ol, dissolved in 10 ml of diethyl ether, were then added dropwise. After the addition had ended, the reaction mixture was heated to 40° C. and stirred at this temperature overnight. After cooling, the reaction was filtered off with suction through kieselguhr, and the kieselguhr was washed repeatedly with diethyl ether. The combined filtrates were washed with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.58 g (62% of theory) of the title compound.

(448) GC-MS (Method 1): R.sub.t=1.23 min; m/z=100 (M).sup.+.

(449) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.24-0.29 (m, 2H), 0.29-0.34 (m, 2H), 1.05 (s, 3H), 1.37 (t, 1H), 1.53 (t, 2H), 3.74-3.80 (m, 2H).

(450) The following compound was obtained analogously to Synthesis Example 1A:

(451) TABLE-US-00016 Example Name/Structure/Starting materials Analytical data 132A 0 GC-MS (Method 6): R.sub.t = 3.86 min; m/z = 214 (M + NH.sub.4).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.25-0.31 (m, 2H), 0.31-0.37 (m, 2H), 0.98 (s, 3H), 1.43 (s, 9H), 2.06-2.11 (m, 2H), 5.76-5.83 (m, 1H), 6.72-6.82 (m, 1H).

(452) The following compound was obtained analogously to Synthesis Example 4A/5A:

(453) TABLE-US-00017 Example Name/Structure/Starting materials Analytical data 133A LC-MS (Method 5): R.sub.t = 1.42 min; m/z = 322 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.04-0.10 (m, 2H), 0.17-0.24 (m, 2H), 0.85 (s, 3H), 1.46 (s, 9H), 3.02 (s, 2H), 5.40 (br. s, 2H), 5.82 (s, 1H), 6.62 (dd, 1H), 6.88 (d, 1H), 7.17 (d, 1H).

Example 134A

(454) tert-Butyl 3-(3-amino-4-chlorophenyl)-4-(1-methylcyclopropyl)butanoate

(455) ##STR00182##

(456) 187 mg (0.58 mmol) of tert-butyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-(1-methylcyclopropyl)but-2-enoate were dissolved in 10 ml of ethyl acetate, and 11 mg (0.06 mmol) of platinum(IV) oxide were added. At RT, the reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure overnight. Another 11 mg (0.06 mmol) of platinum(IV) oxide were added, and the mixture was then once more stirred at RT under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. This gave 36 mg (19% of theory) of the target compound.

(457) LC-MS (Method 5): R.sub.t=1.37 min; m/z=324 (M+H).sup.+.

(458) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=−0.10-0.03 (m, 1H), −0.03-0.04 (m, 1H), 0.13-0.25 (m, 2H), 0.95 (s, 3H), 1.27 (s, 9H), 1.40-1.52 (m, 2H), 2.24-2.33 (m, 1H), 2.47-2.58 (m, 1H, partially obscured by DMSO signal), 2.95-3.05 (m, 1H), 5.19 (br. s, 2H), 6.41 (dd, 1H), 6.65 (d, 1H), 7.05 (d, 1H).

(459) The following compound was prepared analogously to Synthesis Example 99A:

(460) TABLE-US-00018 Example Name/Structure/Starting materials Analytical data 135A LC-MS (Method 8): R.sub.t = 3.27 min; m/z = 570/571 (M − H).sup.−. .sup.1H-NMR (400 MHz, DMSO- d.sub.6): δ [ppm] = −0.14-−0.07 (m, 1H), −0.07-0.02 (m, 1H), 0.12- 0.19 (m, 1H), 0.19-0.25 (m, 1H), 0.80 (d, 3H), 0.93 (d, 3H), 1.19 (2s, 9H), 1.39-1.55 (m, 2H), 2.26-2.38 (m, 1H), 2.48- 2.63 (m, 1H, partially obscured by DMSO signal), 3.05-3.16 (m, 1H), 3.29-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.14 (dd, 1H), 7.06 (d, 1H), 7.34 (d, 1H), 7.39-7.51 (m, 5H), 9.80 (d, 1H).
Working Examples:

Example 1

(461) (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoic acid (Diastereomer 1)

(462) ##STR00184##

(463) 4 ml of concentrated acetic acid and 2 ml of concentrated hydrochloric acid were added to 225 mg (0.45 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoate (diastereomer 1; Example 96A). The reaction mixture was stirred at 100° C. for 2 h. After cooling, the reaction mixture was added to ice-water, and the crystals formed were filtered off with suction. The crystals were washed twice with water and then dried in a high vacuum drying cabinet at 40° C. overnight. This gave 193 mg (88% of theory) of the title compound as a white solid.

(464) LC-MS (Method 7): R.sub.t=1.30 min; m/z=490/492 (M+H).sup.+.

(465) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.68 (d, 3H), 0.80 (d, 3H), 0.84 (d, 3H), 1.70-1.80 (m, 1H), 2.36-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70-2.80 (m, 1H), 3.29-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.00 (dd, 1H), 7.31-7.37 (m, 2H), 7.43-7.50 (m, 4H), 9.82 (s, 1H), 11.95 (br. s, 1H).

(466) [α].sub.D.sup.2°=+111°, c=0.285, methanol.

Example 2

(467) (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoic acid (Diastereomer 2)

(468) ##STR00185##

(469) 4 ml of concentrated acetic acid and 2 ml of concentrated hydrochloric acid were added to 218 mg (0.43 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoate (diastereomer 2; Example 97A). The reaction mixture was stirred at 100° C. for 2 h. After cooling, the reaction mixture was added to ice-water, and the crystals formed were filtered off with suction. The crystals were washed twice with water and then dried in a high vacuum drying cabinet at 40° C. overnight. This gave 188 mg (89% of theory) of the title compound as a white solid.

(470) LC-MS (Method 7): R.sub.t=1.30 min; m/z=490/492 (M+H).sup.+.

(471) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.67 (d, 3H), 0.80 (d, 3H), 0.84 (d, 3H), 1.69-1.80 (m, 1H), 2.39-2.48 (m, 1H), 2.62-2.70 (m, 1H), 2.71-2.79 (m, 1H), 3.29-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.00 (dd, 1H), 7.32-7.38 (m, 2H), 7.41-7.51 (m, 4H), 9.82 (s, 1H), 11.96 (br. s, 1H).

(472) [α].sub.D.sup.20=+82°, c=0.275, methanol.

(473) The compounds listed in the table below were prepared in an analogous manner:

(474) TABLE-US-00019 Example Name/Structure/Starting material Analytical data 3 LC-MS (Method 5): R.sub.t = 1.30 min; m/z = 504/506 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.55 (d, 3H), 0.80 (d, 6H), 1.30 (s, 3H), 1.75-1.88 (m, 1H), 2.46-2.58 (d, 1H, obscured by DMSO signal), 2.69 (d, 1H), 3.28-3.45 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.12 (dd, 1H), 7.33 (d, 1H), 7.43-7.51 (m, 5H), 9.81 (s, 1H), 11.75 (br. s, 1H). [α].sub.D.sup.20 = +95°, c = 0.285, methanol. 4 LC-MS (Method 5): R.sub.5 = 1.30 min; m/z = 504/506 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.56 (d, 3H), 0.80 (d, 6H), 1.30 (s, 3H), 1.75-1.89 (m, 1H), 2.46-2.57 (d, 1H, obscured by DMSO signal), 2.69 (d, 1H), 3.29-3.45 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.12 (dd, 1H), 7.32 (d, 1H), 7.42-7.48 (m, 4H), 7.49 (d, 1H), 9.81 (s, 1H), 11.75 (br. s, 1H). [α].sub.D.sup.20 = +105.7°, c = 0.305, methanol. 5 LC-MS (Method 5): R.sub.t = 1.32 min; m/z = 516/518 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 3H), 1.31 (s, 3H), 1.41-1.52 (m, 1H), 1.52- 1.66 (m, 3H), 1.66-1.78 (m, 2H), 2.37 (d, 1H), 2.45-2.58 (m, 1H, obscured by DMSO signal), 2.64 (d, 1H), 3.28-3.47 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.33 (d, 1H), 7.40-7.52 (m, 5H), 9.81 (s, 1H), 11.83 (br. s, 1H). [α].sub.D.sup.20 = +105°, c = 0.250, methanol. 6 LC-MS (Method 5): R.sub.t = 1.32 min; m/z = 516/518 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 3H), 1.31 (s, 3H), 1.42-1.52 (m, 1H), 1.52- 1.67 (m, 3H), 1.67-1.79 (m, 2H), 2.37 (d, 1H), 2.45-2.58 (m, 1H, obscured by DMSO signal), 2.64 (d, 1H), 3.30-3.47 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.33 (d, 1H), 7.41-7.52 (m, 5H), 9.81 (s, 1H), 11.84 (br. s, 1H). [α].sub.D.sup.20 = +100°, c = 0.30, methanol. 7 0 LC-MS (Method 4): R.sub.t = 1.54 min; m/z = 500/502 (M − H ).sup.−. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.77-0.85 (m, 5H), 0.87-1.02 (m, 1H), 1.15-1.28 (m, 2H), 1.42 (s, 3H), 2.62-2.72 (m, 1H), 3.01 (d, 1H), 3.28-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.09-4.17 (m, 1H), 7.08 (dd, 1H), 7.38-7.53 (m, 6H), 9.92 (d, 1H). 8 LC-MS (Method 5): R.sub.t = 1.32 min; m/z = 484 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.17 (t, 3H), 1.68-1.81 (m, 1H), 2.36-2.47 (m, 1H), 2.56-2.69 (m, 3H), 2.70- 2.79 (m, 1H), 3.27-3.40 (m, 1H, partially obscured by H.sub.2O signal), 4.07 (d, 1H), 6.98 (dd, 1H), 7.20 (d, 2H), 7.30-7.41 (m, 4H), 9.73 (s, 1H), 11.95 (br. s, 1H). 9 LC-MS (Method 5): R.sub.t = 1.28 min; m/z = 508/510 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 2.79H, major diastereomer), 0.84 (t, 6H), 1.25 (d, 0.21H, minor diastereomer), 1.69-1.81 (m, 1H), 2.39-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70- 2.81 (m, 1H), 3.37-3.48 (m, 1H), 4.15 (d, 1H), 7.01 (dd, 1H), 7.29-7.38 (m, 3H), 7.50 (dd, 1H), 7.62 (t, 1H), 9.87 (s, 0.93H, major diastereomer), 10.01 (s, 0.07H, minor diastereomer), 11.96 (br. s, 1H) (86% de). 10 LC-MS (Method 5): R.sub.t = 1.35 min; m/z = 498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.19 (d, 6H), 1.67-1.80 (m, 1H), 2.36-2.47 (m, 1H), 2.60-2.70 (m, 1H), 2.70- 2.79 (m, 1H), 2.81-2.93 (m, 1H), 3.26-3.40 (m, 1H, obscured by H.sub.2O signal), 4.07 (d, 1H), 6.98 (dd, 1H), 7.20-7.28 (m, 2H), 7.30-7.43 (m, 4H), 9.73 (s, 1H), 11.95 (br. s, 1H). 11 LC-MS (Method 5): R.sub.t = 1.19 min; m/z = 474/476 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 2.76H, major diasteromer), 0.80 (d, 3H), 0.84 (d, 3H), 1.25 (d, 0.24H, minor diastereomer), 1.68-1.80 (m, 1H), 2.36-2.47 (m, 1H), 2.60- 2.70 (m, 1H), 2.70-2.80 (m, 1H), 3.29-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.12 (d, 1H), 7.00 (dd, 1H), 7.22 (t, 2H), 7.31-7.37 (m, 2H), 7.45- 7.52 (m, 2H), 9.80 (s, 0.92H, major diastereomer), 9.94 (s, 0.08H, minor diastereomer), 11.96 (br. s, 1H) (84% de). 12 LC-MS (Method 5): R.sub.t = 1.26 min; m/z = 538/540 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.64-0.71 (m, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.68- 1.81 (m, 1H), 2.38-2.47 (m, 1H), 2.61-2.69 (m, 1H), 2.70-2.80 (m, 1H), 3.28-3.44 (m, 1H, partially obscured by H.sub.2O signal), 3.64 (q, 2H), 4.11 (d, 1H), 6.99 (d, 1H), 7.30-7.39 (m, 4H), 7.46 (d, 2H), 9.80 (s, 1H), 11.95 (br. s, 1H). 13 LC-MS (Method 5): R.sub.t = 1.26 min; m/z = 532/534 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.68-1.80 (m, 1H), 1.87-2.04 (m, 2H), 2.36- 2.47 (m, 1H), 2.61-2.69 (m, 1H), 2.70-2.79 (m, 1H), 2.93-3.06 (m, 1H), 3.29-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.10 (d, 1H), 6.99 (dd, 1H), 7.27 (d, 2H), 7.33 (d, 1H), 7.37 (s, 1H), 7.42 (d, 2H), 9.77 (s, 1H), 11.95 (br. s, 1H). 14 LC-MS (Method 5): R.sub.t = 1.39 min; m/z = 512/514 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.27 (s, 9H), 1.68-1.80 (m, 1H), 2.36-2.47 (m, 1H), 2.60-2.69 (m, 1H), 2.70- 2.79 (m, 1H), 3.27-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.08 (d, 1H), 6.97 (dd, 1H), 7.30-7.44 (m, 6H), 9.73 (s, 0.96H, major diastereomer), 9.86 (s, 0.04H, minor diastereomer), 11.95 (br. s, 1H) (92% de). 15 LC-MS (Method 5): R.sub.t = 1.24 min; m/z = 520/522 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.80- 0.88 (m, 6H), 1.68-1.81 (m, 1H), 2.35-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70-2.81 (m, 1H), 3.36- 3.49 (m, 1H), 3.87 (s, 3H), 4.10 (d, 1H), 7.01 (t, 2H), 7.23 (d, 1H), 7.32-7.37 (m, 2H), 7.43 (d, 1H), 9.81 (s, 1H), 11.96 (br. s, 1H). 16 LC-MS (Method 8): R.sub.t = 2.70 min; m/z = 470/472 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.68-1.80 (m, 1H), 2.29 (s, 3H), 2.36-2.47 (m, 1H), 2.61-2.69 (m, 1H), 2.70- 2.79 (m, 1H), 3.26-3.40 (m, 1H, partially obscured by H.sub.2O signal), 4.05 (d, 1H), 6.98 (dd, 1H), 7.17 (d, 2H), 7.29-7.39 (m, 4H), 9.73 (s, 0.96H, major diasteromer), 9.87 (s, 0.04H, minor diastereomer), 11.95 (br. s, 1H) (92% de) 17 00 LC-MS (Method 5): R.sub.t = 1.33 min; m/z = 504/506 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.75- 0.89 (m, 6H), 1.68-1.81 (m, 1H), 2.33 (s, 3H), 2.36-2.59 (m, 1H, partially obscured by DMSO signal), 2.61-2.70 (m, 1H), 2.70- 2.81 (m, 1H), 3.25-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.07 (d, 1H), 7.00 (d, 1H), 7.25-7.39 (m, 3H), 7.39- 7.47 (m, 2H), 9.81 (s, 1H), 11.95 (br. s, 1H). 18 01 LC-MS (Method 8): R.sub.t = 2.71 min; m/z = 498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.84 (d, 3H), 1.52-1.69 (m, 2H), 1.70- 1.81 (m, 1H), 1.81-1.96 (m, 1H), 1.98-2.31 (m, 3H), 2.36-2.47 (m, 1H), 2.61-2.70 (m, 1H), 2.70- 2.80 (m, 1H), 2.80-2.93 (m, 1H), 3.78 (d, 1H), 7.02 (dd, 1H), 7.31-7.39 (m, 2H), 7.44 (q, 4H), 9.78 (s, 1H), 11.95 (br. s, 1H). 19 02 LC-MS (Method 8): R.sub.t = 2.71 min; m/z = 498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H), 1.52-1.69 (m, 2H), 1.70- 1.81 (m, 1H), 1.81-1.96 (m, 1H), 1.98-2.31 (m, 3H), 2.36-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70- 2.79 (m, 1H), 2.80-2.93 (m, 1H), 3.79 (d, 1H), 7.01 (dd, 1H), 7.32-7.39 (m, 2H), 7.43 (q, 4H), 9.77 (s, 1H), 11.95 (br. s, 1H). 20 03 LC-MS (Method 8: R.sub.t = 2.71 min; m/z = 498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.67 (d, 3H), 0.84 (d, 3H), 1.20-1.34 (m, 1H), 1.45- 1.56 (m, 1H), 1.70-1.81 (m, 1H), 1.85-2.19 (m, 3H), 2.28-2.40 (m, 1H), 2.40-2.53 (m, 1H, partially obscured by DMSO signal), 2.61-2.70 (m, 1H), 2.70-2.90 (m, 2H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.34 (d, 1H ), 7.37 (d, 1H), 7.44 (q, 4H), 9.74 (s, 1H), 11.95 (br. s, 1H). 21 04 LC-MS (Method 8): R.sub.t = 2.71 min; m/z = 498/500 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.68 (d, 3H), 0.85 (d, 3H), 1.20-1.34 (m, 1H), 1.45- 1.56 (m, 1H), 1.70-1.81 (m, 1H), 1.85-2.20 (m, 3H), 2.29-2.41 (m, 1H), 2.41-2.53 (m, 1H, partially obscured by DMSO signal), 2.62-2.70 (m, 1H), 2.70-2.90 (m, 2H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.32-7.39 (m, 2H), 7.44 (q, 4H), 9.73 (s, 1H), 11.95 (br. s, 1H).

Example 22

(475) (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid (diastereomer 2)

(476) ##STR00205##

(477) 78 mg (0.14 mmol) of tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate (diastereomer 2; Example 99A) were dissolved in 10 ml of dichloromethane, and 0.33 ml (4.3 mmol) of trifluoroacetic acid was added at RT. The reaction mixture was stirred at RT for 4 h and then diluted with 10 ml of water. The phases were separated, and the aqueous phase was then extracted three more times with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product obtained in this manner was purified by preparative RP HPLC (mobile phase methanol/water 8:2 isocratic). This gave 56 mg of the target compound (81% of theory).

(478) LC-MS (Method 5): R.sub.t=1.20 min; m/z=488/490 (M+H).sup.+.

(479) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.02-0.10 (m, 1H), 0.19-0.33 (m, 2H), 0.44-0.53 (m, 1H), 0.80 (d, 3H), 0.89-0.99 (m, 1H), 2.20-2.29 (m, 1H), 2.47-2.68 (m, 2H, partially obscured by DMSO signal), 3.30-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.36 (d, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H), 12.04 (br. s, 1H).

(480) [α].sub.D.sup.20=+98.8°, c=0.325, chloroform.

(481) The compounds listed in the table below were prepared in an analogous manner:

(482) TABLE-US-00020 Example Name/Structure/Starting material Analytical data 23 06 LC-MS (Method 5): R.sub.t = 1.20 min; m/z = 488/490 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.03-0.12 (m, 1H), 0.19-0.35 (m, 2H), 0.44-0.54 (m, 1H), 0.80 (d, 3H), 0.88-0.99 (m, 1H), 2.20-2.29 (m, 1H), 2.47- 2.69 (m, 2H, partially obscured by DMSO signal), 3.29-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.36 (d, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H), 12.03 (br. s, 1H). [a].sub.D.sup.20 = +57.3°, c = 0.355, chloroform. 24 07 LC-MS (Method 5): R.sub.t = 1.31 min; m/z = 502 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 3H), 1.44- 1.62 (m, 2H), 1.62-1.75 (m, 3H), 1.97-2.02 (m, 1H), 2.29 (dd, 1H), 2.33-2.42 (m, 1H), 2.46 (dd, 1H), 2.87 (td, 1H), 3.36- 3.42 (m, 1H), 4.13 (d, 1H), 7.01 (dd, 1H), 7.33 (d, 1H), 7.37 (t, 1H), 7.43-7.51 (m, 4H), 9.81 (s, 1H), 11.99 (br. s, ca. 1H). 25 08 LC-MS (Method 7): R.sub.t = 1.26 min; m/z = 520/522 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 3H), 0.94 (d, 3H), 1.00 (d, 3H), 1.33-1.40 (m, 1H), 2.70-2.78 (m, 1H), 3.10 (s, 3H), 3.11-3.18 (m, 1H), 3.32- 3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.12 (d, 1H), 7.08 (dd, 1H), 7.33 (dd, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.83 (d, 1H), 11.91 (br. s, ca. 1H). 26 09 LC-MS (Method 5): R.sub.t = 1.27 min (diastereomer 1), m/z = 502/504 (M + H).sup.+; R.sub.t = 1.31 min (diastereomer 2), m/z = 502/504 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 3H), 0.88- 0.96 (m, 5H), 1.66-1.78 (m, 2H), 2.76-2.85 (m, 1H), 3.05-3.17 (m, 1H), 3.30-3.45 (m, 1H, partially obscured by H.sub.2O signal), 3.57- 3.66 (m, 1H), 4.10-4.18 (m, 1H), 7.19 (dd, 1H), 7.40-7.51 (m, 6H), 9.92 (d, 1H). 27 0 LC-MS (Method 5): R.sub.t = 1.18 min; m/z = 506/508 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.65-0.90 (m, 2H), 0.80 (d, 3H), 0.90-1.08 (m, 1H), 1.11-1.31 (m, 1H), 1.56-1.73 (m, 1H), 2.69-2.89 (m, 2H), 3.30- 3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.14 (dd, 1H), 7.39 (d, 1H), 7.42-7.52 (m, 5H), 9.87 (s, 1H), 11.85-12.70 (br. s, 1H). 28 LC-MS (Method 5): R.sub.t = 1.24 min; m/z = 538/540 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.80 (d, 2.29H), 1.21- 1.31 (m, 1.71H), 2.02-2.17 (m, 1H), 2.18-2.39 (m, 3H), 2.40- 2.75 (m, 2H, partially obscured by DMSO signal), 2.91-3.03 (m, 1H), 3.17-3.44 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.05-7.16 (m, 1H), 7.33- 7.53 (m, 6H), 9.85 (s, 0.7H), 9.98 (s, 0.3H), 11.96-12.18 (br. s, 1H). from tert-butyl 3-(4-chloro-3-{[(2S,3R)- 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl- butanoyl]amino}phenyl)-3-(3,3-difluoro- cyclobutyl)propanoate (diastereomer mixture) 29 LC-MS (Method 5): R.sub.t = 1.29 min; m/z = 502/504 (M + H).sup.+.

Example 30

(483) 3-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoic acid (Diastereomer Mixture)

(484) ##STR00213##

(485) 250 mg (0.47 mmol) of ethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate (diastereomer mixture; Example 129A) were dissolved in a mixture of 1.0 ml of methanol, 0.5 ml of THF and 0.5 ml of water, and 40 mg (0.94 mmol) of lithium hydroxide monohydrate were added at 0° C. The mixture was stirred initially at 0° C. for 1 h and then at RT overnight. Another 40 mg (0.94 mmol) of lithium hydroxide monohydrate were then added, and the reaction solution was warmed to 50° C. After further stirring at this temperature overnight, 1 ml of methanol was metered into the reaction mixture, and the mixture was stirred at 60° C. for a further 12 h. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 204 mg (86% of theory) of the title compound as a diastereomer mixture.

(486) LC-MS (Method 7): R.sub.t=1.26 min, m/z=502/504 (M+H).sup.+ (diastereomer 1); R.sub.t=1.27 min, m/z=502/504 (M+H).sup.+ (diastereomer 2); R.sub.t=1.28 min, m/z=502/504 (M+H).sup.+ (diastereomer 3); R.sub.t=1.30 min, m/z=502/504 (M+H).sup.+ (diastereomer 4).

(487) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=−0.20-0.05 (m, 0.85H), 0.13-0.36 (m, 2H), 0.47-0.65 (m, 0.85H), 0.68-0.75 (m, 0.3H), 0.80 (d, 2.63H), 0.93-1.09 (m, 1H), 1.17 (d, 1.5H), 1.21-1.29 (m, 1.87H), 1.84-2.08 (m, 1H), 2.61-2.77 (m, 1H), 3.16-3.27 (m, 0.5H), 3.28-3.43 (m, 0.5H, partially obscured by H.sub.2O signal), 4.09-4.17 (m, 1H), 6.70-6.78 (m, 0.16H), 7.02-7.13 (m, 1H), 7.30-7.53 (m, 5.84H), 9.80-10.01 (m, 1H), 11.79-12.35 (br. m, 1H).

Example 31

(488) 3-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoic acid (Diastereomer Mixture 1)

(489) ##STR00214##

(490) 114 mg (0.21 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate (isomer 1; Example 124A) were dissolved in a mixture of 2 ml of dioxane and 1 ml of water, and 27 mg (0.64 mmol) of lithium hydroxide monohydrate were added. The mixture was stirred at RT overnight. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The precipitated solid was filtered off with suction and dried under high vacuum overnight. This gave 89 mg (80% of theory) of the title compound as a diastereomer mixture in the form of a white solid.

(491) LC-MS (Method 5): R.sub.t=1.26 min; m/z=524/526 (M+H).sup.+.

(492) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 1.63H), 1.04-1.19 (m, 1H), 1.26 (d, 1.37H), 1.36-1.50 (m, 1H), 1.97-2.14 (m, 1H), 2.46-2.82 (m, 3H, partially obscured by DMSO signal), 3.15-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.07-4.17 (m, 1H), 7.17-7.26 (m, 1H), 7.36-7.53 (m, 6H), 9.87 (s, 0.55H), 10.01 (s, 0.45H), 12.16 (br. s, 1H).

Example 32

(493) 3-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoic acid (Diastereomer Mixture 2)

(494) ##STR00215##

(495) 115 mg (0.21 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate (isomer 2; Example 125A) were dissolved in a mixture of 2 ml of dioxane and 1 ml of water, and 27 mg (0.64 mmol) of lithium hydroxide monohydrate were added. The mixture was stirred at RT overnight. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 101 mg (90% of theory) of the title compound as a diastereomer mixture in the form of a colourless oil.

(496) LC-MS (Method 5): R.sub.t=1.26 min; m/z=524/526 (M+H).sup.+.

(497) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 1.68H), 1.05-1.18 (m, 1H), 1.26 (d, 1.32H), 1.35-1.50 (m, 1H), 1.96-2.12 (m, 1H), 2.44-2.82 (m, 3H, partially obscured by DMSO signal), 3.15-3.42 (m, 1H, partially obscured by H.sub.2O signal), 4.08-4.16 (m, 1H), 7.17-7.25 (m, 1H), 7.37-7.52 (m, 6H), 9.87 (s, 0.56H), 10.01 (s, 0.44H), 12.16 (br. s, 1H).

Example 33 and Example 34

(498) (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclobutylpropanoic acid (Diastereomers 1 and 2)

(499) ##STR00216##

(500) The diastereomer mixture obtained above of 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-tri-fluoro-3-methylbutanoyl]amino}phenyl)-3-cyclobutylpropanoic acid (Example 24) was separated further by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; injection volume: 0.40 ml; mobile phase: 90% isohexane/10% isopropanol; flow rate: 15 ml/min; detection: 220 nm; temperature: 25° C.]. 63 mg of diastereomer mixture gave 29 mg of diastereomer 1 (Example 33) and 32 mg of diastereomer 2 (Example 34).

(501) Example 33 (Diastereomer 1):

(502) LC-MS (Method 5): R.sub.t=1.31 min; m/z=502 (M+H).sup.+.

(503) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.45-1.62 (m, 2H), 1.62-1.79 (m, 3H), 1.97-2.03 (m, 1H), 2.24-2.39 (m, 2H), 2.42-2.47 (m, 1H), 2.87 (td, 1H), 3.35-3.40 (m, 1H), 4.13 (d, 1H), 7.01 (dd, 1H), 7.23-7.39 (m, 2H), 7.42-7.54 (m, 4H), 9.81 (s, 1H), 11.98 (br. s, 1H).

(504) [α].sub.D.sup.20=+69°, c=0.260, chloroform.

(505) Example 34 (Diastereomer 2):

(506) LC-MS (Method 5): R.sub.t=1.31 min; m/z=502 (M+H).sup.+.

(507) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.80 (d, 3H), 1.45-1.63 (m, 2H), 1.63-1.76 (m, 3H), 1.98-2.04 (m, 1H), 2.22-2.42 (m, 2H), 2.44-2.48 (m, 1H), 2.87 (td, 1H), 4.13 (d, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.37 (d, 1H), 7.42-7.51 (m, 4H), 9.81 (s, 1H), 12.00 (br. s, 1H).

(508) [α].sub.D.sup.20=+53°, c=0.250, chloroform.

Example 35 and Example 36

(509) 3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-cyclopropylbutanoic acid (Diastereomers 1 and 2)

(510) ##STR00217##

(511) 55 mg (0.11 mmol) of the diastereomer mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-cyclopropylbutanoic acid (Example 29) were separated further by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/ethanol 90:10 (v/v); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 30° C.]:

(512) Example 35 (Diastereomer 1):

(513) Yield: 28 mg

(514) R.sub.t=7.47 min; chemical purity >99%; >99% de

(515) [Column: Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(516) LC-MS (Method 5): R.sub.t=1.26 min; m/z=502/504 (M+H).sup.+.

(517) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=−0.14-0.06 (m, 1H), −0.06-0.03 (m, 1H), 0.22-0.37 (m, 2H), 0.39-0.50 (m, 1H), 0.80 (d, 3H), 1.27-1.36 (m, 1H), 1.45-1.56 (m, 1H), 2.39-2.47 (m, 1H), 2.57-2.66 (m, 1H), 2.99-3.09 (m, 1H), 3.28-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.07 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 1H), 9.82 (s, 1H), 12.02 (br. s, 1H).

(518) [α].sub.D.sup.20=+41°, c=0.260, chloroform.

(519) Example 36 (Diastereomer 2):

(520) Yield: 25 mg

(521) R.sub.t=8.75 min; chemical purity >99%; >98.7% de

(522) [Column: Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; mobile phase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

(523) LC-MS (Method 5): R.sub.t=1.26 min; m/z=502/504 (M+H).sup.+.

(524) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=−0.14-0.07 (m, 1H), −0.06-0.02 (m, 1H), 0.22-0.36 (m, 2H), 0.38-0.49 (m, 1H), 0.80 (d, 3H), 1.27-1.36 (m, 1H), 1.46-1.55 (m, 1H), 2.39-2.47 (m, 1H), 2.58-2.66 (m, 1H), 2.99-3.09 (m, 1H), 3.28-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.13 (d, 1H), 7.07 (dd, 1H), 7.35 (d, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.82 (s, 1H), 12.02 (br. s, 1H).

(525) The following compound was prepared analogously to Example 22:

(526) TABLE-US-00021 Example Name/Structure/Starting material Analytical data 37 LC-MS (Method 7): R.sub.t = 1.34 min; m/z = 516/518 (M + H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = −0.160-−0.09 (m, 1H), −0.09-−0.02 (m, 1H), 0.11-0.18 (m, 1H), 0.18-0.25 (m, 1H), 0.80 (d, 3H), 0.92 (d, 3H), 1.47-1.55 (m, 2H), 2.31-2.42 (m, 1H), 2.57-2.65 (m, 1H), 3.05-3.20 (m, 1H), 3.28-3.43 (m, 1H, partially obscured by H.sub.2O signal), 4.12 (d, 1H), 7.01-7.13 (m, 1H), 7.33 (d, 1H), 7.39-7.51 (m, 5H), 9.81 (d, 1H), 12.03 (br. s, 1H).

B. Assessment of the Pharmacological Activity

(527) The pharmacological effect of the compounds according to the invention can be shown in the following assays:

(528) B-1. Stimulation of Recombinant Soluble Guanylate Cyclase (sGC) In Vitro

(529) Investigations on the stimulation of recombinant soluble guanylate cyclase (sGC) by the compounds according to the invention with and without sodium nitroprusside, and with and without the haem-dependent sGC inhibitor 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), are carried out by the method described in detail in the following reference: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch, “Purified soluble guanylyl cyclase expressed in a baculovirus/Sf9 system: Stimulation by YC-1, nitric oxide, and carbon oxide”, J. Mol. Med. 77 (1999), 14-23. The haem-free guanylate cyclase is obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration).

(530) The activation of sGC by a test substance is reported as x-fold stimulation of the basal activity. The result for Example 22 is shown in Table 1:

(531) TABLE-US-00022 TABLE 1 Stimulation (x-fold) of recombinant soluble guanylate cyclase (sGC) in vitro by Example 22 Concentration Haem-containing sGC Haem-free Example 22 Basal +0.01 μM +10 μM sGC Basal [μM] (n = 5) DEA/NO ODQ (n = 5) 0 1.0 ± 0.0 3.6 ± 1.0  5.1 ± 1.5  1.0 ± 0.0 0.01 1.6 ± 0.3 4.4 ± 1.3  5.7 ± 1.6  1.2 ± 0.1 0.1 1.6 ± 0.5 3.4 ± 0.9  6.1 ± 1.7  1.6 ± 0.5 1.0 2.4 ± 1.0 4.4 ± 1.4  8.4 ± 2.2  4.9 ± 1.5 10 4.9 ± 1.2 7.8 ± 2.5 18.3 ± 5.4 14.2 ± 2.0 [DEA/NO = 2-(N,N-diethylamino)diazenolate 2-oxide; ODQ = 1H-1,2,4-oxadiazolo- [4,3a]quinoxalin-1-one].

(532) It is evident from Table 1 that stimulation both of the haem-containing and of the haem-free enzyme is achieved. Furthermore, combination of Example 22 and 2-(N,N-diethylamino)-diazenolate 2-oxide (DEA/NO), an NO donor, shows no synergistic effect, i.e. the effect of DEA/NO is not potentiated as would be expected with an sGC activator acting via a haem-dependent mechanism. In addition, the effect of the sGC activator according to the invention is not blocked by 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), a haem-dependent inhibitor of soluble guanylate cyclase, but is in fact increased. The results in Table 1 thus confirm the mechanism of action of the compounds according to the invention as activators of soluble guanylate cyclase.

(533) B-2. Action at a Recombinant Guanylate Cyclase Reporter Cell Line

(534) The cellular action of the compounds according to the invention is determined at a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

(535) Representative results for the compounds according to the invention are listed in Table 2:

(536) TABLE-US-00023 TABLE 2 sGC-activating activity in the CHO reporter cell in vitro Example No. MEC [nM] 1 3 2 6.5 3 0.3 4 3 5 0.3 6 1 7 300 8 1 9 1 10 0.3 11 3 12 1 13 0.3 14 0.3 15 3 16 3 17 1 18 300 19 30 20 1000 21 10 22 1.8 23 3 25 10 26 10 27 3 28 30 30 10 31 3 32 3 33 1 34 10 35 0.3 36 3 (MEC = minimum effective concentration).
B-3. Stimulation of sGC Enzyme Activity

(537) Soluble guanylate cyclase (sGC) converts on stimulation GTP into cGMP and pyrophosphate (PPi). PPi is detected with the aid of the assay described below. The signal produced in the assay increases as the reaction progresses and serves as a measure of the sGC enzyme activity under the given stimulation.

(538) To carry out the assay, 29 μl of enzyme solution [0-10 nM soluble guanylate cyclase (prepared according to Hönicka et al., J. Mol. Med. 77, 14-23 (1999)) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1% BSA (fraction V), 0.005% Brij®, pH 7.5] are initially introduced into a microplate, and 1 μl of the substance to be tested (as a serially diluted solution in DMSO) is added. The mixture is incubated at room temperature for 10 min. Then 20 μl of detection mix [1.2 nM Firefly Luciferase (Photinus pyralis luciferase, Promega), 29 μM dehydroluciferin (prepared according to Bitler & McElroy, Arch. Biochem. Biophys. 72, 358 (1957)), 122 μM luciferin (Promega), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1% BSA (fraction V), 0.005% Brij®, pH 7.5] are added. The enzyme reaction is started by adding 20 μl of substrate solution [1.25 mM guanosine 5′-triphosphate (Sigma) in 50 mM TEA, 2 mM MgCl.sub.2, 0.1% BSA (fraction V), 0.005% Brij®, pH 7.5] and measured continuously in a luminometer. The extent of the stimulation by the substance to be tested can be determined relative to the signal of the unstimulated reaction.

(539) The activation of haem-free guanylate cyclase is examined by addition of 25 μM of 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to the enzyme solution and subsequent incubation for 30 minutes and compared to the stimulation of the native enzyme.

(540) Representative results for the compounds according to the invention are listed in Table 3:

(541) TABLE-US-00024 TABLE 3 Activating action at the sGC enzyme in vitro Example No. MEC [nM] EC.sub.50 [nM] 1 1 22 2 4 89 3 1 37 4 2.4 110 5 0.3 5.2 6 1.1 56 10 0.5 10 12 1.1 17 13 0.5 14 14 0.5 8.4 22 2.4 68 25 5.1 220 27 1.7 68 30 17 640 33 0.4 11 35 1 11 (MEC = minimum effective concentration; EC.sub.50 = concentration at 50% of maximum efficacy).
B-4. Vasorelaxant Effect In Vitro

(542) Rabbits are anaesthetized and sacrificed by intravenous injection of thiopental sodium (about 50 mg/kg) and exsanguinated. The saphenous artery is removed and divided into rings 3 mm wide.

(543) The rings are mounted singly on in each case a pair of triangular hooks open at the end and made of 0.3 mm-thick special wire (Remanium®). Each ring is placed under an initial tension in 5 ml organ baths with Krebs-Henseleit solution which is at 37° C., is gassed with carbogen and has the following composition: NaCl 119 mM; KCl 4.8 mM; CaCl.sub.2×2 H.sub.2O 1 mM; MgSO.sub.4×7 H.sub.2O 1.4 mM; KH.sub.2PO.sub.4 1.2 mM; NaHCO.sub.3 25 mM; glucose 10 mM; bovine serum albumin 0.001%. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A/D converters (DAS-1802 HC, Keithley Instruments, Munich) and recorded in parallel on chart recorders. Contractions are induced by addition of phenylephrine.

(544) After several (generally 4) control cycles, the substance to be investigated is added in each further run in increasing dosage, and the level of the contraction achieved under the influence of the test substance is compared with the level of the contraction reached in the last preceding run. The concentration necessary to reduce the contraction reached in the preceding control by 50% is calculated from this (IC.sub.50). The standard application volume is 5 μl. The proportion of DMSO in the bath solution corresponds to 0.1%.

(545) Representative results for the compounds according to the invention are listed in Table 4:

(546) TABLE-US-00025 TABLE 4 Vasorelaxant effect in vitro Example No. IC.sub.50 [nM] 3 801 10 131 14 269 16 767 22 137
B-5. Radiotelemetric Measurement of Blood Pressure and Heart Rate on Conscious SH Rats

(547) A commercially available telemetry system from Data Sciences International DSI, USA, is employed for the measurements on conscious SH rats described below.

(548) The system consists of 3 main components: (1) implantable transmitters, (2) receivers, which are linked via a multiplexer to a (3) data acquisition computer. The telemetry system makes it possible to continuously record the blood pressure and heart rate of conscious animals in their usual habitat.

(549) The investigations are carried out on adult female spontaneously hypertensive rats (SH rats) with a body weight of >200 g. After transmitter implantation, the experimental animals are housed singly in type 3 Makrolon cages. They have free access to standard feed and water. The day/night rhythm in the experimental laboratory is changed by the room lighting at 6.00 am and at 7.00 μm.

(550) The telemetry transmitters (TAM PA-C40, DSI) employed are surgically implanted under aseptic conditions in the experimental animals at least 14 days before the first experimental use. The animals instrumented in this way can be employed repeatedly after the wound has healed and the implant has settled.

(551) For the implantation, the fasted animals are anaesthetized with pentobarbital (Nembutal, Sanofi, 50 mg/kg i.p.) and shaved and disinfected over a large area of their abdomens. After the abdominal cavity has been opened along the linea alba, the liquid-filled measuring catheter of the system is inserted into the descending aorta in the cranial direction above the bifurcation and fixed with tissue glue (VetBonD™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall muscle, and layered closure of the wound is performed. An antibiotic (Tardomyocel COMP, Bayer AG, 1 ml/kg s.c.) is administered postoperatively for prophylaxis of infection.

(552) Outline of Experiment:

(553) The substances to be investigated are administered orally by gavage in each case to a group of animals (n=6). The test substances are dissolved in suitable solvent mixtures, or suspended in 0.5% strength Tylose, appropriate for an administration volume of 5 ml/kg of body weight. A solvent-treated group of animals is employed as control.

(554) The telemetry measuring unit is configured for 24 animals. Each experiment is recorded under an experiment number.

(555) Each of the instrumented rats living in the system is assigned a separate receiving antenna (1010 Receiver, DSI). The implanted transmitters can be activated externally by means of an incorporated magnetic switch and are switched to transmission in the run-up to the experiment. The emitted signals can be detected online by a data acquisition system (Dataquest™ A. R. T. for Windows, DSI) and be appropriately processed. The data are stored in each case in a file created for this purpose and bearing the experiment number.

(556) In the standard procedure, the following are measured for 10-second periods in each case: (1) systolic blood pressure (SBP), (2) diastolic blood pressure (DBP), (3) mean arterial pressure (MAP) and (4) heart rate (HR).

(557) The acquisition of measured values is repeated under computer control at 5-minute intervals. The source data obtained as absolute value are corrected in the diagram with the currently measured barometric pressure and stored as individual data. Further technical details are given in the documentation from the manufacturing company (DSI).

(558) The test substances are administered at 9.00 am on the day of the experiment. Following the administration, the parameters described above are measured over 24 hours. After the end of the experiment, the acquired individual data are sorted using the analysis software (Dataquest™ A. R. T. Analysis). The void value is assumed to be the time 2 hours before administration of the substance, so that the selected data set includes the period from 7.00 am on the day of the experiment to 9.00 am on the following day.

(559) The data are smoothed over a presettable time by determination of the average (15-minute average, 30-minute average) and transferred as a text file to a storage medium. The measured values presorted and compressed in this way are transferred into Excel templates and tabulated.

C. Exemplary Embodiments of Pharmaceutical Compositions

(560) The compounds according to the invention can be converted into pharmaceutical preparations in the following ways:

(561) Tablet:

(562) Composition:

(563) 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

(564) Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

(565) Production:

(566) The mixture of compound according to the invention, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed in a conventional tablet press (see above for format of the tablet). A guideline compressive force for the compression is 15 kN.

(567) Suspension which can be Administered Orally:

(568) Composition:

(569) 1000 mg of the compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

(570) 10 ml of oral suspension correspond to a single dose of 100 mg of the compound according to the invention.

(571) Production:

(572) The Rhodigel is suspended in ethanol, and the compound according to the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

(573) Solution which can be Administered Orally:

(574) Composition:

(575) 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention.

(576) Production:

(577) The compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

(578) i.v. Solution:

(579) The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection containers.