Method for producing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4- chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclo-propylpropanoic acid and the crystalline form thereof for use as a pharmaceutical ingredient

Abstract

The present invention relates to a novel and improved process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (I), to the compound of the formula (I) in crystalline form and to their use for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular, cardiopulmonary and cardiorenal disorders.

Claims

1. A process for preparing the compound of the formula (I) ##STR00127## comprising reacting the compound of the formula (II) ##STR00128## under base-free conditions and using an organosilicon compound with the compound of the formula (VII) ##STR00129## or a salt of this compound, and with removal of the silyl protective group in aqueous acidic solution converting into the compound of the formula (I).

Description

EXPERIMENTAL SECTION

(1) Abbreviations and Acronyms:

(2) abs. absolute acac acetylacetonato BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) cat. catalytic CI chemical ionization (in MS) coe cyclooctene d day(s) TLC thin layer chromatography DCM dichloromethane DMA dimethylacetamide DMF dimethylformamide DMSO dimethyl sulfoxide ee enantiomeric excess EI electron impact ionization (in MS) ent enantiomer/enantiomerically pure eq equivalent(s) ESI electrospray ionization (in MS) EtOAc ethyl acetate GC-MS gas chromatography-coupled mass spectrometry % by weight percent by weight h hour(s) HPLC high-pressure, high-performance liquid chromatography ID internal diameter iPrOAc isopropyl acetate iPrOH isopropanol cone. concentrated LC-MS liquid chromatography-coupled mass spectrometry LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide min minute(s) MS mass spectrometry MTBE 2-methoxy-2-methylpropane NMR nuclear magnetic resonance spectrometry NMP N-methyl-2-pyrrolidone Ph phenyl pTsOH p-toluenesulfonic acid R.sub.f retention index (in TLC) RP-HPLC reversed phase high performance liquid chromatography RRT relative retention time R.sub.t retention time RT room temperature TESCl chlorotriethylsilane THF tetrahydrofuran v/v volume to volume ratio (of a solution) aq. aqueous, aqueous solution

(3) HPLC, LC-MS and GC-MS Methods:

(4) Method A:

(5) Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; reactant gas NH3; source temperature: 200° C.; ionization energy 70 eV.

(6) Method B:

(7) Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow rate: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min.fwdarw.310° C. (maintain for 3 min).

(8) Method C:

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

(10) Method D:

(11) MS instrument type: Thermo Scientific FT-MS; instrument type UHPFC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; mobile phase A: 1 l of water+0.01% formic acid; mobile phase B: 1 l of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

(12) Method E:

(13) Instrument/detector high-performance liquid chromatograph with temperature-controlled column oven, UV detector and data evaluation system. Measurement wavelength: 226, bandwidth: 6 nm, column temperature 15° C., column: Chiralpak IA, length: 250 mm, internal diameter: 4.6 mm, particle size: 5 μm, mobile phase: A: 98% n-heptane+0.1% trifluoroacetic acid, B: 2% isopropanol+0.1% trifluoroacetic acid, flow rate: 1.0 ml/min, run time 20 min equilibration: 1 min, test solution about 2 mg/ml of the substance dissolved in isopropanol, injection volume 10 μl. Isomer 3 (main component): 14.39 min (RRT 1.00) isomer 1 (enantiomer): 12.35 min (RRT 0.86) isomer 2: 12.75 min (RRT 0.89), isomer 4: 16.13 min (RRT 1.12).

(14) Method F:

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

(16) Method G:

(17) Instrument: Waters ACQUITY SQD UPUC System; column: Waters Acquity UPUC HSS T3 1.8 μm 50×1 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 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

(18) Method H:

(19) Stationary phase: Zorbax SB-AQ (length 100 mm, ID 2.1 mm, particle size 1.8 μm); mobile phase A: 2 ml of 70% strength perchloric acid/1 l of water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 45° C., injection volume: 1.5 μl; flow rate: 1.0 ml/min; linear gradient in 4 steps: 8% B.fwdarw.15% B (0.70 min), 15% B.fwdarw.42% B (0.30 min), 42% B.fwdarw.57% B (2.20 min), 57% B.fwdarw.100% B (1.80 min), 1.00 min isocratic at 100% B;

(20) Method I:

(21) Stationary phase: Chiralpak AD-H (length 250 mm, ID 4.6 mm, particle size 5 μm); mobile phase: 0.2 ml of trifluoroacetic acid/1 ml of water/100 ml of 2-propanol/900 ml of isohexane; UV detection at 220 nm; oven temperature: 30° C., injection volume: 5 μl; flow rate: 1.25 ml/min; isocratic (20 min);

(22) Starting Materials and Intermediates

Example 1

Methyl (4-chlorophenyl)acetate

(23) ##STR00111##

(24) At room temperature, 1000.0 g of 4-chlorophenylacetic acid were added to 10 ml of concentrated sulfuric acid (95-97%) in 2.4 l of methanol, the solution was heated to 60° C. and stirred at this temperature for 2 h. The solution was cooled to room temperature and 200.0 g of sodium bicarbonate were added. 2050 ml of methanol were distilled off at 150 to 120 mbar, 2210 ml of toluene and 2100 ml of water were added to the residue and the phases were separated. The organic phase was washed with a solution of 50 g of sodium bicarbonate in 1000 ml of water, washed twice with in each case 600 ml of water and then concentrated to give an oil.

(25) Yield: 1123.2 g (103.8% of theory). According to the NMR, the product contains about 3% toluene.

(26) .sup.1H-NMR (400 MHz, CDCl.sub.3): 3.59 (s, 2H); 3.69 (s, 3H); 7.20-7.80 (m, 4H).

(27) GC-MS (Method B) R.sub.t=4.06 min; 184.0 [M].sup.+.

Example 2

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate (diastereomer mixture)

(28) ##STR00112##

(29) Method A:

(30) 1489.5 ml (2.38 mol, 1.1 eq) of n-butyllithium (1.6 N) in hexane were cooled to −10° C. and 402.1 g (2.49 mol, 1.15 eq) of hexamethyldisilazane were added at −10 to −3° C. over 1.5 h. The resulting suspension was stirred at −6° C. for 10 min, 600 ml of tetrahydrofuran were added and the mixture was cooled to −72° C. Over 90 min, 400.0 g (2.17 mol) of methyl (4-chlorophenyl)acetate were added at at most −65° C. and the mixture was stirred at −78° C. for 0.5 h. A solution of 375.4 g (3.25 mol, 1.5 eq) of 1,1,1-trifluoroacetone in 400 ml of tetrahydrofuran was added over 2.5 h and the mixture was stirred for 10 min. 1000 ml (5 mol) of hydrochloric acid (5N) were then added over 5 min at at most 0° C. and the mixture was warmed to 22° C. and stirred for 0.5 h. The phases were separated and the organic phase was washed with 500 ml of water and concentrated under reduced pressure at 50° C. to give an oil.

(31) Yield: 605.0 g (94.1% of theory)

(32) The substance is present as a diastereomer mixture.

(33) .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.02 (s, 1.9H); 1.55 (s, 1.1H); 1.60 (br. S, 0.4H), 3.60 (s, 0.3H); 3.72 (s, 3H); 3.78 (s, 0.7H); 3.94 (s, 0.3H) 5.48 (s, 0.6H) 7.30-7.40 (m, 4H).

(34) GC-MS (Method C) R.sub.t=4.52 min, 296.0 [M].sup.+; 4.84 min, 296.0 [M].sup.+.

(35) Method B:

(36) In a stirred tank, 59.5 kg (0.140 kmol) of n-butyllithium (1.6 M in hexane) were cooled to 0° C., and 23.6 kg (0.146 kmol) of hexamethyldisilazane were metered in. Stirring was continued for 10 min and 21.4 kg of tetrahydrofuran were metered in. At −70° C., 24.0 kg (0.127 kmol) of methyl chlorophenylacetate were metered in and the reaction mixture was stirred for 3 h. A solution of 25.0 kg (0.218 kmol) of trifluoroacetone in 20.9 kg of tetrahydrofuran was then metered in at −70° C., the temperature of the reaction mixture was adjusted to −2° C. and 30.0 kg of water were metered in. At 10° C., 5.3 kg of ethyl acetate were added and the phases were separated. The organic phase was washed with 0.9 kg of sodium bicarbonate in 35.2 kg of water and then with 17.6 kg of water and 29.8 kg of hydrochloric acid (16.9% strength) and 14.7 kg of water. The organic phase was concentrated at 180 to 100 mbar and a jacket temperature of 40° to 50° C. and the oily product was withdrawn.

(37) Yield: 30.6 kg, 84% pure based on the evaporation residue (68% of theory)

(38) A sample was concentrated under reduced pressure and the evaporation residue was determined to be 84% pure.

(39) MS (DCI) (Method A): 297.1 [M+H].sup.+; 314.1 [M+NH4].sup.+.

Example 3

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-2-enoate (isomer mixture)

(40) ##STR00113##

(41) In a stirred tank, 151.3 kg of pyridine and 59.5 kg (0.170 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate were initially charged and volatile fractions were distilled off at 50 mbar until a bottom temperature of 38° C. had been reached. At 20° C., 39.1 kg (0.306 kmol) of phosphorus oxychloride were metered in. The mixture was heated to reflux temperature and stirred for a further 1.5 h. The mixture was cooled to 80° C. and 112 kg of water were metered in (highly exothermic). At 20° C., 151.4 kg of ethyl acetate were added and the separated organic phase was washed with 38.9 kg of hydrochloric acid (3.6% strength) and 38.2 kg of water and concentrated at 60 to 30 mbar and a jacket temperature of 45° C. to 55° C. 26.7 kg of tetrahydrofuran were added to the residue and the solution was withdrawn.

(42) Yield: 37.5 kg of solution, yield about 79% of theory

(43) The product consists of an isomer mixture.

(44) GC MS (Method B) R.sub.t=3.93 min, 278.1 [M].sup.+; 3.97 min, 278.1 [M].sup.+; 4.12 min, 278.1 [M].sup.+;

Example 4

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-3-enoate (diastereomer mixture)

(45) ##STR00114##

(46) In a stirred tank, 57.8 kg (0.136 kmol) of n-butyllithium (1.6 M in hexane) were cooled to 0° C., and 51.1 kg of tetrahydrofuran were added. 15.3 kg (0.150 kmol) of diisopropylamine were metered in and the mixture was cooled to −75° C. At this temperature, a solution of 18.9 kg (0.068 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-2-enoate (isomer mixture) in 19 kg of tetrahydrofuran was metered in and the reaction mixture was stirred for 1 h. A solution of 16.3 kg (0.272 kmol) of acetic acid in 32.6 kg of tetrahydrofuran was then metered in. At 10° C., 72.5 kg of water and 65.3 kg of ethyl acetate were added, 54.8 kg of hydrochloric acid (18% strength) were metered in and the phases were separated. The organic phase was concentrated at 30 mbar and a jacket temperature of 60° C. The residue (18.4 kg) was diluted with 3.7 kg of polyethylene glycol 400 and the product was distilled on a thin-film evaporator at a jacket temperature of 145° C./1 to 10 mbar.

(47) Yield: 13.6 kg (72% of theory)

(48) GC-MS (Method B) R.sub.t=3.98 min, 278.1 [M].sup.+.

Example 5

Methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture)

(49) ##STR00115##

(50) 0.5 kg of catalyst (5% platinum on carbon, 50% water-wet) was added to a solution of 7.3 kg (0.026 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbut-3-enoate (XXIII) in 7.0 kg of methanol, and the mixture was hydrogenated at 50° C./80 bar. The catalyst was filtered off and the solution was withdrawn.

(51) GC MS (Method B) R.sub.t=4.00 min, 280.1 [M].sup.+; 4.03 min, 280.1 [M].sup.+.

Example 6

rel-(2R,3S)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (enantiomer mixture)

(52) ##STR00116##

(53) At 20° C., 22.9 kg (0.127 kmol) of 30% sodium methoxide in methanol were metered into a solution of 19.8 kg (0.071 kmol) of methyl 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate in 36.3 kg of methanol and the mixture was stirred for 1.5 h. 118.7 kg of water were then metered in, the mixture was stirred for 0.5 h and low-boilers were distilled off up to a bottom temperature of 97° C. During the distillation, 29.7 kg of water were metered in. The mixture was cooled to 5° C. and the precipitated solid was isolated and washed with 16 kg of cold water. The moist product was suspended in 91.3 kg of water, 13.1 kg of hydrochloric acid (20% strength) were metered in at 20° C. and the suspension was stirred for 2 h. The solid was isolated, washed with 38.8 kg of water and dried under reduced pressure at a jacket temperature of 50° C. using nitrogen carrier gas.

(54) Yield: 10.1 kg (53.5% of theory)

(55) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 0.78 (d, 3H); 0.89 (m, 2H); 3.14-3.39 (m, 1H); 3.68 (m, 1H); 7.29-7.55 (m, 4H); 12.82 (br. s, 1H).

(56) LC-MS (Method D) R.sub.t=1.85 min, 265.0243 [M−H].sup.−.

Example 7

(2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid—quinine salt

(57) ##STR00117##

(58) At reflux temperature, a solution of 19.3 kg (0.072 kmol) of rel-(2R,3S)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid in 92.5 kg of ethanol was metered into 17.6 kg (0.054 kmol) of quinine in 173.8 kg of ethanol and the mixture was stirred for 10 min. Over a period of 2.5 h, the mixture was cooled to 0° C. and stirred at this temperature for 1 h and the solid was isolated and washed with 69 kg of ethanol and 33.3 kg of water. The filter cake was then heated to reflux temperature in 236.3 kg of water and 630.9 kg of methanol and stirred for 0.5 h. The mixture was then cooled to 0° C. over a period of 5 h and stirred for 1 h and the solid was isolated and washed with a solution of 20.3 kg of methanol and 7.6 kg of water and then with 33.3 kg of water. The filter cake was then heated to reflux temperature in 98.3 kg of water and 481.4 kg of ethanol and stirred for 0.5 h. The mixture was then cooled to 0° C. over a period of 5 h and stirred for 1 h and the solid was isolated and washed with a solution of 21 kg of methanol and 6.6 kg of water and then with 33.3 kg of water and dried under reduced pressure (30 mbar) at a jacket temperature of 50° C. using nitrogen carrier gas.

(59) Yield: 15.5 kg (35.3% of theory)

(60) .sup.1HNMR (400 MHz, DMSO-d.sub.6): 0.77 (d, 3H); 1.50-1.84 (m, 5H); 2.21-2.37 (m, 1H); 2.54-2.74 (m, 1H); 2.96-3.08 (m, 1H); 3.08-3.42 (m, 13H incl. H.sub.2O); 3.62 (d, 1H); 3.88 (s, 3H); 4.87-5.06 (m, 2H); 5.31-5.43 (m, 1H); 5.79-5.94 (m, 1H); 5.77 (br. s, 1H); 7.33-7.44 (m, 5H); 7.46-7.56 (m, 2H); 7.93 (d, 1H); 8.69 (d, 1H).

(61) LC-MS (Method D) R.sub.t=0.80 min 325.1 [M+H].sup.+ (quinine); 1.85 min 531.0 [2M−H].sup.− 265.0 [M−H].sup.− 221.0 [M-CO.sub.2—H].sup.− (2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid).

(62) HPLC (Method E): 99.5% ee

Example 8

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

(63) ##STR00118##

(64) At 20° C., 27.8 kg (0.190 kmol) of hydrochloric acid (25% strength) were metered into 32.1 kg (0.053 kmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid—quinine salt (1:1) in 268 kg of water and the mixture was stirred for 2.5 h. The solid was isolated and washed with 82.5 kg of water and dried under reduced pressure (30 mbar) at a jacket temperature of 50° C. using nitrogen carrier gas.

(65) Yield: 14.4 kg (100% of theory)

(66) HPLC (Method E): 99.1% ee

(67) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.78 (d, 3H) 3.11-3.38 (m, 1H); 3.68 (d, 1H); 7.29-7.54 (m, 4H); 12.83 (br s, 1H).

(68) LC-MS (Method D) R.sub.t=1.85 min 265.0 [M−H].sup.−.

Example 9

tert-Butyl (2E)-3-cyclopropylprop-2-enoate

(69) ##STR00119##

(70) KOtBu (384 g, 3.42 mol) was suspended in 4 l of toluene, and tert-butyl (diethoxyphosphoryl)acetate (864 g, 3.42 mol) was added at 15° C. to 30° C. After 1 h, the mixture was cooled to 0° C. and dissolved in cyclopropanecarbaldehyde (200 g, 2.85 mol) dissolved in 800 ml of toluene. The mixture was stirred for another 2 h and 5 l of NH.sub.4Cl solution (20%) were then added. The organic phase was separated off, washed with 4 l of NaCl solution (20%) and concentrated. The precipitated solid was filtered off, washed with a small amount of cold toluene and dried under reduced pressure, giving 286 g of a solid (yield 60% of theory).

(71) GC MS (Method F) R.sub.t=1.21 min, M.sup.+=168.1;

(72) .sup.1H-NMR (500 MHz, d6-DMSO): 0.63 (m, 2H); 0.89 (m, 2H); 1.41 (s, 9H); 1.60 (m, 1H); 5.82 (d, 1H); 6.28 (dd, 1H).

Example 10

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

(73) ##STR00120##

(74) (+,−)-BINAP (29 g, 0.00575 eq) and [Rh(COD)Cl].sub.2 (9.8 g, 0.0025 eq) in 1 l of THF were stirred exposed to the air for 15 min. In another vessel, 1.33 kg of tert-butyl (2E)-3-cyclopropylprop-2-enoate (7.92 mol), 630 g of KOH (9.51 mol), 2.21 kg of pinacol 3-amino-4-chlorophenylboronate (8.72 mol) and 9.7 ml of 1,5-cyclooctadiene (0.01 eq) were suspended under nitrogen in a mixture of 9.3 l of THF and 730 ml of iPrOH. This mixture was heated to 60° C. and the catalyst mixture was added. The mixture was stirred at this temperature for a further 9 h. The reaction mixture was cooled to 0° C. and 8 l of water were added. The phases were separated and the aqueous phase was extracted with 2.7 l of EtOAc. The combined organic phases were washed with 2.7 l of concentrated NaCl solution. This solution was returned to the vessel and 2.11 kg (11.1 mol) of pTsOH were added a little at a time at 15° C. to 20° C. After 1 h, the suspension was filtered and the product was washed with EtOAc and dried under reduced pressure, giving 3.4 kg (93% of theory) of a solid.

(75) .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.21 (m, 1H); 0.32 (m, 1H); 0.50 (m, 1H); 0.93 (m, 1H); 1.28 (s, 9H); 2.11 (m, 1H); 2.29 (s, 3H); 2.49 (dd, 1H); 2.59 (dd, 1H); 6.54 (d, 1H); 6.73 (d, 1H); 7.12 (m, 3H); 7.47 (d, 2H).

Example 11

3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid

(76) ##STR00121##

(77) At 22° C., 1.90 kg of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate 4-methylbenzenesulfonate and 154 g of pTsOH (0.2 eq) were suspended in 3.8 l of HOAc. The suspension was heated to 60° C. and stirred for 1 h. The reaction mixture was cooled to 0° C., 8.6 l of water were added and the pH was adjusted to pH=12 using 6.5 kg of concentrated aqueous sodium hydroxide solution (45%) NaOH. The aqueous phase was extracted twice with iPrOAc (3.8 l and 0.8 l). Concentrated aqueous hydrochloric acid (32% strength) was added to the aqueous solution, and 3.5 l of DCM were added. The phases were separated and the organic phase was washed with 0.8 l of water. The crude solution was used for the subsequent crystallization.

(78) For crystallization, three crude solutions were combined. The DCM was removed under reduced pressure and 2.9 l of methylcyclohexane were added. The suspension was concentrated and 2.9 l of methylcyclohexane were added. This operation was repeated, with removal of methylcyclohexane under reduced pressure and addition of a further 2.9 l. After the last addition of methylcyclohexane, the methylcyclohexane was removed under reduced pressure and 0.6 l of DCM and 0.6 l of methylcyclohexane were added. At 45° C., the solution was seeded with 2 g of crystalline product. The suspension was cooled to 0° C., washed with methylcyclohexane and dried under reduced pressure, giving 2.23 kg (78% of theory) of a solid.

(79) .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.21 (m, 1H); 0.31 (m, 1H); 0.48 (m, 1H); 0.92 (m, 1H); 2.11 (m, 1H); 2.55 (dd, 1H); 2.61 (dd, 1H); 6.44 (dd, 1H); 6.65 (d, 1H); 7.06 (d, 1H).

Example 12

(3S)-3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol

(80) ##STR00122##

(81) 1.40 kg of 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid were suspended in 15.5 kg of acetonitrile and 1 l of water. The mixture was heated to 60° C. and 0.7 kg of (1S,2R)-(−)-cis-1-amino-2-indanol was added. The reaction mixture was seeded and, over 5 h, slowly cooled to 22° C. The product was filtered off, suspended in 12 kg of acetonitrile and 0.8 l of water and heated to 75° C. More acetonitrile and water 3.8 l (9.5:0.5; ACN:water) were added until a clear solution had formed. The solution was seeded with crystalline product and the suspension was, over 6 h, cooled to 22° C. The suspension was cooled to 0° C., stirred for 1 h, filtered and washed with acetonitrile. The indanol salt formed was dried under reduced pressure, giving 880 g (39% of theory) of a solid.

(82) HPLC MS (Method G) R.sub.t=0.84 min, MH.sup.+=240.1;

(83) .sup.1H-NMR (500 MHz, d6-DMSO): 0.06 (m, 1H); 0.21 (m, 1H); 0.30 (m, 1H); 0.47 (m, 1H); 0.90 (m, 1H); 2.15 (q, 1H); 2.48 (m, 2H); 2.78 (d, 1H); 2.96 (dd, 1H); 4.12 (s, 1H); 4.28 (s, 1H); 6.45 (dd, 1H); 6.66 (d, 1H); 7.05 (d, 1H); 7.18 (m, 3H); 7.34 (m, 1H).

Example 13

(3S)-3-(3-Amino-4-chlorophenyl)-3-cyclopropylpropanoic acid hydrochloride

(84) ##STR00123##

(85) For salt resolution, several batches of the indanol salt were combined. 1.35 kg of (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid indanol salt were suspended in 13.5 l of EtOAc and 6.75 l of water, and 610 ml of HCl (16% in water) were added. The phases were separated and the organic phase was washed twice with water (2×3.4 l of water), dried with sodium sulfate and concentrated, giving 860 g (100% of theory) of an oily product.

(86) The free amino acid 860 g was dissolved in 1.9 l of EtOAc, and 900 ml of HCl in dioxane (4 M) were added. The product was filtered off, washed with EtOAc and dried, giving 936 g (94% of theory) of a solid having an enantiomeric purity of 99.4%.

(87) HPLC MS (Method G) R.sub.t=0.84 min, MH.sup.+=240.1;

(88) .sup.1H-NMR (500 MHz, d6-DMSO): 0.09 (m, 1H); 0.23 (m, 1H); 0.32 (m, 1H); 0.50 (m, 1H); 0.93 (m, 1H); 2.16 (q, 1H); 2.55 (dd, 1H); 2.63 (dd, 1H); 6.64 (m, 1H); 6.84 (m, 1H); 7.17 (m, 1H).

Example 14

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

(89) ##STR00124##

(90) Method A:

(91) (2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (1.43 kg) was suspended in 6.6 kg of THF, and 28 g of DMF were added. At 20° C., oxalyl chloride (680 g) was added and stirring was continued for 45 min.

(92) In another vessel, (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid hydrochloride (1:1) (1.48 kg) was suspended in 6.6 kg of THF, and 3.45 kg of diisopropylethylamine were added at 20° C. At this temperature, TESCl (1.05 kg) was added, and stirring was continued for 1 h.

(93) At 0° C., the TES-protected amino acid was added slowly to the acid chloride, and the empty vessel was washed with 1 kg of THF. After 1.5 h of stirring, EtOAc (6.2 kg) and 2 N HCl (7.4 kg) were added, and the phases were separated. The organic phase was washed with a further 7.4 kg of 2 N HCl solution and washed twice with 7.4 kg of 10% strength NaCl solution in water. The solution was filtered and washed with EtOAc. The EtOAc was removed under reduced pressure, and 13.6 kg of heptane were added. The distillation was continued, and a further 5.5 kg of heptane were added. The reaction mixture was seeded at 55° C. and slowly cooled to 0° C. The product was filtered off, washed with heptane and dried under reduced pressure, giving 1.72 kg (67% of theory) of the desired product as a solid.

(94) .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.23 (m, 1H); 0.28 (m, 1H); 0.49 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.24 (m, 1H); 2.56 (dd, 1H); 2.64 (dd, 1H); 3.37 (m, 1H); 4.13 (d, 1H); 7.10 (dd, 1H); 7.36 (d, 1H); 7.41 (d, 1H); 7.46 (m, 4H); 9.83 (s, 1H); 12.04 (s, 1H).

(95) Method B:

(96) tert-Butyl (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate (160 g) was dissolved in 2.2 kg of dioxane, and 670 g of HCl (32% in water) were added. The reaction mixture was heated to 50° C. and stirred for 12 h. After cooling to RT, 349 g of heptane and 844 g of water were added and the phases were separated. The aqueous phase was extracted with a mixture of 228 g of heptane and 495 g of MTBE. The organic phases were combined, washed with 1.3 kg of water and dried with sodium sulfate. Two of these batches were combined and the solvent was evaporated. At 40° C., the crude product was dissolved in 220 g of MTBE and 96 g of heptane. At 50° C., this solution was added slowly to 3897 g of heptane. The mixture was seeded with 1.5 g of product and slowly cooled to 0° C. The product was filtered off, washed with heptane and dried under reduced pressure, giving 250 g (88% of theory) as a solid.

(97) .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.23 (m, 1H); 0.28 (m, 1H); 0.49 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.24 (m, 1H); 2.56 (dd, 1H); 2.64 (dd, 1H); 3.37 (m, 1H); 4.13 (d, 1H); 7.10 (dd, 1H); 7.36 (d, 1H); 7.41 (d, 1H); 7.46 (m, 4H); 9.83 (s, 1H); 12.04 (s, 1H).

Example 15

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

(98) ##STR00125##

(99) Under an atmosphere of nitrogen, 806 mg of (1S,4S)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (3.12 mmol, 0.011 eq) and 1.16 g of [Rh(CH.sub.2═CH.sub.2).sub.2Cl].sub.2 (2.97 mmol, 0.01 eq) were stirred in 35 ml of MeOH for 30 min.

(100) In another flask, under an atmosphere of nitrogen, 50 g (297 mmol) of tert-butyl (2E)-3-cyclopropylprop-2-enoate, 82.9 g (327 mmol) of pinacol (3-amino-4-chlorophenyl)boronate and 1.67 g of KOH (29.7 mmol) were suspended in MeOH (350 ml) and water (35 ml) and heated to 50° C. The catalyst solution was added and stirring was continued for 17 h. Water and EtOAc (150 ml) were added and the phases were separated. 73.5 g of pTsOH (386 mmol) were added to the organic phase and the solid formed was isolated, washed with EtOAc and dried under reduced pressure, giving 107 g (77% of theory) with an enantiomeric excess of 97.1%.

Example 16

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

(101) ##STR00126##

(102) (2S,3R)-2-(4-Chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (104 g, 389 mmol) was suspended in 1 l of THF, and 2 ml of DMF were added. At 20° C., oxalyl chloride (54 g, 428 mmol) was added and stirring was continued for 45 min.

(103) In another vessel, tert-butyl (3S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (115 g, 389 mmol) was dissolved in 1 l of THF, and 114 m (3.89 mol) of pyridine were added at 20° C. At this temperature, the acid chloride was added slowly, and stirring was continued for 1 h. The reaction was quenched by addition of 800 ml of 20% strength citric acid, and the phases were separated. The organic phase was further washed with 800 ml of 20% strength citric acid and water (2×800 ml). The solvent was evaporated and the residue was dissolved in 160 ml of MTBE and 650 ml of heptane. The reaction mixture was concentrated to half its original volume and slowly cooled to RT. The product was filtered off, washed with heptane and dried under reduced pressure, giving 183 g (86% of theory) of a solid.

(104) .sup.1H-NMR (500 MHz, d6-DMSO): 0.07 (m, 1H); 0.22 (m, 1H); 0.30 (m, 1H); 0.50 (m, 1H); 0.80 (d, 3H); 0.94 (m, 1H); 2.20 (m, 1H); 2.52 (dd, 1H); 2.62 (dd, 1H); 3.36 (m, 1H); 4.13 (d, 1H); 7.11 (dd, 1H); 7.36 (d, 1H); 7.43 (d, 1H); 7.46 (m, 4H); 9.80 (s, 1H)