STEREOSELECTIVE PROCESS

Abstract

The invention relates to a method for the stereoselective preparation of compounds of formula (IV).

##STR00001##

Claims

1. A method for the preparation of a compound of formula (IV), ##STR00052## wherein R.sup.1a is NC; R.sup.1b is H, CH.sub.3S, Br, CH.sub.3SO.sub.2; A is NC; B is CH.sub.3; or A and B together with the carbon atoms to which they are attached form a ring selected from the group consisting of cyclopentenone, cyclohexenone and furanone; R.sup.2 is F.sub.3C; R.sup.4 is ##STR00053## characterised in that the method comprises step (C), where step (C) is the stereoselective reaction of a compound of formula (I) ##STR00054## with a compound of formula (III) ##STR00055## wherein A, B, R.sup.1a, R.sup.1b, R.sup.2 and R.sup.4 have the meanings as defined above; in the presence of an organo-catalyst of formula (X) ##STR00056## wherein R.sup.3 is selected from the group consisting of ##STR00057##

2. The method according to claim 1, for the preparation of compounds of formula (IV-A) ##STR00058## wherein a compound of formula (I-A) ##STR00059## is reacted with a compound of formula (III) in the presence of an organo-catalyst of formula (X): wherein R.sup.1a, R.sup.1b, R.sup.2 and R.sup.4 have the meanings as defined above.

3. The method according to claim 1, wherein R.sup.3 of organo-catalyst of formula (X) is ##STR00060##

4. The method according to claim 1, wherein step (C) is carried out at a temperature from 0 C. to 70 C.

5. The method according to claim 1, wherein step (C) is carried out in a solvent selected from the group consisting of ethyl acetate, Me-THF, THF, dichloromethane, isopropyl acetate, n-butyl acetate, toluene and DMF.

6. The method according to claim 1, wherein step (C) is carried out using from 0.3 mol % to 10 mol % of the organo-catalyst of formula (X).

7. The method according to claim 1, wherein step (C) is carried out using from 1.0 to 1.5 molar equivalents of the compound of formula (I).

8. The method according to claim 1, wherein step (C) is carried out using 1.0. molar equivalents of compound of formula (III).

9. A method for the preparation of organo-catalyst of formula (X), ##STR00061## wherein R.sup.3 is ##STR00062## characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y) ##STR00063##

10. (canceled)

11. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention solves the problem stated above by means of the method of synthesis described hereinafter.

[0023] The invention relates to a method for the stereoselective preparation of compounds of formula (IV), see scheme 1,

##STR00005##

[0024] wherein

[0025] R.sup.1a is NC;

[0026] R.sup.1b is H, CH.sub.3S, Br, or CH.sub.3SO.sub.2;

[0027] A is NC;

[0028] B is CH.sub.3;

[0029] or A and B together with the carbon atoms to which they are attached form a ring selected from the group consisting of cyclopentenone, cyclohexenone and furanone;

[0030] R.sup.2 is F.sub.3C;

[0031] R.sup.4 is

##STR00006##

[0032] characterised in that the method comprises step (C), where step (C) is the stereoselective reaction of a compound of formula (I)

##STR00007##

[0033] with a compound of formula (III)

##STR00008##

[0034] wherein A, B, R.sup.1a, R.sup.1b, R.sup.2 and R.sup.4 have the meanings as defined above;

[0035] in the presence of an organo-catalyst of formula (X)

##STR00009##

[0036] wherein

[0037] R.sup.3 is selected from the group consisting of

##STR00010##

[0038] Another embodiment of the invention relates to the above method, see scheme 1, for the preparation of compounds of formula (IV-A)

##STR00011##

[0039] wherein a compound of formula (I-A)

##STR00012##

[0040] is reacted with a compound of formula (III) in the presence of an organo-catalyst of formula (X);

[0041] wherein R.sup.1a, R.sup.1b R.sup.2, R.sup.3 and R.sup.4 have the meanings as defined above.

[0042] Another embodiment of the invention relates to the above method, see scheme 1, wherein R.sup.4 of formula (IV) is

##STR00013##

[0043] Another embodiment of the invention relates to the above method, see scheme 1, wherein R.sup.3 of the organo-catalyst of formula (X) is

##STR00014##

[0044] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out at a temperature from 0 C. to 70 C.

[0045] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out at a temperature from 20 C. to 70 C.

[0046] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out at a temperature from 50 C. to 60 C.

[0047] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out in a solvent selected from the group consisting of ethyl acetate, Me-THF, THF, dichloromethane, isopropyl acetate, n-butyl acetate, toluene and DMF.

[0048] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out in a solvent selected from the group consisting of ethyl acetate, Me-THF, THF, dichloromethane and toluene.

[0049] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out in a solvent selected from the group consisting of ethyl acetate, Me-THF, THF and dichloromethane.

[0050] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using from 0.3 mol % to 10 mol % of the organo-catalyst of formula (X).

[0051] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using from 0.5 mol % to 5 mol % of the organo-catalyst of formula (X).

[0052] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using from 0.6 mol % to 1 mol % of the organo-catalyst of formula (X).

[0053] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using from 1.0 to 1.5 molar equivalents of the compound of formula (I).

[0054] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using from 1.0 to 1.2 molar equivalents of the compound of formula (I).

[0055] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using 1.1 molar equivalents of the compound of formula (I).

[0056] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is carried out using 1.0. molar equivalents of the compound of formula (III).

[0057] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (C) is preceded by step (B) wherein the compound of formula (II)

##STR00015##

[0058] is reacted with an inorganic salt to give the compound of formula (III)

##STR00016##

[0059] wherein R.sup.1a, R.sup.1 and R.sup.4 have the meanings as defined above.

[0060] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out at a temperature from 20 to 120 C.

[0061] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out at a temperature from 20 to 80 C.

[0062] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out at a temperature from 25 to 60 C.

[0063] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out using inorganic salts selected from the group consisting of Na.sub.2SO.sub.4, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3, CsF, KF and K.sub.3PO.sub.4.

[0064] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out using inorganic salts selected from the group consisting of Na.sub.2SO.sub.4, K.sub.2CO.sub.3, Na.sub.2CO.sub.3 and Cs.sub.2CO.sub.3.

[0065] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out using inorganic salts selected from the group consisting of Na.sub.2SO.sub.4 and K.sub.2CO.sub.3.

[0066] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out in water and an organic solvent selected from the group consisting of dichloromethane, THF, Me-THF, ethyl acetate, isopropyl acetate, n-butyl acetate and toluene.

[0067] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is carried out in water and an organic solvent selected from the group consisting of dichloromethane, THF, Me-THF and ethyl acetate.

[0068] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (B) is preceded by step (A) wherein the compound of formula (I)

##STR00017##

[0069] is prepared by reacting a substituted aniline of formula (I)

##STR00018##

[0070] with a compound of formula (I)

##STR00019##

[0071] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out at a temperature from 25 to 125 C.

[0072] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out at a temperature from 50 to 120 C.

[0073] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out at a temperature from 70 to 100 C.

[0074] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out in a solvent selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, n-butyl acetate and dioxane.

[0075] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out in a solvent selected from the group consisting of toluene, isopropyl acetate and n-butyl acetate.

[0076] Another embodiment of the invention relates to the above method, see scheme 1, wherein step (A) is carried out in a solvent selected from the group consisting of toluene and isopropyl acetate.

[0077] Another embodiment of the invention relates to the use of a compound of formula (IV) above, for the manufacture of substituted bicyclic dihydropyrimidinones for use as inhibitors of neutrophil elastase activity.

[0078] Another embodiment of the invention relates to a compound of formula (IV) above, for the manufacture of substituted bicyclic dihydropyrimidinones for use as inhibitors of neutrophil elastase activity.

[0079] Each and any of the above definitions for steps (A), (B) and (C) may be combined with each other.

[0080] Another embodiment of the invention relates to a method for the preparation of organo-catalyst of formula (X), see scheme 2

##STR00020##

[0081] wherein R.sup.3 is

##STR00021##

[0082] characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y)

##STR00022##

[0083] Another embodiment of the invention relates to a method for the preparation of an organo-catalyst of formula (X), see scheme 2

##STR00023##

[0084] wherein R.sup.3 is

##STR00024##

[0085] characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y)

##STR00025##

[0086] Another embodiment of the invention relates to a method for the preparation of organo-catalyst of formula (X), see scheme 2

##STR00026##

[0087] wherein R.sup.3 is

##STR00027##

[0088] characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y)

##STR00028##

[0089] Another embodiment of the invention relates to a method for the preparation of organo-catalyst of formula (X), see scheme 2

##STR00029##

[0090] wherein R.sup.3 is

##STR00030##

[0091] characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y)

##STR00031##

[0092] Preparation

[0093] Starting materials are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner.

[0094] Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.

[0095] The following abbreviations are used in the experimental section:

[0096] THFTetrahydrofuran

[0097] DMFDimethylformamide

[0098] Me-THF2-Methyl-tetrahydrofuran

[0099] HPLCHigh performance liquid chromatography

[0100] eeEnantiomer excess

[0101] ESIElectrospray ionization

[0102] MSMass spectroscopy

[0103] CASChemical abstract service

[0104] NMRNuclear magnetic resonance spectroscopy

[0105] MPLCMedium pressure liquid chromatography

[0106] HClHydrochloric acid

[0107] The synthesis according to the invention is illustrated in schemes 1 and 2.

##STR00032##

##STR00033##

EXAMPLES

Example 1

Carbamic Acid, (R)N-[(4-cyanophenyl)[5-oxo-2-[[3-(trifluoromethyl)phenyl]amino]-1-cyclopenten-1-yl]methyl]-, 1,1-dimethylethyl Ester

[0108] ##STR00034##

[0109] At ambient temperature 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one (2.45 g, 10.1 mmol) is suspended in 47 ml ethyl acetate. After addition of 196 mg (0.25 mmol) (R)-3,3-bis[3,5-bis(trifluoromethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogen-phosphate the mixture is cooled to 70 C. Subsequently a solution of 3.08 g (12.69 mmol) carbamic acid, N-[(4-cyanophenyl)methylen]-1,1-dimethylethyl ester in 9 ml ethyl acetate is added while the temperature does not exceed 64 C. After 3 hours at 64 C. cooling is removed and the reaction mixture is stirred for 15 hours. HPLC control indicates almost complete reaction without formation of side products. Solvent is removed under vacuum and the residue is dissolved in 4.9 ml of warm ethyl acetate. After addition of 6.5 ml n-heptane the mixture is seeded with the desired product. Subsequently 6.5 ml n-heptane are added. The resulting yellow suspension is stirred 2.5 h at ambient temperature and filtered. The residue is washed with 5 ml ethyl acetate/heptane 3:8 and dried at 50 C.

[0110] Yield: 3.58 g (7.59 mmol=75%)

[0111] Retention time HPLC (method A): 3.49 min

[0112] HPLC purity: 99.4 area %

[0113] ee: 93.2% (method B)

[0114] ESI-MS: (MH).sup.=470, (M+Na).sup.+=494, (M+H).sup.+=472

Example 2

[0115] Analogous to example 1 it is possible to perform this reaction using other chiral phosphorous acids instead of (R)-3,3-bis[3,5-bis(trifluoromethyl)phenyl]-1,1-binaphthyl 2,2-dilhydrogenphosphate as catalyst.

TABLE-US-00001 TABLE 1 Impact of chiral phosphorous acids on yield and enantioselectivity ee (%, meth- Catalyst-Chemical Yield od Catalyst-Chemical Structure Name/CAS-Number Solvent (%) B) [00035] (R)-3,3-Bis(2,4,6- triisopropylphenyl)-1,1- binaphthyl-2,2-diyl- hydrogenphosphate/ 791616-63-2 MeTHF 82 60 [00036] (R)-3,3-Bis(9- phenanthryl)-1,1- binaphthalene-2,2-diyl- hydrogenphosphate/ 864943-22-6 MeTHF 95 60 [00037] (R)-()-3,3- Bis(triphenylsilyl)-1,1- binaphthyl-2,2-diyl- hydrogenphosphate/ 791616-55-2 MeTHF 84 30

Example 3

Carbamic Acid, (R)N-[(4-cyano-2-methylthiophenyl)[5-oxo-2-[[3-(trifluoromethyl)phenyl] amino]-1-cyclopenten-1-yl]methyl]-, 1,1-dimethylethyl Ester

[0116] ##STR00038##

[0117] At ambient temperature 0.2 g (0.83 mmol) 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one and 23 mg (0.03 mmol) (R)-3,3-bis[3,5-bis(trifluoromethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate are suspended in 5 ml toluene. The mixture is cooled to 41 C. and a solution of 0.296 g (0.91 mmol) carbamic acid, N-[(2-methylthio-4-cyano-phenyl)methylen]-1,1-dimethylethylester in 5 ml toluene is added, while the temperature does not exceed 37 C. After 1 hour at 50 C. the reaction mixture is stirred for 16 h at 33 C. Subsequently the temperature is raised to 8 C. within 6 hours. After 3 days at ambient temperature HPLC indicates incomplete conversion. Solvent is removed under vacuum, a sample of the raw material is dissolved in methanol, water and acetic acid and purified via prep. HPLC.

[0118] Yield: n.d.

[0119] Retention time HPLC (method C): 5.5 min

[0120] ee: 45% (method D)

[0121] If this reaction is performed in dichloromethane incomplete conversion is observed. However, ee increases to 65%.

Example 4

Carbamic Acid, (R)N-[(2-bromo-4-cyanophenyl)[5-oxo-2-[[3-(trifluoromethyl)phenyl] amino]-1-cyclopenten-1-yl]methyl]-, 1,1-dimethylethyl Ester

[0122] ##STR00039##

[0123] At ambient temperature 7.5 g (31.1 mmol) 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one and 600 mg (0.78 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate are suspended in 150 ml ethyl acetate. The mixture is cooled to 75 C. and a solution of 12.4 g (34.2 mmol) carbamic acid, N-[(2-bromo-4-cyanophenyl)methylen]-1,1-dimethylethylester in 50 ml ethyl acetate is added, while the temperature does not exceed 72 C. The reaction mixture is stirred 15 hours while the temperature slowly rises to 20 C. Subsequently the mixture is stirred 1 hour at 0 C. and warmed to ambient temperature. Solvent is removed under vacuum and the residue is purified via MPLC (dichloromethane/methanol 99:1).

[0124] Yield: 14.85 g (27 mmol=87%)

[0125] Retention time HPLC (method E): 0.74 min

[0126] purity (NMR): 90-95%

[0127] ee: 98.5% (method F)

[0128] ESI-MS: (MH).sup.=548, (M+H).sup.+=550

Example 4.1

[0129] At ambient temperature 7.5 g (31.1 mmol) 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one and 600 mg (0.78 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate are suspended in 150 ml ethyl acetate. The mixture is cooled to 30 C. and a solution of 12.4 g (34.2 mmol) carbamic acid, N-[(2-bromo-4-cyanophenyl)methylen]-1,1-dimethylethylester in 50 ml ethyl acetate is added, while the temperature does not exceed 30 C. The reaction mixture is stirred 15 hours at 30 C. Subsequently the mixture is warmed to ambient temperature. About 90% of the solvent is removed under vacuum and the crystallized solid is isolated by filtration.

[0130] Yield: 82-87%, ee=99-100% (Method F).

Example 5

Carbamic Acid, N[(S)-(2-bromo-4-cyanophenyl)[2,5-dihydro-2-oxo-4-[[3-(trifluoromethyl)phenyl]amino]-3-furanyl]methyl]-, 1,1-dimethylethyl Ester

[0131] ##STR00040##

[0132] At ambient temperature 8.6 g (35.3 mmol) 4-[[3-(trifluoromethyl)phenyl]amino]-2(5H)-furanone and 682 mg (0.88 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dilhydrogenphosphate are suspended in 150 ml ethyl acetate. The mixture is cooled to 75 C. and a solution of 14.1 g (38.8 mmol) carbamic acid, N-[(2-bromo-4-cyanophenyl)methylen]-1,1-dimethylethylester in 50 ml ethyl acetate is added, while the temperature does not exceed 72 C. The reaction mixture is stirred 17 hours while the temperature slowly rises to 20 C. Subsequently the mixture is stirred 2 hours at 0 C. and warmed to ambient temperature. Solvent is removed under vacuum and the residue is purified via MPLC (dichloromethane/methanol 99:1).

[0133] Yield: 14.85 g (26.9 mmol=76%)

[0134] Retention time HPLC (method G): 1.29 min

[0135] Purity (NMR): ca. 95%

[0136] ee: 88% (method H)

[0137] ESI-MS: (MH).sup.=550, (M+H).sup.+=552, (M+NH.sub.4).sup.+=569

Example 6

Carbamic Acid, N[(S)-(2-bromo-4-cyanophenyl)[6-oxo-2-[[3-(trifluoromethyl)phenyl]amino]-1-cyclohexen-1-yl]methyl]-, 1,1-dimethylethyl Ester

[0138] ##STR00041##

[0139] Synthesis analogous to example 1 using 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclohexen-1-one (1.31 g=5.13 mmol), carbamic acid, N-[(2-bromo-4-cyanophenyl) methylen]-1,1-dimethylethylester (2.38 g=7.7 mmol) and 97 mg (0.13 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate in ethyl acetate at 25 to 34 C.

[0140] Yield: 1.12 g (2.0 mmol=39%)

[0141] Retention time HPLC (method N): 1.57 min

[0142] Purity (NMR): 80-90%

[0143] ee: 98% (method I)

[0144] ESI-MS: (MH).sup.=562, (M+H).sup.+=564

Example 7

Carbamic Acid, N-[(1R,2E)-2-cyano-1-(4-cyanophenyl)-3-[[3-(trifluoromethyl)phenyl]amino]-2-buten-1-yl]-, 1,1-dimethylethyl Ester

[0145] ##STR00042##

[0146] Synthesis analogous to example 1 using (2E)-3-[[3-(trifluoromethyl)phenyl]amino]-2-butenenitrile (0.5 g=2.21 mmol), carbamic acid, N-[(4-cyanophenyl)methylen]-1,1-dimethylethylester (0.56 g=2.0 mmol) and 17 mg (0.022 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate in ethyl acetate at 55 to 53 C. Raw material purified via prep HPLC.

[0147] Yield: 0.28 g (0.55 mmol=25%)

[0148] Retention time HPLC (method N): 1.56 min

[0149] Purity (NMR): 80-90%

[0150] ee: 87.9% (method K)

[0151] ESI-MS: (MH).sup.=455, (M+H).sup.+=457, (M+NH.sub.4).sup.+=474

Example 8

Carbamic Acid, N-[(1R,2E)-2-cyano-1-(4-cyano-2-methylsulfonylphenyl)-3-[[3-(trifluoromethyl)phenyl]amino]-2-buten-1-yl]-, 1,1-dimethylethyl Ester

[0152] ##STR00043##

[0153] Synthesis analogous to example 1 using (2E)-3-[[3-(trifluoromethyl)phenyl]amino]-2-butenenitrile (0.5 g=2.21 mmol), carbamic acid, N-[(4-cyano-2-methylsufonylphenyl) methylen]-1,1-dimethylethylester (0.75 g=2.43 mmol) and 17 mg (0.022 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate in ethyl acetate at 55 to 53 C. Raw material purified via prep HPLC.

[0154] Yield: 0.48 g (0.9 mmol=41%)

[0155] Retention time HPLC (method N): 1.49 min

[0156] Purity (NMR): 95%

[0157] ee: 90.6% (method L)

[0158] ESI-MS: (MH).sup.=533, (M+H).sup.+=535, (M+NH.sub.4).sup.+=552

Example 9

Carbamic Acid, (R)N-[(4-cyano-2-methylsulfonylphenyl)[5-oxo-2-[[3-(trifluoromethyl) phenyl]amino]-1-cyclopenten-1-yl]methyl]-, 1,1-dimethylethyl Ester

[0159] ##STR00044##

[0160] Synthesis analogous to example 1 using 3-[[3-(trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one (1.3 g=5.24 mmol), carbamic acid, N-[(4-cyano-2-methylsufonylphenyl)methylen]-1,1-dimethylethylester (2.0 g=6.49 mmol) and 96 mg (0.12 mmol) (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate in dichloromethane at 29 to 27 C. Raw material was purified via prep HPLC.

[0161] Yield: 2.89 g (4.15 mmol=77%)

[0162] Retention time HPLC (method N): 1.54 min

[0163] Purity (NMR): 80%

[0164] ee: 96.3% (method M)

[0165] ESI-MS: (MH).sup.=548, (M+H).sup.+=550

[0166] Syntheses of Starting Materials

1. N-[(4-cyanophenyl)methylen]-1,1-dimethylethylester

[0167] This compound was synthesized as described by A. S. Tsai et al (J Am Soc Chem 133 (May 2011), 1248-50) by reacting tert.butyl carbamate, sodium phenylsulfinate and 4-cyanobenzaldehyde in formic acid/water followed by treatment of the resulting intermediate with potassium carbonate in water/dichloromethane. Analytical data of both compounds corresponded well with literature data.

##STR00045##

[0168] Carbamic acid, N-[(2-methylthio 4-cyano-phenyl)methylen]-1,1-dimethylethylester, carbamic acid, N-[(2-bromo-4-cyanophenyl)methylen]-1,1-dimethylethylester, carbamic acid, N-[(2-bromo-4-cyanophenyl)methylen]-1,1-dimethylethylester and carbamic acid, N-[(4-cyano-2-methylsufonylphenyl)methylen]-1,1-dimethylethylester were prepared in analogous manner.

2. 3-[[3-(Trifluoromethyl)phenyl]amino]-2-cyclopenten-1-one

[0169] This compound was synthesized as described by A. A. Abdelselam et al (Austr J Chem 58 (December 2005), 870-6) by reacting cyclopentane-1,3-dione with 3-trifluoromethylaniline. Analytical data corresponded well with literature data.

##STR00046##

3. 4-[[3-(Trifluoromethyl)phenyl]amino]-2(5H)-furanone

[0170] This compound was synthesized as described in WO 2000053581 by reacting 2,4(3H,5H)-furandione with 3-trifluoromethylaniline. Analytical data corresponded well with literature data.

##STR00047##

4. 3-[[3-(Trifluoromethyl)phenyl]amino]-2-cyclohexen-1-one

[0171] This compound was synthesized as described by A. A. Abdelselam et al (Austr J Chem 58 (December 2005), 870-6) by reacting cyclohexane-1,3-dione with 3-trifluoromethylaniline. Analytical data corresponded well with literature data.

##STR00048##

5. (2E)-3-[[3-(trifluoromethyl)phenyl]amino]-2-butenenitrile

[0172] This compound was synthesized as described in WO 2004020412 by reacting 3-amino-2-butenenitrile with 3-trifluoromethylaniline. Analytical data corresponded well with literature data.

##STR00049##

Synthesis of (R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate

(R)-3,3-bis(3,5-bis(trifluoromethyl)phenyl)-[1,1-binaphthalene]-2,2-diol (1)

[0173] ##STR00050##

[0174] Charge (R)-di-bromo-BINOL (6.0 g, 12.5 mmol), (3,5-bis(trifluoromethyl)phenyl)boronic acid (8.067 g, 31.3 mmol), Na.sub.2CO.sub.3 (3.98 g, 38.0 mmol), MeTHF (45 mL) and H.sub.2O (15 mL) to a 250-mL reactor. Purge the mixture with N.sub.2 for 20 min, then add Pd(OAc).sub.2 (14.6 mg, 0.065 mmol) and racemic 4-(2,6-dimethoxyphenyl)-3-(1,1-dimethylethyl)-2,3-dihydro-1,3-benzoxaphosphole (Angew Chem Int Ed 49 (2010), 5879-83, 24.7 mg, 0.075 mmol). Heat the reaction to 70 C. for 2 h, cool down to 20 C. then add 15 mL H.sub.2O. Separate the layers then wash the organic fraction with water (20 mL). Treat the organic fraction with Darco 60 (0.3 h), filter then solvent switch to MeOH (45 mL). Heat the solution to 60 C. then crystallize the product by slow addition of water (45 mL). Cool down to 20 C., filter the product then dry under reduced pressure at 70 C. for 20 h.

[0175] Yield: 8.57 g (91%)

[0176] ee >99.5% (Method O)

[0177] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.23 (s, 4H), 8.11 (s, 2H), 7.99 (d, J=8.2 Hz, 2H), 7.91 (s, 2H), 7.47 (dt, J=7.2, 1.0 Hz, 2H), 7.41 (dt, J=8.0, 1.4 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 5.46 (s, 2H)

(R)-3,3-bis[3,5-bis(trifluormethyl)phenyl]-1,1-binaphthyl-2,2-dihydrogenphosphate

[0178] ##STR00051##

[0179] Charge (R)-3,3-bis(3,5-bis(trifluoromethyl)phenyl)-[1,1-binaphthalene]-2,2-diol (1) (5.5 g, 7.40 mmol), and pyridine (15 mL) to a 250-mL reactor. Slowly add a solution of phosphorus oxychloride (1.71 g, 11.152 mmol) in pyridine (7.5 mL while maintaining the reaction temperature below 30 C. Stir the reaction mixture at 80 C. for 1.5 h, cool down to 40 C. then add water (7.5 mL) followed after 10 min by addition of HCl (6N) solution (37 mL). Heat the reaction to 100 C. for 1 h, cool down to 20 C. then filter the solids. Wash the solids with water (15 mL) then return them to the reactor. Add toluene (60 mL) and HCl (6N) (15 mL). Heat the mixture to 40 C. for 20 min then separate the aqueous fraction. Wash the organic fraction at 30-40 C. with 215 mL 6N HCl then with water (20 mL). Distill toluene to reach 17 mL of product solution, Heat to 60 C. then add heptane (60 mL) to crystallize the product. Cool down to 20 C. then filter, wash with heptane then dry under reduced pressure at 70 C. for 20 h.

[0180] Yield: 3.82 g (66.4%)

[0181] ee >99.5% (Method P)

[0182] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01 (m, 8H), 7.57 (m, 4H), 7.42 (m, 4H), 6.28 (s, 1H).

[0183] HPLC Methods

TABLE-US-00002 Method: A Device-Description Agilent 1200 with DA-Detector Column: Halo-5, 3 50 mm, 5 m Column Supplier: Waters % Sol Gradient/Solvent [0.2% KH.sub.2PO.sub.4, % Sol Flow Temp Time [min] pH = 3] [Acetonitrile] [ml/min] [ C.] 0.00 80 20 2.3 50 4.00 20 80 2.3 50 Method: B Device-Description Agilent 1100 with DAD Column Chiralpak AD-H Column Dimension 150 * 4.6 mm Particle Size 5 m % Sol [0.2% Solvent KH.sub.2PO.sub.4, Gradient pH = % Sol Flow Temp Backpressure time [min] 3] [Acetonitrile] [ml/min] [ C.] [bar] 0.00 90 10 1.0 25 10.00 90 10 1.0 25 Method: C Device-Description Agilent 1200 with DA- and MS-Detector Column: Sunfire, 3 30 mm, 2.5 m Column Supplier: Waters % Sol Gradient/Solvent [H2O, 0.1% % Sol Flow Temp Time [min] TFA] [Acetonitrile] [ml/min] [ C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 Method: D Device-Description Agilent 1260 SFC with DAD and MS Column Daicel Chiralpak IC Column Dimension 4.6 250 mm Particle Size 5 m Solvent Gradient % Sol % Sol [MeOH, Flow Temp Backpressure time [min] [scCO.sub.2] 20 mM ammonia] [ml/min] [ C.] [bar] 0.00 70 30 4 40 150 10.00 70 30 4 40 150 Method: E Device-Description Waters Acquity with DA- and MS-Detector Column: Xbridge BEH C18, 2.1 30 mm, 1.7 m Column Supplier: Waters % Sol Gradient/Solvent [H2O, 0.1% % Sol Flow Temp Time [min] NH3] [Acetonitrile] [ml/min] [ C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60 Method F Device-Description Agilent 1260 SFC with DAD and MS Column Daicel Chiralpak IC Column Dimension 4.6 250 mm Particle Size 5 m Solvent Gradient % Sol % Sol [MeOH, Flow Temp Backpressure time [min] [scCO.sub.2] 20 mM ammonia] [ml/min] [ C.] [bar] 0.00 70 30 4 40 150 10.00 70 30 4 40 150 Method Name: G Device-Description Waters Alliance with DA- and MS-Detector Column: XBridge C18, 4.6 30 mm, 3.5 m Column Supplier: Waters % Sol Gradient/Solvent [H2O, 0.1% % Sol Flow Temp Time [min] NH3] [ACN] [ml/min] [ C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60 Method H Device-Description Agilent 1260 SFC with DAD and MS Column Daicel Chiralpak IA Column Dimension 4.6 250 mm Particle Size 5 m Solvent Gradient % Sol % Sol [MeOH, Flow Temp Backpressure time [min] [scCO.sub.2] 20 mM ammonia] [ml/min] [ C.] [bar] 0.00 80 20 4 40 150 10.00 80 20 4 40 150 Method: I Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralpak-IA Column Dimension 4.6 250 mm Particle Size 5 m Solvent Gradient % Sol % Sol Flow Temp Backpressure time [min] [scCO.sub.2] [MeOH] [ml/min] [ C.] [bar] 0.00 90 10 3 37.5 100 6.00 90 10 3 37.5 100 Method: K Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralpak-IA Column Dimension 4.6 250 mm Particle Size 3 m Solvent Gradient % Sol % Sol Flow Temp Backpressure time [min] [scCO.sub.2] [MeOH] [ml/min] [ C.] [bar] 0.00 90 10 3.5 37.5 120 6.00 90 10 3.5 37.5 120 Method: L Device-Description Agilent 1260 SFC with DAD Column Daicel Chiralpak-IA Column Dimension 4.6 250 mm Particle Size 3 m Solvent Gradient % Sol % Sol Flow Temp Backpressure time [min] [scCO.sub.2] [MeOH] [ml/min] [ C.] [bar] 0.00 95 5 3.5 37.5 120 10.00 95 5 3.5 37.5 120 Method: M Device-Description Agilent 1260 SFC with DAD Column Lux-Cellulose-1 Column Dimension 4.6 250 mm Particle Size 3 m Solvent Gradient % Sol % Sol Flow Temp Backpressure time [min] [scCO.sub.2] [MeOH] [ml/min] [ C.] [bar] 0.00 80 20 3.0 37.5 100 5.00 80 20 3.0 37.5 100 Method: N Device-Description Agilent 1100/1200 Column Sunfire C18 Column Dimension 3.0 30 mm Particle Size 2.5 m Solvent % Sol Flow Gradient [H.sub.2O, 0.2% % Sol [ml/ Temp Backpressure time [min] HCOOH] [Acetonitrile] min] [ C.] [bar] 0.10 97 3 2.3 50 400 1.40 0 100 2.3 50 400 1.60 0 100 2.3 50 400 1.80 97 3 2.3 50 400 Method: O Device-Description Agilent 1100/1200 Column Chiralpak AD-3 Column Dimension 4.6 150 mm Particle Size 3 m Solvent Gradient % Sol % Sol Flow Temp Backpressure time [min] [Heptane] [Isopropanol] [ml/min] [ C.] [bar] 0 99.5 0.5 1.0 25 150 10 99.5 0.5 1.0 25 150 Method: P Device-Description Agilent 1100/1200 Column (R,R) Whelk-01; Cat# 1-780223-300 Column Dimension 4.6 250 mm Particle Size 3.5 m Solvent % Sol Gradient % Sol [Ethanol 0.2% Flow Temp Backpressure time [min] [Heptane] Diethyl amine [ml/min] [ C.] [bar] 0.0 90 10 1.3 25 150 9.0 90 10 1.3 25 150