Method for producing (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrohydro pyrimidine-5-carbonitrile

Abstract

The present invention concerns a new and improved method for preparation of (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile of formula (I), as well as the preparation and use of the crystal form (A) of (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile of formula (I).

Claims

1. A compound of formula (I) ##STR00035## in crystal form (A), characterized in that X-ray diffraction pattern of the compound shows peak maxima of the 2 theta angle at 7.5, 12.4, 15.1, 18.5, 18.7, 22.9, 24.7 and 26.5.

2. A compound of formula (I) ##STR00036## in the crystal form (A), characterized in that the Raman spectrum of the compound shows band maxima at 3075, 2928, 2918, 2236, 2216, 1646, 1605, 1195 and 1004 cm.sup.1.

3. A method for preparing the compound of formula (I) in the crystal form (A) as described in claim 1, comprising crystallizing the compound from an alcohol to provide a crystal paste, and heating the crystal paste to 50-80 C. with stirring for 2-5 hour at this temperature to provide the compound of formula (I) in the crystal form (A).

4. A pharmaceutical composition comprising the compound of formula (I) in the crystal form (A) as described in claim 1 in more than 90 wt. percent of the total quantity of the compound of formula (I).

5. A method for treating pulmonary hypertonia (PH), chronic obstructive lung diseases (COPD), acute lung injury (ALI), acute respiratory disease syndrome (ARDS), pulmonary emphysema, alpha-1-antitrypsin deficiency (AATD), cystic fibrosis (CF), or bronchiectasis, comprising administering an effective amount of the compound of formula (I) crystal form (A) as described in claim 1.

6. A method for promoting wound healing, comprising administering an effective amount of the compound of formula (I) crystal form (A) as described in claim 1.

7. A method for preparing a compound of formula (I) ##STR00037## comprising, a) reacting a compound of formula (IX) ##STR00038## in the presence of a methylation agent and a base to form a compound of formula (XVI); ##STR00039## b) reacting the compound of formula (XVI) in the presence of a palladium catalyst and a secondary amine base to form a compound of formula (XXVI) ##STR00040## in which R.sup.1 stands for methyl, or reacting the compound of formula (XVI) in the presence of a palladium catalyst and a second amine base to form a compound of formula (XXVI), in which R.sup.1 stands for hydrogen; c) reacting the compound of formula XXVI, in which R.sup.1 stands for hydrogen or methyl, in the presence of a cinchona alkaloid and a solvent to form compounds of formulas (XXVIII) and (XXIX) ##STR00041## d) isolating the compound of formula (XXVIII); e) reacting the compound of formula (XXVIII) in the presence of a strong acid to form a compound of formula (XXVII) ##STR00042## f) reacting the compound of formula (XXVII) in the presence of an allyl halide or sulfonate and a base to forma compound of formula (X) ##STR00043## g) reacting the compound of formula (X) in the presence of a methylation agent and a base to form a compound of formula (XXIII) ##STR00044## h) reacting the compound of formula (XXIII) in the presence of a palladium catalyst and a base to form a compound of formula (XXVII) ##STR00045## in which R.sup.1 stands for methyl; i) reacting the compound of formula (XXVII) in the presence of an activation reagent, to form a compound of formula (XIX) ##STR00046## and j) reacting the compound of formula (XIX) in the presence of a dehydrating agent, to provide the compound of formula (I); or optionally, k) after reaction step c) isolating the compound of formula (XXIX); l) reacting the compound of formula (XXIX) in the presence of a strong acid to form a compound for formula (XXX) ##STR00047## m) reacting the compound of formula (XXX) in the presence of an allyl halide or sulfonate and a base to form a compound of formula (XXXI) ##STR00048## n) reacting the compound of formula (XXXI) in the presence of a strong, non-nucleophilic base in a solvent and under simultaneous heating to form the racemate of formula (IX); ##STR00049## and o) reacting the compound of formula (IX) to form the compound of formula (I).

8. The method of claim 7, wherein R.sup.1 in formulas (XXVI), (XXVII), (XXVIII) and (XXIX) is methyl.

9. The method of claim 7, wherein R.sup.1 in formulas (XXVI), (XXVII), (XXVIII) and (XXIX) is hydrogen.

10. The method of claim 7 wherein, after reaction step c), the compound of formula (XXIX) is isolated; the compound of formula (XXIX) is reacted in the presence of a strong acid to form a compound of formula (XXX); the compound of formula (XXX) is reacted in the presence of an allyl halide or sulfonate and a base to form a compound of formula (XXXI); p) the compound of formula (XXXI) is reacted in the presence of a strong, non-nucleophilic base in a solvent and under simultaneous heating to form a racemate of formula (IX); and the compound of formula (IX) is converted to the compound of formula (I).

11. The method of claim 7 further comprising crystallizing the compound of formula (I) in an alcohol to provide a crystal paste, heating the resulting crystal paste to 50-80 C., and stirring for 2-5 hours at this temperature to provide the compound of formula (I) in crystal form (A).

12. The method of claim 7, wherein the cinchona alkaloid is chosen from the group consisting of quinine and quinidine.

13. The method of claim 7 wherein the solvent for reaction step c) is chosen from C.sub.2-C.sub.5 alkyl esters of acetic acid, C.sub.1-C.sub.6 alcohols and mixtures of C.sub.1-C.sub.6 alcohols and waters.

14. The method of claim 7 wherein for reaction step c) for a compound of formula (XXVI) with R.sup.1=methyl, quinidine is used as the cinchona alkaloid and n-butyl acetate as the solvent, and for a compound of formula (XXVI) with R.sup.1=hydrogen, quinine is used as the cinchona alkaloid and a mixture of isopropanol and water is used as the solvent.

15. The method of claim 7 wherein dimethylsulfate is the methylation agent in step a).

16. The method of claim 7 wherein dimethylsulfate is the methylation agent and sodium bis(trimethylsilyl)amide is the base in step g).

17. The method of claim 7 wherein palladium acetate with triphenylphosphine as ligand is used as the palladium catalyst and morpholine is used as the secondary amine base in step b).

18. The method of claim 7 wherein palladium acetate with triphenylphosphine as ligand is used as the palladium catalyst and morpholine is used as the base in step h).

Description

SAMPLE EMBODIMENTS

Example 1

4-formyl-3-fluorobenzonitrile (XV)

(1) 400 g (1.97 mol) of 4-bromo-2-fluorobenzaldehyde (XN) as a solution in 2.0 l of DMF were combined with 183 g (0.433 mol) of potassium hexacyanoferrate (K.sub.4[Fe(CN).sub.6]) and 165.5 g (1.97 mol) of sodium hydrogen carbonate and 2.2 g (9.85 mmol) of palladium acetate was added. Stirring was done for 2.5 hours at 120 C. This was allowed to cool to 20 C. and then 2.0 l of water was added to the batch. Extraction was done with 4.0 l of MtBE and the aqueous phase was again washed with 1.5 l of MtBE. The organic phases were combined and reacted with 21 of water. The MtBE was for the most part distilled off at 30 C. in slight vacuum. The product crystallized out. It was cooled down to 3 C. and stirred for one hour at this temperature. The product was filtered off and again washed with water (twice 0.8 l). Drying was done at 40 C. in vacuum. Yield: 241 g (80% of theory) of a beige-colored solid.

(2) MS (EIpos): m/z=150 [M+H]+

(3) 1H-NMR (400 MHz, DMSO-d6): =7.87 (d, 1H), 7.01 (s, 1H), 8.10 (d, 1H), 10.25 (s, 1H).

Example 2

4-formyl-3-methylsulfonylbenzonitrile (VI)

(4) 200 g (1.34 mol) of 4-formyl-2-fluorobenzonitrile (XV) were provided as a solution in 0.8 l of DMSO and 192 g (1.88 mol) of the sodium salt of methane sulfinic acid was added. Stirring was done for 4 hours at 50 C. This was allowed to cool to 20 C. The reaction mixture was added to 8.0 l of water. The product crystallized out. Stirring was done for one hour at room temperature. The product was filtered off and washed with water (2 times, 0.1 l). Drying was done at 40 C. in vacuum. Yield: 256 g (91% of theory) of a beige-colored solid.

(5) MS (ESIpos): m/z (%)=191.1 (15) [M18].sup.+, 161.0 (100).

(6) 1H-NMR (400 MHz, DMSO-d6): =3.57 (s, 3H), 8.10 (d, 1H), 8.38 (d, 1H), 8.45 (s, 1H), 10.62 (s, 1H).

Example 3

(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Allyl Ester (IX)

(7) To phosphoric acid triethyl ester (124.3 g, 683 mmol) there was added diphosphorus pentoxide (64.6 g, 455 mmol) in 3 portions at 20 C. and stirring was done for 3 h at 40 C. Dilution was then done with THF (115 ml), stirring for 30 min at 20 C., and there was added 4-formyl-3-(methylsulfonyl)benzonitrile (VI) (119 g, 569 mmol) and 1-[3-(trifluoromethyl)phenyl]urea (VII) (116 g, 569 mmol). After this, allyl acetoacetate (VIII) (121 g, 852 mmol) was apportioned for 20 min, whereupon the temperature increased to around 60 C. The mixture was stirred for 4 h at 80 C. For the processing, water (115 ml) was added at 40 C. and stirring was done for 30 min at 25 C. The product was filtered off and washed with water (280 ml). The residue was stirred with MtBE (280 ml) for 20 min, again filtered off and washed with MtBE (220 ml). Drying was done at 40 C. in vacuum. Yield: 259 g (87% of theory) of a beige-colored solid.

(8) MS (ESIpos): m/z (%)=520.2 (100) [M+H].sup.+

(9) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.15 (s, 3H), 3.45 (s, 3H), 4.45 (m, 2H), 4.95 (d, 1H), 5.05 (d, 1H), 5.65 (m, 1H), 6.40 (d, 1H), 7.20 (d, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.85 (br. s, 1H), 8.10 (br. d, 1H), 8.25 (d, 1H), 8.35 (s, 1H).

Example 4

(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid, Allyl Ester (XVI)

(10) (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid allyl ester (IX) (500 g, 0.962 mol) was prepared at 20 C. in THF (2.51) and combined with a 1 M solution of sodium hexamethyldisilazide (NaHMDS) in THF (203 g; 1.107 mol). After 10 min of stirring, dimethylsulfate (243 g; 1.925 mol) was added and the mixture was stirred for 2 h at RT. The reaction mixture was added to a solution of 26% aqueous ammonia solution (315 g; 4.812 mol) in 3 l of water and rinsed with 250 ml of THF. Stirring was done overnight, then cooled to 5 C. The product was filtered off and washed with water (1 l). Drying was done at 40 C. in vacuum.

(11) Yield: 443 g (86% of theory) of a beige-colored solid.

(12) MS (ESIpos): m/z (%)=534.1 (100) [M+H].sup.+; MS (ESIneg): m/z (%)=532.1 (100) [MH].

(13) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.79 (s, 3H), 3.51 (s, 3H), 4.55 (m, 2H), 5.03 (d, 1H), 5.12 (d, 1H), 5.72 (m, 1H), 6.80 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (d, 1H), 8.52 (s, 1H).

Example 5

(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo1l-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid THF-Solvate (XXVI)

(14) (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid, allyl ester (XVI) (485.6 g, 0.910 mol) was prepared at 20 C. in THF (2.275 l) and combined with morpholine (118.9 g; 1.365 mol). Nitrogen was conducted into the reaction mixture for 1 h. Then heating was done to 50 C., the mixture was combined with palladium-(II)-acetate (511 mg; 2.275 mmol) and triphenylphosphine (2388 mg; 9.102 mmol) and stirred for 2 h at 50 C. After cooling, the reaction mixture was placed in 4.5 l of water. 2 N hydrochloric acid was used to adjust to pH=2 and the resulting crystallizate was stirred overnight. The product was filtered off and washed with water (1.8 l). Drying was done at 40 C. in vacuum. Yield: 504 g (98% of theory, referred to the mono-THF solvate) of a beige-colored solid.

(15) MS (ESIpos): m/z (%)=494.0 (100) [M+H].sup.+.

(16) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.76 (m, 4H; THF), 2.08 (s, 3H), 2.77 (s, 3H), 3.48 (s, 3H), 3.60 (m, 4H, THF), 6.72 (s, 1H), 7.75 (m, 2H), 7.82 (m, 1H), 7.92 (br. s, 1H), 8.11 (br. d, 1H), 8.27 (d, 1H), 8.46 (s, 1H), 12.75 (br. s, 1H).

Example 6

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid, Quinidine Salt (XXVIII)

(17) (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid THF-solvate (XXVI) (555 g, 0.910 mol) was prepared at 20 C. in butyl acetate (2.22 l) and combined with (+)-quinidine (334.3 g; 1.03 mol). Heating was then done to 50 C. and stirring for 1 h at 50 C. After cooling to 5 C., filtering was done and the filter cake was stirred with butyl acetate (1.2 l), filtered again, and washed with butyl acetate (0.7 l). Drying was done at 40 C. in vacuum. Yield: 361 g (45% of theory) of a cream-colored solid.

(18) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.58 (m, 2H), 1.79 (m, 1H), 2.04 (m, 1H), 2.07 (s, 3H), 2.33 (m, 1H), 2.77 (s, 3H), 2.79 (m, 1H), 2.90 (m, 2H), 3.21 (m, 1H), 3.33 (m, 2H), 3.51 (s, 3H), 3.90 (s, 3H), 5.11 (d, 1H), 5.14 (d, 1H), 5.53 (br. s, 1H), 6.09 (ddd, 1H), 6.72 (s, 1H), 7.75 (m, 2H), 7.82 (m, 1H), 7.92 (br. s, 1H), 8.11 (br. d, 1H), 8.27 (d, 1H), 8.46 (s, 1H), 12.75 (br. s, 1H).

Example 7

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid (XXVII)

(19) The quinidine salt of (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (XXVIII) (360 g, 0.405 mol) was suspended at 60 C. in a mixture of water (3.9 l) and isopropanol (0.4 l) and adjusted with 2 N of hydrochloric acid to pH=1 and stirred for 1 h at 60 C. After cooling to 20 C., filtering was done, washing with water (0.6 l) and the filter cake was stirred with water (1.2 l), filtered again, and washed with water (1.2 l). Drying was done at 40 C. in vacuum. Yield: 196 g (92% of theory) of a cream-colored solid.

(20) MS (ESIpos): m/z (%)=494.0 (100) [M+H].sup.+.

(21) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.08 (s, 3H), 2.77 (s, 3H), 3.48 (s, 3H), 6.72 (s, 1H), 7.75 (m, 2H), 7.82 (m, 1H), 7.92 (br. s, 1H), 8.11 (br. d, 1H), 8.27 (d, 1H), 8.46 (s, 1H), 12.75 (br. s, 1H).

Example 8

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbamide (XIX)

(22) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (XXVII) (390.5 g, 0.791 mol) was dissolved in THF (3.9 l). To remove residual traces of water, 21 of THF was distilled off at 80 C. bath temperature. This was combined with 1,1-carbonyldiimidazole (192.5 g, 1.187 mol) at 0 C. and stirred for 1 h at 20 C. and for 2 h at 50 C. After this, a 26% ammonia solution (518 g, 7.91 mol) was apportioned at 25 C. and stirring was done for 16 h. The reaction mixture was heated to 50 C. for 2 h, and excess ammonia was gassed out. After cooling, the reaction mixture was slowly added to 7.8 l of water and the resulting crystallizate was stirred overnight. The product was filtered off and washed with water (2.4 l). Drying was done at 40 C. in vacuum. Yield: 361 g (92% of theory) of a cream-colored solid.

(23) MS (ESIpos): m/z (%)=493.0 (100) [M+H].sup.+.

(24) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.73 (s, 3H), 2.73 (s, 3H), 3.45 (s, 3H), 6.55 (s, 1H), 7.34 (br. s, 1H), 7.48 (br. s, 1H), 7.73 (m, 2H), 7.80 (m, 2H), 8.11 (d, 1H), 8.43 (d, 1H), 8.47 (s, 1H).

Example 9

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (I)

(25) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbamide (XIX) (400 g, 0.812 mol) was dissolved in ethyl acetate (1.6 l). This was combined with N-ethyldiisopropylamine (262.4 g, 2.031 mol) at 20 C. and stirred for 15 min at 20 C. After this, a 50% solution of 1-propane phosphonic acid anhydride in ethyl acetate (1.137 kg, 1.79 mol) was apportioned at 2 C., 26%, reflux heated, and stirred for 2 h. This was allowed to cool to 20 C. and 3.4 l of water was added to the batch. After phase separation, the organic phase was washed with saturated sodium hydrogen carbonate solution (1.2 l). The organic phase was heated to 60 C. and distilled off in a slight vacuum while at the same time adding ethanol (toluene denatured). The product crystallizes out. After the crystallization was finished, reflux heating was done and stirring for 4 h. Cooling was done to 20 C. and stirring at this temperature for one hour. The product was filtered off and washed once with water (1.2 l) and once with ethanol (toluene denatured) (0.4 l). Drying was done at 50 C. in vacuum. Yield: 344 g (89% of theory) white crystals of the stable crystal form (A) with a melting point of 232 C., purity: 99.4%, content: 99.3%

(26) MS (ESIpos): m/z (%)=475.1 (100) [M+H].sup.+.

(27) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.81 (s, 3H), 2.70 (s, 3H), 3.52 (s, 3H), 6.48 (s, 1H), 7.65-8.40 (m, 6H), 8.46 (s, 1H).

Example 10

(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid (XXII)

(28) (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid, allyl ester (IX) (420 g, 0.808 mol) was prepared at 20 C. in THF (2.1 l) and combined with morpholine (105.6 g; 1.213 mol). Nitrogen was conducted into the reaction mixture for 1 h. After this, it was combined with bis(triphenylphosphine) palladium-(II)-chloride (284 mg; 0.404 mmol) and triphenylphosphine (424 mg; 1.617 mmol) and the mixture was stirred for 2 h at RT. It was then combined once again with bis(triphenylphosphine) palladium-(II)-chloride (284 mg; 0.404 mmol) and triphenylphosphine (424 mg; 1.617 mmol) and the mixture was stirred for 2 h at RT. The reaction mixture was added to 4 l of water. It was adjusted to pH=2 with 2 N hydrochloric acid and the resulting crystallizate was stirred overnight. The product was filtered off and washed with water (1.71). Drying was done at 40 C. in vacuum.

(29) Yield: 575 g (97% of theory) of a beige-colored solid.

(30) MS (ESIpos): m/z (%)=480.0 (100) [M+H].sup.+.

(31) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.12 (s, 3H), 3.48 (s, 3H), 6.32 (s, 1H), 7.12 (s, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 7.88 (br. s, 1H), 8.13 (br. d, 1H), 8.27 (d, 1H), 8.37 (s, 1H), 12.62 (br. s, 1H).

Example 11

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Quinine Salt (XXIV)

(32) (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid (XXII) (563.7 g, 1.176 mol) was prepared at 20 C. in a mixture of isopropanol/water (9:1; 4.2 l) and combined with ()-quinine (381.4 g; 1.176 mol). After this, it was heated to 50 C. and stirred for 1 h at 50 C. After cooling to 5 C. it was filtered off and the filter cake was washed with a mixture of isopropanol/water (9:1; 1.2 l). Drying was done at 40 C. in vacuum.

(33) Yield: 432 g (46% of theory) of a cream-colored solid.

(34) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.58 (m, 2H), 1.79 (m, 1H), 2.04 (m, 1H), 2.10 (s, 3H), 2.33 (m, 1H), 2.79 (m, 1H), 2.90 (m, 2H), 3.21 (m, 1H), 3.33 (m, 2H), 3.46 (s, 3H), 3.90 (s, 3H), 5.11 (d, 1H), 5.14 (d, 1H), 5.53 (br. s, 1H), 6.09 (m, 1H), 6.33 (s, 1H), 7.10 (s, 1H), 7.73 (m, 2H), 7.82 (m, 1H), 7.90 (br. s, 1H), 8.11 (br. d, 1H), 8.27 (d, 1H), 8.44 (s, 1H), 12.70 (br. s, 1H).

Example 12

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid (XI)

(35) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid, quinine salt (XXIV) (430 g, 0.535 mol) was suspended at 60 C. in a mixture of water (4.2 l) and isopropanol (0.4 l) and adjusted to pH=1 with 2 N hydrochloric acid and stirred for 1 h at 60 C. After cooling to 20 C., filtering was done and the filter cake washed three times with water (0.6 l). Drying was done at 40 C. in vacuum.

(36) Yield: 251 g (98% of theory) of a cream-colored solid.

(37) MS (ESIpos): m/z (%)=480.0 (100) [M+H].sup.+.

(38) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.12 (s, 3H), 3.48 (s, 3H), 6.32 (s, 1H), 7.12 (s, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 7.88 (br. s, 1H), 8.13 (br. d, 1H), 8.27 (d, 1H), 8.37 (s, 1H), 12.62 (br. s, 1H).

Example 13

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Allyl Ester (X)

(39) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid (XI) (250 g, 0.521 mol) was prepared at 20 C. in acetone (1.5 l) and combined with potassium carbonate (72 g; 0.521 mol). After 10 min of stirring, allyl bromide was added (79 g; 652 mol) and the mixture was stirred under reflux for 6 h. After cooling, 1.4 l of water was added to the reaction mixture and stirring was done for 60 min. The product was filtered off, washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying was done at 40 C. in vacuum.

(40) Yield: 258 g (95% of theory) of a cream-colored solid.

(41) MS (ESIpos): m/z (%)=534.1 (100) [M+H].sup.+.

(42) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.79 (s, 3H), 3.51 (s, 3H), 4.55 (m, 2H), 5.03 (d, 1H), 5.12 (d, 1H), 5.72 (m, 1H), 6.80 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (d, 1H), 8.52 (s, 1H).

Example 14

(S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid, Allyl Ester (XXIII)

(43) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-.sub.1-[3-(trifluormethyl)phenyl]-.sub.1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid, allyl ester (X) (250 g, 0.481 mol) was prepared at 20 C. in THF (1.25 l) and combined with a 1 M solution of sodium hexamethyldisilazide (NaHMDS) in THF (102 g; 0.554 mol). After 10 min of stirring, dimethylsulfate was added (122 g; 0.964 mol) and the mixture was stirred for 2 h at RT. The reaction mixture was added to a solution of 26% aqueous ammonia solution (178 g; 2.4 mol) in 1.5 l of water and rinsed with 200 ml of THF. Stirring was done overnight and cooling to 5 C. The product was filtered off and washed with water (0.6 l). Drying was done at 40 C. in vacuum.

(44) Yield: 230 g (89% of theory) of a beige-colored solid.

(45) MS (ESIpos): m/z (%)=534.1 (100) [M+H].sup.+.

(46) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.79 (s, 3H), 3.51 (s, 3H), 4.55 (m, 2H), 5.03 (d, 1H), 5.12 (d, 1H), 5.72 (m, 1H), 6.80 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (d, 1H), 8.52 (s, 1H).

Example 15

(R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid (XXX)

(47) The combined mother liquors and washing liquors from example 11, containing the quinine salt of (R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (XXV) were concentrated down to a crystal paste. This was taken up in water (5.0 l), adjusted with 2 N hydrochloric acid to pH=1 and stirred for 1 h at 60 C. After cooling to 20 C., filtering was done and the filter cake was washed three times with water (1.0 l). Drying was done at 40 C. in vacuum.

(48) Yield: 293 g (52% of theory, referred to the input of XXII) of a cream-colored solid. Ratio of R-enantiomer to S-enantiomer: 88:12.

(49) MS (ESIpos): m/z (%)=480.0 (100) [M+H].sup.+.

(50) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.12 (s, 3H), 3.48 (s, 3H), 6.32 (s, 1H), 7.12 (s, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 7.88 (br. s, 1H), 8.13 (br. d, 1H), 8.27 (d, 1H), 8.37 (s, 1H), 12.62 (br. s, 1H).

Example 16

(R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Allyl Ester (XXXI)

(51) (R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid (XXX) (292 g, 0.609 mol) was prepared at 20 C. in acetone (1.6 l) and combined with potassium carbonate (84 g; 0.609 mol). After 10 min of stirring, allyl bromide was added (92 g; 761 mol) and the mixture was stirred under reflux for 6 h. After cooling, 1.5 l of water was added to the reaction mixture and stirring was done for 60 min. The product is filtered off, washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying is done at 40 C. in vacuum.

(52) Yield: 301 g (95% of theory) of a cream-colored solid.

(53) MS (ESIpos): m/z (%)=534.1 (100) [M+H].sup.+.

(54) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.79 (s, 3H), 3.51 (s, 3H), 4.55 (m, 2H), 5.03 (d, 1H), 5.12 (d, 1H), 5.72 (m, 1H), 6.80 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (d, 1H), 8.52 (s, 111).

Example 17

Isomerization of (R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Allyl Ester (XXXI) into (rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid, Allyl Ester (IX)

(55) (R)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic acid, allyl ester (XXXI) (292 g, 0.609 mol) was prepared at 20 C. in acetone (1.61) and combined with potassium carbonate (84 g; 0.609 mol). After 10 min of stirring, allyl bromide was added (92 g; 761 mol) and the mixture was stirred for 6 h under reflux. After cooling, 1.5 l of water was added to the reaction mixture and stirring was done for 60 min. The product was filtered off, washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying was done at 40 C. in vacuum.

(56) Yield: 301 g (95% of theory) of a cream-colored solid.

(57) MS (ESIpos): m/z (%)=534.1 (100) [M+H].sup.+.

(58) *H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.79 (s, 3H), 3.51 (s, 3H), 4.55 (m, 2H), 5.03 (d, 1H), 5.12 (d, 1H), 5.72 (m, 1H), 6.80 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (d, 1H), 8.52 (s, 1H).

Example 18

Physicochemical Characterization of Compound of Formula (I) in Crystal Form (A)

(59) Parameters of the X-Ray Diffraction Measurement for the Compound of Formula (I) in Crystal Form (A)

(60) Device: Transmission diffractometer PANalytical X'Pert PRO with PIXcel counter (multichannel)

(61) TABLE-US-00001 Scan axis 2 Theta-Omega Start position [2 Th.] 2.0000 End position [2 Th.] 37.9900 Type of divergence diaphragm fixed Size of divergence diaphragm [] 1.0000 Temperature of measurement [ C.] 25 Anode material Cu K-Alpha 1 [] 1.54060 Generator setting 40 mA, 40 kV Diffractometer type Transmission diffractometer Goniometer radius [mm] 240.00 Focus-Div. diaphragm distance [mm] 91.00 Primary beam monochromator focusing X-ray mirror Sample rotation yes

(62) TABLE-US-00002 TABLE 1 Peak maxima [2 Theta] of the X-ray diffraction pattern of the compound (I) in crystal form (A) Peak maximum [2 Theta] Compound (I), crystal form (A) 7.5 10.0 11.5 11.9 12.2 12.4 13.2 14.7 15.1 15.8 16.0 16.5 17.8 18.5 18.7 19.4 19.8 20.0 20.8 20.9 21.8 22.5 22.9 23.1 23.4 23.5 24.0 24.7 25.1 25.3 25.6 26.5 27.1 27.4 28.0 28.1 28.3 28.7 29.2 29.6 30.3 30.5 30.8 31.7 32.2 32.4 33.4 33.8 34.2 34.5
Measurement Conditions for the Raman Spectroscopy for Measurement of the Compound of Formula (I) in Crystal Form (A):

(63) TABLE-US-00003 Device Bruker Raman RFS 100/S Number of Scans 64 Resolution 2-4 cm.sup.1 Laser Power 50 mW Laser Wavelength 1064 mm

(64) TABLE-US-00004 TABLE 2 Band maxima of the Raman spectrum of compound (I) in crystal form (A) Band maximum [cm1] Modification I 3087 3075 3067 3044 3019 2993 2969 2928 2918 2236 2216 2184 1646 1605 1443 1435 1418 1411 1395 1387 1361 1354 1331 1312 1299 1238 1195 1169 1154 1142 1091 1077 1066 1056 1015 1004 994 910 873 795 767 761 746 683 674 645 589 580 535 490 471 457 443 435 403 365 346 329 298 280 255 240 217 190 171 149 128 111

DESCRIPTION OF FIGURES

(65) FIG. 1: X-ray diffraction pattern of compound of formula (I) in crystal form (A)

(66) FIG. 2: Raman spectrum of compound of formula (I) in crystal form (A)