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

Abstract

The invention relates to a new and improved method for preparation of (4S)-4-[4-cyano-2-(methyl sulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)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-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile of formula (I).

Claims

1. A method for preparing a compound of formula (XXVII) ##STR00029## comprising: a) reacting a compound of formula (XXVI) ##STR00030## in the presence of a cinchona alkaloid and a solvent to form compounds of formulas (XXVIII) and (XXIX) ##STR00031## b) isolating a compound of formula (XXVIII); and c) reacting the compound of formula (XXVIII) in the presence of a strong acid to form a compound of formula (XXVII), where R.sup.1 in the compound of formulas (XXVI), (XXVII), (XXVIII) and (XXIX) is hydrogen or methyl.

2. The method of claim 1, wherein the cinchona alkaloid is chosen from the group consisting of quinine and quinidine.

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

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

5. A compound of formula (XXVII) ##STR00032## wherein the compound is a quinidine salt and R.sup.1 is hydrogen or methyl.

6. The compound of claim 5 wherein R.sup.1 is hydrogen.

7. The compound of claim 5 wherein R.sup.1 is methyl.

Description

EXEMPLARY EMBODIMENTS

Example 1 4-formyl-3-fluorobenzonitrile (XV)

(1) 400 g (1.97 mol) of 4-bromo-2-fluorobenzaldehyde (XIV) as a solution in 2.0 l of DMF was 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. The result was stirred 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 performed 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 mixed with 21 of water. The MtBE was for the most part distilled off at 30 C. in a 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 (two times, 0.8 leach). Drying was performed at 40 C. in vacuum. Yield: 241 g (800/% 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) was 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. This was stirred for 4 hours at 50 C. The result was allowed to cool to 20 C. The reaction mixture was added to 8.01 of water. The product crystallized out. This was stirred for one hour at room temperature. The product was filtered off and washed with water (2 times, 0.1 l each). Drying was carried out at 40 C. in vacuum. Yield: 256 g (91% of theory) of a beige-colored solid.

(5) MS (ESIpos): mz (%)=191.1 (15) [M-18]+, 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 the result was stirred for 3 h at 40 C. This was then diluted with THF (115 ml), stirred for 30 min at 20 C., and 4-formyl-3-(methylsulfonyl)benzonitrile (VI) (119 g, 569 mmol) and 1-[3-(trifluoromethyl)phenyl]urea (VII) (116 g, 569 mmol) were added. 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 this was stirred 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 carried out 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]+

(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-(methyl sulfonyl)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, dimethyl sulfate (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. This was stirred overnight, then cooled to 5 C. The product was filtered off and washed with water (1 l). Drying was carried out 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]+; MS (ESIneg): m/z (%)=532.1 (100) [MH].sup..

(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-(methyl sulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[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. The mixture was then heated to 50 C., 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 carried out at 40 C. in vacuum. Yield: 504 g (98% of theory, in relation 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). This was then heated to 50 C. and stirred for 1 h at 50 C. After cooling to 5 C., filtering was performed, and the filter cake was stirred with butyl acetate (1.2 l), filtered again, and washed with butyl acetate (0.7 L). Drying was carried out 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-(trifluoromethyl)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-(trifluoromethyl)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., the result was filtered, washed 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 carried out 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-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbamide (XIX)

(22) (S)-4-[4-cyano-2-(methyl sulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)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, 2 l 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. A 26% aqueous ammonia solution (518 g, 7.91 mol) was then apportioned at 25 C. and the result was stirred 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 carried out 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, 1), 8.47 (s, 1H).

Example 9

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

(25) (S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)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. A 50% solution of 1-propane phosphonic acid anhydride in ethyl acetate (1.137 kg, 1.79 mol) was then apportioned at 2 C., 26%0, heated under reflux, and stirred for 2 h. This was allowed to cool to 20 C. and 3.4 l of water were 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. When crystallization was finished, the result was heated under reflux and stirred for 4 h. This was cooled to 20 C. and stirred 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 carried out at 50 C. in vacuum. Yield: 344 g (89%0 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. This was then 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. This 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 (1.7 l). Drying was carried out 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-(trifluoromethyl)phenyl]-1,2,3,4-tetra-hydropyrimidine-5-carboxylic Acid Quinine Salt (XXIV)

(32) (rac)-4-[4-cyano-2-(methyl sulfonyl)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; 4.21) and combined with ()-quinine (381.4 g; 1.176 mol). This was then heated to 50 C. and stirred for 1 h at 50 C. After cooling to 5 C. it was filtered and the filter cake was washed with a mixture of isopropanol/water (9:1; 1.2 l). Drying was carried out 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-(trifluoromethyl)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-(trifluoromethyl)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 carried out, and the filter cake was washed three times with water (0.6 l). Drying was carried out 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-(trifluoromethyl)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-(trifluoromethyl)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 this was stirred for 60 min. The product was filtered off, and washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying was carried out 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-ds): =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-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid Allyl Ester (XXIII)

(43) (S)-4-[4-cyano-2-(methyl sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-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, dimethyl sulfate 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. This was stirred overnight and cooled to 5 C. The product was filtered off and washed with water (0.6 l). Drying was carried out 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-1l-[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-(trifluoromethyl)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 performed, and the filter cake was washed three times with water (1.0 l). Drying was carried out at 40 C. in vacuum.

(48) Yield: 293 g (52% of theory, related 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-(methyl sulfonyl)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 (1.61) 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 under reflux for 6 h. After cooling, 1.5 l of water was added to the reaction mixture and this was stirred for 60 min. The product is filtered off, washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying is carried out 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, 1H).

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--[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 the result was stirred for 60 min. The product was filtered off, washed twice with water (0.6 l) and twice with MtBE (0.6 l). Drying was carried out 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) .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 18

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

(60) Parameters of the X-ray diffraction measurement for the compound of formula (I) in crystal form (A):

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

(62) TABLE-US-00001 Scan axis 2 Theta-Omega Start position [2Th.] 2.0000 End position [2Th.] 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 Distance between focus and div. diaphragm 91.00 [mm] Primary beam monochromator focusing X-ray mirror Sample rotation yes

(63) 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):

(64) 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

(65) 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

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

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