Method for producing pyrrole derivative, and intermediate thereof

Abstract

The present invention provides a method for producing an atropisomer of a pyrrole derivative having excellent mineralocorticoid receptor antagonistic activity, and an intermediate thereof. A method for producing an atropisomer of a pyrrole derivative using a compound represented by (B) [wherein R.sup.1 represents a C1-C4 alkyl group, and R.sup.2 represents a 2-hydroxyethyl group or a carboxymethyl group] as a production intermediate. ##STR00001##

Claims

1. A method for resolving an atropisomer of the following formula (C): ##STR00030## wherein R.sup.1 represents a C1-C4 alkyl group, comprising: (a) treating a compound of formula (C) with an optically active amine to provide an optically active amine salt comprised of an atropisomer of the compound and the optically active amine; and (b) removing the optically active amine from the optically active amine salt obtained in step (a) under acidic condition to provide an atropisomer of the compound of formula (C).

2. The method according to claim 1, wherein the optically active amine is one compound selected from the group of the following compounds: ##STR00031##

3. The method according to claim 1, wherein the optically active amine is (R)-(+)-1-(1-naphthyl)ethylamine.

4. A method for resolving an atropisomer of the following formula (II) comprising: ##STR00032## (a) treating a compound of formula (II) with an optically active amine to provide an optically active amine salt comprised of an atropisomer of the compound and the optically active amine; and (b) removing the optically active amine from the optically active amine salt obtained in step (a) under acidic condition to provide an atropisomer of the compound of formula (II), the atropisomer of the compound of formula (II) having formula (IIa) ##STR00033##

5. The method according to claim 1, wherein the atropisomer of the compound of formula (C) is (S)-2-[4-ethoxycarbonyl-3-methyl-2-[2(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]acetic acid.

6. A method for obtaining an optically active amine salt of an atropisomer of formula (C): ##STR00034## wherein R.sup.1 represents a C1-C4 alkyl group, comprising treating a compound of formula (C) with an optically active amine to provide an optically active amine salt comprised of an atropisomer of the compound and the optically active amine.

7. The method according to claim 6, wherein the optically active amine is one compound selected from the group of the following compounds: ##STR00035##

8. The method according to claim 6, wherein the optically active amine is (R)-(+)-1-(1-naphthyl)ethylamine.

Description

DESCRIPTION OF EMBODIMENTS

(1) Hereinafter, the present invention will be described in more detail by showing Examples of the present invention and the like, however, the scope of the present invention is not limited thereto.

EXAMPLES

Example 1

2-Bromo-1-[2-(trifluoromethyl)phenyl]propan-1-one

(2) ##STR00023##

(3) To 1-[2-(trifluoromethyl)phenyl]propan-1-one (75 g (370 mmol)), t-butyl methyl ether (750 mL) and bromine (1.18 g (7.4 mmol)) were added. The resulting mixture was stirred at 15 to 30° C. for about 30 minutes, and after it was confirmed that the color of bromine disappeared, the mixture was cooled to 0 to 5° C. While maintaining the temperature at 0 to 10° C., bromine (59.13 g (370 mmol)) was added thereto, and the resulting mixture was stirred. After the mixture was stirred for about 2.5 hours, a 10 w/v % aqueous potassium carbonate solution (300 mL) was added thereto while maintaining the temperature at 0 to 25° C., and sodium sulfite (7.5 g) was further added thereto, followed by heating to 20 to 30° C. This solution was subjected to liquid separation, and to the obtained organic layer, water (225 mL) was added to wash the organic layer. Thereafter, the organic layer was concentrated under reduced pressure, whereby a t-butyl methyl ether solution (225 mL) of the title compound was obtained.

(4) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.91 (3H, d, J=4.0 Hz), 4.97 (1H, q, J=6.7 Hz), 7.60-7.74 (4H, m.

Example 2

Ethyl 2-cyano-3-methyl-4-oxo-4-[2-(trifluoro-methyl)phenyl]butanoate

(5) ##STR00024##

(6) To the 2-bromo-1-[2-(trifluoromethyl)phenyl]-propan-1-one/t-butyl methyl ether solution (220 mL) obtained in Example 1, dimethylacetamide (367 mL), ethyl cyanoacetate (53.39 g (472 mmol)), and potassium carbonate (60.26 g (436 mmol)) were sequentially added, and the resulting mixture was heated to 45 to 55° C. and stirred. After the mixture was stirred for about 2 hours, the mixture was cooled to 20 to 30° C., and then water (734 mL) and toluene (367 mL) were added thereto to effect extraction. Then, water (513 mL) was added to the resulting organic layer to wash the organic layer (washing was performed twice). Thereafter, the obtained organic layer was concentrated under reduced pressure, whereby a toluene solution (220 mL) of the title compound was obtained.

(7) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.33-1.38 (6H, m), 3.80-3.93 (2H, m), 4.28-4.33 (2H, m), 7.58-7.79 (4H, m).

Example 3

Ethyl 2-chloro-4-methyl-5-[2-(trifluoro-methyl)phenyl]-1H-pyrrole-3-carboxylate

(8) ##STR00025##

(9) To the toluene solution (217 mL) of ethyl 2-cyano-3-methyl-4-oxo-4-[2-(trifluoromethyl)phenyl]-butanoate obtained by the production method of Example 2, ethyl acetate (362 mL) and thionyl chloride (42.59 g (358 mmol)) were added at 20 to 30° C., and the resulting mixture was cooled to −10 to 5° C. Then, hydrogen chloride gas (52.21 g (1432 mmol)) was blown into the mixture, and concentrated sulfuric acid (17.83 g (179 mmol)) was further added thereto, and the resulting mixture was heated and stirred at 15 to 30° C. After the mixture was stirred for about 20 hours, ethyl acetate (1086 mL) was added thereto, followed by heating to 30 to 40° C., and water (362 mL) was added thereto, and then, the resulting mixture was subjected to liquid separation. To the organic layer obtained by liquid separation, water (362 mL) was added, followed by liquid separation, and then, a 5 w/v % aqueous sodium hydrogen carbonate solution (362 mL) was added thereto, followed by liquid separation.

(10) Subsequently, the organic layer was concentrated under reduced pressure, and toluene (579 mL) was further added thereto, followed by concentration under reduced pressure, and then, toluene (72 mL) was added thereto, and the resulting mixture was cooled to 0 to 5° C. After the mixture was stirred for about 2 hours, the deposited crystal was filtered and washed with toluene (217 mL) cooled to 0 to 5° C. The obtained wet crystal product was dried under reduced pressure at 40° C., whereby the title compound was obtained (97.55 g, yield: 82.1%).

(11) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.38 (3H, t, J=7.1 Hz), 2.11 (3H, s), 4.32 (2H, q, J=7.1 Hz), 7.39 (1H, d, J=7.3 Hz), 7.50-7.62 (2H, m), 7.77 (1H, d, J=8.0 Hz), 8.31 (1H, br).

Example 4

Ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(12) ##STR00026##

(13) To ethyl 2-chloro-4-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrrole-3-carboxylate (97.32 g (293 mmol)) obtained by the production method of Example 3, ethanol (662 mL), tetrahydrofuran (117 mL), water (49 mL), sodium formate (25.91 g (381 mmol)), and a 5% palladium-carbon catalyst (water content: 52.1%, 10.16 g) were added at room temperature, and the resulting mixture was heated to 55 to 65° C. and stirred. After the mixture was stirred for about 1 hour, the mixture was cooled to 40° C. or lower, and tetrahydrofuran (97 mL) and a filter aid (KC Flock, Nippon Paper Industries) (4.87 g) were added thereto. Then, the catalyst was filtered, and the residue was washed with ethanol (389 mL). The filtrate and the ethanol solution used for washing were combined, and the combined solution was concentrated under reduced pressure. Thereafter, water (778 mL) was added thereto and the mixture was stirred at 20 to 30° C. for 0.5 hours or more. The deposited crystal was filtered and washed with a mixed solution of ethanol/water=7/8 (292 mL). The thus obtained wet crystal product was dried under reduced pressure at 40° C., whereby the title compound was obtained (86.23 g, yield: 98.9%).

(14) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.35 (3H, t, J=7.1 Hz), 2.18 (3H, s), 4.29 (2H, m), 7.40-7.61 (4H, m), 7.77 (1H, d, J=7.9 Hz), 8.39 (1H, br).

Example 5

Ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(5-1) Production Method 1

(5-1-1) Ethyl (RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(15) ##STR00027##

(16) To ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (65.15 g (219 mmol)) obtained by the production method of Example 4, N,N-dimethylacetamide (261 mL), ethylene carbonate (28.95 g (328.7 mmol)), and 4-dimethylaminopyridine (2.68 g (21.9 mmol)) were sequentially added at room temperature, and the resulting mixture was heated to 105 to 120° C. and stirred. After the mixture was stirred for about 10 hours, the mixture was cooled to 20 to 30° C., and toluene (1303 mL) and water (326 mL) were added thereto, and the organic layer was extracted. Then, water (326 mL) was added to the organic layer to wash the organic layer (washing was performed three times). The obtained organic layer was concentrated under reduced pressure, and ethanol (652 mL) was added thereto, and the resulting mixture was further concentrated under reduced pressure. Thereafter, ethanol (130 mL) was added thereto, whereby an ethanol solution (326 mL) of the title compound was obtained.

(17) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.35 (3H, t, J=7.1 Hz), 1.84 (1H, broad singlet), 2.00 (3H, s), 3.63-3.77 (4H, m), 4.27 (2H, m), 7.35-7.79 (5H, m).

(5-1-2) (S)-Ethyl 1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(18) After ethyl (RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (5.00 g (14.6 mmol)) produced according to (5-1-1) was dissolved by adding acetonitrile (50 mL) thereto, vinyl propionate (4.8 mL (43.9 mmol)) and an immobilized lipase, Novozyme 435 (Novozymes Japan Ltd.) (50 mg) were added thereto, and the resulting mixture was stirred at 20 to 30° C. for about 7 hours. After stirring, the immobilized lipase was filtered off, and the filtrate was concentrated under reduced pressure. Subsequently, the concentrated residue was dissolved by adding toluene (25 mL) thereto, and then, silica gel (for example, 60N, Kanto Chemical Co., Inc., spherical and neutral, 40 to 50 μm mesh was used) (10.00 g) was added thereto, and the resulting mixture was stirred for about 1 hour. After stirring, the silica gel was filtered with toluene (50 mL) (this filtrate was discarded), and subsequently, the silica gel was washed with ethyl acetate (50 mL), and the obtained filtrate was concentrated under reduced pressure. Then, to the obtained concentrated residue, toluene (10 mL) and ethylcyclohexane (10 mL) were added thereto, and the resulting mixture was cooled to −17 to −15° C. and stirred for 0.5 hours or more. Thereafter, ethylcyclohexane (100 mL) was slowly added thereto while keeping the temperature at −17 to −5° C., and the resulting mixture was stirred for 1 hour or more. The resulting crystal was filtered and washed with ethylcyclohexane (10 mL) cooled to −17 to −15° C., and the obtained wet crystal product was dried under reduced pressure, whereby the title compound (1.16 g) was obtained (yield: 23.2%). The enantiomeric excess of the obtained crystal was about 92.4% ee (calculated according to Example 5-1-3).

(19) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.35 (3H, t, J=7.1 Hz), 1.84 (1H, broad singlet), 2.00 (3H, s), 3.63-3.77 (4H, m), 4.27 (2H, m), 7.35-7.79 (5H, m).

(5-1-3) HPLC Determination Method for Enantiomeric Excess

(20) About 10 mg of a sample was collected and diluted with a mobile phase to 10 mL, whereby a sample solution was prepared. Column: DAICEL CHIRALPAK AD-H (4.6 mm I.D.×250 mm) Mobile phase: n-hexane:ethanol=95:5 Detection: UV 254 nm Flow rate: about 1.0 mL/min Column temperature: constant temperature of around 40° C. Measurement time: about 10 min Injection volume: 5 μL

(21) The enantiomeric excess was calculated according to the following formula using the peak area ratios of the S form (retention time: about 11 min) and the R form (retention time: about 9 min).
% ee={[(the peak area ratio of the title compound (S form))−(the peak area ratio of the R form)]÷[(the peak area ratio of the title compound (S form))+(the peak area ratio of the R form)]}×100

(5-2) Production Method 2

(5-2-1) (RS)-2-[4-Ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)-phenyl]-1H-pyrrol-1-yl]acetic acid

(22) ##STR00028##

(23) To ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (20.00 g (67.3 mmol)) produced according to Example 4, N,N-dimethylacetamide (190 mL) was added at room temperature, and subsequently, potassium t-butoxide (9.06 g (80.8 mmol)) was added thereto using N,N-dimethylacetamide (10 mL). After the resulting mixture was cooled to about 15° C., ethyl bromoacetate (9.0 mL (80.8 mmol)) was added thereto. After the resulting mixture was stirred for about 1 hour, a 5 N aqueous sodium hydroxide solution (27 mL) and water (40 mL) were added thereto, and the resulting mixture was stirred at room temperature for about 1 hour. Thereafter, water (300 mL) and ethyl acetate (200 mL) were added thereto, and the resulting mixture was stirred, followed by liquid separation. To the aqueous layer, ethyl acetate (400 mL) and 5 N hydrochloric acid (41 mL) were added to effect extraction, and the obtained organic layer was washed 5 times with water (100 mL) and further washed with a saturated sodium chloride solution (100 mL), and then dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel 200 g, methylene chloride/methanol=100/0 to 9/1), whereby (RS)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoro-methyl)phenyl]-1H-pyrrol-1-yl]acetic acid (22.49 g, (63.3 mmol, yield: 94.1%)) was obtained.

(24) On the other hand, in the case where purification is desired, it is also possible to isolate (RS)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)-phenyl]-1H-pyrrol-1-yl]acetic acid as an amine salt by using dicyclohexylamine. For example, (RS)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]-acetic acid (20.00 g (56.3 mmol)) was dissolved in diisopropyl ether (600 mL), and dicyclohexylamine (10.21 g (56.3 mmol)) was added thereto. After the resulting mixture was stirred at room temperature for about 24 hours, the deposited crystal was filtered and washed with diisopropyl ether (100 mL). The wet crystal product was dried under reduced pressure, whereby (RS)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)-phenyl]-1H-pyrrol-1-yl]acetic acid dicyclohexylamine salt (28.23 g (yield: 93.5%)) was obtained.

(5-2-2) (S)-2-[4-Ethoxycarbonyl-3-methyl-2-[2-(trifluoro-methyl)phenyl]-1H-pyrrol-1-yl]acetic Acid Cinchonine Salt (Entry 4 in Table 2)

(25) (RS)-2-[4-Ethoxycarbonyl-3-methyl-2-[2-(trifluoro-methyl)phenyl]-1H-pyrrol-1-yl]acetic acid (500.8 mg (1.41 mmol)) was dissolved by adding t-butyl methyl ether (7.5 mL) thereto at room temperature, and further cinchonine (207.8 mg (0.706 mmol)) was added thereto at room temperature, and the resulting mixture was stirred for about 19 hours. The deposited crystal was filtered and washed with t-butyl methyl ether (1.5 mL). The wet crystal product was dried under reduced pressure, whereby (S)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]acetic acid cinchonine salt (344.4 mg (yield: 37.6%)) was obtained. The diastereomeric excess of the obtained crystal was about 94.8% de.

(26) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 0.80-0.94 (m, 1H), 1.26-1.40 (m, 3H), 1.50-2.23 (m, 7H), 2.51-2.53 (m, 1H), 2.98-3.39 (m, 4H), 3.96-4.55 (m, 5H), 5.05-5.26 (m, 2H), 5.91-6.00 (m, 1H), 6.12-6.15 (m, 1H), 6.57 (broad singlet), 6.91-7.19 (m, 2H), 7.24-7.95 (m, 8H), 8.03-8.11 (m, 1H), 9.00-9.11 (m, 1H).

(5-2-3) HPLC Determination Method for Diastereomeric Excess

(27) About 10 mg of a sample is collected and diluted with a mobile phase to 10 mL, whereby a sample solution is prepared. Column: DAICEL CHIRALCEL OD-RH (4.6 mm I.D.×150 mm) Mobile phase: Mobile phase A: a 0.1 v/v % acetic acid solution: acetonitrile=1:9 Mobile phase B: water:acetonitrile=2:8 Mobile phase A: Mobile phase B=1:1 Detection: UV 254 nm Flow rate: about 1.0 mL/min Column temperature: constant temperature of around 40° C. Measurement time: about 10 min Injection volume: 5 μL

(28) The diastereomeric excess was calculated according to the following formula using the peak area ratios of the S form (retention time: about 5 min) and the R form (retention time: about 4 min)
% de={[(the peak area ratio of the title compound (S form))−(the peak area ratio of the R form)]÷[(the peak area ratio of the title compound (S form))+(the peak area ratio of the R form)]}×100

(5-2-4) Effect of Optically Active Amine

(29) After (RS)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]acetic acid (25 mg (0.07 mmol)) was dissolved in diisopropyl ether (0.5 mL), each of the various optically active amines (0.5 equivalents) was added thereto, and the resulting mixture was stirred at room temperature for about 19 hours. After stirring, the mixture was centrifuged, and the diastereomeric excess in the supernatant was determined by HPLC. The diastereomeric excess and yield of the precipitate (crystal, the target compound was in the S form) were calculated from the measured values (solubility and diastereomeric excess) of the supernatant and shown in Table 1.

(30) TABLE-US-00001 TABLE 1 Entry Optically active amine Supernatant % de Precipitate % de Yield (%) 1 (R)-(+)-1-phenylethylamine 10 (R form)  7 (S form) 58.6 2 (R)-(+)-1-(4-chlorophenyl)ethylamine 19 (R form) 22 (S form) 46.7 3 (R)-1-(1-naphthyl)ethylamine 84 (R form) 85 (S form) 49.5 4 quinine 67 (R form) 71 (S form) 48.7 5 cinchonine 76 (R form) 84 (S form) 47.3

(31) Among the optically active amines, high selectivity was observed in the case of R-1-(1-naphthyl)ethylamine, quinine, and cinchonine. On the other hand, in the case of R-(+)-1-(p-tolyl)ethylamine and cinchonidine, a different isomer (R form) was obtained as a precipitate.

(32) Subsequently, by using cinchonine (0.5 equivalents), the type of solvent was examined, and the results are shown in Table 2. The amount of solvent was 15 times (v/v) the amount of sample, and the stirring time was about 19 hours at room temperature. The calculation methods for the diastereomeric excess and yield are the same as those for Table 1.

(33) TABLE-US-00002 TABLE 2 Entry Solvent % de Yield (%) 1 isopropyl acetate 98.5 23.5 2 t-butyl acetate 97.6 26.3 3 cyclopentyl methyl ether 97.1 30.7 4 t-butyl methyl ether 94.8 37.6

(34) In each of the solvents, good results with respect to selectivity were obtained.

(5-2-5) Ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(35) To an amine salt, for example, a R-1-(1-naphthyl)ethylamine salt of (S)-2-[4-ethoxycarbonyl-3-methyl-2-[2-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]acetic acid (101.3 mg (0.19 mmol)), ethyl acetate (2 mL), water (0.5 mL), and 1 N hydrochloric acid (0.23 mL) were added at room temperature, and the resulting mixture was stirred, followed by liquid separation. The organic layer was washed with a saturated sodium chloride solution (0.5 mL), and then dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. After the residue was dissolved by adding tetrahydrofuran (1 mL) thereto, sodium borohydride (22 mg, 0.582 mmol) was added thereto, and the resulting mixture was stirred at room temperature for about 1 hour. Subsequently, a boron trifluoride-ether complex (0.0586 mL, 0.48 mmol) was added thereto, and the resulting mixture was stirred for about 1 hour. The reaction mixture was subjected to an analysis by HPLC, the production ratio of the title compound was 97.7% (HPLC peak area ratio).

Example 6

(RS)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid

(36) ##STR00029##

(37) To the solution of ethyl (RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate/ethanol solution (321 mL) obtained by the production method of Example 5, water (128.6 mL) and sodium hydroxide (21.4 g (519 mmol)) were added at room temperature, and the resulting mixture was heated and stirred at 65 to 78° C. After stirring for about 6 hours, the mixture was cooled to 20 to 30° C., and water (193 mL) was added thereto, and then, the pH of the mixture was adjusted to 5.5 to 6.5 with 6 N hydrochloric acid while keeping the temperature at 20 to 30° C. To the mixture whose pH was adjusted, (RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrrole-3-carboxylic acid (6.4 mg) was added as a seed crystal, and water (193 mL) was further added thereto. Then, the mixture was cooled to 0 to 5° C., and again, the pH of the mixture was adjusted to 3 to 4 with concentrated hydrochloric acid, and the mixture was stirred for about 1 hour. Thereafter, the deposited crystal was filtered and washed with a 20% aqueous ethanol solution (93 mL) cooled to 0 to 5° C. The thus obtained wet crystal product was dried under reduced pressure at 40° C., whereby the title compound was obtained (64.32 g, yield: 95.0).

(38) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.87 (3H, s), 3.38-3.68 (4H, m), 7.43-7.89 (5H, m).

Example 7

(S)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid quinine salt

(7-1) (S)-1-(2-Hydroxyethyl)-4-methyl-5-[2-(trifluoro-methyl)phenyl]-1H-pyrrole-3-carboxylic acid quinine salt

(39) Acetone (1,150 mL) was added to quinine (21.23 g (65.5 mmol)), and the resulting mixture was heated and stirred under reflux (about 50° C.). After it was confirmed that quinine was dissolved, (RS)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (41.00 g (130.9 mmol)) was added thereto using acetone (82 mL). After stirring for about 1 hour, the resulting mixture was slowly cooled to 0 to 5° C. (adequate cooling rate: about 0.3° C./min) and stirred for about 0.5 hours at that temperature. The resulting crystal was filtered and washed with acetone (205 mL) cooled to 0 to 5° C., whereby a crude wet crystal product (59.52 g) of the title compound was obtained (when a portion of the crude wet crystal product was dried under reduced pressure and the entire amount thereof was converted to a dry weight basis, the amount of the dry product was 35.35 g, and the yield was 42.2%). The diastereomeric excess of the obtained salt was about 94.8% de. Subsequently, to the obtained wet crystal product (59.52 g), ethanol (53 mL) and ethyl acetate (71 mL) were added, and the resulting mixture was heated and stirred under reflux (about 78° C.). After the mixture was stirred for about 1 hour, ethyl acetate (583 mL) was added thereto, and the resulting mixture was stirred under reflux again. Thereafter, the mixture was slowly cooled to 0 to 5° C. and stirred for about 0.5 hours at that temperature. The resulting crystal was filtered and washed with ethyl acetate (141 mL) cooled to 0 to 5° C. The obtained wet crystal product was dried under reduced pressure, whereby the title compound (32.48 g) was obtained (overall yield: 41.5%). The diastereomeric excess of the obtained salt was about 99.3% de.

(40) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.87-1.89 (1H, m), 1.30-2.20 (9H, m), 2.41-2.49 (2H, m), 2.85-3.49 (6H, m), 3.65-3.66 (1H, m), 3.88 (3H, s), 4.82 (1H, broad singlet), 4.92-5.00 (2H, m), 5.23-5.25 (1H, m), 5.60 (1H, br), 5.80-6.00 (1H, m), 7.36-7.92 (9H, m), 8.67 (1H, d, J=4.6 Hz).

(7-2) HPLC Determination for Diastereomeric Excess (% de) of (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrrole-3-carboxylic acid quinine salt

(41) About 10 mg of a sample was collected and diluted with a mobile phase to 20 mL, whereby a sample solution was prepared. Column: DAICEL CHIRALCEL OD-RH (4.6 mm I.D.×150 mm, 5 μm) Mobile phase: a 0.1 v/v % aqueous acetic acid solution (prepared by mixing 1 mL of acetic acid in 1000 mL of distilled water): acetonitrile=75:25 Detection: UV 220 nm Flow rate: about 1.0 mL/min Column temperature: constant temperature of around 40° C. Measurement time: about 25 min Injection volume: 5 μL

(42) The diastereomeric excess (% de) was calculated according to the following formula using the peak area ratios of the S form (retention time: about 14.5 min) and the R form (retention time: about 15.5 min).
% de={[(the peak area ratio of the title compound (S form))−(the peak area ratio of the R form)]÷[(the peak area ratio of the title compound (S form))+(the peak area ratio of the R form)]}×100

Example 8

Ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

(8-1) Production Method 1

(43) To the (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid quinine salt (32.00 g (50.2 mmol)) obtained in Example (7-1), ethyl acetate (480 mL) and a 2 N aqueous hydrochloric acid solution (160 mL) were added, and the resulting mixture was stirred, followed by liquid separation. The obtained organic layer was concentrated under reduced pressure (to 160 mL or less), ethyl acetate (160 mL) was added thereto, and the resulting mixture was further concentrated under reduced pressure. After completion of the concentration under reduced pressure, the amount of the liquid was adjusted (to 320 mL) by adding ethyl acetate, and the resulting mixture was cooled to 0 to 5° C. Subsequently, to this mixture, oxalyl chloride (11.2 mL (130.5 mmol)) was added while keeping the temperature at 0 to 10° C., and then, the resulting mixture was heated to 20 to 30° C. and stirred for about 1 hour. Ethanol (16 mL) was further added thereto, and the resulting mixture was heated and stirred under reflux for about 0.5 hours (about 78° C.) Thereafter, the mixture was cooled to 40° C. or lower, and a 5 w/v % aqueous sodium bicarbonate solution (160 mL) was added thereto, and the resulting mixture was stirred, followed by liquid separation. The resulting organic layer was concentrated under reduced pressure (to 96 mL), and methanol (160 mL) and a 5 w/v % aqueous sodium bicarbonate solution (64 mL) were added thereto, and the resulting mixture was stirred for 1 hour or more. Subsequently, toluene (800 mL) and a 20 w/v % aqueous sodium chloride solution (64 mL) were added thereto, and the resulting mixture was stirred, followed by liquid separation. To the resulting organic layer, a 20 w/v % aqueous sodium chloride solution (160 mL) was further added, and the resulting mixture was stirred, followed by liquid separation. The obtained organic layer was concentrated under reduced pressure (to 64 mL), and ethylcyclohexane (64 mL) was added thereto, and the resulting mixture was cooled to −17 to −15° C. and stirred for 0.5 hours or more. Thereafter, ethylcyclohexane (640 mL) was slowly added thereto while keeping the temperature at −17 to −5° C., and the resulting mixture was stirred for 1 hour or more. The resulting crystal was filtered and washed with ethylcyclohexane (64 mL) cooled to −17 to −15° C., and the obtained wet crystal product was dried under reduced pressure, whereby the title compound (14.20 g) was obtained (yield: 81.4%). The enantiomeric excess of the obtained crystal was about 99.3% ee (the enantiomeric excess was calculated according to Example (5-1-3)).

(44) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.35 (3H, t, J=7.1 Hz), 1.84 (1H, broad singlet), 2.00 (3H, s), 3.63-3.77 (4H, m), 4.27 (2H, m), 7.35-7.79 (5H, m).

(8-2) Production Method 2

(45) To the (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid quinine salt (20.00 g (31.4 mmol)), ethyl acetate (300 mL) and a 2 N aqueous hydrochloric acid solution (100 mL) were added, and the resulting mixture was stirred, followed by liquid separation. The obtained organic layer was concentrated under reduced pressure. After completion of the concentration under reduced pressure, the resulting residue was dissolved by adding N,N-dimethylacetamide (50 mL) thereto, and then, potassium carbonate (6.51 g (47.1 mmol)) and ethyl iodide (3.0 mL (37.6 mmol)) were added thereto, and the resulting mixture was heated to about 60° C. and stirred for about 2 hours. Thereafter, the mixture was cooled to 40° C. or lower, and toluene (350 mL) was added thereto, and the resulting mixture was further cooled to 0 to 5° C. Subsequently, a saturated sodium chloride solution (100 mL) was added thereto, and the resulting mixture was heated to room temperature. Then, toluene (150 mL) and water (100 mL) were further added thereto, and the resulting mixture was stirred, followed by liquid separation. The obtained organic layer was washed by adding a saturated sodium chloride solution (100 mL), and then concentrated under reduced pressure.

(46) Ethylcyclohexane (40 mL) was added thereto at room temperature, and the resulting mixture was cooled to −17 to −15° C. and stirred for 0.5 hours or more. Thereafter, a seed crystal was added thereto, and further ethylcyclohexane (400 mL) was slowly added thereto while keeping the temperature at −17 to −5° C., and the resulting mixture was stirred for 1 hour or more. The resulting crystal was filtered and washed with ethylcyclohexane (40 mL) cooled to −17 to −15° C., and the obtained wet crystal product was dried under reduced pressure, whereby the title compound (8.79 g) was obtained (yield: 82.1%).

Example 9

(S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

(47) Tetrahydrofuran (45 mL) was added to ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrrole-3-carboxylate (3.00 g (8.8 mmol)) obtained in Example 8 and 4-(methylsulfonyl) aniline (2.56 g (15.0 mmol)), and the resulting mixture was heated and stirred (60° C. or higher). To this liquid, a tetrahydrofuran solution of ethylmagnesium bromide (about 1 mol/L) (32.37 g (30.8 mmol)) was slowly added while keeping the temperature at 60° C. or higher. The resulting mixture was stirred for about 1 hour and then cooled to 0 to 5° C., and a 2 N aqueous hydrochloric acid solution (30 mL) and isobutyl acetate (75 mL) were added thereto, and the resulting mixture was stirred, followed by liquid separation. Subsequently, the resulting organic layer was washed with a 2 N aqueous hydrochloric acid solution (15 mL) (washing was repeated 4 times), and further washed with a 20 w/v % aqueous sodium chloride solution (30 mL). After the organic layer was concentrated under reduced pressure, the amount of the liquid was adjusted (to 30 mL) by adding isobutyl acetate, and the resulting mixture was stirred at room temperature for about 1 hour. Thereafter, the mixture was cooled to −15 to −10° C. and stirred for about 1 hour at that temperature. Thereafter, methylcyclohexane (15 mL) was added thereto, and the resulting mixture was further stirred for about 1 hour. The deposited crystal was filtered and washed with methylcyclohexane (12 mL) cooled to −15 to −10° C., and the obtained wet crystal product was dried under reduced pressure, whereby the title compound (3.90 g) was obtained (yield: 92.4%). The enantiomeric excess of the obtained crystal was about 99.8% ee.

Formulation Example 1

Capsule

(48) The crystal (5 g) obtained in Example 9, lactose (115 g), cornstarch (58 g), and magnesium stearate (2 g) are mixed using a V-type mixer, and the resulting mixture is filled in a capsule (180 mg per capsule), whereby a capsule is obtained.

Formulation Example 2

Tablet

(49) The crystal (5 g) obtained in Example 9, lactose (90 g), cornstarch (34 g), crystalline cellulose (20 g), and magnesium stearate (1 g) are mixed using a V-type mixer, and the resulting mixture is tableted (a mass of 150 mg per tablet) using a tableting machine, whereby a tablet is obtained.

Formulation Example 3

Suspension

(50) A dispersion medium in which methyl cellulose is dispersed or dissolved in purified water is prepared. The crystal obtained in Example 9 is weighed and placed in a mortar and kneaded well while adding the above-mentioned dispersion medium thereto in small portions, and then, purified water is added thereto, whereby a suspension (100 g) is prepared.