JP2015038053A - Method for producing 4-(2-methyl-1-imidazolyl)-2,2-phenylbutane amide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially producing 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutane amide (imidafenacin), which is a selective muscarine receptor antagonist, in a high yield and purity.SOLUTION: Imidafenacin is produced by once isolating methane sulfonate or p-toluensulfonate of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile, purifying it, and thereafter hydrolyzing it in a lower alcohol in the presence of an alkali metal oxide without neutralizing.

Description

  The present invention relates to a production intermediate of 4- (2-methyl-1-imidazolyl) -2,2-phenylbutanamide (abbreviated as imidafenacin), which is known as a selective muscarinic receptor antagonist, and an intermediate thereof. The present invention relates to a method for producing the high-purity imidafenacin used.

Imidafenacin [Formula (I)]

Has selective and potent muscarinic receptor antagonism, treatment of gastrointestinal motility disorders such as irritable bowel syndrome, diverticular disease, functional diarrhea, esophageal anorexia, cardia spasm, biliary tract, urethral spasm, It is known to be an imidazole derivative that is useful for pharmaceutical uses such as treatment of urinary incontinence and chronic airway obstructive disease (Patent Document 1, Non-Patent Documents 1 to 4).

  On the other hand, a method for producing imidafenacin is also specifically disclosed (Patent Documents 2 to 5, Non-Patent Document 4). In the methods disclosed therein, hydrolysis of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is carried out in a highly concentrated acid solution (for example, 70% sulfuric acid solution) under heating. (Patent Document 2, Non-Patent Document 4). In addition, synthetic adsorbents such as HP-20 are used for purification of imidafenacin (Patent Documents 3 to 4). In addition, after preparing and purifying an acid salt such as hydrochloride or phosphate of imidafenacin or a hydrate of these salts, recrystallization of the obtained imidafenacin crude product using an operation method of neutralization crystallization By doing so, we have obtained imidafenacin drug substance. On the other hand, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or a hydrate of a salt thereof was once isolated as a production intermediate, isolated and purified, and then hydrolyzed. And the manufacturing method which obtains imidafenacin is also disclosed (patent document 5).

WO95 / 15951 pamphlet JP-A-7-215943 Japanese Patent Laid-Open No. 2003-201281 JP 2010-13485 A WO2006 / 064945 pamphlet

Bioorganic & Medicinal Chemistry Letters 8 (1998) 1807-1812 Bioorganic & Medicinal Chemistry Letters 8 (1998) 2163-2168 Bioorganic & Medicinal Chemistry Letters 8 (1998) 2163-2168 Bioorganic & Medicinal Chemistry 7 (1999) 1151-1116

In the methods disclosed in these documents, a synthetic adsorbent such as HP-20 must be used during purification, and there is a possibility that the synthetic adsorbent is mixed into the drug substance. Moreover, in the preparation of acidic salts such as hydrochloride or phosphate of imidafenacin, and their purification and alkali-neutralization crystallization methods, quality degradation due to acid / alkali decomposition is considered. Furthermore, hydrolysis of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is carried out under heating in a highly concentrated acid solution (for example, 70% sulfuric acid solution), resulting in a low yield. In addition, quality degradation is also conceivable.
Therefore, in order to industrially produce high-quality imidafenacin as a pharmaceutical, there are still problems with its simple operability, purification efficiency, isolation yield, etc., and find a production method suitable for actual production It is necessary to make further improvements as much as possible.

  As a result of intensive studies to solve the above problems, the present inventors have found that as a production intermediate, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate or After isolating and purifying p-toluenesulfonate, a simple method for producing imidafenacin by hydrolysis in a lower alcohol in the presence of an alkali metal hydroxide without neutralization was found, and further studies were made. The present invention has been completed.

The production scheme is shown below.

That is, the present invention is a method for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising the following steps:
i) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is obtained by reacting 4-bromo-2,2-diphenylbutyronitrile and 2-methylimidazole in toluene. And ii) a ketone solvent or toluene containing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i), or a ketone solvent and a lower alcohol solvent; Of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by allowing methanesulfonic acid or p-toluenesulfonic acid to act on a mixed solution of toluene or a mixed solution of toluene and a lower alcohol solvent. A step of obtaining methanesulfonate or p-toluenesulfonate, and iii) 4- (2-methyl-1) obtained in step ii) -Imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate or p-toluenesulfonate recrystallized from a mixture of a ketone solvent and a lower alcohol solvent or a mixture of toluene and a lower alcohol solvent And iv) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate or p-toluenesulfonate obtained in step iii) in the lower alcohol system A step of hydrolysis in the presence of an alkali metal hydroxide in a solvent, followed by purification,
The process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide can be provided.

Methanesulfonic acid of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile as an intermediate in the production of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide It has been clarified that, after isolation and purification as a salt or p-toluenesulfonic acid salt, hydrolysis with an alkali metal hydroxide allows the reaction to proceed in high yield and reduce the generation of impurities. Further, high-quality 4- (2-methyl-1-imidazolyl) -2 is obtained only by recrystallization without going through a purification step of the crude product with a synthetic adsorbent or an isolation and purification step of the acidic salt of the crude product. , 2-diphenylbutanamide can be provided in good yield.
According to the present invention, a production method with good yield and industrially advantageous is established by a simple operation of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. It can be provided as a quality drug substance drug substance.

The methanesulfonate or p-toluenesulfonate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile of the present invention is easily obtained.
That is,
i) 2-bromo-2,2-diphenylbutyronitrile and 4-bromo- in 2-10 mL, preferably 2-3.5 mL of toluene, per 1 g of 4-bromo-2,2-diphenylbutyronitrile 4- (2-methyl-1-imidazolyl) -2,2-diphenyl is reacted with 4-10 molar equivalents, preferably 6 molar equivalents, of 2-methylimidazole to 2,2-diphenylbutyronitrile. A step of obtaining butyronitrile, and ii) a ketone solvent containing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) (for example, acetone, 2-butanone) Methyl isobutyl ketone, preferably acetone or toluene, or a ketone solvent (for example, acetone, 2-butanone, methyl isobutyl ketone). Preferably, acetone and a lower alcohol solvent (methanol, ethanol, 1-propanol, 2-propanol, butanol, pentanol, etc.), preferably a mixed solution of 2-propanol or toluene and a lower alcohol solvent (methanol, ethanol). 4- (2-methyl-1-imidazolyl) -2,2 by allowing methanesulfonic acid or p-toluenesulfonic acid to act on a mixed solution with 1-propanol, 2-propanol, butanol, pentanol, etc.) A step of obtaining a methanesulfonate or p-toluenesulfonate of diphenylbutyronitrile, and iii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyro obtained in step ii) Nitrile methanesulfonate or p-toluenesulfonate Solvent (for example, acetone, 2-butanone, methyl isobutyl ketone), preferably acetone and lower alcohol solvent (for example, methanol, ethanol, 1-propanol, 2-propanol, butanol, pentanol), preferably 2-propanol Or a purification step by recrystallization from a mixed solution of toluene and a mixed solution of toluene and a lower alcohol solvent (methanol, ethanol, 1-propanol, 2-propanol, butanol, pentanol, etc.),
The methanesulfonate or p-toluenesulfonate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile can be easily obtained by a production method characterized by comprising

Subsequently, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide was obtained from 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in iii) above. Of methanesulfonate or p-toluenesulfonate.
That is,
iv) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate or p-toluenesulfonate obtained in step iii) was mixed with a lower alcohol solvent (methanol, ethanol 1-propanol, 2-propanol, butanol, pentanol, etc.), preferably 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile 5 g Alkali metal hydroxide (water) in propanol or in 4-5 mL of 2-propanol to 1 g of p-toluenesulfonate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile Lithium oxide, sodium hydroxide, potassium hydroxide, etc.), preferably 4- (2-methyl-1-imidazolyl) -2 After the presence hydrolysis of potassium hydroxide 2-diphenyl butyronitrile 6 molar equivalents relative methanesulfonate or p- toluenesulfonate nitrile, purifying,
4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide can be easily obtained by a production method characterized by containing

  Hereinafter, the present invention will be described more specifically with reference to examples, comparative examples, and test examples of the present invention. However, the present invention is not limited to these examples.

4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate 4-bromo-2,2-diphenylbutyronitrile (95%) 126.4 g (0.4 mol) , 199 g (2.4 mol) of 2-methylimidazole (99%) and 360 mL of toluene were refluxed with heating and stirring for 12 hours. After cooling to about 40 ° C., 400 mL of water was added and stirred at about 40 ° C. for 0.5 hour. After the layers were separated and the organic layer was separated, the aqueous layer was extracted with 100 mL of toluene. The layers were separated, the organic layer was separated, and the organic layers were combined and extracted and washed with 350 mL of 2% aqueous sodium hydrogen carbonate solution, and then extracted and washed 5 times with 350 mL of 2% aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and washed with toluene. After distilling off the solvent under reduced pressure, the residue (132 g) was dissolved in 600 mL of acetone, and 38.5 g (0.4 mol) of methanesulfonic acid was added dropwise with stirring at about 45 ° C. to precipitate the above crude crystals. . Stir at room temperature overnight and then at 5-10 ° C. for 1 hour, filtered, washed with acetone and dried to 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonic acid 120.1 g of crude salt crystals were obtained.
HPLC purity: 99.3%

The obtained crude crystals were dissolved by heating in 310 mL of 2-propanol, 120 mL of 2-butanone was added, the mixture was heated to reflux, filtered while hot, and washed with 190 mL of 2-butanone. The whole filtrate was heated to about 70 ° C. and then stirred overnight at room temperature for crystallization. The mixture was further stirred at 5 to 10 ° C. for about 1 hour, collected by filtration, washed with acetone, and dried to give 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate. 3 g (total yield 70.0%) was obtained.

HPLC purity: 99.8%
Melting point: 166-168 ° C (uncorrected)
1H-NMR [400 MHz, CDCl3 (TMS)] δ: 2.55 (3H, s, CH3S03H), 2.79 (3H, s, CH3), 2.96-3.00 (2H, m, CH2), 4.13-4.17 (2H, m, CH2), 7.19 (1H, d, J = 2Hz, imidazole-H), 7.22 (1H, d, J = 2Hz, imidazole-H), 7 .33-7.45 (10H, m, phenyl-H)

4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutanamide 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonic acid obtained in Example 1 A mixture of 109.31 g (0.275 mol) of salt, 547 mL of 2-propanol and 108.92 g (1.65 mol) of potassium hydroxide (85% granules) was stirred under reflux for 7.5 hours. After cooling to about 40 ° C., the reaction solution was poured into 1460 mL of water. Next, the mixture was stirred at 46 to 35 ° C. for 1 hour for crystallization, and then allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration, washed with warm water of about 50 ° C., then washed with water, and dried to obtain 85.0 g of the above crude crystals.
HPLC purity: 99.1%

  The obtained crude crystals were dissolved by heating in 840 mL of 2-propanol, 1.7 g of activated carbon was added, and the mixture was heated and stirred. Next, after filtration and washing with 10 mL of 2-propanol, the whole filtrate was dissolved again by heating and stirred at room temperature overnight to allow crystallization. The precipitated crystals were collected by filtration, washed with 2-propanol, and dried to obtain 79 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (total yield: 89.9%).

HPLC purity: 99.9%
mp 195-195.5 ° C (uncorrected)
1H-NMR [400 MHz, CDCl3 (TMS)]: 2.21 (3H, s, CH3), 2.68-2.73 (2H, m, CH2), 3.75-3.80 (2H, m, CH2), 5.40 and 6.03 (2H, each br s, NH2), 6.71 (1H, d, J = 1.2 Hz, imidazole-H), 6.83 (1H, d, J = 1) .2 Hz, imidazole-H), 7.30-7.42 (10H, m, phenyl-H)

4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate 4-bromo-2,2-diphenylbutyronitrile (97%) 247.6 g (0.8 mol) Then, a mixture of 402.2 g (4.8 mol) of 2-methylimidazole (98%) and 740 mL of toluene was refluxed with heating and stirring for 12 hours. After standing overnight at room temperature, 800 mL of water was added at about 40 ° C., and the mixture was stirred at about 40 ° C. for 0.5 hour. After the layers were separated and the organic layer was separated, the aqueous layer was extracted with 200 mL of toluene. The layers were separated, the organic layer was separated, and the organic layers were combined, extracted and washed with a 2% aqueous sodium hydrogen carbonate solution, and then extracted and washed 5 times with a 2% aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and washed with toluene. After distilling off the solvent under reduced pressure, the residue (258 g) was dissolved in 1.2 L of acetone, and 76.9 g (0.8 mol) of methanesulfonic acid was added dropwise with stirring at about 45 ° C. to precipitate the above crude crystals. I let you. Stir at about 50 ° C. for about 30 minutes, then at room temperature overnight, then at 5-10 ° C. for 1 hour, filtered, washed with acetone and dried to 4- (2-methyl-1-imidazolyl) -2,2 -Crude crystals (245.4 g) of diphenylbutyronitrile methanesulfonate were obtained.
HPLC purity: 98.9%

  The obtained crude crystals were dissolved by heating in a mixed solution of 640 mL of 2-propanol and 200 mL of 2-butanone, filtered while hot, and washed with 440 mL of 2-butanone. The whole filtrate was heated to about 75 ° C. and then stirred overnight at room temperature to cause crystallization. The mixture was further stirred at 5 to 10 ° C. for about 1 hour, collected by filtration, washed with acetone, and dried to give 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate. 5 g (total yield 72.5%) was obtained.

HPLC purity: 99.5%
Melting point: 166-167.5 ° C (uncorrected)
1H-NMR [400 MHz, CDCl3 (TMS)] δ: 2.55 (3H, s, CH3S03H), 2.79 (3H, s, CH3), 2.96-3.00 (2H, m, CH2), 4.13-4.17 (2H, m, CH2), 7.19 (1H, d, J = 2Hz, imidazole-H), 7.22 (1H, d, J = 2Hz, imidazole-H), 7 .33-7.45 (10H, m, phenyl-H).
Q-MS (ESI ^<+> ) m / z: 302 [M + 1] ^< +>

4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutanamide 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonic acid obtained in Example 3 A mixture of 119.3 g (0.3 mol) of salt, 597 mL of 2-propanol and 118.8 g (1.8 mol) of potassium hydroxide (85% granules) was stirred for 11 hours under reflux. After cooling to about 40 ° C., the reaction solution was poured into 1.6 L of water. Next, the mixture was stirred at 50-30 ° C. for 1.5 hours for crystallization, and then left overnight at room temperature. The precipitated crystals were collected by filtration, washed with warm water at about 50 ° C., then washed with water, and dried to obtain 92.2 g of the above crude crystals.
HPLC purity: 99.2%

The obtained crude crystals were dissolved by heating in 875 mL of 2-propanol, 1.9 g of activated carbon was added, and the mixture was heated and stirred. Subsequently, after filtration and washing with 50 mL of 2-propanol, the entire filtrate was dissolved again by heating, and stirred overnight at room temperature for crystallization. Precipitated crystals were collected by filtration, washed with 2-propanol, and dried to obtain 85.5 g (total yield: 89.2%) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. .
HPLC purity: 99.9%
Melting point: 194.5-195 ° C (uncorrected)
1H-NMR [400 MHz, CDCl3 (TMS)]: 2.21 (3H, s, CH3), 2.68-2.73 (2H, m, CH2), 3.75-3.80 (2H, m, CH2), 5.40 and 6.01 (2H, ech br s, NH2), 6.71 (1H, d, J = 1.2 Hz, imidazole-H), 6.83 (1H, d, J = 1) .2 Hz, imidazole-H), 7.30-7.42 (10H, m, phenyl-H)

4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile / p-toluenesulfonate 4-bromo-2,2-diphenylbutyronitrile 15 g (0.05 mol), 2-methyl A mixture of 24.6 g (0.3 mol) of imidazole and 35 mL of toluene was refluxed with heating and stirring for 12 hours. After cooling to about 40 ° C., 80 mL of water was added and stirred at about 40 ° C. for 0.5 hour. After the layers were separated and the organic layer was separated, the aqueous layer was extracted with toluene. The layers were separated, the organic layer was separated, and the organic layers were combined and extracted and washed with a 2% aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and washed with toluene. After distilling off the solvent under reduced pressure, the residue was dissolved by heating in 300 mL of toluene, and 9.5 g (0.05 mol) of p-toluenesulfonic acid monohydrate was added. After dissolving with stirring at about 80 ° C., the mixture was stirred overnight at room temperature to precipitate the crystals. The precipitated crystals were collected by filtration, washed with toluene, and then dried to give 17.0 g (71. 7) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile / p-toluenesulfonate. 8%).

HPLC purity: 97.4%
Melting point: 150-151.5 ° C (uncorrected)
1H-NMR [400 MHz, DMSO-d6 (TMS)] δ: 2.28 [3H, s, CH3 (p-toluenesulfonic acid)], 2.43 (3H, s, CH3), 3.13-3. 17 (2H, m, CH2), 4.06-4.10 (2H, m, CH2), 7.10-7.13 (2H, m, benzene-H), 7.35-7.52 (12H , M, benzene-H), 7.54 (1H, d, J = 2 Hz, imidazole-H), 7.71 (1H, J = 2 Hz, imidazole-H)
Q-MS (ESI ^<+> ) m / z: 302 [M + 1] ^< +>

4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide 2-propanol 40 mL, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile / p-toluenesulfonic acid A mixture of 9.47 g (0.02 mol) of salt and 7.92 g (0.12 mol) of potassium hydroxide (85% granules) was stirred under reflux for 7.5 hours. After cooling to about 40 ° C., 150 mL of purified water was added dropwise to the reaction solution. Next, after stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, washed with water, and dried to obtain 6.4 g of the above crude crystals. The obtained crude crystals were recrystallized from 2-propanol, and the precipitated crystals were collected by filtration and dried to give 5.3 g (83%) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. )

HPLC purity: 98.4%
mp 195-195.5 ° C (uncorrected)
1H-NMR [400 MHz, CDCl3 (TMS)]: 2.21 (3H, s, CH3), 2.68-2.73 (2H, m, CH2), 3.75-3.80 (2H, m, CH2), 5.40 and 6.00 (2H, each br s, NH2), 6.71 (1H, d, J = 1.2 Hz, imidazole-H), 6.83 (1H, d, J = 1) .2 Hz, imidazole-H), 7.30-7.42 (10H, m, phenyl-H)
Q-MS (ESI ⁺ ) m / z: 320 [M + 1] ⁺

<Comparative Example 1>
4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile-phosphate dimethyl sulfoxide 45 mL, 4-bromo-2,2-diphenylbutyronitrile 90 g (0.2998 mol) and 2- A mixture of 123 g (1.5 mol) of methylimidazole was stirred at an internal temperature of 105 ° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, the organic layer was separated, and washed with water and 2.5% acetic acid. After distilling off the solvent under reduced pressure, the residue was dissolved in 360 mL of ethanol, and a solution of 34.6 g (0.3 mol) of 85% phosphoric acid in 180 mL of ethanol was added dropwise at 31 to 32 ° C. After completion of dropping, the mixture was stirred at 27 to 31 ° C. for 15 hours. The precipitated crystals were collected by filtration and washed with ethanol. Drying gave 88 g of crude crystals of phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile. Subsequently, the obtained crude crystals were dissolved by heating in 2.2 L of ethanol, insoluble matters were filtered off while hot, and the filtrate was gradually cooled with stirring. The precipitated crystals were collected by filtration at a liquid temperature of 32 ° C. and washed with 175 mL of ethanol. The obtained crystals were dried under reduced pressure to obtain 78.5 g (65.6%) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate.

HPLC purity: 93.5%
Melting point: 177-179 ° C (uncorrected).
1H-NMR [400 MHz, DMSO-d6 (TMS)] δ: 2.24 (3H, s, CH3), 3.00-3.05 (2H, m, CH2), 3.89-3.94 (2H , M, CH2), 6.97 (1H, d, J = 1.6 Hz, imidazole-H), 7.29 (1H, d, J = 1.6 Hz, imidazole-H), 7.30-7. 53 (10H, m, phenyl-H)
Q-MS (ESI ^<+> ) m / z: 302 [M + 1] ^< +>

<Comparative example 2>
4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide 2-propanol 40 mL, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate 8 g ( 0.02 mol) and 13.2 g (0.2 mol) of potassium hydroxide (85% granules) were stirred under reflux for 5 hours. After cooling to about 40 ° C., 200 mL of purified water was added dropwise to the reaction solution. Next, after stirring at 18 to 23 ° C., the precipitated crystals were collected by filtration, washed with water (375 mL), and dried to obtain the above crude crystals. The obtained crude crystals were recrystallized from 2-propanol, and then the precipitated crystals were collected by filtration and dried under reduced pressure to give 4.7 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (73 .6%).

HPLC purity: 96.5%
Melting point: 191-192 ° C. (uncorrected)
Q-MS (ESI ⁺ ) m / z: 320 [M + 1] ⁺
1H-NMR [400 MHz, DMSO-d6 (TMS)] δ: 2.03 (3H, s, CH3), 2.63-2.67 (2H, m, CH2), 3.54-3.57 (2H , M, CH2), 6.68 (1H, d, J = 1.2 Hz, imidazole-H), 6.90 (1H, brs, NH), 6.92 (1H, d, J = 1.2 Hz) , Imidazole-H), 7.25-7.39 (11H, m, phenyl-H and NH).

<Test Example 1>
The HPLC (liquid chromatographic method) purity of Examples 1 to 6 and Comparative Examples 1 and 2 was measured by the following [HPLC measurement conditions].

[HPLC measurement conditions]
Detector: UV absorptiometer (measurement wavelength: 227 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography (Inertsil ODS-3V).
Column temperature: Constant temperature around 35 ° C. Mobile phase: Dissolve 2.16 g of 1-octane sodium sulfonate in diluted phosphoric acid (1 → 1000), make 1000 mL as mobile phase A, and acetonitrile as mobile phase B , Methanol as mobile phase C. Forty minutes after sample injection, linear concentration gradient from mobile phase A / mobile phase B / mobile phase C mixture (12: 5: 3) to mobile phase B / mobile phase A / mobile phase C mixture (12: 5: 3) The solution is fed under control, and the mobile phase B / mobile phase A / mobile phase C mixed solution (12: 5: 3) is fed for the next 10 minutes.
Flow rate: Adjust so that the retention time of imidafenacin [formula (I)] is 9 to 10 minutes (about 1 mL / min).
Area measurement range: About 5 times the retention time of imidafenacin [formula (I)] (about 50 minutes)

  Methanesulfonic acid of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile as an intermediate in the production of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide It has been clarified that, after isolation and purification as a salt or p-toluenesulfonic acid salt, hydrolysis with an alkali metal hydroxide allows the reaction to proceed in high yield and reduce the generation of impurities. Further, high-quality 4- (2-methyl-1-imidazolyl) -2 is obtained only by recrystallization without going through a purification step of the crude product with a synthetic adsorbent or an isolation and purification step of the acidic salt of the crude product. , 2-diphenylbutanamide can be provided in good yield.

According to the present invention, a production method with good yield and industrially advantageous is established by a simple operation of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. It can be provided as a quality drug substance drug substance.

Claims (6)

A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising the following steps:
i) 4-bromo-2,2-diphenylbutyronitrile and 4-bromo-2,2-diphenylbutyronitrile in 2-4 mL of toluene per 1 g of 4-bromo-2,2-diphenylbutyronitrile A step of obtaining 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by reacting with 4 to 10 molar equivalents of 2-methylimidazole, and ii) in step i) Ketone solvent or toluene containing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile, or a mixture of a ketone solvent and a lower alcohol solvent, or a toluene and lower alcohol solvent 4- (2-methyl-1-imidazolyl) -2,2 by allowing methanesulfonic acid or p-toluenesulfonic acid to act on the mixed solution of A step of obtaining a methanesulfonate or p-toluenesulfonate of diphenylbutyronitrile, and iii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyro obtained in step ii) A purification step by recrystallization of a nitrile methanesulfonate or p-toluenesulfonate from a mixture of a ketone solvent and a lower alcohol solvent or a mixture of toluene and a lower alcohol solvent, and iv) in step iii) The resulting 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate or p-toluenesulfonate in a lower alcohol solvent in the presence of an alkali metal hydroxide. A step of purification after hydrolysis,
A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising: A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising the following steps:
i) 4-bromo-2,2-diphenylbutyronitrile and 4-bromo-2,2- in 2.5 to 3.5 mL of toluene per 1 g of 4-bromo-2,2-diphenylbutyronitrile After reacting 5 to 7 molar equivalents of 2-methylimidazole with respect to diphenylbutyronitrile, the reaction mixture is washed with water and an aqueous solution of sodium bicarbonate and / or an aqueous solution of sodium chloride, and concentrated to give 4- (2 -Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile, and ii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) 4- (2-methyl-1-imida) by allowing methanesulfonic acid to act on a ketone solvent or a mixed solution of a ketone solvent and a lower alcohol solvent. Zolyl) -2,2-diphenylbutyronitrile methanesulfonate, and iii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step ii) Purification step by recrystallization from a mixture of a ketone solvent and a lower alcohol solvent, and iv) 4- (2-methyl-1-imidazolyl) -2,2 obtained in step iii) A step of purifying methanesulfonate of diphenylbutyronitrile after hydrolysis in the presence of an alkali metal hydroxide in a lower alcohol solvent;
And a process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising the following steps:
i) 4-bromo-2,2-diphenylbutyronitrile and 4-bromo-2,2- in 2.5 to 3.5 mL of toluene per 1 g of 4-bromo-2,2-diphenylbutyronitrile After reacting 6 molar equivalents of 2-methylimidazole with respect to diphenylbutyronitrile, the reaction mixture is washed with water and an aqueous solution of sodium bicarbonate and / or an aqueous solution of sodium chloride and concentrated to give 4- (2-methyl). -1-imidazolyl) -2,2-diphenylbutyronitrile and ii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) Methanesulfonic acid of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by reacting methanesulfonic acid with a solution of acetone And iii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate obtained in step ii) with 2-butanone and 2-propanol. And iv) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile methanesulfonate obtained in the step iii) is converted into 4- (2- 2- (Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile in 1 mL of methanesulfonate in 5 mL of 2-propanol in 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyrate A step of hydrolysis after the hydrolysis in the presence of 6 molar equivalents of potassium hydroxide with respect to methanesulfonate of ronitrile;
And a process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide, comprising the following steps:
i) 4-bromo-2,2-diphenylbutyronitrile and 4-bromo-2,2-diphenylbutyronitrile in 2-3 mL of toluene per 1 g of 4-bromo-2,2-diphenylbutyronitrile After reacting with 6 molar equivalents of 2-methylimidazole, the reaction mixture was washed with water and an aqueous sodium bicarbonate solution and / or an aqueous sodium chloride solution and concentrated to give 4- (2-methyl-1-imidazolyl). ) -2,2-diphenylbutyronitrile, and ii) a toluene solution containing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i). 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is reacted with p-toluenesulfonic acid to give p-toluenesulfuric acid. A step of obtaining phonate, and iii) p-toluenesulfonate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step ii) -Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile, 1 g of p-toluenesulfonate, 4- (2-methyl-1-imidazolyl) -2,2 in 4-5 mL of 2-propanol A step of hydrolysis after the hydrolysis in the presence of 6 molar equivalents of potassium hydroxide to p-toluenesulfonate of diphenylbutyronitrile,
And a process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. Formula (IIa)

A methanesulfonate salt of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile represented by the formula: Formula (IIb)

4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile p-toluenesulfonate represented by the formula