JP5087059B2 - Process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide - Google Patents

Description

  The present invention uses a production intermediate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (abbreviated as KRP-197), which is a selective muscarinic receptor antagonist, and an intermediate thereof. This relates to the manufacturing method of KRP-197.

は抗コリン作用、とりわけ選択的で強力なムスカリン受容体拮抗作用を有するイミダゾール誘導体であり、過敏性腸症候群、憩室疾患、機能性下痢、食道無弛緩症、噴門痙攣等の消化管自動運動性障害治療、胆道、尿道の痙攣、尿失禁等の治療、慢性気道閉塞性疾患の治療等の医薬用途に有用であることが知られている（特開平；WO9515951；宮地弘幸ら、Bioorg. Med. Chem. Lett.（1988）8（14），1807-1812；ibid．，（1988），8（16），2163-2168；ibid．，（1989），9（20），3003-3008；宮地弘幸ら、Bioorg. Med. Chem.，（1999），7（6），1151-1161）。 KRP-197 (Formula (1))

Is an imidazole derivative with an anticholinergic action, especially a selective and potent muscarinic receptor antagonistic action. It is known to be useful for medical use such as treatment, biliary tract, urethral spasm, urinary incontinence, chronic airway obstructive disease, etc. (Japanese Patent Laid-Open No. WO9515951; Lett. (1988) 8 (14), 1807-1812; ibid., (1988), 8 (16), 2163-2168; ibid., (1989), 9 (20), 3003-3008; Hiroyuki Miyaji et al. Bioorg. Med. Chem., (1999), 7 (6), 1151-1161).

  On the other hand, a method for producing KRP-197 is also specifically disclosed (Japanese Patent Laid-Open No. 7-215943; Hiroyuki Miyachi et al., Bioorg. Med. Chem., (1999), 7 (6), 1151-1161). However, it has been necessary to devise improvements in operability, purification efficiency, yield, etc., and find a manufacturing method suitable for actual production.

  In order to industrially produce high-quality KRP-197 as a pharmaceutical product, it is necessary to improve the operability and yield of the manufacturing process to meet the actual production level, increase the purity, or reduce harmful solvents. Need to be resolved.

  As a result of intensive studies to solve the above problems, the present inventors have found that 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or its intermediate as a production intermediate The inventors have found that KRP-197 can be produced with high yield by simple operation by isolating a salt hydrate and then hydrolyzing it, thereby completing the present invention.

That is, the present invention reacts 4-bromo-2,2-diphenylbutyronitrile and 2-methylimidazole to obtain 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile, Is isolated as a phosphate or its hydrate, then hydrolyzed in the presence of an alkali metal hydroxide, and then purified using a synthetic adsorbent. It has been found that KRP-197 can be obtained, and an industrial scale production method has been completed (scheme).

  The phosphate salt of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or its hydrate of the present invention is a novel compound without specific disclosure, and its usefulness is also known. It was not done.

  Furthermore, conventionally, hydrolysis of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile was carried out in a highly concentrated acid solution (for example, 70% sulfuric acid solution) under heating. On the other hand, if the phosphate or hydrate of the salt is carried out under reflux of water or alcohol in the presence of an alkali metal hydroxide, the impurities are reduced, the yield is improved, and the subsequent purification is simplified. As a result, the present invention has been completed as an industrial method.

  The phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile of the present invention or a hydrate of the salt thereof can be easily obtained. That is, 4-bromo-2,2-diphenylbutyronitrile and an excess amount of 2-methylimidazole in an organic solvent such as dimethylformamide, N-methylpyrrolidone, N, N′-dimethylimidazolidinone, dimethylsulfoxide, 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is obtained by heating from 150 ° C. to 150 ° C. and stirring. This was extracted with a water-insoluble solvent such as ethyl acetate, concentrated, dissolved in an alcohol such as ethanol, and an equivalent amount of a phosphoric alcohol solution was added dropwise to the resulting solution to precipitate 4- (2-methyl-1- Imidazolyl) -2,2-diphenylbutyronitrile phosphate or its salt hydrate is obtained. The following nitrile group hydrolysis reaction can be used as it is. To obtain a purified product, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate can be obtained by recrystallization with an alcohol such as ethanol.

  Hydrolysis of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or its hydrate is a hydrous acidic solution such as sulfuric acid or polyphosphoric acid or a hydrous alkali metal hydroxide aqueous solution. In particular, the reaction is carried out by heating to 10 ° C. to 150 ° C. and stirring, preferably water-soluble organic solvents such as alcohols containing alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

  After hydrolysis, if the reaction solution is diluted with water, crude crystals of KRP-197 can be obtained with good yield. It is convenient to use a synthetic adsorbent for purification. As the synthetic adsorbent, HP-1MG, HP-20, SP-800, and SP-850 are used, and HP-20 is preferable. KRP-197 crude crystals are dissolved in an aqueous hydrochloric acid solution, added to the synthetic adsorbent HP-20, and eluted with water. The eluate is adjusted to pH 9.5 to 9.6 with an aqueous sodium bicarbonate solution to obtain precipitated crystals. If this is washed and dried, high-quality KRP-197 can be obtained.

  When the phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or its hydrate of the present invention is used, a large amount of impurities is not generated during hydrolysis. The reaction proceeds at a high yield, and high-quality KRP-197 can be obtained in a high yield simply by purifying the crude crystals with a synthetic adsorbent. Thus, the present invention provides an excellent industrial production method for KRP-197.

  In producing KRP-197, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile as an intermediate was isolated and purified as an intermediate, and then alkali metal It has been clarified that the hydrolysis proceeds with a high yield without hydrolyzing with a hydroxide without generating a large amount of impurities. Next, it was revealed that high quality KRP-197 can be provided in high yield only by purifying the crude product with a synthetic adsorbent.

  According to the present invention, an industrially advantageous production method of KRP-197 has been established, and it has become possible to provide a high-purity and high-quality pharmaceutical product.

<Example>
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate>
A mixture of 40 mL of dimethyl sulfoxide, 80.8 g (0.266 mol) of 4-bromo-2,2-diphenylbutyronitrile and 109 g (1.33 mol) of 2-methylimidazole was stirred at an internal temperature of 95 to 105 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, 160 mL of ethyl acetate and 160 mL of water were added, and the organic layer was separated and washed with 320 mL of water and 320 mL of 2.5% acetic acid. After distilling off the solvent under reduced pressure, the residue was dissolved in 320 mL of ethanol, and a solution of 30.7 g (0.266 mol) of 85% phosphoric acid in 160 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 160 mL of ethanol. It was dried at 60 ° C. for 18 hours to obtain 78.1 g (73.3%) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate.
The next reaction was used at this stage.
The phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile was further purified for analysis as follows.
That is, 1000mL
A 4-neck flask was charged with 35.0 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate and 875 mL of ethanol, and the mixture was heated to reflux for 23 minutes. The insoluble material was filtered off while hot, and the filtrate was gradually cooled with stirring. The precipitated crystals were collected by filtration at a liquid temperature of 28 ° C., washed with 175 mL of ethanol, and then air-dried at 60 ° C. for 2 hours to obtain 25.0 g (71.5%) of a recrystallized product. The obtained recrystallized product and 875 mL of ethanol were charged into a 1 L 4-neck flask and dissolved under reflux. The solution was gradually cooled, and 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 at 60 ° C. for 15 hours and then dried under reduced pressure at 100 ° C. for 8 hours to give 19.5 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate (55.7%) was obtained.
Melting point: 180-181 ° C.
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.17 (3H, s, CH 3),
2.96-3.00 (2H, m, CH2), 3.84-3.88 (2H, m, CH2), 6.84 (1H, d, J = 1.5Hz, imidazole-H), 7.20 (1H, d, J = 1.5Hz, imidazole -H), 7.33-7.51 (10H, m, Ph-H).
MS (EI ⁺ ):
m / e 301 [M] ⁺ , 274, 192.
Elemental analysis values:
Calcd. For C ₂₀ H ₁₉ N ₃・ H ₃ PO ₄
; C: 60.15 H: 5.55 N: 10.52
(%) Found
; C: 60.20 H: 5.52 N: 10.50.

<4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutanamide (KRP-197)>
Mixture of 375 mL of isopropyl alcohol, 75.0 g (0.188 mol) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate and 124 g (1.88 mol) of potassium hydroxide (85% granules) Was stirred under reflux for 5 hours. After cooling to 38 ° C., the reaction solution was added dropwise to 1875 mL of water. After stirring at 15-30 ° C. for 1 hour, the precipitated crystals were collected by filtration and washed with water (375 mL) to obtain crude crystals of KRP-197.
2 crude crystals
It was dissolved in 225 mL of mol / L hydrochloric acid, added to 600 mL of a synthetic adsorbent (HP-20), and eluted with 6000 mL of water. The eluate was filtered and washed with 225 mL of water. A 1 mol / L sodium carbonate aqueous solution was added to the filtrate at 15 ° C. to adjust the pH to 9.5. After stirring at 15 ° C. for 1 hour, the precipitated crystals were collected by filtration and washed with 225 mL of water to obtain 57.9 g of undried crystals. 56.2 g of the obtained undried crystals was suspended in 375 mL of water, refluxed for 30 minutes, and then cooled to 27 ° C. The precipitated crystals were collected by filtration and washed with water. It was dried under reduced pressure at 60 ° C. for 18 hours to obtain 44.7 g (74.5%) of KRP-197.

<Hydrate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate>
10.0 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate obtained by the method of Example 1 was added to ethanol water (80%).
It was dissolved by heating in 50.0 mL, and the precipitated crystals were collected by filtration at a liquid temperature of 23 ° C.
The obtained crystals were dried under reduced pressure at 60 ° C. to obtain 7.85 g of phosphate hydrate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile.
Melting point: 179-180 ° C
Moisture: 3.5%
Elemental analysis: C ₂₀ H ₁₉ N ₃・ H ₃ PO ₄・ 1 / 2H ₂ O
Calculated (%); C: 58.82 H: 5.68 N: 10.29
Measurement (%); C: 58.81 H: 5.58 N: 10.39

Claims (7)

By reacting 4-bromo-2,2-diphenylbutyronitrile with 2-methylimidazole and subsequently washing the reaction mixture with water and acetic acid, 4- (2-methyl-1-imidazolyl) -2,2 -After obtaining diphenylbutyronitrile, the obtained 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is dissolved in ethanol, and then phosphoric acid is added to the ethanol solution. 4- (2), characterized in that 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or a hydrate of the salt thereof is obtained by dropping an ethanol solution. -Method for producing a phosphate of methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of the salt thereof. A method for producing a phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of a salt thereof according to claim 1, comprising the following steps:
i) reacting 4-bromo-2,2-diphenylbutyronitrile with 5-molar equivalents of 2-methylimidazole to 4-bromo-2,2-diphenylbutyronitrile, followed by reaction of the reaction mixture with water and acetic acid Obtaining 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by washing with
ii) 4-Bromo-2,2-diphenyl of step i) was added to a solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) in ethanol. A step of obtaining a phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by dropwise adding a solution in which 1 molar equivalent of phosphoric acid is dissolved in ethanol with respect to butyronitrile;
And a method for producing a phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of the salt thereof. By reacting 4-bromo-2,2-diphenylbutyronitrile with 2-methylimidazole and subsequently washing the reaction mixture with water and acetic acid, 4- (2-methyl-1-imidazolyl) -2,2 -After obtaining diphenylbutyronitrile, the obtained 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is dissolved in ethanol, and then phosphoric acid is added to the ethanol solution. A 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate obtained by dropping an ethanol solution or a hydrate of a salt thereof is used as a production intermediate. And 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- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by reacting 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile with phosphoric acid Obtaining a phosphate or a hydrate of the salt thereof,
ii) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate obtained in step i) or a hydrate of its salt is hydrolyzed to give 4- (2 A step of obtaining crude crystals of -methyl-1-imidazolyl) -2,2-diphenylbutanamide;
iii) 4- (2-Methyl-1-imidazolyl) is obtained by purifying the crude crystals of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide obtained in step ii) with a synthetic adsorbent. ) -2,2-diphenylbutanamide, A method for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide. A process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide according to claim 4, comprising the following steps:
i) 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is added to a solution of ethanol in phosphoric acid dropwise to a solution of 4- (2-methyl-1-imidazolyl). ) -2,2-diphenylbutyronitrile phosphate or a salt hydrate thereof,
ii) The phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) or a hydrate of a salt thereof is hydrolyzed in the presence of an alkali metal hydroxide. A step of obtaining a crude crystal of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide by decomposing, and
iii) 4- (2-Methyl-1-imidazolyl) is obtained by purifying the crude crystals of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide obtained in step ii) with a synthetic adsorbent. ) -2,2-diphenylbutanamide,
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 according to claim 4, comprising the following steps:
i) 4- (2-methyl-1-imidazolyl) -2 by reacting 4-bromo-2,2-diphenylbutyronitrile with 2-methylimidazole and then washing the reaction mixture with water and acetic acid , 2-diphenylbutyronitrile is obtained,
ii) A solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) in ethanol was added dropwise to a solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile in ethanol. 2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or a salt hydrate thereof,
iii) The phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or its hydrate obtained in step ii) is hydrolyzed in the presence of an alkali metal hydroxide. A step of obtaining a crude crystal of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide by decomposing, and
iv) 4- (2-Methyl-1-imidazolyl) was obtained by purifying the crude crystals of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide obtained in step iii) with a synthetic adsorbent. ) -2,2-diphenylbutanamide,
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 according to claim 4, comprising the following steps:
i) After reacting 4-bromo-2,2-diphenylbutyronitrile with 5-molar equivalent of 2-methylimidazole with respect to 4-bromo-2,2-diphenylbutyronitrile, the reaction mixture is mixed with water and acetic acid. A step of obtaining 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile by washing with
ii) 4-Bromo-2,2-diphenyl of step i) was added to a solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) in ethanol. The solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or its salt was added dropwise by adding dropwise a solution of 1 molar equivalent of phosphoric acid in ethanol relative to butyronitrile. Obtaining a hydrate,
iii) The phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or its hydrate obtained in step ii) is hydrolyzed in the presence of an alkali metal hydroxide. A step of obtaining a crude crystal of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide by decomposing, and
iv) 4- (2-Methyl-1-imidazolyl) was obtained by purifying the crude crystals of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide obtained in step iii) with a synthetic adsorbent. ) -2,2-diphenylbutanamide,
And a process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide.