JP4433365B2

JP4433365B2 - Process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide

Info

Publication number: JP4433365B2
Application number: JP2002310463A
Authority: JP
Inventors: 靖賢岩井; 淳一郎雨田; 靖浩相澤; 道郎大野田
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Kyorin Pharmaceutical Co Ltd
Priority date: 2001-10-31
Filing date: 2002-10-25
Publication date: 2010-03-17
Anticipated expiration: 2022-10-25
Also published as: JP2003201281A

Description

【０００１】
【発明の属する技術分野】
本発明は選択的なムスカリン受容体拮抗作用薬である4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブタンアミド（KRP-197と略す）の製造中間体及びその中間体を用いたKRP-197の製造方法に関するものである。
【０００２】
【従来の技術】
KRP-197（式（１））

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）。
【０００３】
一方、KRP-197の製造方法についても具体的に開示（特開平7-215943；宮地弘幸ら、Bioorg. Med. Chem.，（1999），7（6），1151-1161）されている。しかしながら操作性、精製効率および収率等について改善工夫を行い、実生産に適合する製造法を見出す必要があった。
【０００４】
【発明が解決しようとする課題】
医薬品として高品質のKRP-197を工業的に生産していくためには、実生産レベルに適う製造工程の操作性や収率の改善、純度の向上或いは有害な溶剤等の削減と言った課題を解決する必要がある。
【０００５】
【課題を解決するための手段】
本発明者らは、上記課題を解決するため、鋭意研究を重ねた結果、製造中間体として4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩またはその塩の水和物を一旦単離し、ついで加水分解することによりKRP-197が簡便な操作で、収率良く製造できることを見出し、本発明を完成させたものである。
【０００６】
すなわち、本発明は4-ブロモ-2,2-ジフェニルブチロニトリルと2-メチルイミダゾールを反応させ、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルを得、これをリン酸塩又はその水和物として単離し、ついでアルカリ金属水酸化物の存在下加水分解した後、合成吸着剤を用いて精製することにより、簡便な操作で収率良く、かつ高純度のKRP-197が得られることを見出し、工業的スケールの製造方法を完成したものである（スキーム）。

【０００７】
本発明の4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩又はその水和物は具体的開示の無い新規化合物であり、かつその有用性についても知られていなかった。
【０００８】
また、従来、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルの加水分解が高濃度酸溶液（例えば70％硫酸溶液）中、加熱下で行われていたのに対し、そのリン酸塩又はその塩の水和物をアルカリ金属水酸化物存在下で水またはアルコール等の還流下によって行えば、不純物が少なく、収率が向上し、その後の精製も簡便になることを見出し、工業的方法として本発明を完成したものである。
【０００９】
本発明の4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩またはその塩の水和物は容易に得られる。すなわち、4-ブロモ-2,2-ジフェニルブチロニトリルと過剰量の2-メチルイミダゾールをジメチルホルムアミド、N-メチルピロリドン、N,N’-ジメチルイミダゾリジノン、ジメチルスルホキシドなどの有機溶媒中、60℃から150℃に加温し攪拌することにより4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルを得る。これを酢酸エチルなどの非水溶性溶媒で抽出し、濃縮後エタノールようなアルコールに溶かし、これに当量のリン酸アルコール溶液を滴下攪拌することにより析出晶として4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩又はその塩の水和物が得られる。次のニトリル基の加水分解反応にはこのまま用いる事ができる。精製品を得るにはさらにエタノールのようなアルコール類で再結晶すると、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩を得ることができる。
【００１０】
4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩又はその水和物の加水分解は硫酸、ポリリン酸等の含水酸性溶液又は含水アルカリ金属水酸化物水溶液中で10℃から150℃に加温し攪拌することによって行われるが、好ましくは、水酸化ナトリウム、水酸化カリウムなどのアルカリ金属水酸化物を含むアルコール等の水溶性有機溶媒である。
【００１１】
加水分解した後、反応液を水で希釈すればKRP-197の粗結晶が収率良く得られる。精製には合成吸着剤を用いるのが簡便である。合成吸着剤としては、ＨＰ−１ＭＧ、ＨＰ−２０、ＳＰ−８００、ＳＰ−８５０が用いられ、好ましくはＨＰ−２０である。KRP-197粗結晶を塩酸水溶液に溶かし、合成吸着剤ＨＰ−２０に付加し、水で溶出し、溶出液を炭酸水素ナトリウム水溶液でｐＨ9.5〜9.6に調整し、析出晶を得る。これを水洗乾燥すれば、高品質なKRP-197を得ることができる。
【００１２】
本発明の4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩又はその水和物を用いれば、加水分解の際、多量の不純物の生成を伴うことなく、高収率で反応が進行し、粗結晶を合成吸着剤により精製するだけで、収率よく、高品質なKRP-197を得ることができる。このように本発明によりKRP-197の優れた工業的生産方法が提供される。
【００１３】
【実施例】
次に本発明を具体例によって説明するが、これらの例によって本発明が限定されるものではない。
【００１４】
＜実施例１＞ 4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリル・リン酸塩
ジメチルスルホキシド40mL、4-ブロモ-2,2-ジフェニルブチロニトリル80.8ｇ（0.266mol）及び2-メチルイミダゾール109g（1.33mol）の混合物を内温95〜105℃で5時間攪拌した。反応混合物を室温まで放冷し、酢酸エチル160mL及び水160mLを加え、有機層を分離後、水320mL及び2.5％酢酸320mLで洗浄した。溶媒を減圧留去後、残留物をエタノール320mLに溶解し、85％リン酸30.7g（0.266mol）をエタノール160mLに溶解した液を31〜32℃で滴下した。滴下終了後、27〜31℃で15時間攪拌した。析出結晶を濾取し、エタノール160mLで洗浄した。60℃で18時間乾燥し、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩 78.1g（73.3％）を得た。
次の反応には、この段階のものを用いた。
なお、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩は分析のためにさらに次のようにして精製した。
すなわち、1000mL ４頚フラスコ中に、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩35.0g、エタノール875 mLを仕込み、23分間加熱還流した。不溶物を熱時濾去し、濾液を攪拌下徐々に冷却した。液温28℃で析出晶を濾取、エタノール175 mLで洗浄後、60℃で2時間送風乾燥し、再結晶品25.0g(71.5％)を得た。得られた再結晶品及びエタノール875 mLを、1L ４頚フラスコ中に仕込み、還流下溶解させた。徐々に冷却し、液温32℃で析出晶をろ取、エタノール175 mLで洗浄した。得られた結晶を60℃で15時間減圧乾燥、次いで、100℃で8時間減圧乾燥して4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩19.5g(55.7％)を得た。
融点： 180-181℃．
¹H NMR(400MHz, d₆-DMSO): δ2.17(3H,ｓ,CH3), 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.
元素分析値: Calcd. for C₂₀H₁₉N₃・H₃PO₄ ; C: 60.15 H: 5.55 N: 10.52
（％） Found ; C: 60.20 H: 5.52 N: 10.50.
【００１５】
＜実施例２＞ 4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブタンアミド（KRP-197）
イソプロピルアルコール375mL、4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩75.0g（0.188mol）及び水酸化カリウム（85％顆粒）124g（1.88mol）の混合物を還流下５時間攪拌した。38℃まで冷却後、反応液を水1875mLに滴下した。15〜30℃で１時間攪拌後、析出結晶を濾取、水洗（375mL）し、KRP-197の粗結晶を得た。
粗結晶を2 mol/L塩酸225mLに溶解して、合成吸着剤(HP-20) 600mLに付加し、水6000mLで溶出した。溶出液を濾過し、水225mLで洗浄した。濾液に1mol/L炭酸ナトリウム水溶液を15℃で添加し、ｐＨ9.5に調整した。15℃で１時間攪拌後、析出結晶を濾取し、水225mLで洗浄、未乾燥結晶57.9gを得た。得られた未乾燥結晶56.2gを水375mLに懸濁し、30分間還流した後、27℃まで冷却した。析出結晶を濾取し、水洗した。60℃で18時間減圧乾燥し、KRP-197 44.7ｇ（74.5％）を得た。
＜実施例３＞ 4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩の水和物
実施例１の方法により得た4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩 10.0gをエタノール水(80％) 50.0mLに加熱溶解し，液温23℃で析出晶を濾取した。
得られた結晶を60℃で減圧乾燥して4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルのリン酸塩の水和物 7.85ｇを得た。

【００１６】
【発明の効果】
KRP-197を製造するにあたり、中間体として4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブチロニトリルをリン酸塩又はその水和物として単離し、精製した後、アルカリ金属水酸化物で加水分解すると、多量の不純物の生成を伴う事無く、高収率で反応が進行することが明らかとなった。次いで粗生成物を合成吸着剤による精製工程だけで高品質なKRP-197を収率良く提供できることが明らかとなった。
【００１７】
本発明により、KRP-197の工業的に有利な製造方法が確立され、高純度、高品質の医薬品として提供することが可能となった。[0001]
BACKGROUND OF THE INVENTION
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.
[0002]
[Prior art]
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).
[0003]
On the other hand, the production method of 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.
[0004]
[Problems to be solved by the invention]
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.
[0005]
[Means for Solving the Problems]
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.
[0006]
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).

[0007]
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.
[0008]
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.
[0009]
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 4- (2-methyl-1-imidazolyl) was precipitated as crystals by stirring dropwise with an equivalent amount of a phosphoric alcohol solution. ) -2,2-diphenylbutyronitrile phosphate or a hydrate of the salt 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.
[0010]
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. Among them, it is carried out by heating to 10 ° C. to 150 ° C. and stirring, preferably a water-soluble organic solvent such as alcohol containing an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.
[0011]
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.
[0012]
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 in 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.
[0013]
【Example】
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
[0014]
<Example 1> 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile-phosphate dimethyl sulfoxide 40 mL, 4-bromo-2,2-diphenylbutyronitrile 80.8 g (0.266 mol) ) And 2-methylimidazole 109 g (1.33 mol) were stirred at an internal temperature of 95-105 ° 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, in a 1000 mL 4-neck flask, 35.0 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate and 875 mL of ethanol were charged and refluxed 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): δ2.17 (3H, s, CH3), 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 value: 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.
[0015]
Example 2 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.
The crude crystals were dissolved in 225 mL of 2 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.
<Example 3> Hydrate of phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile 4- (2-Methyl-1-) obtained by the method of Example 1 10.0 g of imidazolyl) -2,2-diphenylbutyronitrile phosphate was dissolved in 50.0 mL of ethanol (80%) with heating, 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.

[0016]
【The invention's effect】
In preparing KRP-197, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile was isolated as a phosphate or hydrate thereof as an intermediate, purified, and then alkali metal It has been clarified that the hydrolysis proceeds with a high yield without generating a large amount of impurities when hydrolyzed with hydroxide. 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.
[0017]
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.

Claims

A method for producing a phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of a salt thereof, comprising the following steps:
i) 4-bromo-2,2-diphenylbutyronitrile and 4-bromo-2,2-diphenylbutyronitrile in 0.5 ml of dimethyl sulfoxide per 1 g of 4-bromo-2,2-diphenylbutyronitrile After reacting 5 mole equivalents of 2-methylimidazole to nitrile, washing the reaction mixture with water and acetic acid, and ii) 4- (2-methyl-1-imidazolyl) obtained in step i) A step of allowing an ethanol solution of phosphoric acid to act on an ethanol solution containing -2,2-diphenylbutyronitrile;
And a method for producing a phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of the salt thereof.

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 0.5 ml of dimethyl sulfoxide per 1 g of 4-bromo-2,2-diphenylbutyronitrile A step of reacting 5 molar equivalents of 2-methylimidazole with respect to the nitrile, and then washing the reaction mixture with water and acetic acid;
ii) 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile obtained in step i) is dissolved in ethanol and reacted with an ethanol solution of phosphoric acid to give 4- (2 -Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile, a step of obtaining a hydrate of a phosphate or a salt thereof, and iii) 4- (2-methyl-1-) obtained in step ii) Imidazolyl) -2,2-diphenylbutyronitrile phosphate or its salt hydrate is hydrolyzed in the presence of an alkali metal hydroxide and then purified using a synthetic adsorbent;
And a process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide.