JP2003201281A - Method for producing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutane amide - Google Patents
Method for producing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutane amideInfo
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- JP2003201281A JP2003201281A JP2002310463A JP2002310463A JP2003201281A JP 2003201281 A JP2003201281 A JP 2003201281A JP 2002310463 A JP2002310463 A JP 2002310463A JP 2002310463 A JP2002310463 A JP 2002310463A JP 2003201281 A JP2003201281 A JP 2003201281A
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- Prior art keywords
- imidazolyl
- methyl
- diphenylbutyronitrile
- phosphate
- krp
- Prior art date
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Abstract
Description
【0001】[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。TECHNICAL FIELD The present invention relates to 4- (2-methyl-1-imidazolyl)-which is a selective muscarinic receptor antagonist.
The present invention relates to an intermediate for producing 2,2-diphenylbutanamide (abbreviated as KRP-197) and a method for producing KRP-197 using the intermediate.
【0002】[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;WO95
15951;宮地弘幸ら、Bioorg. Med. Chem. Lett.(198
8)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)。2. Description of the Related Art KRP-197 (Formula (1)) Is an imidazole derivative that has anticholinergic activity, especially selective and potent muscarinic receptor antagonism. It is known to be useful for medical applications, such as treatment, biliary tract, urethral spasm, treatment of urinary incontinence, treatment of chronic airway obstructive disease, etc. (Japanese Patent Laid-Open No. WO95 / 95).
15951; Hiroyuki Miyaji et al., Bioorg. Med. Chem. Lett. (198
8) 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】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。On the other hand, a method for producing KRP-197 is also specifically disclosed (Japanese Patent Laid-Open No. 7-215943; Hiroyuki Miyaji et al., Bioorg. Med.
Chem., (1999), 7 (6), 1151-1161).
However, it was necessary to find ways to improve the operability, purification efficiency, yield, etc. and find a manufacturing method suitable for actual production.
【0004】[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。[Problems to be Solved by the Invention]
In order to industrially produce KRP-197, it is necessary to solve problems such as improvement of operability and yield of manufacturing process suitable for actual production level, improvement of purity or reduction of harmful solvents. is there.
【0005】[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。Means for Solving the Problems The inventors of the present invention have conducted extensive studies in order to solve the above problems, and as a result, 4- (2-methyl-1-imidazolyl) -2,2-diphenyl as a production intermediate was obtained. By once isolating the butyronitrile phosphate or its hydrate, and then hydrolyzing KRP-197 by a simple operation, it was found that it can be produced in good yield, the present invention has been completed. is there.
【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)。
That is, the present invention reacts 4-bromo-2,2-diphenylbutyronitrile with 2-methylimidazole to give 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile. The resulting product 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 to obtain a simple operation with good yield, and It was found that high-purity KRP-197 was obtained, and the industrial scale manufacturing method was completed (scheme).
【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。4- (2-methyl-1-imidazolyl) -2 of the present invention,
2-Diphenylbutyronitrile phosphate or its hydrate is a novel compound without specific disclosure, and its usefulness has not been known.
【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。Further, conventionally, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile is hydrolyzed 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 by refluxing water or alcohol in the presence of an alkali metal hydroxide, impurities are reduced and the yield is improved. The present invention has been completed as an industrial method by finding out that it is simple.
【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。4- (2-methyl-1-imidazolyl) -2 of the present invention,
2-Diphenylbutyronitrile phosphate or its hydrate is easily obtained. That is, 4-bromo-2,2-diphenylbutyronitrile and an excess amount of 2-methylimidazole are added to dimethylformamide, N-methylpyrrolidone, N,
4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile can be obtained by heating and stirring in an organic solvent such as N'-dimethylimidazolidinone or dimethylsulfoxide from 60 ° C to 150 ° C. obtain. This is extracted with a non-water-soluble solvent such as ethyl acetate, concentrated and dissolved in an alcohol such as ethanol, and an equivalent amount of a phosphate alcohol solution is added dropwise to the mixture to stir to precipitate 4- (2-methyl-1-imidazolyl). ) -2,2-Diphenylbutyronitrile phosphate or its hydrate is obtained. It can be used as it is for the next hydrolysis reaction of the nitrile group. To obtain a purified product, recrystallize with alcohols such as ethanol.
A phosphate of (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile can be obtained.
【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。4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate or its hydrate is hydrolyzed by hydrous acidic solution of sulfuric acid, polyphosphoric acid or the like or hydrous alkali metal water. It is carried out by heating and stirring in an aqueous oxide solution from 10 ° C. to 150 ° C., preferably a water-soluble organic solvent such as alcohol containing an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. .
【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、H
P−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。After hydrolysis, the reaction solution can be diluted with water.
The crude crystals of KRP-197 are obtained in good yield. It is convenient to use a synthetic adsorbent for purification. As a synthetic adsorbent, H
P-1MG, HP-20, SP-800, SP-850
Is used, preferably HP-20. KRP-197
The crude crystals are dissolved in a hydrochloric acid aqueous solution, added to a synthetic adsorbent HP-20, and eluted with water. The eluate is adjusted to pH 9.5 to 9.6 with an aqueous sodium hydrogen carbonate solution to obtain precipitated crystals. If this is washed with water and dried, high quality KRP-197 can be obtained.
【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。4- (2-methyl-1-imidazolyl) -2 of the present invention,
If 2-diphenylbutyronitrile phosphate or its hydrate is used, the reaction proceeds in a high yield without any generation of a large amount of impurities during hydrolysis, and crude crystals are synthesized by a synthetic adsorbent. High-quality KRP-197 can be obtained in good yield simply by purification. Thus, the present invention provides an excellent industrial production method of KRP-197.
【0013】[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。EXAMPLES The present invention will be described below with reference to specific examples, but the present invention is not limited to these examples.
【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(0.26
6mol)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(7
1.5%)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17
5 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℃.1
H 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.Example 1 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate dimethyl sulfoxide 40 mL, 4-bromo-2,2-diphenylbutyronitrile 80.8 g A mixture of (0.266 mol) 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, ethyl acetate
160 mL and 160 mL of water were added, the organic layer was separated, and then washed with 320 mL of water and 320 mL of 2.5% acetic acid. After evaporating the solvent under reduced pressure, the residue was dissolved in 320 mL of ethanol, and 85% phosphoric acid 30.7 g (0.26
A solution of 6 mol) dissolved in 160 mL of ethanol was added dropwise at 31 to 32 ° C. After the 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. 18 at 60 ° C
After drying for 4 hours, 78.1 g (73.3%) of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate was obtained. The one at this stage was used for the next reaction. In addition, 4-
The phosphate of (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile was further purified for analysis as follows. That is, 35.0 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate and 875 mL of ethanol were placed in a 1000 mL 4-necked flask and heated under reflux for 23 minutes. The insoluble matter was filtered off while hot, and the filtrate was gradually cooled with stirring. Precipitated crystals were collected by filtration at a liquid temperature of 28 ° C, ethanol 175
After washing with mL, blow dry at 60 ° C for 2 hours to recrystallize 25.0 g (7
1.5%). Obtained recrystallized product and ethanol 875 mL
Was charged into a 1 L 4-necked flask and dissolved under reflux.
Cool slowly and collect the precipitated crystals by filtration at a liquid temperature of 32 ℃.
It was washed with 5 mL. 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 4- (2-methyl-1-
19.5 g (55.7%) of phosphate of imidazolyl) -2,2-diphenylbutyronitrile 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】<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75.0
g(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-1
97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1
mol/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。
融点:179〜180℃
水分: 3.5 %
元素分析値 : C20H19N3・H3PO4・1/2H2O
計算値(%); C: 58.82 H: 5.68 N: 10.29
測定値(%); C: 58.81 H: 5.58 N: 10.39<Example 2> 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (KRP-197) 375 mL of isopropyl alcohol, 4- (2-methyl-1-imidazolyl) -2, 2-diphenylbutyronitrile phosphate 75.0
g (0.188mol) and potassium hydroxide (85% granules) 124g
The mixture (1.88 mol) was stirred under reflux for 5 hours. After cooling to 38 ° C., the reaction solution was added dropwise to 1875 mL of water. 1 at 15-30 ℃
After stirring for an hour, the precipitated crystals were collected by filtration, washed with water (375 mL), and KRP-1
97 crude crystals were obtained. The crude crystals were dissolved in 225 mL of 2 mol / L hydrochloric acid, added to 600 mL of the synthetic adsorbent (HP-20), and eluted with 6000 mL of water. The eluate was filtered and washed with 225 mL of water. 1 in the filtrate
A mol / L sodium carbonate aqueous solution was added 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 water.
It was washed with 225 mL to obtain 57.9 g of undried crystals. The obtained undried crystals (56.2 g) were suspended in water (375 mL) and refluxed for 30 minutes, and then 27 ° C.
Cooled down. The precipitated crystals were collected by filtration and washed with water. 18 at 60 ° C
After drying under reduced pressure for 4 hours, 44.7 g (74.5%) of KRP-197 was obtained. Example 3 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate hydrate 4- (2-methyl-1-) obtained by the method of Example 1 Imidazolyl) -2,2-diphenylbutyronitrile phosphate (10.0 g) was dissolved by heating in ethanol water (80%) (50.0 mL) and the precipitated crystals were collected by filtration at a liquid temperature of 23 ° C. The crystals obtained were dried under reduced pressure at 60 ° C.
7.85 g of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile phosphate hydrate were obtained. Mp: 179 to 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 found (% ); C: 58.81 H: 5.58 N: 10.39
【0016】[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。INDUSTRIAL APPLICABILITY In producing KRP-197, 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile as an intermediate is isolated as a phosphate or its hydrate and purified. After that, it was clarified that the hydrolysis proceeds with an alkali metal hydroxide and the reaction proceeds in a high yield without the production of a large amount of impurities. Then, it became clear that high-quality KRP-197 could be provided in good yield only by purifying the crude product with a synthetic adsorbent.
【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。According to the present invention, an industrially advantageous production method of KRP-197 has been established, and it has become possible to provide KRP-197 as a high-purity, high-quality pharmaceutical product.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 大野田 道郎 長野県伊那市上牧6387−5 Fターム(参考) 4H039 CA71 CF40 ─────────────────────────────────────────────────── ─── Continued front page (72) Inventor Michiro Onoda 6387-5 Kamimaki, Ina City, Nagano Prefecture F-term (reference) 4H039 CA71 CF40
Claims (4)
ェニルブチロニトリルのリン酸塩又はその塩の水和物。1. A phosphate of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyronitrile or a hydrate of its salt.
ェニルブチロニトリルにリン酸を作用させる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の製造方法。2. 4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyronitrile which reacts phosphoric acid with 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutyro A process for producing a nitrile phosphate or a hydrate of a salt thereof.
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
を製造中間体とする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の製造方法。3. 4- (2-Methyl-1-imidazole) -2,2-diphenylbutyronitrile phosphate or a hydrate of a salt thereof is used as a production intermediate. -Imidazolyl) -2,2-
A method for producing diphenylbutanamide.
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を特徴とする請求項3記
載の4-(2-メチル-1-イミダゾリル)-2,2-ジフェニルブタ
ンアミドの製造方法。4. Isolated 4- (2-methyl-1-imidazolyl)-
The 4,2-diphenylbutyronitrile phosphate or its hydrate is hydrolyzed in the presence of an alkali metal hydroxide and then purified using a synthetic adsorbent. A method for producing-(2-methyl-1-imidazolyl) -2,2-diphenylbutanamide.
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