• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】14493

【品名】alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile

【CA登记号】86-29-3

【 分 子 式 】C14H11N

【 分 子 量 】193.24808

【元素组成】C 87.01% H 5.74% N 7.25%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(II)

The reaction of N-(2-chloroethyl)-2-azabicyclo[2.2.2]octane (I) with diphenylacetonitrile (II) by means of KOH in refluxing methyl ethyl ketone gives 4-[2-azabicyclo[2.2.2]octan-2-yl]-2,2-diphenylbutyronitrile (III), which by reaction with NaN3 in DMF at 125 C is converted into 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]octan-2-yl)propyl]-1H-tetrazole (IV). Finally, this compound is treated with refluxing acetic anhydride.

1 Adelstein, G.W.; Yen, C.H.; Dajani, E.Z.; Bianchi, R.G.; 3,3-Diphenyl-3-(2-alkyl-1,3,4-ozadiazol-5-yl)propylcycloalkylamine, a novel series of antidiarrheal agents. J Med Chem 1976, 19, 10, 1221-25.
2 Adelstein, G.W. (Pharmacia Corp.); 1,1-Diaryl-1-oxadiazolalkylamines. DE 2514183; DE 2514229; FR 2265367; FR 2265376; GB 1456943; GB 1494943; JP 50135081; JP 50135086; US 3917615 .
3 Castaner, J.; Hillier, K.; Nufenoxole. Drugs Fut 1978, 3, 7, 533.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 39972 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane C9H16ClN 详情 详情
(II) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(III) 39973 4-(2-azabicyclo[2.2.2]oct-2-yl)-2,2-diphenylbutanenitrile C23H26N2 详情 详情
(IV) 39974 2-[3,3-diphenyl-3-(1H-1,2,3,4-tetraazol-5-yl)propyl]-2-azabicyclo[2.2.2]octane C23H27N5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

Darifenacin can be obtained by three related ways: 1) The decarboxylation of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) by heating at 154 C in cyclohexanol/2-cyclohexenone gives 3(R)-hydroxypyrrolidine (II), which is N-tosylated with p-toluenesulfonyl chloride and pyridine yielding (III). The reaction of (III) with methyl p-toluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords 1-tosyl-3(S)-(tosyloxy)pyrrolidine (IV), which is condensed with 2,2-diphenylacetonitrile (V) by means of NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(S)-yl]acetonitrile (VI). Elimination of the tosyl group of (VI) with HBr and phenol in refluxing water yields 2,2-diphenyl-2-[2(S)-pyrrolidinyl]acetonitrile (VII), which by treatment with 95% H2SO4 at 100 C is converted into the corresponding acetamide (VIII). The condensation of (VIII) with 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) by means of potassium carbonate in industrial methylated spirits affords the ketonic amide (X), which is finally reduced with H2 over Pd/C in acetic acid. The intermediate 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) has been obtained by Friedel-Crafts condensation of 2,3-dihydrobenzofuran (XI) with chloroacetyl chloride by means of AlCl3 in dichloromethane. 3) The condensation of 5-(2-bromoethyl)benzofuran (XV), with the previously obtained acetamide (VIII) by means of K2CO3 in refluxing acetonitrile affords the condensation product (XVI), which is hydrogenated with H2 over Pd/C in hot acetic acid.

1 Graul, A.; Castaner, J.; Darifenacin. Drugs Fut 1996, 21, 11, 1105.
2 Cross, P.E.; Mackenzie, A.R. (Pfizer Inc.); Pyrrolidine derivs. AU 9051402; EP 0388054; JP 1990282360; JP 1995149640; US 5096890 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 14490 (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine 2799-21-5 C4H9NO 详情 详情
(III) 14491 (3R)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-ol C11H15NO3S 详情 详情
(IV) 14492 (3S)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl 4-methylbenzenesulfonate C18H21NO5S2 详情 详情
(V) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(VI) 14494 2-[(3S)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetonitrile C25H24N2O2S 详情 详情
(VII) 14495 2,2-diphenyl-2-[(3S)tetrahydro-1H-pyrrol-3-yl]acetonitrile C18H18N2 详情 详情
(VIII) 14496 2,2-diphenyl-2-[(3S)tetrahydro-1H-pyrrol-3-yl]acetamide C18H20N2O 详情 详情
(IX) 14497 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1-ethanone C10H9ClO2 详情 详情
(X) 14498 2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetamide C28H28N2O3 详情 详情
(XI) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(XII) 14500 2-(2,3-dihydro-1-benzofuran-5-yl)acetic acid 69999-16-2 C10H10O3 详情 详情
(XIII) 14501 2-(2,3-dihydro-1-benzofuran-5-yl)-1-ethanol C10H12O2 详情 详情
(XIV) 14502 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran C10H11BrO 详情 详情
(XV) 14503 5-(2-bromoethyl)-1-benzofuran C10H9BrO 详情 详情
(XVI) 14504 2-[(3S)-1-[2-(1-benzofuran-5-yl)ethyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetamide C28H28N2O2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

Alkylation of diphenylacetonitrile (I) with dibromoethane provided bromide (II). This was condensed with 2-methylimidazole (III) in the presence of Et3N in DMF to afford the substituted imidazole (IV). Finally, hydrolysis of the cyano group of (IV) with 70% sulfuric acid produced the target amide.

1 Miyachi, H.; et al.; Synthesis and antimuscarinic activity of a series of 4-(1-imidazolyl)-2,2-diphenylbutyramides: Discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem 1999, 7, 6, 1151.
2 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(III) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(IV) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.

1 Miyachi, H.; Kiyota, H.; Segawa, M.; Design, synthesis and antimuscarinic activity of some imidazolium derivatives. Bioorg Med Chem Lett 1999, 9, 20, 3003.
2 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(IV) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(V) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情
(VI) 47152 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide 170105-16-5 C20H21N3O 详情 详情
(VII) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情

合成路线5

该中间体在本合成路线中的序号:(I)

Diphenylacetonitrile (I) was alkylated with 1,3-dibromopropane (II) in the presence of NaH in DMF to afford the bromopropyl derivative (III). Subsequent condensation of bromide (III) with 4-(4-chlorophenyl)-4-hydroxypiperidine (IV) gave the tertiary amine (V). This was then quaternized with methyl iodide to furnish the corresponding piperidinium salt.

1 May, K.; Bauman, J.G.; Ng, H.P.; et al.; Discovery of novel non-peptide CCR1 receptor antagonists. J Med Chem 1999, 42, 22, 4680.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(III) 43750 5-bromo-2,2-diphenylpentanenitrile C17H16BrN 详情 详情
(IV) 35870 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine 39512-49-7 C11H14ClNO 详情 详情
(V) 43751 5-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-2,2-diphenylpentanenitrile C28H29ClN2O 详情 详情
Extended Information