【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% |
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 |