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【结 构 式】

【分子编号】28827

【品名】2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione

【CA登记号】

【 分 子 式 】C11H13ClN2OS

【 分 子 量 】256.7558

【元素组成】C 51.46% H 5.1% Cl 13.81% N 10.91% O 6.23% S 12.49%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

The condensation of 3-hydroxy-1-methylpyrrolidine (I) with 2-chloronicotinic acid (II) by means of NaH in DMSO gives sodium 2-(1-methylpyrrolidin-3-yloxy)pyridine-3-carboxylate (III), which is then cyclized by a treatment with dry HCl in chloroform followed by a reaction with triphenylphosphine and CCl4 yielding finally 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f]-1,4-oxazepin-5(2H)-one (IV). The reaction of (IV) with P2S5 and K2S in refluxing toluene affords the corresponding thione (V), which is finally treated with 40% aqueous dimethylamine in ethanol at 100 C in a pressure vessel, and with fumaric acid (VI) in methanol.

1 Cale, A.D. Jr.; Franko, B.V.; Leonard, C.A. (A.H. Robins Co. Inc.); Fused aromatic oxazepinones and sulphur analogues thereof and their preparation and use in counteracting histamine. EP 0107930; ES 8607956; ES 8802574; US 4592866; US 4604388 .
2 Pento, J.T.; Castaner, R.M.; Serradell, M.N.; Castaner, J.; AHR-11325. Drugs Fut 1987, 12, 10, 924.
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) 28823 1-methyl-3-pyrrolidinol 13220-33-2 C5H11NO 详情 详情
(II) 28824 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid 2942-59-8 C6H4ClNO2 详情 详情
(III) 28825 sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]nicotinate C11H13N2NaO3 详情 详情
(IV) 28826 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one C11H13ClN2O2 详情 详情
(V) 28827 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione C11H13ClN2OS 详情 详情
(VI) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

Reaction of 2-chloronicotinic acid (I) with an ethanolic solution of potassium tert-butoxide affords 2-ethoxynicotinic acid (II), which is further converted to the corresponding ethyl ester (III) by alkylation with iodoethane in the presence of Cs2CO3. Nitration of (III) employing ammonium nitrate and trifluoroacetic anhydride leads to ethyl 2-ethoxy-5-nitropyridine-3-carboxylate (IV). This is then reduced to the aminopyridine (V) by catalytic hydrogenation over Raney Ni. Diazotization of amine (V), followed by treatment with SO2 and CuCl2 gives rise to the sulfonyl chloride (VI). Acid chloride (VI) is subsequently coupled to N-ethylpiperazine (VII), producing sulfonamide (VIII). Alkaline hydrolysis of ethyl ester (VIII) yields the intermediate pyridinecarboxylic acid (IX)

1 Street, S.D.A.; Wood, A.; Bunnage, M.E.; Mathias, J.P. (Pfizer Inc.; Pfizer Ltd.); Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. WO 9954333 .
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) 28827 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione C11H13ClN2OS 详情 详情
(II) 62092 2-ethoxynicotinic acid C8H9NO3 详情 详情
(III) 62093 ethyl 2-ethoxynicotinate C10H13NO3 详情 详情
(IV) 62094 ethyl 2-ethoxy-5-nitronicotinate C10H12N2O5 详情 详情
(V) 62095 ethyl 5-amino-2-ethoxynicotinate C10H14N2O3 详情 详情
(VI) 62096 ethyl 5-(chlorosulfonyl)-2-ethoxynicotinate C10H12ClNO5S 详情 详情
(VII) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情
(VIII) 62097 ethyl 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinate C16H25N3O5S 详情 详情
(IX) 62098 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinic acid C14H21N3O5S 详情 详情
Extended Information