【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% |
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 |