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【结 构 式】

【药物名称】

【化学名称】N-[1(S)-(4-Aminobenzyl)-2-(4-ethyl-1-piperidinyl)-2-oxoethyl]-4-[1(S)-benzyl-2-(2-hydroxyethoxy)ethylamino]pyridine-3-sulfonamide

【CA登记号】200269-57-4

【 分 子 式 】C32H43N5O5S

【 分 子 量 】609.79401

【开发单位】Novartis (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1

The condensation of N-(tert-butoxycarbonyl)-4-nitro-L-phenylalanine (I) with 4-ethylpiperiine (II) by means of diisopropylethylamine (DIEA) in dichloromethane gives the corresponding protected piperidide (III), which is treated with TFA to eliminate the carbamate group yielding (IV). The sulfonation of (IV) with 4-chloropyridine-3-sulfonyl chloride (V) by means of DIEA in dichloromethane affords the sulfonamide (VI), which is condensed with 2-(2(S)-amino-3-phenylpropoxy)ethanol (VII) by means of DIEA in ethanol giving the intermediate (VIII). Finally, the reduction of the nitro group of (VIII) with H2 over Pd/C in methanol affords the target compound.

1 Brundish, D.E.; Brown, L.N.; Le Grand, D.M.; Menear, K.A.; Smith, G.P.; Allen, M.C.; Butler, P.I.; Cockroft, X.-L.; Matthews, I.T.W.; Walker, C.V.; Wathey, W.B. (Novartis AG); Thrombin inhibitors. WO 9746553 .
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) 28516 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid C14H18N2O6 详情 详情
(II) 30451 4-ethylpiperidine C7H15N 详情 详情
(III) 30452 tert-butyl (1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate C21H31N3O5 详情 详情
(IV) 30453 (2S)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone C16H23N3O3 详情 详情
(V) 28521 4-chloro-3-pyridinesulfonyl chloride C5H3Cl2NO2S 详情 详情
(VI) 30454 4-chloro-N-[(1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide C21H25ClN4O5S 详情 详情
(VII) 30455 2-[[(2S)-2-amino-3-phenylpropyl]oxy]-1-ethanol C11H17NO2 详情 详情
(VIII) 30456 4-[[(1S)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-N-[(1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide C32H41N5O7S 详情 详情

合成路线2

The intermediate 2-(2(S)-amino-3-phenylpropoxy)ethanol (VII) has been obtained as follows: The condensation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (IX) with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium hydrogen sulfate and NaOH in dichloromethane/water gives 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]acetic acid tert-butyl ester (XI), which is reduced with LiAlH4 in THF yielding 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]ethanol (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in methanol/acetic acid affording the target intermediate (VII).

1 Brundish, D.E.; Brown, L.N.; Le Grand, D.M.; Menear, K.A.; Smith, G.P.; Allen, M.C.; Butler, P.I.; Cockroft, X.-L.; Matthews, I.T.W.; Walker, C.V.; Wathey, W.B. (Novartis AG); Thrombin inhibitors. WO 9746553 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 30455 2-[[(2S)-2-amino-3-phenylpropyl]oxy]-1-ethanol C11H17NO2 详情 详情
(IX) 30457 (2S)-2-(dibenzylamino)-3-phenyl-1-propanol 111060-52-7 C23H25NO 详情 详情
(X) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XI) 30458 tert-butyl 2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]acetate C29H35NO3 详情 详情
(XII) 30459 2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]-1-ethanol C25H29NO2 详情 详情
Extended Information