-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-Hydroxy-3-[2-oxo-3(S)-(thieno[2,3-c]pyridin-2-ylsulfonamido)pyrrolidin-1-ylmethyl]benzamidine

【CA登记号】

【分子式】C₁₉H₁₉N₅O₄S₂

【分子量】445.52238

【开发单位】Aventis Pharma (Originator)

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

合成路线1 合成路线2

合成路线1

Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).

参考文献中间体

【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 .

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)	21351	2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde	90-02-8	C₇H₆O₂	详情	详情
(II)	31671	2-hydroxy-5-iodobenzaldehyde		C₇H₅IO₂	详情	详情
(III)	31672	5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde		C₁₁H₁₃IO₄	详情	详情
(IV)	31673	[5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol		C₁₁H₁₅IO₄	详情	详情
(V)	31674	2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene		C₁₁H₁₄BrIO₃	详情	详情
(VI)	29493	(2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid		C₉H₁₈N₂O₄	详情	详情
(VII)	29492	tert-butyl (3S)-2-oxopyrrolidinylcarbamate		C₉H₁₆N₂O₃	详情	详情
(VIII)	31675	tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate		C₂₀H₂₉IN₂O₆	详情	详情
(IX)	31676	tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate		C₂₁H₂₉N₃O₆	详情	详情
(X)	31677	3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile		C₁₂H₁₃N₃O₂	详情	详情

合成路线2

Thienylacrylic acid (XII), prepared from thiophene aldehyde (XI), was activated as the mixed anhydride with ethyl chloroformate and then treated with NaN3 to yield acyl azide (XIII). Cyclization of (XIII) in the presence of Bu3P in boiling diphenyl ether generated the thienopyridine system (XIV). Chlorination of (XIV) with POCl3 afforded the chloro derivative (XV). After lithium-bromine exchange with n-butyllithium, the resulting organolithium derivative (XVI) was treated with SO2 and further oxidized to sulfonyl chloride (XVII) with SO2Cl2. Coupling of (XVII) with aminopyrrolidinone (X) yielded sulfonamide (XVIII). Conversion of the nitrile of (XVIII) to the corresponding imidate (XIX), followed by reaction with ammonia produced benzamidine (XX). Finally, hydrogenolytic dechlorination of (XX) over Pd/C provided the title compound.

参考文献中间体

【1】 Ewing, W.R.; Davis, R.S.; Becker, M.R.; et al.; Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 18, 2753.
【2】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	31677	3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile	C₁₂H₁₃N₃O₂	详情	详情
(XI)	31660	5-bromo-3-thiophenecarbaldehyde	C₅H₃BrOS	详情	详情
(XII)	38299	(E)-3-(5-bromo-3-thienyl)-2-propenoic acid	C₇H₅BrO₂S	详情	详情
(XIII)	38300	(E)-3-(5-bromo-3-thienyl)-2-propenoyl azide	C₇H₄BrN₃OS	详情	详情
(XIV)	38301	2-bromothieno[2,3-c]pyridin-7(6H)-one	C₇H₄BrNOS	详情	详情
(XV)	38302	2-bromo-7-chlorothieno[2,3-c]pyridine	C₇H₃BrClNS	详情	详情
(XVI)	38303	(7-chlorothieno[2,3-c]pyridin-2-yl)lithium	C₇H₃ClLiNS	详情	详情
(XVII)	38304	7-chlorothieno[2,3-c]pyridine-2-sulfonyl chloride	C₇H₃Cl₂NO₂S₂	详情	详情
(XVIII)	38305	7-chloro-N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]thieno[2,3-c]pyridine-2-sulfonamide	C₁₉H₁₅ClN₄O₄S₂	详情	详情
(XIX)	38306	ethyl 3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidoate	C₂₁H₂₁ClN₄O₅S₂	详情	详情
(XX)	38307	3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidamide	C₁₉H₁₈ClN₅O₄S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)