GW-273629, -Drug Synthesis Database

【结构式】

【药物名称】GW-273629

【化学名称】2(R)-Amino-3-[2-(1-iminoethylamino)ethylsulfonyl]propionic acid

【CA登记号】

【分子式】C₇H₁₅N₃O₄S

【分子量】237.2793

【开发单位】GlaxoSmithKline (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, CARDIOVASCULAR DRUGS, Treatment of Shock, Inducible Nitric Oxide Synthase (NOS-2) Inhibitors

合成路线1 合成路线2

合成路线1

Reductive cleavage of L-cystine (I) with sodium in liquid ammonia produced cysteine, which was subsequently alkylated with 2-(N-benzyloxycarbonylamino)ethyl tosylate (II) to afford thioether (III). After protection of (III) as the N-Boc derivative (IV), sulfur oxidation by means of Oxone(R) produced sulfone (V). The benzyloxycarbonyl protecting group of (V) was then cleaved by transfer hydrogenolysis employing formic acid and palladium catalyst, and the resulting amine (VI) was converted to amidine (VIII) by reaction thioacetimidate (VII). The Boc protecting group of (VIII) was finally removed by acidic treatment.

参考文献中间体

【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	42188	(2R)-2-amino-3-[[(2R)-2-amino-2-carboxyethyl]disulfanyl]propionic acid	C₆H₁₂N₂O₄S₂	详情	详情
(II)	42170	2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate	C₁₇H₁₉NO₅S	详情	详情
(III)	42189	(2R)-2-amino-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]propionic acid	C₁₃H₁₈N₂O₄S	详情	详情
(IV)	42190	(2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	C₁₈H₂₆N₂O₆S	详情	详情
(V)	42191	(2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	C₁₈H₂₆N₂O₈S	详情	详情
(VI)	42192	(2R)-3-[(2-aminoethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	C₁₀H₂₀N₂O₆S	详情	详情
(VII)	42175	1-naphthylmethyl ethanimidothioate	C₁₃H₁₃NS	详情	详情
(VIII)	42193	(2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-(ethanimidoylamino)ethyl]sulfonyl]propionic acid	C₁₂H₂₃N₃O₆S	详情	详情

合成路线2

In a related procedure, N-Boc-L-cysteine tert-butyl ester (X) was prepared by reduction of N-Boc-cystine tert-butyl ester (IX) with dithiothreitol (DTT). Alkylation of thiol (X) with tosylate (II) afforded thioether (XI). After oxidation of (XI) to sulfone (XII), transfer hydrogenolysis using ammonium formate and palladium hydroxide on carbon removed the benzyloxycarbonyl group to furnish amine (XIII). This was converted to amidine (XIV) by treatment with thioacetimidate (VII). Finally, deprotection of the Boc group and the tert-butyl ester of (XIV) by means of HCl in dioxan afforded the title compound.

参考文献中间体

【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	42170	2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate	C₁₇H₁₉NO₅S	详情	详情
(VII)	42175	1-naphthylmethyl ethanimidothioate	C₁₃H₁₃NS	详情	详情
(IX)	42194	di(tert-butyl) (6R,11R)-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahexadecane-6,11-dicarboxylate	C₂₄H₄₄N₂O₈S₂	详情	详情
(X)	42195	tert-butyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-sulfanylpropanoate	C₁₂H₂₃NO₄S	详情	详情
(XI)	42196	tert-butyl (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]propanoate	C₂₂H₃₄N₂O₆S	详情	详情
(XII)	42197	tert-butyl (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propanoate	C₂₂H₃₄N₂O₈S	详情	详情
(XIII)	42198	tert-butyl (2R)-3-[(2-aminoethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propanoate	C₁₄H₂₈N₂O₆S	详情	详情
(XIV)	42199	tert-butyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-(ethanimidoylamino)ethyl]sulfonyl]propanoate	C₁₆H₃₁N₃O₆S	详情	详情

Extended Information