274150, GW-274150, -Drug Synthesis Database

【结构式】

【药物名称】274150, GW-274150

【化学名称】S-[2-(1-Iminoethylamino)ethyl]-L-homocysteine
　　　　　　2(S)-Amino-7-(1-iminoethylamino)-5-thiaheptanoic acid

【CA登记号】210354-22-6, 210354-23-7 (undefined isomer)

【分子式】C₈H₁₇N₃O₂S

【分子量】219.30759

【开发单位】GlaxoSmithKline (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, Asthma Therapy, CARDIOVASCULAR DRUGS, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Shock, Treatment of Upper Respiratory Tract Disorders, Nitric Oxide Synthase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Reductive cleavage of L-homocystine (I) with sodium in liquid ammonia produced homocysteine, which was subsequently alkylated with 2-(N-benzyloxycarbonyl-amino)ethyl tosylate (II) to afford thioether (III). The benzyloxycarbonyl protecting group of (III) was cleaved with HBr to give diamine (IV). Finally, condensation with ethyl acetimidate (V) furnished the target amidine.

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.
【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 .

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)	42169	(2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butyric acid		C₈H₁₆N₂O₄S₂	详情	详情
(II)	42170	2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate		C₁₇H₁₉NO₅S	详情	详情
(III)	42171	(2S)-2-amino-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]butyric acid		C₁₄H₂₀N₂O₄S	详情	详情
(IV)	42172	(2S)-2-amino-4-[(2-aminoethyl)sulfanyl]butyric acid		C₆H₁₄N₂O₂S	详情	详情
(V)	12831	ethyl ethanimidoate	1000-84-6	C₄H₉NO	详情	详情

合成路线2

Alternatively, amino acid (III) was protected as the N-Boc derivative (VI), and the benzyloxycarbonyl group was then cleaved by transfer hydrogenolysis employing formic acid and palladium catalyst. The resulting amine (VII) was converted to amidine (IX) by reaction with S-(1-naphthylmethyl)thioacetimidate hydrochloride (VIII). 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.
【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	42171	(2S)-2-amino-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]butyric acid	C₁₄H₂₀N₂O₄S	详情	详情
(VI)	42173	(2S)-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₉H₂₈N₂O₆S	详情	详情
(VII)	42174	(2S)-4-[(2-aminoethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₁H₂₂N₂O₄S	详情	详情
(VIII)	42175	1-naphthylmethyl ethanimidothioate	C₁₃H₁₃NS	详情	详情
(IX)	42176	(2S)-2-[(tert-butoxycarbonyl)amino]-4-[[2-(ethanimidoylamino)ethyl]sulfanyl]butyric acid	C₁₃H₂₅N₃O₄S	详情	详情

合成路线3

In a further procedure, N-Boc-L-homocysteine tert-butyl ester (XI) was prepared by reduction of N-Boc-homocystine tert-butyl ester (X) with dithiothreitol (DTT). Alkylation of thiol (XI) with tosylate (II) afforded thioether (XII). An alternative synthetic access to (XII) consisted in the esterification of carboxylic acid (VI), prepared as above, by means of either N,N-dimethylformamide di-O-t-butyl acetal or O-t-butyl 1,1,1-trichloroacetimidate. Transfer hydrogenolysis of (XII) using ammonium formate and palladium hydroxide on carbon removed the benzyloxycarbonyl group to furnish (XIII). This was converted to amidine (XIV) by treatment with S-(1-naphthylmethyl)thioacetimidate hydrochloride (VIII). 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.
【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 .

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
(VI)	42173	(2S)-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butyric acid	C₁₉H₂₈N₂O₆S	详情	详情
(VIII)	42175	1-naphthylmethyl ethanimidothioate	C₁₃H₁₃NS	详情	详情
(X)	42177	di(tert-butyl) (6S,13S)-2,2,17,17-tetramethyl-4,15-dioxo-3,16-dioxa-9,10-dithia-5,14-diazaoctadecane-6,13-dicarboxylate	C₂₆H₄₈N₂O₈S₂	详情	详情
(XI)	42178	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-sulfanylbutanoate	C₁₃H₂₅NO₄S	详情	详情
(XII)	42179	tert-butyl (2S)-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butanoate	C₂₃H₃₆N₂O₆S	详情	详情
(XIII)	42180	tert-butyl (2S)-4-[(2-aminoethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butanoate	C₁₅H₃₀N₂O₄S	详情	详情
(XIV)	42181	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[[2-(ethanimidoylamino)ethyl]sulfanyl]butanoate	C₁₇H₃₃N₃O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)