Targinine hydrochloride, L-NMMA.HCl, L-NMA.HCl, 546C88, -Drug Synthesis Database

【结构式】

【药物名称】Targinine hydrochloride, L-NMMA.HCl, L-NMA.HCl, 546C88

【化学名称】Nomega-Methyl-L-arginine hydrochloride
　　　　　　N5-(Methylamidino)-L-ornithine hydrochloride

【CA登记号】156706-47-7, 17035-90-4 (free base), 53308-83-1 (monoacetate salt)

【分子式】C₇H₁₇ClN₄O₂

【分子量】224.69214

【开发单位】GlaxoSmithKline (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, ANTIINFECTIVE THERAPY, Antimigraine Drugs, Treatment of Septic Shock, Nitric Oxide Synthase Inhibitors

合成路线1 合成路线2

合成路线1

546C88 has been obtained by several related ways: 1) The reaction of N-methylthiourea (I) with methyl iodide gives N,S-dimethylisothiouronium iodide (II), which is then condensed with L-ornithine (III) by means of NaOH or copper acetate. 2) The oxidation of N-methylthiourea (I) with peracetic acid in acetic acid gives N-methylamidinosulfonic acid (IV), which is then condensed with L-ornithine (III) by means of K2CO3 in water. 3) The reaction of cyanogen bromide (V) with methylamine (VI) by means of Na2CO3 in THF gives N-methylcyanamide (VII), which is condensed with pyrazole (VIII) by means of HCl in refluxing dioxane to yield N1-methylpyrazole-1-carboxamidine (IX). Finally, this compound is condensed with L-ornithine (III) by means of LiOH in water. 4) The reaction of cellulose (X) with cyanogen bromide (V) by means of K2CO3 in water/DMF gives the corresponding polymeric cyanate ester (XI), which is condensed with methylamine (VI) to yield the polymeric N-methylamidino compound (XII). Finally, this compound is condensed with L-ornithine (III) by means of CuCO3 in water.

参考文献中间体

【1】 Patthy, A.; Bajusz, S.; Patthy, L.; Preparation and characterization of NG-mono-, di- and trimethylated arginines. Acta Biochim Biophys Acad Sci Hung 1977, 12, 3, 191-6.
【2】 Wroblewski, T.; Castañer, J.; Prous, J.R.; 546C88. Drugs Fut 1998, 23, 2, 123.
【3】 Dowd, P.; Zhang, W.; Hershline, R.; A highly efficient preparation of NG-methyl-L-arginine and NG-methyl-D-arginine. Synth Commun 1994, 24, 19, 2789-92.
【4】 Reporter, M.; Corbin, J.L.; A convenient preparation of NG-methylarginine. Anal Biochem 1974, 57, 1, 310-2.
【5】 Pundak, S.; Wilchek, M.; Synthesis of guanidino-N-alkylarginines by the use of polymeric pseudoureas. J Org Chem 1981, 46, 808-9.
【6】 Hodson, H.F. (Glaxo Wellcome plc); NG-Monomethyl-L-arginine hydrochloride derivs. and their use in the treatment of septic shock. EP 0651741; JP 1995509239; US 5767312; WO 9402453 .
【7】 Gillies, I. (Glaxo Wellcome plc); Process for the preparation of NG-monomethyl-L-arginine hydrochloride. WO 9730972 .
【8】 Patel, R.; Mahal, A.S.; Burford, D.L.W. (Glaxo Wellcome plc); Process for preparing NG-monoalkyl-L-arginine and related cpds. WO 9426701 .

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)	17283	N-methylthiourea	598-52-7	C₂H₆N₂S	详情	详情
(II)	17284	(methylamino)(methylsulfanyl)methaniminium iodide		C₃H₉IN₂S	详情	详情
(III)	17285	L-ornithine	70-26-8	C₅H₁₂N₂O₂	详情	详情
(IV)	17286	imino(methylamino)methanesulfonic acid		C₂H₆N₂O₃S	详情	详情
(VII)	17287	N-methylcyanamide		C₂H₄N₂	详情	详情
(VIII)	17288	Pyrazole; 1H-pyrazole	288-13-1	C₃H₄N₂	详情	详情
(IX)	17289	N-methyl-1H-pyrazole-1-carboximidamide		C₅H₈N₄	详情	详情
(XII)	17290	[[hydroxy(imino)methyl]amino]methane		C₂H₆N₂O	详情	详情

合成路线2

5) The reaction of L-ornithine (III) with benzaldehyde by means of LiOH gives Ndelta-benzylidene-L-ornitine (XIII), which is treated first with benzyl chloroformate and NaOH and hydrolyzed with HCl to afford Nalpha-(benzyloxycarbonyl)-L-ornithine (XIV). The condensation of (XIV) with N,S-dimethylisothiouronium iodide (II) by means of NaOH gives Nalpha-(benzyloxycarbonyl)-Nomega-methyl-L-arginine (XV), which is finally deprotected by hydrogenation with H2 over Pd/C.

参考文献中间体

【1】 Sala, A.; Ferrario, F.; Trupiano, F.; Levi, S.; Multigram synthesis of NG-methyl-(L-)-arginine and its analytical characterization. Synth Commun 1991, 21, 99-105.
【2】 Wroblewski, T.; Castañer, J.; Prous, J.R.; 546C88. Drugs Fut 1998, 23, 2, 123.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	17284	(methylamino)(methylsulfanyl)methaniminium iodide		C₃H₉IN₂S	详情	详情
(III)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情
(III)	17285	L-ornithine	70-26-8	C₅H₁₂N₂O₂	详情	详情
(XIII)	17291	(2S)-2-amino-5-[[(E)-benzylidene]amino]pentanoic acid		C₁₂H₁₆N₂O₂	详情	详情
(XIV)	17292	(2S)-5-amino-2-[[(benzyloxy)carbonyl]amino]pentanoic acid		C₁₃H₁₈N₂O₄	详情	详情
(XV)	17293	(2S)-2-[[(benzyloxy)carbonyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid		C₁₅H₂₂N₄O₄	详情	详情

Extended Information