NPS-1408.HCl((R)-isomer), NPS-1407.HCl, -Drug Synthesis Database

【结构式】

【药物名称】NPS-1408.HCl((R)-isomer), NPS-1407.HCl

【化学名称】(-)-4,4-Bis(3-fluorophenyl)butan-2(S)-amine hydrochloride

【CA登记号】186495-93-2, 170018-83-4 (free base)

【分子式】C₁₆H₁₈ClF₂N

【分子量】297.77836

【开发单位】NPS Pharmaceuticals (Originator)

【药理作用】Antiepileptic Drugs, Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists

合成路线1 合成路线2

合成路线1

The desired enantiomer was prepared by two chiral routes. Monoalkylation of (S)-alpha-methylbenzylamine (I) with benzyl bromide in N,N'-dimethylpropyleneurea gave the chiral secondary amine (II). Diastereoselective Michael addition of the lithium amide of (II) to benzyl crotonate (III) provided adduct (IV). The chiral ester (IV) was then reacted with the Grignard reagent (V) to yield the diaryl carbinol (VI). This was subsequently dehydrated to (VII) using H2SO4 in glacial HOAc. Double bond reduction and N-debenzylation of (VII) over Pearlman抯 catalyst provided the target primary amine, which was finally isolated as the hydrochloride salt.

参考文献中间体

【1】 Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411.
【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 .
【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 .
【4】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 .

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)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(II)	38470	(1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine	38235-77-7	C₁₅H₁₇N	详情	详情
(III)	46908	benzyl (E)-2-butenoate		C₁₁H₁₂O₂	详情	详情
(IV)	46909	benzyl (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]butanoate		C₂₆H₂₉NO₂	详情	详情
(V)	35384	bromo(3-fluorophenyl)magnesium		C₆H₄BrFMg	详情	详情
(VI)	46910	(3S)-3-[benzyl[(1S)-1-phenylethyl]amino]-1,1-bis(3-fluorophenyl)-1-butanol		C₃₁H₃₁F₂NO	详情	详情
(VII)	46911	(2S)-N-benzyl-4,4-bis(3-fluorophenyl)-N-[(1S)-1-phenylethyl]-3-buten-2-amine; N-benzyl-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methyl-2-propenyl]-N-[(1S)-1-phenylethyl]amine		C₃₁H₂₉F₂N	详情	详情

合成路线2

In an alternative procedure, nitrile (IX) was obtained by Horner-Emmons reaction of 3,3'-difluorobenzophenone (VIII) with diethyl (cyanomethyl)phosphonate. Catalytic hydrogenation of the olefinic double bond of (IX) provided the diaryl propionitrile (X), which was reduced to aldehyde (XI) using DIBAL. The chiral auxiliary (R)-1-amino-2-(methoxymethyl)pyrrolidine (XII) was then condensed with aldehyde (XI) to form hydrazone (XIII). Diastereoselective addition of methyllithium to the imino group yielded (XIV). Then, reductive cleavage of the resulting hydrazine (XIV) produced the title amine, which was converted to the corresponding hydrochloride.

参考文献中间体

【1】 Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	35707			C₃₉H₅₈O₈Si	详情	详情
(IX)	35708			C₃₆H₅₄O₈Si	详情	详情
(X)	35709			C₄₂H₆₈O₈Si₂	详情	详情
(XI)	46912	3,3-bis(3-fluorophenyl)propanal		C₁₅H₁₂F₂O	详情	详情
(XII)	46913	(2R)-2-(methoxymethyl)pyrrolidinylamine; (2R)-2-(methoxymethyl)-1-pyrrolidinamine	59983-39-0	C₆H₁₄N₂O	详情	详情
(XIII)	46914	(2R)-N-[(E)-3,3-bis(3-fluorophenyl)propylidene]-2-(methoxymethyl)-1-pyrrolidinamine; N-[(E)-3,3-bis(3-fluorophenyl)propylidene]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine		C₂₁H₂₄F₂N₂O	详情	详情
(XIV)	46915	(2R)-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methylpropyl]-2-(methoxymethyl)-1-pyrrolidinamine; N-[(1S)-3,3-bis(3-fluorophenyl)-1-methylpropyl]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine		C₂₂H₂₈F₂N₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)