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【结 构 式】

【分子编号】53998

【品名】5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide

【CA登记号】n/a

【 分 子 式 】C16H26BrN5O2

【 分 子 量 】400.31894

【元素组成】C 48.01% H 6.55% Br 19.96% N 17.49% O 7.99%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(XII)

The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). Boc deprotection in (VII) with HCl affords intermediate (VIII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to provide the perhydro-1,4-diazepine (IX). Cbz deprotection in (IX) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (X), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XI) by means of ethyl chloroformate and TEA to yield the target amide (XII). Finally, this compound is treated with fumaric acid (XIII) in ethanol to afford the desired fumarate salt.

参考文献 中间体
合成目标
【1】 Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
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) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 51660 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate C12H15NO5 详情 详情
(III) 53991 benzyl (1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethylcarbamate n/a C12H16N2O4 详情 详情
(IV) 53992 benzyl (1R)-2-hydroxy-1-[(methylamino)methyl]ethylcarbamate n/a C12H18N2O3 详情 详情
(V) 53993 benzyl (1R)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-(hydroxymethyl)ethylcarbamate n/a C17H26N2O5 详情 详情
(VI) 53994 (2R)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate n/a C18H28N2O7S 详情 详情
(VII) 53995 benzyl (1S)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-[(ethylamino)methyl]ethylcarbamate n/a C19H31N3O4 详情 详情
(VIII) 53996 benzyl (1R)-2-(ethylamino)-1-[(methylamino)methyl]ethylcarbamate n/a C14H23N3O2 详情 详情
(IX) 53997 benzyl (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylcarbamate n/a C16H25N3O2 详情 详情
(X) 17802 (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine C8H19N3 详情 详情
(XI) 17801 5-bromo-2-methoxy-6-(methylamino)nicotinic acid C8H9BrN2O3 详情 详情
(XII) 53998 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide n/a C16H26BrN5O2 详情 详情
(XIII) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). The condensation of (VII) with ethyl bromoacetate (VIII) affords the aminoacetate (IX), which is selectively deprotected with HCl to provide the intermediate (X). The cyclization of (X) by means of NaOEt gives the perhydro-1,4-diazepin-2-one (XI), which is reduced with BH3/THF to yield the perhydro-1,4-diazepine (XII). Cbz deprotection in (XII) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XIV) by means of ethyl chloroformate and TEA to yield the target amide (XV). Finally, this compound is treated with fumaric acid (XVI) in ethanol to afford the desired fumarate salt.

参考文献 中间体
合成目标
【1】 Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
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) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 51660 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate C12H15NO5 详情 详情
(III) 53991 benzyl (1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethylcarbamate n/a C12H16N2O4 详情 详情
(IV) 53992 benzyl (1R)-2-hydroxy-1-[(methylamino)methyl]ethylcarbamate n/a C12H18N2O3 详情 详情
(V) 53993 benzyl (1R)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-(hydroxymethyl)ethylcarbamate n/a C17H26N2O5 详情 详情
(VI) 53994 (2R)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate n/a C18H28N2O7S 详情 详情
(VII) 53995 benzyl (1S)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-[(ethylamino)methyl]ethylcarbamate n/a C19H31N3O4 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 53999 ethyl 2-[{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(ethyl)amino]acetate n/a C23H37N3O6 详情 详情
(X) 54000 ethyl 2-[[(2R)-2-{[(benzyloxy)carbonyl]amino}-3-(methylamino)propyl](ethyl)amino]acetate n/a C18H29N3O4 详情 详情
(XI) 54001 benzyl (6S)-4-ethyl-1-methyl-2-oxo-1,4-diazepan-6-ylcarbamate n/a C16H23N3O3 详情 详情
(XII) 53997 benzyl (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylcarbamate n/a C16H25N3O2 详情 详情
(XIII) 17802 (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine C8H19N3 详情 详情
(XIV) 17801 5-bromo-2-methoxy-6-(methylamino)nicotinic acid C8H9BrN2O3 详情 详情
(XV) 53998 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide n/a C16H26BrN5O2 详情 详情
(XVI) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XI)

The protection of the NH2 group of L-serine (I) with Ts-Cl and TEA gives N-tosyl-L-serine (II), which is converted into the N-methylamide (III). The cyclization of (III) by means of diisopropylazodicarboxylate (DIAD) yields the N-tosylaziridine (IV), which is treated with ethylamine (V) to afford the diaminopropionamide (VI). The reduction of the amide group of (VI) with LiAlH4 provides the triaminopropane (VII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to give the perhydro-1,4-diazepine (VIII). Ts deprotection in (VIII) by means of HBr affords the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (IX), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (X) by means of ethyl chloroformate and TEA to yield the target amide (XI). Finally, this compound is treated with fumaric acid (XII) in ethanol to afford the desired fumarate salt.

参考文献 中间体
合成目标
【1】 Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
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) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 54002 methyl (2S)-3-hydroxy-2-{[(4-methylphenyl)sulfonyl]amino}propanoate n/a C11H15NO5S 详情 详情
(III) 54003 (2S)-3-hydroxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]amino}propanamide n/a C11H16N2O4S 详情 详情
(IV) 54004 (2S)-N-methyl-1-[(4-methylphenyl)sulfonyl]-2-aziridinecarboxamide n/a C11H14N2O3S 详情 详情
(V) 10928 Ethanamine 75-04-7 C2H7N 详情 详情
(VI) 54005 (2S)-3-(ethylamino)-N-methyl-2-{[(4-methylphenyl)sulfonyl]amino}propanamide n/a C13H21N3O3S 详情 详情
(VII) 54006 N-{(1R)-2-(ethylamino)-1-[(methylamino)methyl]ethyl}-4-methylbenzenesulfonamide n/a C13H23N3O2S 详情 详情
(VIII) 54007 N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-4-methylbenzenesulfonamide n/a C15H25N3O2S 详情 详情
(IX) 17802 (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine C8H19N3 详情 详情
(X) 17801 5-bromo-2-methoxy-6-(methylamino)nicotinic acid C8H9BrN2O3 详情 详情
(XI) 53998 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide n/a C16H26BrN5O2 详情 详情
(XII) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XIX)

The reaction of N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (VIII) with (Boc)2O in chloroform gives N-(tert-butoxycarbonyl)-N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (IX), which is condensed with the chiral aziridine (X) by heating at 80 C to yield the diaminobutyric ester (XI). Selective elimination of the Boc protecting group of (XI) with HCl in methanol affords the methylamino intermediate (XII), which is treated with NaOH in ethanol/water to provide the carboxylic acid (XIII). The cyclization of (XIII) by means of DEC gives the perhydro-1,4-diazepin-5-one derivative (XIV), which is debenzylated by means of 1-chloroethyl chloroformate to yield the 6(S)-(benzyloxycarbonylamino)-4-methylperhydro-1,4-diazepin-5-one (XV). The reductive alkylation of (XV) with acetaldehyde, NaBH4 and TEA in methanol affords the 1-ethyl derivative (XVI), which is deprotected by means of conc. HBr to provide 6(S)-amino-1-ethyl-4-methylperhydro-1,4-diazepin-5-one (XVII). The reduction of (XVII) with BH3/THF gives 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XVIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (VII) by means of ethyl chloroformate and TEA to yield the target amide (XIX). Finally, this compound is treated with fumaric acid (XX) in ethanol to afford the desired fumarate salt.

参考文献 中间体
合成目标
【1】 Kato, S.; Hirokawa, Y.; Morie, T.; Harada, H.; Yoshida, N. (Dainippon Pharmaceutical Co., Ltd.); (R)-5-Bromo-N-(1-ethyl-4-methylhexahydro-1H-1, 4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, process for producing the same and medicinal compsn. containing the same. EP 0855397; JP 1997100276; JP 1997118669; US 5945415; WO 9705129 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 17801 5-bromo-2-methoxy-6-(methylamino)nicotinic acid C8H9BrN2O3 详情 详情
(VIII) 54009 N~1~-methyl-N~2~-(3-methylbenzyl)-1,2-ethanediamine; N-methyl-N-{2-[(3-methylbenzyl)amino]ethyl}amine n/a C11H18N2 详情 详情
(IX) 54010 tert-butyl methyl{2-[(3-methylbenzyl)amino]ethyl}carbamate n/a C16H26N2O2 详情 详情
(X) 54011 1-benzyl 2-methyl (2S)-1,2-aziridinedicarboxylate n/a C12H13NO4 详情 详情
(XI) 54012 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(3-methylbenzyl)amino]butanoate n/a C29H41N3O6 详情 详情
(XII) 54013 methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[[2-(methylamino)ethyl](3-methylbenzyl)amino]butanoate n/a C24H33N3O4 详情 详情
(XIII) 54014 (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[[2-(methylamino)ethyl](3-methylbenzyl)amino]butanoic acid n/a C23H31N3O4 详情 详情
(XIV) 54015 benzyl (6S)-4-methyl-1-(3-methylbenzyl)-5-oxo-1,4-diazepan-6-ylcarbamate n/a C22H27N3O3 详情 详情
(XV) 54016 benzyl (6S)-1-methyl-7-oxo-1,4-diazepan-6-ylcarbamate n/a C14H19N3O3 详情 详情
(XVI) 54017 benzyl (6S)-1-ethyl-4-methyl-5-oxo-1,4-diazepan-6-ylcarbamate n/a C16H23N3O3 详情 详情
(XVII) 54018 (6S)-6-amino-1-ethyl-4-methyl-1,4-diazepan-5-one n/a C8H17N3O 详情 详情
(XVIII) 17802 (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine C8H19N3 详情 详情
(XIX) 53998 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide n/a C16H26BrN5O2 详情 详情
(XX) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情
Extended Information