【结 构 式】 |
【分子编号】51660 【品名】methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate 【CA登记号】 |
【 分 子 式 】C12H15NO5 【 分 子 量 】253.25484 【元素组成】C 56.91% H 5.97% N 5.53% O 31.59% |
合成路线1
该中间体在本合成路线中的序号:(II)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.
【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:(II)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.
【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:(I)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with 2-mercaptobenzothiazole (II) by means of DIAD and PPh3 in THF gives the thioether (III), which is reduced with NaBH4 and CaCl2 in THF to yield the alcohol (IV). The cyclization of (IV) with 2,2-dimethoxypropane (V) by means of TsOH in dichloromethane affords the oxazolidine (VI), which is oxidized at the thioether group by means of Mo7O24(NH4)6 and H2O2 in ethanol to provide the sulfone (VII). The condensation of (VII) with 7-iodoisatin (VIII) employing LiHMDS and DMPU in THF gives the adduct (IX), which is condensed with the boronic ester (X) -obtained by reaction of the tyrosine derivative (XI) with bis(pinacolato)diboron, KOH and Pd(dppf)Cl2 in hot DMSO- by means of K2CO3 and Pd(dppf)Cl2 in aqueous DME to yield the coupled product (XII). The hydrolysis of the ester group of (XII) with LiOH, followed by condensation with asparagine benzyl ester (XIII) by means of HOAT, EDC and NMM in dichloromethane affords the amide (XIV). This is oxidized at its exocyclic double bond by means of OsO4 and pyridine in THF/methanol to provide the diol (XV).
【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
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) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
(II) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
(III) | 61814 | methyl (2R)-3-(1,3-benzothiazol-2-ylsulfanyl)-2-{[(benzyloxy)carbonyl]amino}propanoate | C19H18N2O4S2 | 详情 | 详情 | |
(IV) | 61815 | benzyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-(hydroxymethyl)ethylcarbamate | C18H18N2O3S2 | 详情 | 详情 | |
(V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(VI) | 61816 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfanyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O3S2 | 详情 | 详情 | |
(VII) | 61817 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O5S2 | 详情 | 详情 | |
(VIII) | 61824 | 7-iodo-1H-indole-2,3-dione | C8H4INO2 | 详情 | 详情 | |
(IX) | 61818 | benzyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H21IN2O4 | 详情 | 详情 | |
(X) | 61820 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C23H36BNO8 | 详情 | 详情 | |
(XI) | 61819 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-iodo-4-(methoxymethoxy)phenyl]propanoate | C17H24INO6 | 详情 | 详情 | |
(XII) | 61821 | benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C39H45N3O10 | 详情 | 详情 | |
(XIII) | 61825 | benzyl (2S)-2,4-diamino-4-oxobutanoate | C11H14N2O3 | 详情 | 详情 | |
(XIV) | 61822 | benzyl (4S)-4-({7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C49H55N5O12 | 详情 | 详情 | |
(XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with Ts-Cl gives the corresponding tosylate (II), which is condensed with 4-phenoxythiophenol (III) to yield the thioether (IV). The oxidation of (IV) with Oxone affords the sulfone (V), which is N-deprotected with H2 over Pd/C to provide compound (VI) with a free amino group. The methylation of (VI) with methyl iodide gives the N-methyl derivative (VII), which is finally treated with hydroxylamine to afford the target hydroxamic acid.
【1】 Bedell, L.; Becker, D.P.; Barta, T.E.; et al.; alpha-Amino-beta-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1. Bioorg Med Chem Lett 2001, 11, 20, 2719. |
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) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
(II) | 51655 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[[(4-methylphenyl)sulfonyl]oxy]propanoate | C19H21NO7S | 详情 | 详情 | |
(III) | 26254 | 4-phenoxybenzenethiol; 4-phenoxyphenylhydrosulfide | C12H10OS | 详情 | 详情 | |
(IV) | 51656 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-[(4-phenoxyphenyl)sulfanyl]propanoate | C24H23NO5S | 详情 | 详情 | |
(V) | 51657 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-[(4-phenoxyphenyl)sulfonyl]propanoate | C24H23NO7S | 详情 | 详情 | |
(VI) | 51658 | methyl (2R)-2-amino-3-[(4-phenoxyphenyl)sulfonyl]propanoate | C16H17NO5S | 详情 | 详情 | |
(VII) | 51659 | methyl (2R)-2-(methylamino)-3-[(4-phenoxyphenyl)sulfonyl]propanoate | C17H19NO5S | 详情 | 详情 |