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【结 构 式】 
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【分子编号】50614 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-4-[((3S)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl)disulfanyl]butyric acid 【CA登记号】 |
【 分 子 式 】C24H28N2O8S2 【 分 子 量 】536.627 【元素组成】C 53.72% H 5.26% N 5.22% O 23.85% S 11.95% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of tetrahydrofuran (I) with HBr gives 4-bromobutanol (II), which is oxidized with NaOCl and TEMPO to yield the aldehyde (III). The reaction of (III) with ethyleneglycol and Ts-OH provides the cyclic ketal (IV), which is submitted to a Grignard condensation with diethyl oxalate (V) and Mg to give the alpha-ketoester (VI). The hydrolysis of (VI) with LiOH yields the corresponding alpha-ketoacid (VII), which is submitted to a stereoselective amination with ammonia and phenylalanine dehydrogenase to afford 2(S)-amino-5-(1,3-dioxol-2-yl)pentanoic acid (VIII). The reaction of (VIII) with SOCl2 and Me-OH provides 2(S)-amino-5,5-dimethoxypentanoic acid methyl ester (IX). The reaction of L- homocystine (X) with Boc2O gives the N-protected-L-homocystine (XI), which is condensed with pentanoic ester (IX) to yield the dimeric adduct (XII). The cleavage of (XII) with dithiothreitol (DTT) affords the monomeric intermediate (XIII), which is finally cyclized by means of Ms-OH to provide the target pyrido[2,1-b][1,3]thiazepine intermediate (XIV).
| 【1】 Patel, R.N.; Enzymatic synthesis of chiral intermediates for omapatrilat, an antihypertensive drug. Biomol Eng 2001, 17, 6, 167. |
| 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) | 41419 | tetrahydrofuran | 109-99-9 | C4H8O | 详情 | 详情 |
| (II) | 50608 | Tetramethylene Bromohydrin; 4-Bromo-1-butanol;4-bromobutan-1-ol | 33036-62-3 | C4H9BrO | 详情 | 详情 |
| (III) | 50609 | 4-bromobutanal | C4H7BrO | 详情 | 详情 | |
| (IV) | 50610 | 2-(3-bromopropyl)-1,3-dioxolane | C6H11BrO2 | 详情 | 详情 | |
| (V) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VI) | 50611 | ethyl 5-(1,3-dioxolan-2-yl)-2-oxopentanoate | C10H16O5 | 详情 | 详情 | |
| (VII) | 50612 | 5-(1,3-dioxolan-2-yl)-2-oxopentanoic acid | C8H12O5 | 详情 | 详情 | |
| (VIII) | 50613 | (2S)-2-amino-5-(1,3-dioxolan-2-yl)pentanoic acid | C8H15NO4 | 详情 | 详情 | |
| (IX) | 22504 | methyl (2S)-2-amino-6,6-dimethoxyhexanoate | C9H19NO4 | 详情 | 详情 | |
| (X) | 42169 | (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butyric acid | C8H16N2O4S2 | 详情 | 详情 | |
| (XI) | 50614 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-[((3S)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl)disulfanyl]butyric acid | C24H28N2O8S2 | 详情 | 详情 | |
| (XII) | 50615 | dimethyl (7S,10S,17S,20S)-10,17-bis[[(benzyloxy)carbonyl]amino]-3,24-dimethoxy-9,18-dioxo-2,25-dioxa-13,14-dithia-8,19-diazahexacosane-7,20-dicarboxylate | C42H62N4O14S2 | 详情 | 详情 | |
| (XIII) | 50616 | methyl (2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-sulfanylbutanoyl)amino]-6,6-dimethoxyhexanoate | C21H32N2O7S | 详情 | 详情 | |
| (XIV) | 50617 | (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid | C18H22N2O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The activation of N,N'-bis(benzyloxycarbonyl)-L-homocystine (I) with N-hydroxysuccinimide (II) by means of DCC gives the activated diester (III), which is condensed with N-(tert-butoxycarbonyl)-L-lysine (IV) by means of K2CO3, yielding the protected peptide (V). The selective deprotection of the epsilon amino groups of (V) by means of formic acid affords the dimeric peptide (VI), which is cleaved with dithiothreitol (DTT) to provide benzyloxycarbonyl-L-homocysteinyl-L-lysine (VII). The oxidation of (VII) with L-lysine epsilon aminotransferase (S. paucimobili or rec. E. coli) furnishes the formyl derivative (VIII), which is finally cyclized in acid medium to afford, through the nonisolated intermediate (IX), the target pyrido[2,1-b][1,3]thiazepine intermediate (X).
| 【1】 Patel, R.N.; Enzymatic synthesis of chiral intermediates for omapatrilat, an antihypertensive drug. Biomol Eng 2001, 17, 6, 167. |
| 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) | 50614 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-[((3S)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl)disulfanyl]butyric acid | C24H28N2O8S2 | 详情 | 详情 | |
| (II) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (III) | 50618 | benzyl (1S)-3-([(3S)-3-[[(benzyloxy)carbonyl]amino]-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-4-oxobutyl]disulfanyl)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]propylcarbamate | C32H34N4O12S2 | 详情 | 详情 | |
| (IV) | 50619 | N(epsilon)-Boc-L-lysine | C11H22N2O4 | 详情 | 详情 | |
| (V) | 50620 | (10S,13S,20S,23S)-13,20-bis[[(benzyloxy)carbonyl]amino]-23-[4-[(tert-butoxycarbonyl)amino]butyl]-10-carboxy-2,2-dimethyl-4,12,21-trioxo-3-oxa-16,17-dithia-5,11,22-triazatetracosan-24-oic acid | C46H68N6O14S2 | 详情 | 详情 | |
| (VI) | 50621 | (5S,12S,15S)-15-(4-aminobutyl)-5-([[(1S)-5-amino-1-carboxypentyl]amino]carbonyl)-12-[[(benzyloxy)carbonyl]amino]-3,13-dioxo-1-phenyl-2-oxa-8,9-dithia-4,14-diazahexadecan-16-oic acid | C36H52N6O10S2 | 详情 | 详情 | |
| (VII) | 50622 | (2S)-6-amino-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-sulfanylbutanoyl)amino]hexanoic acid | C18H27N3O5S | 详情 | 详情 | |
| (VIII) | 50623 | (2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-sulfanylbutanoyl)amino]-6-oxohexanoic acid | C18H24N2O6S | 详情 | 详情 | |
| (IX) | 50624 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-sulfanylbutanoyl)-6-hydroxy-2-piperidinecarboxylic acid | C18H24N2O6S | 详情 | 详情 | |
| (X) | 50617 | (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid | C18H22N2O5S | 详情 | 详情 |