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【结 构 式】 
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【分子编号】22504 【品名】methyl (2S)-2-amino-6,6-dimethoxyhexanoate 【CA登记号】 |
【 分 子 式 】C9H19NO4 【 分 子 量 】205.2542 【元素组成】C 52.67% H 9.33% N 6.82% O 31.18% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)3) The condensation of 2(S)-phthalimido-4-(triphenylmethoxy)butyric acid (XVII) with 2(S)-amino-6,6-dimethoxyhexanoic acid methyl ester (XVIII) by means of BOP in methylene chloride gives the corresponding amide (XIX), which is treated with p-toluenesulfonic acid in methanol to eliminate the trityl group, yielding (XX) with a free hydroxy group. The reaction of (XX) with thioacetic acid by means of triphenylphosphine/diisopropyl azidodicarboxylate in THF affords the thioacetate (XXI), which is cyclized with sodium methoxide in methanol as before, giving the protected pyridothiazepinone (XXII). Finally, this compound is deprotected with hydrazine in methanol to afford the previously reported intermediate (VI). 4) The intermediates 2(S)-phthalimido-4-(triphenylmethoxy)butyric acid (XVII) and 2(S)-amino-6,6-dimethoxyhexanoic acid methyl ester (XVIII) have been obtained as follows: 4a) The condensation of L-homoserine (XXIII) with phthalimide-N-carboxylic acid ethyl ester (XXIV) by means of Na2CO3 in water gives 4-hydroxy-2(S)-phthalimidobutyric acid (XXV), which is then treated with trityl chloride and triethylamine in chloroform to yield intermediate (XVII). 4b) The condensation of 6-hydroxy-L-norleucine (XVI) with phthalimide (XXIV) as before gives 6-hydroxy-2(S)-phthalimidohexanoic acid (XXVI), which is esterified with methyl iodide/Cs2CO3 in DMF to yield the methyl ester (XXVII). The oxidation of (XXVII) with oxalyl chloride in dichloromethane affords aldehyde (XXVIII), which is treated with trimethyl orthoformate/p-toluenesulfonic acid to give the dimethylketal (XXIX). Finally, this compound is deprotected with hydrazine in methanol, yielding intermediate (XVIII).
| 【1】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269. |
| 【2】 Robl, J.A.; Kronenthal, D.R.; Goderey, J.D. Jr. (Bristol-Myers Squibb Co.); Bicyclic carboxylic acids and their derivs. as NEP and ACE inhibitors. EP 0629627; JP 1995048259; US 5508272 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 22492 | methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C11H18N2O3S | 详情 | 详情 | |
| (XVI) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
| (XVII) | 22503 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(trityloxy)butyric acid | C31H25NO5 | 详情 | 详情 | |
| (XVIII) | 22504 | methyl (2S)-2-amino-6,6-dimethoxyhexanoate | C9H19NO4 | 详情 | 详情 | |
| (XIX) | 22505 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(trityloxy)butanoyl]amino]-6,6-dimethoxyhexanoate | C40H42N2O8 | 详情 | 详情 | |
| (XX) | 22506 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-hydroxybutanoyl]amino]-6,6-dimethoxyhexanoate | C21H28N2O8 | 详情 | 详情 | |
| (XXI) | 22507 | methyl (2S)-2-[[(2S)-4-(acetylsulfanyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanoyl]amino]-6,6-dimethoxyhexanoate | C23H30N2O8S | 详情 | 详情 | |
| (XXII) | 22508 | methyl (4S,7S,10aS)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C19H20N2O5S | 详情 | 详情 | |
| (XXIII) | 22509 | (2S)-2-amino-4-hydroxybutyric acid | 672-15-1 | C4H9NO3 | 详情 | 详情 |
| (XXIV) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (XXV) | 22511 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-hydroxybutyric acid | C12H11NO5 | 详情 | 详情 | |
| (XXVI) | 22512 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid | C14H15NO5 | 详情 | 详情 | |
| (XXVII) | 22513 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate | C15H17NO5 | 详情 | 详情 | |
| (XXVIII) | 22514 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate | C15H15NO5 | 详情 | 详情 | |
| (XXIX) | 22515 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6,6-dimethoxyhexanoate | C17H21NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |