|
【结 构 式】 
|
【分子编号】22492 【品名】methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate 【CA登记号】 |
【 分 子 式 】C11H18N2O3S 【 分 子 量 】258.3416 【元素组成】C 51.14% H 7.02% N 10.84% O 18.58% S 12.41% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The condensation of S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) with 6-hydroxy-L-norleucine methyl ester (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and hydroxybenzotriazole (HOBT) in dichloromethane gives the corresponding dipeptide (III), which is oxidized with oxalyl chloride in dichloromethane, yielding the aldehyde (IV). The cyclization of (IV) by means of sodium methoxide and trifluoroacetic acid affords the perhydro-pyridothiazepinone (V), which is deprotected with trimethylsilyl iodide (TMS-I) in dichloromethane to give (VI) with a free amino group (1). The acylation of (VI) with 2(S)-(acetylsulfanyl)-3-phenylpropionic acid (VII) by means of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in dichloromethane yields the corresponding amide (VIII), which is finally deprotected with NaOH in methanol and treated with HCl. 2) The intermediates S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) and 6-hydroxy-L-norleucine (II) have been obtained as follows: 2a) The protection of 3-aminotetrahydrothiophen-2-one (IX) with N-(benzyloxycarbonyloxy)succinimide gives the expected carbamate (X), which is treated first with KOH and then with acetic anhydride, yielding S-acetyl-N-(benzyloxycarbonyl)-DL-homocysteine (XI). Finally, this compound is submitted to optical resolution with (S)-alpha-methylbenzylamine to afford intermediate (I). 2b) The alkylation of acetamidomalonic acid diethyl ester (XII) with 4-acetoxybutyl bromide (XIII) by means of NaH in DMF gives the alkylated ester (XIV), which by a decarboxylative saponification yields 6-acetoxy-DL-norleucine (XV). Optical resolution of (XV) by means of porcine kidney acylase/LiOH in water affords pure 6-hydroxy-L-norleucine (XVI), which is finally esterified with methanol/HCl to intermediate (II).
| 【1】 Robl, J.A.; Sun, C.-Q.; Stevenson, J.; et al.; Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1997, 40, 11, 1570. |
| 【2】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 | |
| (I) | 22487 | (2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butyric acid | C14H17NO5S | 详情 | 详情 | |
| (II) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (III) | 22489 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-hydroxyhexanoate | C21H30N2O7S | 详情 | 详情 | |
| (IV) | 22490 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-oxohexanoate | C21H28N2O7S | 详情 | 详情 | |
| (V) | 22491 | methyl (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C19H24N2O5S | 详情 | 详情 | |
| (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 | |
| (VII) | 22493 | (2S)-2-(acetylsulfanyl)-3-phenylpropionic acid | C11H12O3S | 详情 | 详情 | |
| (VIII) | 22494 | methyl (4S,7S,10aS)-4-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C22H28N2O5S2 | 详情 | 详情 | |
| (IX) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
| (X) | 22496 | benzyl 2-oxotetrahydro-3-thiophenylcarbamate | C12H13NO3S | 详情 | 详情 | |
| (XI) | 22497 | acetyl-N-[(benzyloxy)carbonyl]homocysteine | C14H17NO5S | 详情 | 详情 | |
| (XII) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (XIII) | 22499 | 4-bromobutyl acetate | C6H11BrO2 | 详情 | 详情 | |
| (XIV) | 22500 | diethyl 2-(acetamido)-2-[4-(acetoxy)butyl]malonate | C15H25NO7 | 详情 | 详情 | |
| (XV) | 22501 | 6-(acetoxy)norleucine | C8H15NO4 | 详情 | 详情 | |
| (XVI) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |