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【结 构 式】 
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【分子编号】22495 【品名】3-aminodihydro-2(3H)-thiophenone 【CA登记号】10593-85-8 |
【 分 子 式 】C4H7NOS 【 分 子 量 】117.17172 【元素组成】C 41% H 6.02% N 11.95% O 13.65% S 27.37% |
合成路线1
该中间体在本合成路线中的序号：(I)Erdosteine (III) can be obtained in a two-step synthesis starting from homocysteine thiolactone (I). (I) is acylated in chloroform with chloroacetyl chloride (A) to the amide (II). Subsequent reaction with thioglycolic acid (B) gives rise to (III).
| 【1】 Gobetti, M.; Pedrazzoli, A.; Bradamante, S.; DL-S-[2-[N-3-(2-Oxotetrahydrothienyl)acetamido]]-thioglycolic acid: A novel mucolytic agent of the class of homocysteine thiolactone derivatives. Farm Sci Ed 1986, 41, 1, 69-79. |
| 【2】 Fregnan, G.B.; Pappalardo, M.; ERDOSTEINE < Rec INN >. Drugs Fut 1990, 15, 9, 887. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (B) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
| (I) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
| (II) | 31177 | 2-chloro-N-(2-oxotetrahydro-3-thiophenyl)acetamide | 84611-22-3 | C6H8ClNO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Triethylamine is added to thiolactic acid (I) and 2-thiophencarbonyl chloride (II) in tetrahydrofuran. Mix is cooled at -5 C under agitation and thionyl chloride is added keeping the temperature between 0 and 10 C. A solution of homocysteine thiolactone hydrochloride and triethylamine in water is then added to the reaction, keeping the temperature below 10 C. The reaction is carried out for 1 h at room temperature under agitation, after which the solvent is evaporated at reduced pressure. Water is used to wash and diethyl ether to extract. The organic phase is dried on Na2SO4 anhydrous and the solvent is eliminated at reduced pressure. The raw product obtained from a mix of dichloromethane/diethyl ether (60/40) is crystallized (MR-889).
| 【1】 Quadro, G.; MR-889. Drugs Fut 1990, 15, 10, 997. |
| 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) | 24361 | 2-sulfanylpropionic acid; 2-mercaptopropionic acid | 57965-30-7 | C3H6O2S | 详情 | 详情 |
| (II) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (III) | 31190 | 2-[(2-thienylcarbonyl)sulfanyl]propionic acid | C8H8O3S2 | 详情 | 详情 | |
| (IV) | 31191 | S-(2-chloro-1-methyl-2-oxoethyl) 2-thiophenecarbothioate | C8H7ClO2S2 | 详情 | 详情 | |
| (V) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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 |