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【结 构 式】 
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【分子编号】14643 【品名】L-cysteine; (R)-2-Amino-3-mercaptopropionic acid 【CA登记号】52-90-4 |
【 分 子 式 】C3H7NO2S 【 分 子 量 】121.16012 【元素组成】C 29.74% H 5.82% N 11.56% O 26.41% S 26.47% |
合成路线1
该中间体在本合成路线中的序号：(I)The cyclization of pyridine-3-carbaldehyde (II) with L-cysteine (I) in ethanol gives the thiazolidine derivative (III), which is treated with formic acid yielding the 3-formylthiazolidine derivative (IV). The cyclization of (IV) with 2-chloropropenenitrile (V) by means of acetic anhydride affords 3-(3-pyridil)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile (VI), which is finally hydrolyzed to the target carboxamide by means of KOH in tert-butanol.
| 【1】 Fabre, J.-L.; Farge, D.; James, C.; Lavé, D. (Aventis SA); Novel 1H,3H-pyrrolo[1,2-c]thiazole derivs., their preparation and medicaments containing them. EP 0115979; US 4529728 . |
| 【2】 Lavé, D.; James, C.; Rajoharison, H.; Bost, P.E.; Cavero, I.; PYRROLO[1,2-c]THIAZOLE DERIVATIVES: POTENT PAF RECEPTOR ANTAGONISTS. Drugs Fut 1989, 14, 9, 891. |
| 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) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 43711 | (4R)-3-formyl-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C10H10N2O3S | 详情 | 详情 | |
| (V) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (VI) | 43712 | 3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carbonitrile | C12H9N3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The alkylation of ethyl 1,3-dithiane-2-carboxylate (I) with 1,5-dibromopentane (II) by means of NaH in DMF gives ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate (III), which is treated with NBS in acetonitrile water to open the dithiane ring yielding ethyl 7-bromo-2-oxoheptanoate (IV). Hydrolysis of the ester group of (IV) with 50% HBr affords 7-bromo-2-oxoheptanoic acid (V), which is condensed with 2,2-dimethylcyclopropanecarboxamide (VI) in refluxing toluene giving 7-bromo-2-(2,2-dimethycyclopropanecarboxamido)-2-octenoic acid (VII). Finally, this compound is condensed with L-cysteine (VIII) by means of NaOH in water.
| 【1】 Graham, D.W.; Rogers, E.F.; Kahan, F.M. (Merck & Co., Inc.); 2-(Cyclopropanecarboxamido)-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same a thiennamycin-type compound. EP 0048301 . |
| 【2】 Castaner, J.; Serradell, M.N.; Cilastatin. Drugs Fut 1984, 9, 5, 320. |
| 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) | 30559 | ethyl 1,3-dithiane-2-carboxylate | 20462-00-4 | C7H12O2S2 | 详情 | 详情 |
| (II) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
| (III) | 30561 | ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate | C12H21BrO2S2 | 详情 | 详情 | |
| (IV) | 30562 | ethyl 7-bromo-2-oxoheptanoate | C9H15BrO3 | 详情 | 详情 | |
| (V) | 30563 | 7-bromo-2-oxoheptanoic acid | C7H11BrO3 | 详情 | 详情 | |
| (VI) | 30564 | 2,2-dimethylcyclopropanecarboxamide | C6H11NO | 详情 | 详情 | |
| (VII) | 30565 | (Z)-7-bromo-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid | C13H20BrNO3 | 详情 | 详情 | |
| (VIII) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation of 7-chloro-2-oxoheptanoic acid ethyl ester (I) with (S)-2,2-dimethylcyclopropanecarboxamide (II) by means of TsOH in refluxing toluene gives (S)-7-chloro-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (III), which is hydrolyzed in aq. NaOH to yield the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R)-cysteine (V) by means of NaOH in water to afford the target Cilastatino.
| 【1】 Tyagi, O.D.; Kumar, Y.; Srivastava, T.K. (Ranbaxy Laboratories Ltd.); Process for the preparation of cilastatin. WO 03018544 . |
| 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) | 61845 | propyl 7-chloro-2-oxoheptanoate | C10H17ClO3 | 详情 | 详情 | |
| (II) | 61846 | (1S)-2,2-dimethylcyclopropanecarboxamide | C6H11NO | 详情 | 详情 | |
| (III) | 61847 | propyl (Z)-7-chloro-2-({[(1S)-2,2-dimethylcyclopropyl]carbonyl}amino)-2-heptenoate | C16H26ClNO3 | 详情 | 详情 | |
| (IV) | 61848 | (Z)-7-chloro-2-({[(1S)-2,2-dimethylcyclopropyl]carbonyl}amino)-2-heptenoic acid | C13H20ClNO3 | 详情 | 详情 | |
| (V) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 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 cyclization of pyridine-3-carbaldehyde (II) with L-cysteine (I) in ethanol gives the thiazolidine derivative (III), which is treated with formic acid, yielding a diastereomeric mixture of formyl derivatives from which the desired (2R,4R)-(IV) is isolated by crystallization. The cyclization of (2R,4R)-(IV) with ethyl 2,3-dichloropropionate (V) by means of TsCl and Et3N affords (2R)-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid ethyl ester (VI), which is hydrolyzed with NaOH to the corresponding free acid (VII). Finally, this compound is condensed with 3-aminobenzophenone (VIII) by means of SOCl2 to provide the target amide.
| 【1】 (Aventis SA); 1H,3H-pyrrolo[1,2-c]thiazole derivs.. EP 0253711; FR 2601015; JP 1988022589 . |
| 【2】 Rajoharison, H.G. (Aventis Pharma SA); Process for the preparation of dextrorotatory 3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]-7-thiazolecarboxylic acid. EP 0297987; US 4906757 . |
| 【3】 Lavé, D.; James, C.; Rajoharison, H.; Bost, P.E.; Cavero, I.; PYRROLO[1,2-c]THIAZOLE DERIVATIVES: POTENT PAF RECEPTOR ANTAGONISTS. Drugs Fut 1989, 14, 9, 891. |
| 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) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 43713 | (2R,4R)-3-formyl-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C10H10N2O3S | 详情 | 详情 | |
| (V) | 43714 | ethyl 2,3-dichloropropanoate | 6628-21-3 | C5H8Cl2O2 | 详情 | 详情 |
| (VI) | 43715 | ethyl (3R)-3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carboxylate | C14H14N2O2S | 详情 | 详情 | |
| (VII) | 43716 | (3R)-3-(3-pyridinyl)-1H-pyrrolo[1,2-c][1,3]thiazole-7-carboxylic acid | C12H10N2O2S | 详情 | 详情 | |
| (VIII) | 39112 | 3-Aminobenzophenone; (3-aminophenyl)(phenyl)methanone | 2835-78-1 | C13H11NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Fudosteine has been obtained by two similar ways: 1) By condensation of L-cysteine (I) with 3-bromopropyl alcohol (II) by means of NaOH in water at room temperature. 2) By condensation of L-cysteine (I) with allyl alcohol (III) by means of potassium persulfate in water.
| 【1】 Castaner, J.; Leeson, P.; Wroblewski, T.; Fudosteine. Drugs Fut 1998, 23, 4, 374. |
| 【2】 Barnsley, E.A.; The formation of 2-hydroxypropylmercapturic acid from 1-halogenopropanes in the rat. Biochem J 1996, 100, 362-72. |
| 【3】 Itoh, Y.; Mizuno, H.; Kiyohara, C.; Sato, S.; Katori, T. (SSP Co., Ltd.); Expectorant comprising hydroxy-alkylcysteine deriv. EP 0346882; EP 0346883; JP 1990003674; US 4906665 . |
| 【4】 Ito, Y.; Kuriyama, T.; Ogawa, M.; Sato, S.; Kuraishi, T. (SSP Co., Ltd.); Preparation method of S-hydroxypropyl-L-cysteine. JP 1996119932 . |
合成路线6
该中间体在本合成路线中的序号：(V)The esterification of 3-(benzoylsulfanyl)-2(S)-methylpropionic acid with 4-nitrophenol (II) by means of DCC in dichloromethane gives the corresponding ester (III), which is condensed with S-(4-cyclohexylbenzyl)-L-cysteine (IV) (obtained by alkylation of L-cysteine (V) with 4-cyclohexylbenzyl bromide (VI)) to yield the corresponding amide (VII). Finally, this compound is debenzoylated by a treatment with aqueous NH4OH.
| 【1】 Horiuchi, M.; Fujimura, K.; Suhara, H. (Santen Pharmaceutical Co., Ltd.); Novel sulfur-containing amino acid derivs.. EP 0947502; JP 1998130225; US 6046235; WO 9809943 . |
| 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) | 35379 | (2S)-3-(benzoylsulfanyl)-2-methylpropionic acid | C11H12O3S | 详情 | 详情 | |
| (II) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (III) | 35380 | 4-nitrophenyl (2S)-3-(benzoylsulfanyl)-2-methylpropanoate | C17H15NO5S | 详情 | 详情 | |
| (IV) | 35381 | (2R)-2-amino-3-[(4-cyclohexylbenzyl)sulfanyl]propionic acid | C16H23NO2S | 详情 | 详情 | |
| (V) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
| (VI) | 35382 | 1-(bromomethyl)-4-cyclohexylbenzene | C13H17Br | 详情 | 详情 | |
| (VII) | 35383 | (2R)-2-[[(2S)-3-(benzoylsulfanyl)-2-methylpropanoyl]amino]-3-[(4-cyclohexylbenzyl)sulfanyl]propionic acid | C27H33NO4S2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Alkylation of L-cysteine (I) with cyclopentylmethyl methanesulfonate (II) produced the cysteine thioether (III). A tert-butoxycarbonyl group was subsequently introduced into the amino group of (III) by using di-tert-butyl dicarbonate and NaOH. The resultant N-Boc-cysteine thioether (V) was finally coupled with p-methoxybenzylamine (VI) by means of EDC and HOBt to furnish the corresponding amide.
| 【1】 Seko, T.; et al.; Structure-activity study and analgesic efficacy of amino acid derivatives as N-type calcium channel blockers. Bioorg Med Chem Lett 2001, 11, 16, 2067. |
| 【2】 Seko, T.; Kato, M. (Ono Pharmaceutical Co., Ltd.); Amino acid derivs.. EP 0997147; WO 9902146 . |
| 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) | 14643 | L-cysteine; (R)-2-Amino-3-mercaptopropionic acid | 52-90-4 | C3H7NO2S | 详情 | 详情 |
| (II) | 51117 | cyclopentylmethyl methanesulfonate | C7H14O3S | 详情 | 详情 | |
| (III) | 51118 | (2R)-2-amino-3-[(cyclopentylmethyl)sulfanyl]propionic acid | C9H17NO2S | 详情 | 详情 | |
| (IV) | 51119 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-[(cyclopentylmethyl)sulfanyl]propionic acid | C14H25NO4S | 详情 | 详情 | |
| (V) | 15908 | 3-methoxy-2,6-dimethyl-4(1H)-pyridinone | C8H11NO2 | 详情 | 详情 |