|
【结 构 式】 
|
【分子编号】11360 【品名】(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine 【CA登记号】82717-96-2 |
【 分 子 式 】C15H21NO4 【 分 子 量 】279.33608 【元素组成】C 64.5% H 7.58% N 5.01% O 22.91% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of 1-cyclopentenylpyrrolidino (I) with methyl 2-acetylamino-3-chloropropionate (II) in DMF gives methyl 2-acetylamino-3-(2-oxocyclopentyl)propionate (III), which is cyclized in refluxing concentrated HCl and reduced with H2 over Pd/C in acetic acid yielding cis,endo-2-azabicyclo[3.3.0]octan-3-carboxylic acid (IV). Esterification of (IV) with SOCl2 and benzyl alcohol affords the corresponding benzyl ester (V), which is condensed with N-(1-ethoxycarbonyl-3-phenylpropyl)alanine (VI) by means of dicyclohexylcarbodiirnide (DCC) in DMF affording benzyl N-(1-ethoxycarbonyl-3-phenylpropyl)alanyl-cis,endo-2-azabicyclo[3.3.0]octan-3-carboxylate (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Teetz, V.; et al. (Aventis Pharma AG); Method for making 2-azabicyclo[3.3.0]octane-3-carboxylic acids. DE 3226768; EP 0079022; EP 0150263; JP 2104526; JP 2104573; JP 4217949; US 4727160; US 5053519 . |
| 【2】 Mannhold, R.; Serradell, M.N.; Castaner, J.; Ramipril. Drugs Fut 1985, 10, 5, 400. |
| 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) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (I) | 29359 | 1-(1-cyclopenten-1-yl)pyrrolidine | 7148-07-4 | C9H15N | 详情 | 详情 |
| (II) | 29360 | methyl (2S)-2-(acetamido)-3-chloropropanoate | C6H10ClNO3 | 详情 | 详情 | |
| (III) | 29361 | methyl (2R)-2-(acetamido)-3-(2-oxocyclopentyl)propanoate | C11H17NO4 | 详情 | 详情 | |
| (IV) | 29362 | (2S,3aS,6aS)octahydrocyclopenta[b]pyrrole-2-carboxylic acid | C8H13NO2 | 详情 | 详情 | |
| (V) | 29363 | benzyl (2S,3aS,6aS)octahydrocyclopenta[b]pyrrole-2-carboxylate | 93779-31-8 | C15H19NO2 | 详情 | 详情 |
| (VI) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (VII) | 29364 | benzyl (2S,3aS,6aS)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate | C30H38N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The esterification of (3aR,7aS)-octahydroindole-2(S)-carboxylic acid (I) with benzyl alcohol (II) by means of SOCl2 gives the corresponding benzyl ester (III), which is condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) by means of 1-hydroxybenzotriazole, N-ethylmorpholine and dicyclohexylcarbodiimide (DCC) in DMF giving the benzyl ester (V) of the desired product. Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Ubach, H.; Henning, R.; Teetz, V.; Geiger, R.; Becker, R.; Gaul, H. (Aventis SA); Novel bicyclic amino acid derivs., process for their preparation and their use , as well as bicyclic amino acids as intermediates and process for their preparation. DE 3151690; EP 0084164; EP 0170775; JP 1989301659; JP 1989301695 . |
| 【2】 Prous, J.; Castaner, J.; TRANDOLAPRIL < Rec INN >. Drugs Fut 1989, 14, 8, 778. |
| 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) | 19512 | (2S,3aR,7aS)octahydro-1H-indole-2-carboxylic acid | 145438-94-4 | C9H15NO2 | 详情 | 详情 |
| (II) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (III) | 19514 | benzyl (2S,3aR,7aS)octahydro-1H-indole-2-carboxylate | 144540-71-6 | C16H21NO2 | 详情 | 详情 |
| (IV) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (V) | 19516 | benzyl (2S,3aR,7aS)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)octahydro-1H-indole-2-carboxylate | 98677-37-3 | C31H40N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)A new synthesis of spirapril has been described: The cyclization of N-benzyloxycarbonyl-4-oxo-(S)-proline (I) with ethanedithiol by means of boron trifluoride ethearate in glacial acetic acid gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (II), which is deprotected with HBr in acetic acid to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (III). This compound is then condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) by means of N-hydroxysuccinimide (NOS) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (DMCC) in DMF, or by means of N,N-disuccinimidyl carbonate and pyridine.
| 【1】 Swiss, G.F.; Neustadt, B.R.; McNamara, P.; Baum, T.; Smith, E.M.; Gold, E.H.; Sybertz, E.J.; Angiotensin converting enzyme inhibitors: Spirapril and related. J Med Chem 1989, 32, 7, 1600-6. |
| 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) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (II) | 11358 | (8S)-7-[(Benzyloxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C15H17NO4S2 | 详情 | 详情 | |
| (III) | 11359 | (8S)-1,4-Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C7H11NO2S2 | 详情 | 详情 | |
| (IV) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)A new synthesis of spirapril has been reported: The cyclization of N-benzyloxycarbonyl-4-oxo-(S)-proline (I) with ethandithiol by means of boron trifluoride ethearate in dichloromethane gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (II), which is treated with concentrated HCl to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (III). The protection of (III) with tert-butoxycarbonyl chloride and with trimethylsilylethanol in the usual manner affords N-(tert-butoxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxyli c acid 2-(trimethylsilyl)ethyl ester (IV), which is condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (V) by a first treatment with p-toluenesulfonic acid and a condensation step with dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HBT), giving spirapril 2-(trimethylsilyl)ethyl ester (VI). Finally, this ester is hydrolyzed with tetrabutylammonium fluoride trihydrate in DMF.
| 【1】 Powell, J.R.; Cushman, D.W.; Krapcho, J.; Turk, C.; DeForrest, J.M.; Spitzmiller, E.R.; Karanewsky, D.S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; et al.; Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines. J Med Chem 1988, 31, 6, 1148. |
| 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) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (II) | 11358 | (8S)-7-[(Benzyloxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C15H17NO4S2 | 详情 | 详情 | |
| (III) | 11359 | (8S)-1,4-Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C7H11NO2S2 | 详情 | 详情 | |
| (IV) | 11364 | 7-(tert-butyl) 8-[2-(trimethylsilyl)ethyl] (8S)-1,4-dithia-7-azaspiro[4.4]nonane-7,8-dicarboxylate | C17H31NO4S2Si | 详情 | 详情 | |
| (V) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (VI) | 11366 | 2-(trimethylsilyl)ethyl (8S)-7-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C27H42N2O5S2Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)The condensation of (IX) with alanine benzyl ester (X) with sodium cyanoboohydride as before gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (XI), which is submitted to fractional crystallization with maleic acid yielding N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine benzyl ester (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol yielding the free acid (XIII). Finally, this compound is condensed with spirane (IV) through the N-hydroxysuccinimide ester, in the usual way.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 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) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
| (X) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XI) | 27321 | ethyl 2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XIII) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XV)This compound can be obtained by two related ways: 1) The condensation of 2-O-(p-toluenesulfonyl)-D-lactoyl chloride (IV) with 1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (VIII) by means of potassium tert-butoxide in THF gives 1-methyl-2-oxo-3-[2(R)-(p-toluenesulfonyloxy)propionyl]imidazolidine-4(S)-carboxylic acid tert-butyl ester (IX), which is then condensed with 2(S)-amino-4-phenylbutyric acid ethyl ester (X) by means of triethylamine in DMSO yielding 3-[N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (XI). Finally, this compound is hydrolyzed with HCl in dioxane - water. The starting compounds (IV) and (VIII) are obtained as follows: a) The condensation of D-lactic acid methyl ester with p-toluenesulfonyl chloride and triethylamine gives the corresponding sulfonate (II), which is hydrolyzed with NaOH to the free acid (III). Finally, this compound is treated with refluxing SOCl2 to give acid chloride (IV). b) The esterification of 3-(benzyloxycarbonyl)-2-oxoimidazolidine-4(S)-carboxylic acid (V) with tert-butanol gives the corresponding ester (VI), which is methylated with methyl iodide and K2CO3 to 3-(benzyloxycarbonyl)-1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (VII). This compound is debenzylated by hydrogenation with H2 over Pd/C to afford imidazolidine ester (VIII). 2) The condensation of 2(S)-bromo-4-phenylbutyric acid ethyl ester (XII) with L-alanine benzyl ester (XIII) by means of K2CO3 in DMSO gives N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine benzyl ester (XIV), which is debenzylated by hydrogenation as before yielding the free acid (XV). The esterification of (XV) with N-hydroxysuccinimide gives the corresponding active ester (XVI), which is finally condensed with imidazolidine ester (VIII) by means of potassium tert-butoxide to afford the precursor (XI) already obtained.
| 【1】 Yoneda, N.; Kato, S.; Hayashi, K.; Ochiai, K. (Tanabe Seiyaku Co., Ltd.); Agents for the treatment of hypertension. JP 1985013715 . |
| 【2】 Yoneda, N.; Kato, J.; Hayashi, K.; Ochiani, T.; Kinashi, K. (Tanabe Seiyaku Co., Ltd.); Quinolinecarboxylic acid derivs. and method for their preparation. EP 0095163; ES 8603427; US 4508727 . |
| 【3】 Hayashi, K.; Kubota, H. (Tanabe Seiyaku Co., Ltd.); Process for preparing optically active 2-oxoimidazolidine derivs. EP 0373881 . |
| 【4】 Kato, J.; Hayashi, K.; Ishida, R.; Yoneda, N.; Ochiai, T.; Kubo, M.; Nunami, K.-I.; Studies on angiotensin converting enzyme inhibitors. 4. Synthesis and angiotensin converting enzyme inhibitory activities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acid derivatives. J Med Chem 1989, 32, 2, 289. |
| 【5】 Hayashi, K.; Kubota, H.; Yamagishi, M.; Nunami, K.-I.; Nishimoto, S.; Studies on angiotensin converting enzyme inhibitors. V. The diastereoselective synthesis of 2-oxoimidazolidine derivatives. Chem Pharm Bull 1991, 39, 6, 1374. |
| 【6】 Prous, J.; Castaner, J.; Imidapril Hydrochloride. Drugs Fut 1992, 17, 7, 551. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 | |
| (I) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
| (II) | 15653 | Methyl (2S)-2-{[(4-methylphenyl)sulfonyl]oxy}propanoate | C11H14O5S | 详情 | 详情 | |
| (III) | 15654 | (2R)-2-[[(4-methylphenyl)sulfonyl]oxy]propionic acid | C10H12O5S | 详情 | 详情 | |
| (IV) | 15655 | (1R)-2-chloro-1-methyl-2-oxoethyl 4-methylbenzenesulfonate | C10H11ClO4S | 详情 | 详情 | |
| (V) | 15656 | (4S)-3-[(benzyloxy)carbonyl]-2-oxotetrahydro-1H-imidazole-4-carboxylic acid | C12H12N2O5 | 详情 | 详情 | |
| (VI) | 15657 | 1-benzyl 5-(tert-butyl) (5S)-2-oxotetrahydro-1H-imidazole-1,5-dicarboxylate | C16H20N2O5 | 详情 | 详情 | |
| (VII) | 15658 | 1-benzyl 5-(tert-butyl) (5S)-3-methyl-2-oxotetrahydro-1H-imidazole-1,5-dicarboxylate | C17H22N2O5 | 详情 | 详情 | |
| (VIII) | 15659 | tert-butyl (4S)-1-methyl-2-oxotetrahydro-1H-imidazole-4-carboxylate | C9H16N2O3 | 详情 | 详情 | |
| (IX) | 15660 | tert-butyl (4S)-1-methyl-3-((2R)-2-[(4-methylphenyl)sulfonyl]propanoyl)-2-oxotetrahydro-1H-imidazole-4-carboxylate | C19H26N2O7S | 详情 | 详情 | |
| (X) | 15661 | ethyl (2S)-2-amino-4-phenylbutanoate | C12H17NO2 | 详情 | 详情 | |
| (XI) | 15662 | tert-butyl (4S)-3-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1-methyl-2-oxotetrahydro-1H-imidazole-4-carboxylate | C24H35N3O6 | 详情 | 详情 | |
| (XII) | 15663 | ethyl (2S)-2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (XIII) | 10898 | benzyl (2R)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XIV) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XV) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (XVI) | 15667 | ethyl (2S)-2-([(1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate | C19H24N2O6 | 详情 | 详情 |