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【结 构 式】

【分子编号】32151

【品名】(2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid

【CA登记号】13485-59-1

【 分 子 式 】C8H14N2O3

【 分 子 量 】186.21084

【元素组成】C 51.6% H 7.58% N 15.04% O 25.78%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(II)

by reductocondensation of 4-phenyl-2-oxo butyric acid (IX) with L-alanyl-L-proline (IV) by means of sodium cyanoborohydride and NaOH in water.

1 Wyvratt, M.J.; Harris, E.E.; Patchett, A.A.; Tristram, E.W. (Merck & Co., Inc.); Carboxyalkyl dipeptide derivs., process for preparing them and pharmaceutical compsn. containing them. EP 0012401 .
2 Tristram, E.W.; Patchett, A.A.; Harris, E.E.; Wyvratt, M.J. (Merck & Co., Inc.); Amino acid derivs. as antihypertensives. US 4472380 .
3 Prous, J.; Castaner, J.; Enalaprilat. Drugs Fut 1986, 11, 8, 647.
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) 23959 2-oxo-4-phenylbutyric acid C10H10O3 详情 详情
(II) 32151 (2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid 13485-59-1 C8H14N2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

Treatment of alanine (I) with phosgene in THF provides N-carboxyanhydride derivative (II), which is then coupled to proline (III) by means of KOH and K2CO3 in THF/H2O or acetonitrile to provide dipeptide (IV). Coupling of (IV) to ethyl 2-oxo-4-phenylbutyrate (V) by means of H2 over Raney-Ni in EtOH (or EtOH/HOAc), followed by the corresponding work-up for isomer separation, yields derivative (VI). (In turn, ketoester (V) can be obtained by treatment of 2-phenylethyl bromide (VII) with Mg turnings in refluxing THF, followed by reaction of the resulting Grignard reagent with diethyl oxalate (VIII) in THF). Finally, the desired product is obtained by saponification of the ethyl ester group of (VI) with NaOH.

1 Blacklock, T.J.; et al.; Synthesis of semisynthetic dipeptides using N-carboxyanhydrides and chiral induction on Raney nickel. A method practical for large scale. J Org Chem 1988, 53, 4, 836.
2 Reider, P.J.; Huffman, M.A.; Leblond, C.; Sun, Y. (Merck & Co., Inc.); Improved stereoselective process for enalapril. WO 0017228 .
3 Blacklock, T.J.; Shuman, R.F. (Merck & Co., Inc.); Process for preparing polypeptides. US 4510083 .
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) 50831 L-Alanine; L-2-Aminopropionic acid; (S)-(+)-2-Aminopropionic acid; L-2-Aminopropionic acid; (S)-2-Aminopropionic acid; (S)-(+)-Alanine 56-41-7 C3H7NO2 详情 详情
(II) 50829 (4S)-4-methyl-1,3-oxazolidine-2,5-dione; S-Alanine-N-carboxylic acid anhydride 2224-52-4 C4H5NO3 详情 详情
(III) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(IV) 32151 (2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid 13485-59-1 C8H14N2O3 详情 详情
(V) 50832 ethyl 2-oxo-4-phenylbutanoate C12H14O3 详情 详情
(VI) 50830 (2S)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-2-pyrrolidinecarboxylic acid C20H28N2O5 详情 详情
(VII) 20730 1-(2-bromoethyl)benzene;1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 103-63-9 C8H9Br 详情 详情
(VIII) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情

合成路线3

该中间体在本合成路线中的序号:(II)

By reductocondensation of ethyl 2-oxo-4-phenylbutyrate (I) with alanylproline (II) by means of sodium cyanoborohydride or H2 over Raney-Ni or Pd/C in water.

1 Patchett, A.A.; et al.; A new class of angiotensin-converting anzyme inhibitors. Nature 1980, 288, 280-283.
2 Hopkins, S.J.; Serradell, M.N.; Blancafort, P.; Castaner, J.; Enalapril maleate. Drugs Fut 1982, 7, 8, 556.
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) 20896 Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester 64920-29-2 C12H14O3 详情 详情
(II) 32151 (2S)-1-[(2S)-2-aminopropanoyl]-2-pyrrolidinecarboxylic acid 13485-59-1 C8H14N2O3 详情 详情
Extended Information