(2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】31253

【品名】(2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide

【CA登记号】

【分子式】C₁₁H₁₇N₅O₂

【分子量】251.28848

【元素组成】C 52.58% H 6.82% N 27.87% O 12.73%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

The reduction of N-benzyloxycarbonylprolinamide (I) with H2 over Pd/c in methanol gives prolinamide (II), which is condensed with N-benzyloxycarbonylhistidyl hydrazide (III) by means of NaNO2 - HCl in ethyl acetate yielding N-benzyloxycarbonylhistidylprolinamide (IV), The hydrolysis of (IV) with HBr in acetic acid affords histidylprolinamide (V), which is finally condensed with gamma-carboxy-gamma-butyrolactone (VI) by means of pentachlorophenol and dicyclohexylcarbodiimide in DMF. Compound (VI) is prepared by reaction of alpha-aminoglutaric acid (VII) with NaNO2 and 2N H2SO4 in water.

参考文献中间体

合成目标

【1】 Fujino, M.; Nishimura, P.; Nagawa, Y.; Fukuda, N.; US 4100152 .
【2】 Bauce, L.G.; Goren, H.J.; Synthesis of a series of residue 1-(pyroglutamic acid) analogs of thyrotropin releasing hormone. Intl J Pept Protein Res 1979, 14, 3, 216-226.
【3】 Larsen, S.D.; Stephenson, G.A.; Bunnell, C.A.; Reutzel, S.M.; Nichols, J.R. (Eli Lilly and Company); Intermediates and process for preparing olanzapine. US 6020487 .

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)	37076	benzyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate		C₁₃H₁₆N₂O₃	详情	详情
(II)	37077	(2R)-2-pyrrolidinecarboxamide		C₅H₁₀N₂O	详情	详情
(III)	36138	benzyl (1S)-2-hydrazino-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate	49706-31-2	C₁₄H₁₇N₅O₃	详情	详情
(IV)	36139	benzyl (1S)-2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate		C₁₉H₂₃N₅O₄	详情	详情
(V)	31253	(2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide		C₁₁H₁₇N₅O₂	详情	详情
(VI)	37075	5-oxotetrahydro-2-furancarboxylic acid		C₅H₆O₄	详情	详情
(VII)	28752	DL-2-Amino propane dicarboxylic acid; DL-2-Aminopentanoic acid; glutamic acid; DL-glutamic acid; (+/-)-2-Aminoglutaric acid	617-65-2	C₅H₉NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The synthesis of thyrotropin releasing hormone (TRH) analogues is described as follows: The reduction of N-benzyloxycarbonylprolinamide (I) with H2 over Pd/C in methanol gives prolinamide (II), which is condensed with N-benzyloxy-carbonylhistidyl hydrazide (III) by means of NaNO2 - HCl in ethyl acetate yielding N-benzyloxycarbonylhistidylprolinamide (IV). The hydrolysis of (IV) with HBr in acetic acid affords histidylprolinamide (V), which is finally condensed with 6-methyl-5-oxothiomorpholinyl-3-carboxylic acid (VI) by means of 1-hydroxybenzotriazole, dicyclohexylcarbodiimide and triethylamine in DMF.

参考文献中间体

合成目标

【1】 US 4045556 .
【2】 Goren, H.J.; Bauce, L.G.; Synthesis of a series of residue 1-(pyroglutamic acid) analogs of thyrotropin releasing hormone. Intl J Pept Protein Res 1979, 14, 216-226.
【3】 Pento, J.T.; CG-3703. Drugs Fut 1983, 8, 12, 1007.

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)	36136	benzyl (2S)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate	34079-31-7	C₁₃H₁₆N₂O₃	详情	详情
(II)	36137	(2S)-2-pyrrolidinecarboxamide;L-prolinamide	7531-52-4	C₅H₁₀N₂O	详情	详情
(III)	36138	benzyl (1S)-2-hydrazino-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate	49706-31-2	C₁₄H₁₇N₅O₃	详情	详情
(IV)	36139	benzyl (1S)-2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate		C₁₉H₂₃N₅O₄	详情	详情
(V)	31253	(2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide		C₁₁H₁₇N₅O₂	详情	详情
(VI)	36140	(3R,6R)-6-methyl-5-oxo-3-thiomorpholinecarboxylic acid		C₆H₉NO₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The methylation of 4,5-dihydroorotic acid benzyl ester (I) with methyl iodide gives the corresponding 1-methyl derivative (II), which is debenzylated by hydrogenolysis with H2 over Pd/C yielding (S)-1-methyl-4,5-dihydroorotic acid (III). Finally, this compound is condensed with L-histidyl-L-prolinamide (IV) by means of dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (HONSU) in DMF.

参考文献中间体

合成目标

【1】 Sugano, H.; Ishida, R.; Yamamura, M. (Tanabe Seiyaku Co., Ltd.); Dihydroorotic acid derivs. and process for their preparation. JP 1986033197 .
【2】 Sugano, H.; Ishida, R.; Yamamura, M. (Tanabe Seiyaku Co., Ltd.); Dihydroorotic acid derivs., process for their preparing and pharmaceutical compsn. containing them. EP 0168042; ES 8705463; ES 8707738; ES 8800208; US 4665056 .
【3】 Sugano, H.; Ishida, R.; Yamamura, M. (Tanabe Seiyaku Co., Ltd.); Therapeutic agent for central nervous system disorders. JP 1987234029 .
【4】 Prous, J.; Castaner, J.; TA-0910. Drugs Fut 1991, 16, 2, 127.
【5】 Suzuki, M.; Sugano, H.; Matsumoto, K.; Yamamura, M.; Ishida, R.; Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety. J Med Chem 1990, 33, 8, 2130-37.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	31250	benzyl (4S)-2,6-dioxohexahydro-4-pyrimidinecarboxylate	C₁₂H₁₂N₂O₄	详情	详情
(II)	31251	benzyl (4S)-1-methyl-2,6-dioxohexahydro-4-pyrimidinecarboxylate	C₁₃H₁₄N₂O₄	详情	详情
(III)	31252	(4S)-1-methyl-2,6-dioxohexahydro-4-pyrimidinecarboxylic acid	C₆H₈N₂O₄	详情	详情
(IV)	31253	(2S)-1-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-pyrrolidinecarboxamide	C₁₁H₁₇N₅O₂	详情	详情

Extended Information