benzyl 3-aminopropanoate -Drug Synthesis Database

【结构式】

【分子编号】30194

【品名】benzyl 3-aminopropanoate

【CA登记号】27019-47-2

【分子式】C₁₀H₁₃NO₂

【分子量】179.21876

【元素组成】C 67.02% H 7.31% N 7.82% O 17.85%

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：(II)

The condensation of 1-methylpyrole-3-carboxylic acid (I) with beta-alanine benzyl ester (II) by means of diethyl phosphorocyanidate (PCA) in DMF gives the corresponding amide (III), which is debenzylated with H2 over Pd/C in THF yielding the substituted beta-alanine (IV). The cyclization of (IV) by means of polyphosphoric acid (PPA) at 100 C affords the pyrroloazepine (V), which is alkylated with 1-bromo-3-chloropropane (VI) and potassium tert-butoxide in THF giving the 3-chloropropyl derivative (VII). The condensation of (VII) with 1-(4-fluorophenyl)piperazine (VIII) by means of K2CO3 and NaI in refluxing acetonitrile yields the expected addition product (IX), which is selectively reduced at the 8-position with NaBH4 in ethanol affording the 8-hydroxy derivative (X) as a racemic mixture. Finally, this compound is submitted to optical resolution by chiral chromatography providing the target chiral compound.

参考文献中间体

合成目标

【1】 Shibata, M.; Ogata, A.; Hayashi, Y.; Kamei, T.; Mizuno, A.; Shimamoto, T.; Takiguchi, C.; Inomata, N.; Nakanishi, K.; Oka, N.; Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds. Chem Pharm Bull 2000, 48, 5, 623.
【2】 Mizuno, A.; Shibata, M.; Iwamori, T.; Shimamoto, T.; Nakanishi, K.; Inomata, N. (Suntory Ltd.); Pyrroloazepine derivs.. EP 0807632; US 5962448; WO 9720845 .

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)	30193	1-methyl-1H-pyrrole-3-carboxylic acid		C₆H₇NO₂	详情	详情
(II)	30194	benzyl 3-aminopropanoate	27019-47-2	C₁₀H₁₃NO₂	详情	详情
(III)	30195	benzyl 3-[[(1-methyl-1H-pyrrol-3-yl)carbonyl]amino]propanoate		C₁₆H₁₈N₂O₃	详情	详情
(IV)	30196	N-[(1-methyl-1H-pyrrol-3-yl)carbonyl]-beta-alanine		C₉H₁₂N₂O₃	详情	详情
(V)	30197	1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione		C₉H₁₀N₂O₂	详情	详情
(VI)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(VII)	30198	5-(3-chloropropyl)-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione		C₁₂H₁₅ClN₂O₂	详情	详情
(VIII)	12143	1-(4-Fluorophenyl)piperazine	2252-63-3	C₁₀H₁₃FN₂	详情	详情
(IX)	30199	5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione		C₂₂H₂₇FN₄O₂	详情	详情
(X)	30200	5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-8-hydroxy-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one		C₂₂H₂₉FN₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Intermediate (VII) was coupled with beta-alanine benzyl ester (VIII) to give amide (IX). After hydrogenolysis of the benzyl ester of (IX), the acetate esters were removed by treatment with ammonia in MeOH, THF.

参考文献中间体

合成目标

【1】 Miyajima, K.; Nekado, T.; Ikeda, K.; Achiwa, K.; Synthesis of Tn, sialyl Tn and HIV-1-derived peptide antigen conjugates having a lipid A analog as an immunoadjuvant for synthetic vaccines. Chem Pharm Bull 1998, 46, 11, 1676.
【2】 Ikeda, K.; et al.; Lipid A and related compounds. XXXVII. Determination of favorable binding linkages of lipid A analog to antigen moiety for synthetic vaccines. Chem Pharm Bull 2000, 48, 1, 32.
【3】 Miyajima, K.; et al.; Synthesis of TN and sialyl TN antigen-lipid an analog conjugates for synthetic vaccines. Chem Pharm Bull 1997, 45, 9, 1544.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	41412	(2S)-3-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-3-[[(3R)-3-(tetradecanoyloxy)tetradecanoyl]amino]tetrahydro-2H-pyran-2-yl)oxy]-2-(tetradecanoylamino)propionic acid		C₅₇H₁₀₂N₂O₁₄	详情	详情
(VIII)	30194	benzyl 3-aminopropanoate	27019-47-2	C₁₀H₁₃NO₂	详情	详情
(IX)	41413	(1R)-1-[2-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-[[(2S)-3-[[3-(benzyloxy)-3-oxopropyl]amino]-3-oxo-2-(tetradecanoylamino)propyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate		C₆₇H₁₁₃N₃O₁₅	详情	详情
(X)	41414	N-[(2S)-3-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-3-[[(3R)-3-(tetradecanoyloxy)tetradecanoyl]amino]tetrahydro-2H-pyran-2-yl)oxy]-2-(tetradecanoylamino)propanoyl]-beta-alanine		C₆₀H₁₀₇N₃O₁₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Treatment of methyl pyrrole-2-carboxylate (I) with KOtBu and 18-crown-6 in Et2O, followed by reaction with ethyl iodide (II) in Et2O, yields methyl 1-ethylpyrrole-2-carboxylate (III), which is then subjected to saponification with NaOH to afford carboxylic acid (IV). Condensation of (IV) with beta-alanine benzyl ester p-toluene sulfonate (V) in the presence of diethyl phosphorocyanidate (DEPC) and Et3N in DMF provides benzyl ester (VI), which is then hydrogenated over Pd/C in THF, furnishing carboxylic acid (VII). Cyclization of (VII) with polyphosphoric acid (PPA) affords derivative (VIII), which is then treated with NaH in DMF and alkylated with chloro derivative (IX) in DMF to produce compound (X). Finally, treatment of (X) with hydroxylamine hydrochloride and NaOAc affords the target compound.

参考文献中间体

合成目标

【1】 Mizuno, A.; Miya, M.; Inomata, N.; Tatsuoka, T.; Ishihara, T. (Suntory Ltd.); Pyrroloazepine cpd.. EP 0557526; JP 1993503481; US 5399557; WO 9303032 .
【2】 Yamaki, A.; Tatsuoka, T.; Miya, M.; Nakanishi, K.; Mizuno, A.; Takiguchi, C.; Hidaka, T.; Kamei, T.; Shibata, M.; Inomata, N.; Studies on antihypertensive agents with antithrombotic activity. 2. Syntheses and pharmacological evaluation of pyrrolo[2,3-c]azepine derivatives. Chem Pharm Bull 2000, 48, 8, 1129.

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)	45616	methyl 1H-pyrrole-2-carboxylate		C₆H₇NO₂	详情	详情
(II)	10925	Iodoethane;ethyl iod	75-03-6	C₂H₅I	详情	详情
(III)	45617	methyl 1-ethyl-1H-pyrrole-2-carboxylate		C₈H₁₁NO₂	详情	详情
(IV)	45618	1-ethyl-1H-pyrrole-2-carboxylic acid		C₇H₉NO₂	详情	详情
(V)	30194	benzyl 3-aminopropanoate	27019-47-2	C₁₀H₁₃NO₂	详情	详情
(VI)	45619	benzyl 3-[[(1-ethyl-1H-pyrrol-2-yl)carbonyl]amino]propanoate		C₁₇H₂₀N₂O₃	详情	详情
(VII)	45620	N-[(1-ethyl-1H-pyrrol-2-yl)carbonyl]-beta-alanine		C₁₀H₁₄N₂O₃	详情	详情
(VIII)	45621	1-ethyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione		C₁₀H₁₂N₂O₂	详情	详情
(IX)	45622	1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine		C₁₃H₁₈ClFN₂	详情	详情
(X)	45623	1-ethyl-7-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione		C₂₃H₂₉FN₄O₂	详情	详情

Extended Information