1-methyl-1H-pyrrole-3-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】30193

【品名】1-methyl-1H-pyrrole-3-carboxylic acid

【CA登记号】

【分子式】C₆H₇NO₂

【分子量】125.12712

【元素组成】C 57.59% H 5.64% N 11.19% O 25.57%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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：(I)

The condensation of 1-methylpyrrole-3-carboxylic acid (I) with 3-(3-chloropropylamino)propionic acid ethyl ester (II) by means of WSC and TEA gives the corresponding amide (III), which is hydrolyzed with NaOH to yield the amino acid (IV). The cyclization of (IV) by means of Ms-OH and P2O5 affords the pyrroloazepinedione (V), which is condensed with 1-(4-fluorophenyl)piperazine (VI) by means of K2CO3 or NaHCO3 and NaI to provide the adduct (VII). Finally, this compound is regioselectively monoreduced with NaBH4 to give the racemic alcohol (VIII), which is submitted to optical resolution by crystallization of its L-(+)-tartrate salt to afford the target (S)-enantiomer.

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.

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)	50957	ethyl 3-[(3-chloropropyl)amino]propanoate		C₈H₁₆ClNO₂	详情	详情
(III)	50958	ethyl 3-[(3-chloropropyl)[(1-methyl-1H-pyrrol-3-yl)carbonyl]amino]propanoate		C₁₄H₂₁ClN₂O₃	详情	详情
(IV)	50959	N-(3-chloropropyl)-N-[(1-methyl-1H-pyrrol-3-yl)carbonyl]-beta-alanine		C₁₂H₁₇ClN₂O₃	详情	详情
(V)	30198	5-(3-chloropropyl)-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione		C₁₂H₁₅ClN₂O₂	详情	详情
(VI)	12143	1-(4-Fluorophenyl)piperazine	2252-63-3	C₁₀H₁₃FN₂	详情	详情
(VII)	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
(VIII)	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

Extended Information