3-[2-(carboxymethyl)phenyl]propanoic acid -Drug Synthesis Database

【结构式】

【分子编号】53198

【品名】3-[2-(carboxymethyl)phenyl]propanoic acid

【CA登记号】n/a

【分子式】C₁₁H₁₂O₄

【分子量】208.21388

【元素组成】C 63.45% H 5.81% O 30.74%

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：(IV)

Heck coupling of 2-bromophenylacetic acid (I) with acrylic acid (II) produces the dicarboxylic acid adduct (III). Subsequent catalytic hydrogenation of the olefinic double bond of (III) gives rise to the saturated diacid (IV). Then, Friedel-Crafts intramolecular cyclization of (IV) in hot H2SO4 affords indanone (V). Bromination of (V) in AcOH yields 2-bromo-1-oxoindan-4-ylacetic acid (VI). Esterification of (VI) is carried out via conversion to the corresponding acid chloride, followed by quenching with EtOH to provide the ethyl ester (VII). Condensation of bromo indanone (VII) with diethyl imidazole-2,4-dicarboxylate (VIII) furnishes the imidazolyl indanone (IX). Ring closure of keto ester (IX) with ammonium acetate in refluxing AcOH produces the tetracyclic compound (X). The ethyl ester groups of (X) are finally hydrolyzed under basic conditions to yield the title dicarboxylic acid.

参考文献中间体

合成目标

【2】 Aloup, J.-C.; Bouquerel, J.; Damour, D.; Hardy, J.-C.; Jimonet, P.; Manfre, M.; Mignani, S.; Nemecek, P. (Aventis Pharma SA); 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivs., preparation thereof, intermediates thereof and drugs containing same. EP 0880522; FR 2743366; JP 2000505073; US 5990108; WO 9725328 .
【1】 Mignani, S.; et al.; 9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): Selective anticonvulsive and neuroprotective AMPA antagonist. Bioorg Med Chem 2002, 10, 5, 1627.

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)	62312	2-Bromophenylacetic acid; O-Bromophenylacetic Acid; o-BROMOPHENYLACETIC ACID; OBPAA	18698-97-0	C₈H₇BrO₂	详情	详情
(II)	19139	acrylic acid	79-10-7	C₃H₄O₂	详情	详情
(III)	62313	(Z)-3-[2-(2-hydroxy-2-oxoethyl)phenyl]-2-propenoic acid		C₁₁H₁₀O₄	详情	详情
(IV)	53198	3-[2-(carboxymethyl)phenyl]propanoic acid	n/a	C₁₁H₁₂O₄	详情	详情
(V)	53199	2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid	n/a	C₁₁H₁₀O₃	详情	详情
(VI)	62314	2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid		C₁₁H₉BrO₃	详情	详情
(VII)	53201	ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate	n/a	C₁₃H₁₃BrO₃	详情	详情
(VIII)	62315	diethyl 1H-imidazole-2,4-dicarboxylate		C₉H₁₂N₂O₄	详情	详情
(IX)	62316	diethyl 1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]-1H-imidazole-2,4-dicarboxylate		C₂₂H₂₄N₂O₇	详情	详情
(X)	62317	ethyl 9-(2-ethoxy-2-oxoethyl)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate		C₂₀H₁₉N₃O₅	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 cyclization of 3-[2-(carboxymethyl)phenyl]propionic acid (I) in the presence of conc. H2SO4 at 100 C gives 2-(1-oxoindan-4-yl)acetic acid (II), which is esterified with (COCl)2 and EtOH to yield the ethyl ester (III). The bromination of (III) with Br2 in HOAc affords 2-(2-bromo-1-oxoindan-4-yl)acetic acid ethyl ester (IV). The condensation of (IV) with 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylic acid ethyl ester (V) (obtained by cyclization of hydroxyamidinocarboxylic acid ethyl ester (VI) with ethynylphosphonic acid diethyl ester (VII) in the presence of TEA) provides the adduct (VIII). The cyclization of (VIII) with ammonium acetate in refluxing acetic acid gives the tetracyclic phosphonate (IX), which is finally hydrolyzed with refluxing aqueous HCl to yield the target phosphonic acid.

参考文献中间体

合成目标

【1】 Boireau, A.; Böhme, G.A.; Canton, T.; et al.; RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: Synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2001, 299, 1, 314.
【2】 Jimonet, P.; Bouquerel, J.; Bohme, G.A.; et al.; Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists wit longer durations of action. Bioorg Med Chem Lett 2001, 11, 2, 127.
【3】 Aloup, J.-C.; Hardy, J.-C.; Mignani, S.; Jimonet, P.; Audiau, F.; Barreau, M.; Manfre, F.; Damour, D.; Ribeill, Y.; Genevois-Borella, A.; Nemecek, P. (Aventis Pharma SA); 5H-10H-Imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one derivs., preparation thereof, and drugs containing said derivs.. WO 9631511 .

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)	53198	3-[2-(carboxymethyl)phenyl]propanoic acid	n/a	C₁₁H₁₂O₄	详情	详情
(II)	53199	2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid	n/a	C₁₁H₁₀O₃	详情	详情
(III)	53200	ethyl 2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetate	n/a	C₁₃H₁₄O₃	详情	详情
(IV)	53201	ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate	n/a	C₁₃H₁₃BrO₃	详情	详情
(V)	53202	ethyl 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylate	n/a	C₁₀H₁₇N₂O₅P	详情	详情
(VI)	53203	ethyl 2-(hydroxyamino)-2-iminoacetate	n/a	C₄H₈N₂O₃	详情	详情
(VII)	53204	diethyl ethynylphosphonate	n/a	C₆H₁₁O₃P	详情	详情
(VIII)	53205	ethyl 4-(diethoxyphosphoryl)-1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]-1H-imidazole-2-carboxylate	n/a	C₂₃H₂₉N₂O₈P	详情	详情
(IX)	53206	ethyl 2-[2-(diethoxyphosphoryl)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl]acetate	n/a	C₂₁H₂₄N₃O₆P	详情	详情

Extended Information