(2R)-2-methoxy-2-phenylethanoic acid -Drug Synthesis Database

【结构式】

【分子编号】50060

【品名】(2R)-2-methoxy-2-phenylethanoic acid

【CA登记号】3966-32-3

【分子式】C₉H₁₀O₃

【分子量】166.1766

【元素组成】C 65.05% H 6.07% O 28.88%

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：(VI)

Protection of 3-amino-5-Boc-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (I) by treatment with ethyl chloroformate and DIEA gives the 1-ethoxycarbonyl derivative (II). After conversion of 4-(4-methylpiperazinyl)benzoic acid (III) to the corresponding acid chloride by means of oxalyl chloride and DMF, coupling with the amino heterocycle (II) furnishes the amide (IV). The N-Boc group of (IV) is then selectively deprotected under acidic conditions to give (V). Activation of (R)-α-methoxyphenylacetic acid (VI) with oxalyl choride and DMF gives the acid chloride (VII), which is coupled with the deprotected pyrrolopyrazole (V) to yield amide (VIII). Finally, the ethoxycarbonyl group of (VIII) is removed by treatment with Et3N in MeOH to provide the title compound (1, 2). Scheme 1.

参考文献中间体

合成目标

【1】 Fancelli, D., Forte, B., Moll, J., Varasi, M., Vianello, P. (Pfizer Italia Srl). Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors. EP 1644376, US 2005032839, WO 2005005427.
【2】 Fancelli, D., Moll, J., Varasi, M. et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 2006, 49(24): 7247-51.

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)	65715	tert-Butyl 3-amino-4,6-dihydropyrrolo[3,4-C]pyrozole-5-carboxylate; 5-Boc-3-amino-4,6-dihydropyrrolo[3,4-c]pyrozole	398491-59-3	C₁₀H₁₆N₄O₂	详情	详情
(II)	65716	Ethyl 5-(tert-butoxycarbonyl)-3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylate; 3-Amino-5-((tert-butoxy)carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester; 3-Amino-5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole	398495-65-3	C₁₃H₂₀N₄O₄	详情	详情
(III)	65717	4-(4-Methylpiperazino)benzoic acid; 4-(4-Methylpiperazin-1-yl)benzoic acid	86620-62-4	C₁₂H₁₆N₂O₂	详情	详情
(IV)	65718	1-Ethyl 5-(2-methyl-2-propanyl) 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate	761443-69-0	C₂₅H₃₄N₆O₅	详情	详情
(V)	65719	Ethyl 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate	761443-50-9	C₂₀H₂₆N₆O₃	详情	详情
(VI)	50060	(2R)-2-methoxy-2-phenylethanoic acid	3966-32-3	C₉H₁₀O₃	详情	详情
(VII)	16302	(2R)-2-methoxy-2-phenylethanoyl chloride		C₉H₉ClO₂	详情	详情
(VIII)	65720			C₂₉H₃₄N₆O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Electrophilic bromination of chromene (XII) with N-bromosuccinimide in moist DMSO produced the trans-bromohydrin (XIII). The racemic (XIII) was then resolved by esterification with (R)-alpha-methoxyphenylacetic acid (XIV), using DCC as the coupling reagent, and subsequent chromatographic separation of the diastereomeric mixture. Hydrolysis of the desired bromoester isomer (XV) under basic conditions gave rise to the chiral cis-epoxide (XVI). The target amino alcohol (XVII) was then obtained by regioselective ring opening of epoxide (XVI) with ethanolic ammonia in a pressure vessel. Finally, coupling of (XVII) with nicotinoyl chloride (XVIII) furnished the title amide.

参考文献中间体

合成目标

【1】 Manley, P.W. (Novartis AG; Novartis Deutschland GmbH); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans, their use as pharmaceuticals. EP 0623129; WO 9412493 .
【2】 Manley, P.W. (Novartis AG); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans. US 5574049 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	50058	4-(2,2-dimethyl-2H-chromen-6-yl)-2-methylpyridine		C₁₇H₁₇NO	详情	详情
(XIII)	50059	(3R,4R)-4-bromo-2,2-dimethyl-6-(2-methyl-4-pyridinyl)-3,4-dihydro-2H-chromen-3-ol		C₁₇H₁₈BrNO₂	详情	详情
(XIV)	50060	(2R)-2-methoxy-2-phenylethanoic acid	3966-32-3	C₉H₁₀O₃	详情	详情
(XV)	50061	(3R,4R)-4-bromo-2,2-dimethyl-6-(2-methyl-4-pyridinyl)-3,4-dihydro-2H-chromen-3-yl (2R)-2-methoxy-2-phenylethanoate		C₂₆H₂₆BrNO₄	详情	详情
(XVI)	50062	4-[(1aS,7bS)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-2-methylpyridine		C₁₇H₁₇NO₂	详情	详情
(XVII)	50063	(3S,4R)-4-amino-2,2-dimethyl-6-(2-methyl-4-pyridinyl)-3,4-dihydro-2H-chromen-3-ol		C₁₇H₂₀N₂O₂	详情	详情
(XVIII)	10753	Nicotinoyl chloride		C₆H₄ClNO	详情	详情

Extended Information