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【结 构 式】

【分子编号】52193

【品名】3-Fluoro-p-toluic acid; 3-Fluoro-4-methylbenzoic acid

【CA登记号】350-28-7

【 分 子 式 】C8H7FO2

【 分 子 量 】154.1407832

【元素组成】C 62.34% H 4.58% F 12.33% O 20.76%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(I)

The reaction of 3-fluoro-4-methylbenzoic acid (I) with malonic acid monoethyl ester potassium salt (II) by means of CDI and MgCl2 in THF gives 3-(3-fluoro-4-methylphenyl)-3-oxopropionic acid ethyl ester (III), which can alternatively be obtained by condensation of 3'-fluoro-4'-methylacetophenone (IV) with diethyl carbonate (V) by means of NaH in THF. The condensation of ketoester (III) with 5-(2-nitrovinyl)-2,3-dihydrobenzofuran (VI) (obtained by condensation of 2,3-dihydrobenzofuran-5-carbaldehyde (VII) with nitromethane (VIII) by means of NH4OAc in hot acetic acid) yields the adduct (IX), which is reductively cyclized by hydrogenation with H2 over Raney-Ni in acetic acid, followed by a treatment with TFA to afford the pyrrolidine (X) as a mixture of isomers. The isomerization of (X) with DBU in refluxing toluene provides (rac)-(trans,trans)-pyrrolidine derivative (XI), which is hydrolyzed with NaOH and protected with Boc2O to give the racemic carboxylic acid (XII), which is suitable for optical resolution. The optical resolution of (XII) is performed with (R)-(+)-alpha-methylbenzylamine and the resulting chiral acid is esterified with HCl and ethanol, yielding the (R,R,S)-esterified precursor (XIII). The condensation of (XIII) with 2-bromo-N,N-dibutylacetamide (XIV) by means of DIEA in acetonitrile affords the chiral pyrrolidine-carboxylate (XV), which is finally hydrolyzed with NaOH to provide the target carboxylic acid.

1 Jae, H.-S.; et al.; Pyrrolidine-3-carboxylic acids as endothelin antagonists.5. Highly selective potent, and orally active ETA antagonists. J Med Chem 2001, 44, 23, 3978.
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) 52193 3-Fluoro-p-toluic acid; 3-Fluoro-4-methylbenzoic acid 350-28-7 C8H7FO2 详情 详情
(II) 52194 ethyl propionate C5H10O2 详情 详情
(III) 52195 ethyl 3-(3-fluoro-4-methylphenyl)-3-oxopropanoate C12H13FO3 详情 详情
(IV) 52196 1-(3-fluoro-4-methylphenyl)-1-ethanone C9H9FO 详情 详情
(V) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(VI) 52197 5-[(E)-2-nitroethenyl]-2,3-dihydro-1-benzofuran C10H9NO3 详情 详情
(VII) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(VIII) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(IX) 52199 methyl 3-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylbenzoyl)-4-nitrobutanoate C21H20FNO6 详情 详情
(X) 52200 methyl 4-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate C21H22FNO3 详情 详情
(XI) 52201 methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate C20H20FNO4 详情 详情
(XII) 52202 (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylic acid C24H26FNO6 详情 详情
(XIII) 52203 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate C21H22FNO4 详情 详情
(XIV) 20685 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide C10H20BrNO 详情 详情
(XV) 52204 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate C31H41FN2O5 详情 详情
Extended Information