【结 构 式】 |
【分子编号】28316 【品名】2-(4-methylphenyl)acetic acid 【CA登记号】622-47-9 |
【 分 子 式 】C9H10O2 【 分 子 量 】150.1772 【元素组成】C 71.98% H 6.71% O 21.31% |
合成路线1
该中间体在本合成路线中的序号:(XI)Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.
【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
【2】 Muller, U.; Connell, R.; Goldmann, S.; Grutzmann, R.; Beuck, M.; Bischoff, H.; Denzer, D.; Domdey-Bette, A.; Wohlfeil, S. (Bayer AG); Cycloalkano-indole- and -azaindole derivs.. CA 2159546; DE 4435477; EP 0705831; JP 1996225526; US 5684014 . |
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) | 41793 | 4,6-dimethyl-2-pyridinamine; 4,6-dimethyl-2-pyridinylamine | 5407-87-4 | C7H10N2 | 详情 | 详情 |
(II) | 41794 | 2-chloro-4,6-dimethylpyridine | 30838-93-8 | C7H8ClN | 详情 | 详情 |
(III) | 41795 | 2-hydrazino-4,6-dimethylpyridine | C7H11N3 | 详情 | 详情 | |
(IV) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
(V) | 41796 | 2,4-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole | C13H16N2 | 详情 | 详情 | |
(VI) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
(VII) | 41798 | tert-butyl 2-[4-(bromomethyl)phenyl]-2-cyclopentylacetate | C18H25BrO2 | 详情 | 详情 | |
(VIII) | 41799 | tert-butyl 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetate | C31H36N2O2 | 详情 | 详情 | |
(IX) | 41800 | 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetic acid | C27H28N2O2 | 详情 | 详情 | |
(X) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
(XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
(XII) | 41801 | tert-butyl 2-(4-methylphenyl)acetate | C13H18O2 | 详情 | 详情 | |
(XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
(XIV) | 41802 | tert-butyl 2-cyclopentyl-2-(4-methylphenyl)acetate | C18H26O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XI)Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV) by means of MsOH in refluxing toluene gives the ester (XVI), which is diastereoselectively condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-menthyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydantoin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), which is condensed with the already described alpha-carboline (VI) by means of t-BuOK in DMF to yield the adduct (XIX). Hydrolysis of (XIX) with HBr in formic acid affords the chiral cyclopentylacetic acid (XX), which is treated with SOCl2 in refluxing CH2Cl2 to provide the corresponding acyl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of TEA in hot toluene.
【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
【2】 Fey, P.; Naab, P.; Lenfers, J.-B.; Van Laak, K. (Bayer AG); Process for the preparation of enantiomerically pure cycloalkano-indol -and azaindol -and pyrimido[1,2a]indolcarboxycyclic acids and their activated derivs.. CA 2201435; DE 19613549; EP 0799829; JP 1998045759; US 5952498 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
(X) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
(XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
(XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
(XV) | 41803 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; L-menthol | 2216-51-5 | C10H20O | 详情 | 详情 |
(XVI) | 41804 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(4-methylphenyl)acetate | C19H28O2 | 详情 | 详情 | |
(XVII) | 41805 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-(4-methylphenyl)ethanoate | C24H36O2 | 详情 | 详情 | |
(XVIII) | 41806 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-[4-(bromomethyl)phenyl]-2-cyclopentylethanoate | C24H35BrO2 | 详情 | 详情 | |
(XIX) | 41807 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoate | C37H46N2O2 | 详情 | 详情 | |
(XX) | 41808 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoic acid | C27H28N2O2 | 详情 | 详情 | |
(XXI) | 41809 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoyl chloride | C27H27ClN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)The reaction of 2-(4-methylphenyl)acetic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with thiophene (III) by means SnCl4 yielding 2-(4-methylphenyl)-1-(2-thienyl)ethanone (IV). The reduction of (IV) with hydrazine and KOH in hot triethylene glycol affords 2-[2-(4-methylphenyl)ethyl]thiophene (V), which is condensed with 3,3-dimethylglutaric anhydride (VI), by means of AlCl3 in hot nitrobenzene giving the 5-oxopentanoic acid derivative (VII). The reduction of (VII) with hydrazine and KOH as before yields the pentanoic acid derivative (VIII), which is condensed with 4-(2,3,4-trimethoxybenzyl)piperazine (IX) by means of oxalyl chloride to afford the acyl piperazine (X). Finally, the amide group of (X) is reduced with LiAlH4 in ethyl ether.
【1】 Wierzbicki, M.; et al.; Amino derivatives of phenyl alkyl thiophene as inhibitors of bone resorption. Structure-activity relationship. Arzneim-Forsch Drug Res 1998, 48, 8, 840. |
【2】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Brisset, M.; Tordjman, C. (ADIR et Cie.); Thiophene derivs., process for their preparation and pharmaceutical compsns. containing them. AU 9166901; EP 0429370; FR 2655043; JP 1991190872; US 5061704 . |
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) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
(II) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
(III) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
(IV) | 28317 | 2-(4-methylphenyl)-1-(2-thienyl)-1-ethanone | C13H12OS | 详情 | 详情 | |
(V) | 28318 | 2-(4-methylphenethyl)thiophene | C13H14S | 详情 | 详情 | |
(VI) | 25549 | 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione | 4160-82-1 | C7H10O3 | 详情 | 详情 |
(VII) | 28319 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]-5-oxopentanoic acid | C20H24O3S | 详情 | 详情 | |
(VIII) | 28320 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]pentanoic acid | C20H26O2S | 详情 | 详情 | |
(IX) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
(X) | 28321 | 3,3-dimethyl-5-[5-(4-methylphenethyl)-2-thienyl]-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-pentanone | C34H46N2O4S | 详情 | 详情 |