Implitapide, BAY-13-9952, -Drug Synthesis Database

【结构式】

【药物名称】Implitapide, BAY-13-9952

【化学名称】2(S)-Cyclopentyl-2-[4-(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-ylmethyl)phenyl]-N-[2-hydroxy-1(R)-phenylethyl]acetamide

【CA登记号】177469-96-4

【分子式】C₃₅H₃₇N₃O₂

【分子量】531.70404

【开发单位】Bayer (Originator), PPD (Codevelopment)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ApoB Secretion Inhibitors, Microsomal Triglyceride Transfer Protein (MTTP) Inhibitors

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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

Extended Information