Rimonabant hydrochloride, SR-141716A, Acomplia, -Drug Synthesis Database

【结构式】

【药物名称】Rimonabant hydrochloride, SR-141716A, Acomplia

【化学名称】5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)pyrazole-3-carboxamide hydrochloride

【CA登记号】158681-13-1, 168273-06-1 (free base)

【分子式】C₂₂H₂₂Cl₄N₄O

【分子量】500.25884

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Alzheimer's Dementia, Treatment of , Antiobesity Drugs, Antiparkinsonian Drugs, Cognition Disorders, Treatment of, Extrapyramidal Disorders, Treatment of, METABOLIC DRUGS, NEUROLOGIC DRUGS, Smoking Cessation, Aid to, Treatment of Nutritional Disorders, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, Cannabinoid CB1 Antagonists

合成路线1 合成路线2

合成路线1

Claisen condensation of 4-chloropropiophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide afforded the corresponding diketo ester lithium salt (II). This was condensed with 2,4-dichlorophenylhydrazine (III) to afford hydrazone (IV), which was further cyclized to pyrazole (V) in refluxing HOAc. In an improved procedure, 4-chloropropiophenone (I) was initially converted to the silyl enol ether (VI) using chlorotrimethylsilane and triethylamine. Acylation of (VI) with ethyl chloroglyoxylate in the presence of ZnCl2 produced diketo ester (VII). Condensation of (VII) with hydrazine (III), followed by acid cyclization of the intermediate hydrazone (IV), also produced pyrazole (V). Hydrolysis of ethyl ester (V) gave carboxylic acid (VIII), which was then activated as the acid chloride (IX). Finally, coupling of acid chloride (IX) with N-aminopiperidine (X) furnished the title hydrazide.

参考文献中间体

【1】 Rinaldi, M.; Anne-Archard, G.; Barth, F.; Casellas, P.; Congy, C.; Martinez, S. (Sanofi-Synthélabo); Substd. N-piperidino 3-pyrazolecarboxamide. CA 2136893; EP 0576357; EP 0656354; FR 2692575; FR 2713224; FR 2713225; JP 1994073014; JP 1995309841; JP 2001026541; US 5624941 .

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)	29196	1-(4-Chlorophenyl)-1-propanone; 4-Chloropropiophenone	6285-05-8	C₉H₉ClO	详情	详情
(II)	52989	lithium (Z)-1-(4-chlorophenyl)-4-ethoxy-2-methyl-3,4-dioxo-1-buten-1-olate	n/a	C₁₃H₁₂ClLiO₄	详情	详情
(III)	35778	1-(2,4-dichlorophenyl)hydrazine	5446-18-4	C₆H₆Cl₂N₂	详情	详情
(IV)	52990	ethyl 4-(4-chlorophenyl)-2-[(E)-2-(2,4-dichlorophenyl)hydrazono]-3-methyl-4-oxobutanoate	n/a	C₁₉H₁₇Cl₃N₂O₃	详情	详情
(V)	52991	ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate	n/a	C₁₉H₁₅Cl₃N₂O₂	详情	详情
(VI)	52992	(Z)-1-(4-chlorophenyl)-1-propenyl trimethylsilyl ether; {[(Z)-1-(4-chlorophenyl)-1-propenyl]oxy}(trimethyl)silane	n/a	C₁₂H₁₇ClOSi	详情	详情
(VII)	52993	ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate	n/a	C₁₃H₁₃ClO₄	详情	详情
(VIII)	52994	5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid	n/a	C₁₇H₁₁Cl₃N₂O₂	详情	详情
(IX)	52995	5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride	n/a	C₁₇H₁₀Cl₄N₂O	详情	详情
(X)	35781	1-piperidinylamine; 1-piperidinamine	2213-43-6	C₅H₁₂N₂	详情	详情

合成路线2

The reaction of Rimonabant (I) with BuLi and 1-chloro-2-iodoethane gives a mixture of the iodo derivatives (II) and (III), which are separated by chromatography. The desired isomer (II) is then hydrogenated with tritium over Pd/C in ethanol.

参考文献中间体

【1】 Seltzman, H.H.; et al.; Tritiation of SR141716 by metallation-iodination-reduction: Tritium-proton nOe study. J Label Compd Radiopharm 2002, 45, 1, 59.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	58224	5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide	C₂₂H₂₁Cl₃N₄O	详情	详情
(II)	58225	5-(4-chlorophenyl)-1-(2,4-dichloro-6-iodophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide	C₂₂H₂₀Cl₃IN₄O	详情	详情
(III)	58226	5-(4-chlorophenyl)-1-(2,4-dichloro-3-iodophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide	C₂₂H₂₀Cl₃IN₄O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)