AM-251, 4'-I-SR-141716A, -Drug Synthesis Database

【结构式】

【药物名称】AM-251, 4'-I-SR-141716A

【化学名称】1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide

【CA登记号】183232-66-8

【分子式】C₂₂H₂₁Cl₂IN₄O

【分子量】555.24927

【开发单位】Research Triangle Institute (Originator), University of Aberdeen (Originator), University of Connecticut (Originator)

【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Cannabinoid CB1 Inverse Agonists

合成路线1 合成路线2

合成路线1

Claisen condensation of 4'-bromopropiophenone (I) with diethyl oxalate using lithium bis(trimethylsilyl)amide provided the lithium salt of diketone (II). Subsequent condensation of (III) with 2,4-dichlorophenyl hydrazine (III), followed by cyclization of the intermediate hydrazone in refluxing AcOH yielded the desired pyrazole (IV). After hydrolysis of the ester group of (IV), the resulting carboxylic acid was converted to acid chloride (V) by treatment with SOCl2. Coupling of (V) with 1-aminopiperidine (VI) gave amide (VII). Conversion of (VII) to the tributyl-stannyl derivative (VIII) was achieved by reaction with hexabutylditin in the presence of catalytic tetrakis(triphenylphosphine)palladium. The desired iodo compound was then obtained by treatment of (VIII) with NaI and chloramine-T.

参考文献中间体

【1】 Lan, R.; et al.; Preparation of iodine-123 labeled AM251: A potential SPECT radioligand for the brain cannabinoid CB1 receptor. J Label Compd Radiopharm 1996, 38, 10, 875.

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)	35776	1-(4-bromophenyl)-1-propanone	10342-83-3	C₉H₉BrO	详情	详情
(II)	35777			C₁₃H₁₂BrLiO₄	详情	详情
(III)	35778	1-(2,4-dichlorophenyl)hydrazine	5446-18-4	C₆H₆Cl₂N₂	详情	详情
(IV)	35779	ethyl 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate		C₁₉H₁₅BrCl₂N₂O₂	详情	详情
(V)	35780	5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride		C₁₇H₁₀BrCl₃N₂O	详情	详情
(VI)	35781	1-piperidinylamine; 1-piperidinamine	2213-43-6	C₅H₁₂N₂	详情	详情
(VII)	35782	5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide		C₂₂H₂₁BrCl₂N₄O	详情	详情
(VIII)	35783	1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(tributylstannyl)phenyl]-1H-pyrazole-3-carboxamide		C₃₄H₄₈Cl₂N₄OSn	详情	详情

合成路线2

Propiophenone (IX) was condensed with diethyl oxalate to give diketone (X). Reaction with hydrazine (III) afforded pyrazole (XI). Nitration of (XI) by nitronium tetrafluoborate in acetonitrile gave a mixture of para- and ortho-nitrated compounds (XIIa-b), which were used without separation. Ester hydrolysis, followed by chlorination to (XIIIa-b) and condensation with 1-aminopiperidine (VI) gave the corresponding mixture of para- and ortho-nitro amides, which were separated by flash chromatography. The required para-isomer (XIV) was reduced by hydrazine and Raney Nickel to aniline (XV). This was finally converted to the title iodide via the reaction of the diazonium salt with NaI.

参考文献中间体

【1】 Fan, P.; Liu, Q.; Lan, R.; et al.; Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 1999, 42, 4, 769.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIa)	35786	ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(2-nitrophenyl)-1H-pyrazole-3-carboxylate		C₁₉H₁₅Cl₂N₃O₄	详情	详情
(XIIb)	35787	ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate		C₁₉H₁₅Cl₂N₃O₄	详情	详情
(XIIIa)	35788	1-(2,4-dichlorophenyl)-4-methyl-5-(2-nitrophenyl)-1H-pyrazole-3-carbonyl chloride		C₁₇H₁₀Cl₃N₃O₃	详情	详情
(XIIIb)	35789	1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-1H-pyrazole-3-carbonyl chloride		C₁₇H₁₀Cl₃N₃O₃	详情	详情
(III)	35778	1-(2,4-dichlorophenyl)hydrazine	5446-18-4	C₆H₆Cl₂N₂	详情	详情
(VI)	35781	1-piperidinylamine; 1-piperidinamine	2213-43-6	C₅H₁₂N₂	详情	详情
(IX)	33531	propiophenone	93-55-0	C₉H₁₀O	详情	详情
(X)	35784			C₁₃H₁₃LiO₄	详情	详情
(XI)	35785	ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate		C₁₉H₁₆Cl₂N₂O₂	详情	详情
(XIV)	35790	1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide		C₂₂H₂₁Cl₂N₅O₃	详情	详情
(XV)	35791	5-(4-aminophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide		C₂₂H₂₃Cl₂N₅O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)