SNC-80, -Drug Synthesis Database

【结构式】

【药物名称】SNC-80

【化学名称】(+)-4-[(alphaR)-alpha-[(2S,5R)-4-Allyl-2,5-dimethylpiperazin-1-yl]-3-methoxybenzyl]-N,N-diethylbenzamide

【CA登记号】156727-74-1

【分子式】C₂₈H₃₉N₃O₂

【分子量】449.64193

【开发单位】GlaxoSmithKline (Originator), National Institutes of Health (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Opioid Analgesics, delta-Opioid Agonists

合成路线1 合成路线2 合成路线3

合成路线1

Friedel-Crafts acylation of toluene (II) with 3-methoxybenzoyl chloride (I) gave benzophenone (III). Subsequent methyl group oxidation using KMnO4 afforded carboxylic acid (IV), which was further converted to amide (V) by activation with SOCl2, followed by treatment with diethylamine. Reduction of the keto group of (V) by means of NaBH4 yielded alcohol (VI). The required benzhydryl chloride (VII) was then prepared by treatment of alcohol (VI) with concentrated HCl.

参考文献中间体

【1】 Evans, S.M.; Lenz, G.R.; Probes of receptor mediated phenomena 19. Synthesis of (+)-4-[(alphaR)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. Chemtracts - Org Chem 1994, 7, 6, 395.
【2】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena: 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80). J Med Chem 1997, 40, 5, 695.
【3】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. J Med Chem 1994, 14, 37, 2125.

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)	16760	3-methoxybenzoyl chloride	1711-05-3	C₈H₇ClO₂	详情	详情
(II)	12890	Toluene	108-88-3	C₇H₈	详情	详情
(III)	56245	(3-methoxyphenyl)(4-methylphenyl)methanone		C₁₅H₁₄O₂	详情	详情
(IV)	56246	4-(3-methoxybenzoyl)benzoic acid		C₁₅H₁₂O₄	详情	详情
(V)	56247	N,N-diethyl-4-(3-methoxybenzoyl)benzamide		C₁₉H₂₁NO₃	详情	详情
(VI)	56248	N,N-diethyl-4-[hydroxy(3-methoxyphenyl)methyl]benzamide		C₁₉H₂₃NO₃	详情	详情
(VII)	56249	4-[chloro(3-methoxyphenyl)methyl]-N,N-diethylbenzamide		C₁₉H₂₂ClNO₂	详情	详情

合成路线2

The alkylation of trans-2,5-dimethylpiperazine (VIII) with allyl bromide gave rise to a racemic mixture of N-allylpiperazines, which was resolved using (-)-camphoric acid. The desired (2R,5S)-piperazine (IX) was then alkylated with benzhydryl chloride (VII) producing a mixture of the title compound and its benzhydryl epimer (X), which were separated by flash column chromatography.

参考文献中间体

【1】 Evans, S.M.; Lenz, G.R.; Probes of receptor mediated phenomena 19. Synthesis of (+)-4-[(alphaR)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. Chemtracts - Org Chem 1994, 7, 6, 395.
【2】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena: 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80). J Med Chem 1997, 40, 5, 695.
【3】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. J Med Chem 1994, 14, 37, 2125.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	56249	4-[chloro(3-methoxyphenyl)methyl]-N,N-diethylbenzamide	C₁₉H₂₂ClNO₂	详情	详情
(VIII)	20687	(2R,5S)-2,5-dimethylpiperazine	C₆H₁₄N₂	详情	详情
(IX)	20690	(2R,5S)-1-allyl-2,5-dimethylpiperazine	C₉H₁₈N₂	详情	详情
(X)	56250	4-[(S)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide	C₂₈H₃₉N₃O₂	详情	详情

合成路线3

In a different synthetic strategy, 4-formylbenzoic acid (XI) was first coupled to diethylamine by means of EDC to yield N,N-diethyl 4-formylbenzamide (XII). The intermediate iminium salt produced by condensation between aldehyde (XII) and the chiral piperazine (IX) was then isolated as the benzotriazole adduct (XIII). Displacement of the benzotriazolyl group by the Grignard reagent (XIV) produced the title diastereoisomer as the major product, which was further enriched by recrystallization from acetonitrile/water.

参考文献中间体

【1】 Report from ASCO 2002 - Docetaxel improves survival in node-positive early-stage breast cancer patients. Oncology (USA) 2002, 16, 8, 1054.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	20690	(2R,5S)-1-allyl-2,5-dimethylpiperazine		C₉H₁₈N₂	详情	详情
(XI)	18922	4-formylbenzoic acid	619-66-9	C₈H₆O₃	详情	详情
(XII)	45932	N,N-diethyl-4-formylbenzamide		C₁₂H₁₅NO₂	详情	详情
(XIII)	56251	4-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](1H-1,2,3-benzotriazol-1-yl)methyl]-N,N-diethylbenzamide		C₂₇H₃₆N₆O	详情	详情
(XIV)	35984	bromo(3-methoxyphenyl)magnesium	36282-40-3	C₇H₇BrMgO	详情	详情

Extended Information