SCH-72788, -Drug Synthesis Database

【结构式】

【药物名称】SCH-72788

【化学名称】1-[1(S)-[4-(1,3-Benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2(R)-methyl-4-[4-methyl-1-(propylsulfonyl)piperidin-4-yl]piperazine

【CA登记号】203180-40-9

【分子式】C₂₉H₄₁N₃O₆S₂

【分子量】591.79462

【开发单位】Schering-Plough (Originator)

【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Muscarinic M2 Antagonists

合成路线1 合成路线2

合成路线1

Lithiation of 5-bromo-1,3-benzodioxole (I), followed by reaction with elemental sulfur gave disulfide (II), which was reduced to thiol (III) by using LiAlH4. In an alternative procedure, thiol (III) was prepared by chlorosulfonation of benzodioxole (IV) and then reduction of the resulting sulfonyl chloride (V) with LiAlH4. Condensation of thiol (III) with p-fluoroacetophenone (VI) provided the diaryl sulfide (VII). Asymmetric reduction of the keto group of (VII) employing borane-dimethyl sulfide complex in the presence of the chiral oxazaborole auxiliary (VIII) yielded the (R)-alcohol (IX), which was converted to mesylate (XI) by oxidation with MCPBA to sulfone (X), a treatment with methanesulfonyl chloride and triethylamine. Alkylation of benzyl (R)-3-methylpiperazine-1-carboxylate (XII) with the chiral mesylate (XI) gave adduct (XIII). The benzyloxycarbonyl protecting group of (XIII) was then removed by acid hydrolysis, yielding piperazine (XIV).

参考文献中间体

【1】 Muscarinic antagonists. WO 9805292 .

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)	10124	5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene	2635-13-4	C₇H₅BrO₂	详情	详情
(II)	50640	5-(1,3-benzodioxol-5-yldisulfanyl)-1,3-benzodioxole; di(1,3-benzodioxol-5-yl) disulfide		C₁₄H₁₀O₄S₂	详情	详情
(III)	28620	1,3-benzodioxole-5-thiol		C₇H₆O₂S	详情	详情
(IV)	50641	1,3-Dioxaindane; 1,3-Benzodioxole; methylenedioxybenzene; 1,2-methylenedioxybenzene; catechol methylene ether	274-09-9	C₇H₆O₂	详情	详情
(V)	50642	1,3-benzodioxole-5-sulfonyl chloride		C₇H₅ClO₄S	详情	详情
(VI)	37684	1-(4-fluorophenyl)-1-ethanone	403-42-9	C₈H₇FO	详情	详情
(VII)	50643	1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanone		C₁₅H₁₂O₃S	详情	详情
(VIII)	28292	(S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole	112022-81-8	C₁₈H₂₀BNO	详情	详情
(IX)	50644	(1R)-1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanol		C₁₅H₁₄O₃S	详情	详情
(X)	50645	(1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanol		C₁₅H₁₄O₅S	详情	详情
(XI)	50646	(1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl methanesulfonate		C₁₆H₁₆O₇S₂	详情	详情
(XII)	50647	benzyl (3R)-3-methyl-1-piperazinecarboxylate		C₁₃H₁₈N₂O₂	详情	详情
(XIII)	50648	benzyl (3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methyl-1-piperazinecarboxylate		C₂₈H₃₀N₂O₆S	详情	详情
(XIV)	50649	(2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone		C₂₀H₂₄N₂O₄S	详情	详情

合成路线2

Condensation of piperazine (XIV) with N-Boc-4-piperidinone (XV) in the presence of titanium isopropoxide as the dehydrating reagent, followed by addition of diethylaluminum cyanide to the intermediate iminium salt, provided the alpha-aminonitrile (XVI). The cyano group of (XVI) was subsequently displaced with methylmagnesium bromide, affording the methyl derivative (XVII). After acid cleavage of the Boc protecting group of (XVII), the resulting piperidine (XVIII) was finally acylated with propanesulfonyl chloride to furnish the corresponding sulfonamide.

参考文献中间体

【1】 Muscarinic antagonists. WO 9805292 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	50649	(2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone		C₂₀H₂₄N₂O₄S	详情	详情
(XV)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(XVI)	50650	tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-cyano-1-piperidinecarboxylate		C₃₁H₄₀N₄O₆S	详情	详情
(XVII)	50651	tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-methyl-1-piperidinecarboxylate		C₃₁H₄₃N₃O₆S	详情	详情
(XVIII)	50652	(2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methyl-4-(4-methyl-4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methyl-4-(4-methyl-4-piperidinyl)piperazinyl]ethyl]phenyl sulfone		C₂₆H₃₅N₃O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)