benzyl (3R)-3-methyl-1-piperazinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】50647

【品名】benzyl (3R)-3-methyl-1-piperazinecarboxylate

【CA登记号】

【分子式】C₁₃H₁₈N₂O₂

【分子量】234.2982

【元素组成】C 66.64% H 7.74% N 11.96% O 13.66%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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

该中间体在本合成路线中的序号：(IV)

The reaction of the chiral benzyl alcohol (I) with 4-chlorobenzenesulfonyl chloride (II) and DABCO in toluene gives the sulfonate (III), which is condensed with the monoprotected piperazine (IV) by means of K2CO3 in hot toluene/acetonitrile to yield the adduct (V). The deprotection of (V) by means of hot aqueous HCl affords the piperazine derivative (VI), which is condensed with the acyl piperidine (VII) --obtained by condensation of 4,6-dimethylpyrimidine-5-carboxylic acid (VIII) with 4-piperidone (IX) --by means of acetone cyanohydrin or NaCN/AcOH to provide the cyano adduct (X). Finally, this compound is treated with AlMe3 and Me-MgCl in THF/toluene to yield the target compound.

参考文献中间体

合成目标

【1】 Gala, D.; Leong, W.; Jones, A.D.; Shi, X.; Chen, M.; D'sa, B.A.; Zhu, M.; Xiao, T.; Tang, S.; Goodman, A.J.; Nielsen, C.M.; Lee, G.M.; Gamboa, J.A. (Schering Corp.); Synthesis of piperidine and piperazine cpds. as CCR5 antagonists. WO 0384950 .

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)	64951	(1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]-1-ethanol		C₁₀H₁₁F₃O₂	详情	详情
(II)	15787	4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride	98-60-2	C₆H₄Cl₂O₂S	详情	详情
(III)	64952	(1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl 4-chlorobenzenesulfonate		C₁₆H₁₄ClF₃O₄S	详情	详情
(IV)	50647	benzyl (3R)-3-methyl-1-piperazinecarboxylate		C₁₃H₁₈N₂O₂	详情	详情
(V)	64953	benzyl (3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate		C₂₃H₂₇F₃N₂O₃	详情	详情
(VI)	64946	2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether		C₁₅H₂₁F₃N₂O	详情	详情
(VII)	64954	1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-piperidinone		C₁₂H₁₅N₃O₂	详情	详情
(VIII)	64955	4,6-dimethyl-5-pyrimidinecarboxylic acid		C₇H₈N₂O₂	详情	详情
(IX)	27115	4-piperidinone	40064-34-4	C₅H₉NO	详情	详情
(X)	64956	1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-((3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazinyl)-4-piperidinecarbonitrile		C₂₈H₃₅F₃N₆O₂	详情	详情

Extended Information