(S)-(-)-OSU-6162, -Drug Synthesis Database

【结构式】

【药物名称】(S)-(-)-OSU-6162

【化学名称】(S)-(-)-3-[3-(Methanesulfonyl)phenyl]-1-propylpiperidine

【CA登记号】146798-66-5, 160777-43-5 ((R)-isomer)

【分子式】C₁₅H₂₃NO₂S

【分子量】281.42006

【开发单位】Pfizer (Proprietary), Carlsson Research (Originator)

【药理作用】Antiparkinsonian Drugs, Antipsychotic Drugs, Extrapyramidal Disorders, Treatment of, Huntington's Disease, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Receptor Ligands

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with Pd(OAc)4, CO and MeOH, yielding 3-(1-propylpiperidin-3(S)-yl)benzoic acid methyl ester (III). The reaction of (III) with sodium azide and H2SO4 affords the aniline (IV), which by reaction with NaNO2, HBr and CuBr provides 3(S)-(3-bromophenyl)-1-propylpiperidine (V). The reaction of (V) with dimethyl disulfide and n-BuLi gives the thioether (VI), which is oxidized with MCPBA to afford the target sulfone, which is easily separated from the N-oxide (VII) also formed in the oxidation process. The N-oxide (VII) can be reduced to the target compound by means of TiCl4 and NaI in acetonitrile.

参考文献中间体

【1】 Sonesson, C.; et al.; Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: Synthesis and structure-activity relationships. J Med Chem 1994, 37, 17, 2735.
【2】 Svensson, K.A.I.; Wikström, H.V.; Carlsson, P.A.E.; Boije, A.M.P.; Waters, R.N.; Sonesson, C.A.; Stjerulof, N.P.; Andersson, B.R. (Pharmacia Corp.); New centrally acting substd. phenylazacycloalkanes. EP 0641320; JP 1994509561; US 5462947; WO 9218475 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43381	3-[(3S)-1-propylpiperidinyl]phenol	C₁₄H₂₁NO	详情	详情
(II)	43382	3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate	C₁₅H₂₀F₃NO₃S	详情	详情
(III)	43383	methyl 3-[(3S)-1-propylpiperidinyl]benzoate	C₁₆H₂₃NO₂	详情	详情
(IV)	43384	3-[(3S)-1-propylpiperidinyl]phenylamine; 3-[(3S)-1-propylpiperidinyl]aniline	C₁₄H₂₂N₂	详情	详情
(V)	43385	(3S)-3-(3-bromophenyl)-1-propylpiperidine	C₁₄H₂₀BrN	详情	详情
(VI)	43386	(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide	C₁₅H₂₃NS	详情	详情
(VII)	43387	(3S)-3-[3-(methylsulfonyl)phenyl]-1-propyl-1-piperidiniumolate	C₁₅H₂₃NO₃S	详情	详情

合成路线2

The condensation of 3-(methylsulfonyl)bromobenzene (I) with diethyl(3-pyridyl)borane (II) by means of Pd(PPh3)4, KOH and tetrabutylammonium iodide (TBAI) gives 3-[3-(methylsulfonyl)phenyl]pyridine (III), which is hydrogenated with H2 over PtO2 in methanol, yielding the racemic piperidine (IV). The optical resolution of (IV) with (+)-tartaric acid affords the (S)-enantiomer (V), which is alkylated by reductocondensation with propionic aldehyde and NaBH(O-tBu)3 in dichloroethane and HOAc.

参考文献中间体

【1】 Sonesson, C.; Lindborg, J.; An efficient synthesis of the novel dopamine autoreceptor antagonist S-(-)-OSU6162, via Palladium catalyzed cross-coupling reaction. Tetrahedron Lett 1994, 35, 48, 9063.

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)	43388	(3-bromophenyl)(methyl)dioxo-lambda(6)-sulfane; 3-bromophenyl methyl sulfone		C₇H₇BrO₂S	详情	详情
(II)	20086	3-(diethylboryl)pyridine		C₉H₁₄BN	详情	详情
(III)	43389	methyl 3-(3-pyridinyl)phenyl sulfone; 3-[3-(methylsulfonyl)phenyl]pyridine		C₁₂H₁₁NO₂S	详情	详情
(IV)	43390	methyl 3-(3-piperidinyl)phenyl sulfone; 3-[3-(methylsulfonyl)phenyl]piperidine		C₁₂H₁₇NO₂S	详情	详情
(V)	43391	methyl 3-[(3S)piperidinyl]phenyl sulfone; (3S)-3-[3-(methylsulfonyl)phenyl]piperidine		C₁₂H₁₇NO₂S	详情	详情
(VI)	15966	propionaldehyde	123-38-6	C₃H₆O	详情	详情

合成路线3

The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with triisopropylsilylthiol sodium salt and Pd(PPh3)4 to yield the sill sulfanyl compound (III). The desilylation of (III) with HCl in methanol affords the thiophenol (IV), which is methylated with 13C- and 2H-labeled methyl iodide and TEA in dichloromethane, providing the methylsulfanyl derivative (V). Finally, this compound is oxidized to the target sulfone with MCPBA and trifluoroacetic acid.

参考文献中间体

【1】 Chaudhary, A.G.; McGrath, J.P.; Improved synthesis of stable isotope labeled and carbon-14 labeled (S)-(-)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride; (-)-OSU-6162. J Label Compd Radiopharm 2000, 43, 7, 683.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43381	3-[(3S)-1-propylpiperidinyl]phenol	C₁₄H₂₁NO	详情	详情
(II)	43382	3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate	C₁₅H₂₀F₃NO₃S	详情	详情
(III)	43392	3-[(3S)-1-propylpiperidinyl]phenyl triisopropylsilyl sulfide; (3S)-1-propyl-3-[3-[(triisopropylsilyl)sulfanyl]phenyl]piperidine	C₂₃H₄₁NSSi	详情	详情
(IV)	43393	3-[(3S)-1-propylpiperidinyl]phenylhydrosulfide; 3-[(3S)-1-propylpiperidinyl]benzenethiol	C₁₄H₂₁NS	详情	详情
(V)	43386	(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide	C₁₅H₂₃NS	详情	详情
(V)	45317	methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide; (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine	C₁₅H₂₃NS	详情	详情

合成路线4

The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with triisopropylsilylthiol sodium salt and Pd(PPh3)4 to yield the sill sulfanyl compound (III). The desilylation of (III) with HCl in methanol affords the thiophenol (IV), which is methylated with 14C-labeled methyl iodide and TEA in dichloromethane, providing the methylsulfanyl derivative (V). Finally, this compound is oxidized to the target sulfone with MCPBA and trifluoroacetic acid.

参考文献中间体

【1】 Chaudhary, A.G.; McGrath, J.P.; Improved synthesis of stable isotope labeled and carbon-14 labeled (S)-(-)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride; (-)-OSU-6162. J Label Compd Radiopharm 2000, 43, 7, 683.

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)	43381	3-[(3S)-1-propylpiperidinyl]phenol		C₁₄H₂₁NO	详情	详情
(II)	43382	3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate		C₁₅H₂₀F₃NO₃S	详情	详情
(III)	43392	3-[(3S)-1-propylpiperidinyl]phenyl triisopropylsilyl sulfide; (3S)-1-propyl-3-[3-[(triisopropylsilyl)sulfanyl]phenyl]piperidine		C₂₃H₄₁NSSi	详情	详情
(IV)	43393	3-[(3S)-1-propylpiperidinyl]phenylhydrosulfide; 3-[(3S)-1-propylpiperidinyl]benzenethiol		C₁₄H₂₁NS	详情	详情
(V)	43386	(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide		C₁₅H₂₃NS	详情	详情
(V)	45318	(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide		C₁₅H₂₃NS	详情	详情
(V)	53280	(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide	n/a	C₁₅H₂₃NS	详情	详情

Extended Information