Preclamol, 3-PPP-(-), -Drug Synthesis Database

【结构式】

【药物名称】Preclamol, 3-PPP-(-)

【化学名称】(-)-(S)-[1-Propylpiperidin-3(S)-yl]phenol
　　　　　　(-)-1-Propyl-3(S)-(3-hydroxyphenyl)piperidine

【CA登记号】85966-89-8, 75240-91-4 (racemate)

【分子式】C₁₄H₂₁NO

【分子量】219.32957

【开发单位】AstraZeneca (Originator)

【药理作用】Antiparkinsonian Drugs, Antipsychotic Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Dopamine Receptor Agonists

合成路线1 合成路线2

合成路线1

The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.

参考文献中间体

【1】 Arvidsson, F.L.E.; et al.; EP 0030526 .
【2】 Sanchez, D.; Nilsson, J.L.G.; Hacksell, U.; Lindberg, P.; Carlsson, A.; Arvidsson, L.E.; Svensson, U.; Hjorth, S.; Wikstroem, H.; 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J Med Chem 1981, 24, 12, 1475-82.
【3】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	19502	Propyl bromide; 1-Bromopropane	106-94-5	C₃H₇Br	详情	详情
(B)	20178	propionic acid	79-09-4	C₃H₆O₂	详情	详情
(I)	35983	m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether	2398-37-0	C₇H₇BrO	详情	详情
(II)	35984	bromo(3-methoxyphenyl)magnesium	36282-40-3	C₇H₇BrMgO	详情	详情
(III)	13265	3-Bromopyridine	626-55-1	C₅H₄BrN	详情	详情
(IV)	35985	3-(3-methoxyphenyl)pyridine; methyl 3-(3-pyridinyl)phenyl ether		C₁₂H₁₁NO	详情	详情
(V)	35986	3-(3-methoxyphenyl)-1-propylpyridinium bromide		C₁₅H₁₈BrNO	详情	详情
(VI)	35987	3-(3-methoxyphenyl)-1-propylpiperidine; methyl 3-(1-propyl-3-piperidinyl)phenyl ether		C₁₅H₂₃NO	详情	详情
(VII)	35988	3-(3-methoxyphenyl)piperidine; methyl 3-(3-piperidinyl)phenyl ether		C₁₂H₁₇NO	详情	详情

合成路线2

The condensation of (3-methoxyphenyl)acetonitrile (VIII) with 3-bromopropyltetrahydropyranyl ether (IX) by means of lithium diisopropylamide in THF gives 2-(3-methoxyphenyl)-5-tetrahydropyranyloxypentanonitrile (X), which is oxidized with chromic anhydride-H2SO4 yielding 4-cyano-3-(3-methoxyphenyl)butyric acid (XI). The hydrolysis of (XI) with KOH in ethanol-water affords 2-(3-methoxyphenyl)glutaric acid (XII), which is anhydrized with refluxing acetic anhydride giving 2-(3-methoxyphenyl)glutaric anhydride (XIII). The reaction of (XIII) with propylamine (C) in refluxing benzene yields 2-(3-methoxyphenyl)-N-propylglutarimide (XIV), which is demethylated with BBr3 in methylene chloride to 2-(3-hydroxyphenyl)-N-propylglutarimide (XV). The benzylation of (XV) with benzyl bromide and K2CO3 in DMF affords 2-(3-benzyloxyphenyl)-N-propylglutarimide (XVI), which is reduced with LiAlH4 in THF giving 3-(3-benzyloxyphenyl)-N-propylpiperidine (XVII). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in AcOH.

参考文献中间体

【1】 Brands, F.T.L.; Loozen, H.J.J.; An efficient synthesis of 3-arylpiperidines. J R Neth Chem Soc 1981, 100, 9, 333-336.
【2】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(VIII)	24061	3-methoxyphenylacetonitrile; 2-(3-methoxyphenyl)acetonitrile	19924-43-7	C₉H₉NO	详情	详情
(IX)	29460	2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether		C₉H₁₇BrO₂	详情	详情
(X)	35989	2-(3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile		C₁₈H₂₅NO₃	详情	详情
(XI)	35990	4-cyano-4-(3-methoxyphenyl)butyric acid		C₁₂H₁₃NO₃	详情	详情
(XII)	35991	2-(3-methoxyphenyl)pentanedioic acid		C₁₂H₁₄O₅	详情	详情
(XIII)	35992	3-(3-methoxyphenyl)dihydro-2H-pyran-2,6(3H)-dione		C₁₂H₁₂O₄	详情	详情
(XIV)	35993	3-(3-methoxyphenyl)-1-propyl-2,6-piperidinedione		C₁₅H₁₉NO₃	详情	详情
(XV)	35994	3-(3-hydroxyphenyl)-1-propyl-2,6-piperidinedione		C₁₄H₁₇NO₃	详情	详情
(XVI)	35995	3-[3-(benzyloxy)phenyl]-1-propyl-2,6-piperidinedione		C₂₁H₂₃NO₃	详情	详情
(XVII)	35996	benzyl 3-(1-propyl-3-piperidinyl)phenyl ether; 3-[3-(benzyloxy)phenyl]-1-propylpiperidine		C₂₁H₂₇NO	详情	详情
(C)	23923	1-propanamine	107-10-8	C₃H₉N	详情	详情

Extended Information