4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine -Drug Synthesis Database

【结构式】

【分子编号】35870

【品名】4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine

【CA登记号】39512-49-7

【分子式】C₁₁H₁₄ClNO

【分子量】211.691

【元素组成】C 62.41% H 6.67% Cl 16.75% N 6.62% O 7.56%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(III)

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (VIII) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IX). The reaction of (IX) with HCl in methanol yields the corresponding free butanone (X), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (XI). Finally, this compound is treated with Br2 in chloroform.

参考文献中间体

合成目标

【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(I)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情
(II)	28203	2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane	3308-94-9	C₁₂H₁₄ClFO₂	详情	详情
(III)	35870	4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine	39512-49-7	C₁₁H₁₄ClNO	详情	详情
(IX)	35871	4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol		C₂₃H₂₇ClFNO₃	详情	详情
(X)	35872	4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone	52-86-8	C₂₁H₂₃ClFNO₂	详情	详情
(XI)	35873	1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone		C₂₄H₃₂FNO₂Sn	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IV). The reaction of (IV) with HCl in methanol yields the corresponding free butanone (V), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (VI). Finally, this compound is treated with 75Br2 or 77Br2 and dichloramin T in methanol or H2O2 in acetic acid.

参考文献中间体

合成目标

【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(I)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情
(II)	28203	2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane	3308-94-9	C₁₂H₁₄ClFO₂	详情	详情
(III)	35870	4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine	39512-49-7	C₁₁H₁₄ClNO	详情	详情
(IV)	35871	4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol		C₂₃H₂₇ClFNO₃	详情	详情
(V)	35872	4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone	52-86-8	C₂₁H₂₃ClFNO₂	详情	详情
(VI)	35873	1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone		C₂₄H₃₂FNO₂Sn	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Treatment of 2-oxo-3,3-diphenyl-tetrahydrofuran (I) with HBr(g) yields bromo derivative (II), which is then converted into butyryl chloride derivative (III) by means of thionyl chloride in refluxing chloroform. Reaction of derivative (III) with dimethylamine (IV) in toluene affords dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (V), which is then condensed with 4-(4-chlorophenyl)-4-piperidinol (VI) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to provide N,N-dimethyl butyramide derivative (VII). Finally, the target product is obtained by N-oxidation of the piperidine ring in (VII) by heating with H2O2 in MeOH/methylbenzene or in 4-methyl-2-pentanone.

参考文献中间体

合成目标

【1】 Cooymans, L.P.; Wals, L. (Janssen Pharmaceutica NV); Novel alpha,alpha-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides. EP 0219898; JP 1987087569; US 4824853; US 4898873 .
【2】 Niemegeers, C.J.E.J.; Janssen, P.A.J.; Stokbroekx, R.A.; Vandenberk, J. (Janssen Pharmaceutica NV); 2,2-Diaryl-4-(4'-aryl-4'-hydroxy-piperidino)-butyramides. US 3714159 .

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)	48324	alpha,alpha-Diphenyl-gamma-butyrolactone; 4-Methoxychalcone; (4-Methoxybenzylidene)acetophenone; Dihydro-3,3-diphenyl-2(3H)-furanone; 4-Hydroxy-2,2-diphenylbutyric acid gamma-lactone; alpha,alpha-Diphenylbutyrolactone	959-33-1	C₁₆H₁₄O₂	详情	详情
(II)	48325	4-bromo-2,2-diphenylbutyric acid		C₁₆H₁₅BrO₂	详情	详情
(III)	48326	4-bromo-2,2-diphenylbutanoyl chloride		C₁₆H₁₄BrClO	详情	详情
(IV)	19443	N-methylmethanamine; N,N-dimethylamine	124-40-3	C₂H₇N	详情	详情
(V)	48327	N-[3,3-diphenyldihydro-2(3H)-furanylidene]-N-methylmethanaminium bromide		C₁₈H₂₀BrNO	详情	详情
(VI)	35870	4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine	39512-49-7	C₁₁H₁₄ClNO	详情	详情
(VII)	48328	4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-N,N-dimethyl-2,2-diphenylbutanamide		C₂₉H₃₃ClN₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Diphenylacetonitrile (I) was alkylated with 1,3-dibromopropane (II) in the presence of NaH in DMF to afford the bromopropyl derivative (III). Subsequent condensation of bromide (III) with 4-(4-chlorophenyl)-4-hydroxypiperidine (IV) gave the tertiary amine (V). This was then quaternized with methyl iodide to furnish the corresponding piperidinium salt.

参考文献中间体

合成目标

【1】 May, K.; Bauman, J.G.; Ng, H.P.; et al.; Discovery of novel non-peptide CCR1 receptor antagonists. J Med Chem 1999, 42, 22, 4680.

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)	14493	alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile	86-29-3	C₁₄H₁₁N	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	43750	5-bromo-2,2-diphenylpentanenitrile		C₁₇H₁₆BrN	详情	详情
(IV)	35870	4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine	39512-49-7	C₁₁H₁₄ClNO	详情	详情
(V)	43751	5-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-2,2-diphenylpentanenitrile		C₂₈H₂₉ClN₂O	详情	详情

Extended Information