4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine -Drug Synthesis Database

【结构式】

【分子编号】15723

【品名】4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine

【CA登记号】3888-65-1

【分子式】C₁₁H₁₄FNO

【分子量】195.2367032

【元素组成】C 67.67% H 7.23% F 9.73% N 7.17% O 8.19%

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：(IV)

N-Benzyl-4-piperidone (I) was reacted with a Grignard reagent prepared from 4-fluorobromobenzene (II) to give the carbinol (III). The benzyl group was removed by catalytic hydrogenation and the resulting amine (IV) was alkylated with 3-bromopropionaldehyde ethylene acetal (V) to the alcohol (VI). Ring closure in hydrochloric acid gave the bicyclic endo-alcohol [(±)-VII] along with some of the exo-isomer removed by crystallization. [(±)-VII] was resolved by crystallization with (R,R)-tartaric acid mono-4-chloroanilide (VIII) to give [(+)-VII] of yet unknown absolute configuration. The latter was acylated with propionic anhydride followed by crystallization with hydrogen chloride in ether to furnish the end product.

参考文献中间体

合成目标

【1】 Sólyom, S.; Abraham, G.; Szölössy, M.; Borsi, J.; Vitális, B.; Karimné Tapfer, M.; Szabóné Bady, E.; Csuzdi, E.; Goldschmidtné Horváth, K.; Máté, G.; Ling, I.; Miklósné Kovács, A. (Gyogyszerkutato Intezet Kft.); New 1-azabicycloalkane derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0556342; JP 1994505706; WO 9207854 .
【2】 Nogradi, M.; GYKI-46903. Drugs Fut 1993, 18, 5, 421.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
((+/-)-VII	15726	(rac)-[(4R,5S)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol]		C₁₄H₁₆FNO	详情	详情
((R,R)-VII)	15727	(2R,3R)-4-(4-chloroanilino)-2,3-dihydroxy-4-oxobutyric acid		C₁₀H₁₀ClNO₅	详情	详情
((+)-VII)	64680	(4R,5S)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol		C₁₄H₁₆FNO	详情	详情
(I)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(III)	15722	1-benzyl-4-(4-fluorophenyl)-4-piperidinol		C₁₈H₂₀FNO	详情	详情
(IV)	15723	4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine	3888-65-1	C₁₁H₁₄FNO	详情	详情
(V)	15724	2-(2-bromoethyl)-1,3-dioxolane	18742-02-4	C₅H₉BrO₂	详情	详情
(VI)	15725	1-[2-(1,3-dioxolan-2-yl)ethyl]-4-(4-fluorophenyl)-4-piperidinol		C₁₆H₂₂FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

E-5842 was prepared by reacting (I) with citric acid monohydrate in ethanol. The base (I) can be obtained by two ways: 1) By condensation of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (III) or 8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene chloride (IV) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) or 1H-1,2,4-triazole, respectively, in dimethylformamide in the presence of potassium hydrogencarbonate. 2) By dehydration of 1-[4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidyl]butyl]-1H-1,2,4-triazole (VI) in refluxing hydrochloric acid/ethanol. The piperidinol (VI) can be obtained by two procedures: a) By condensation of 4-(4-fluorophenyl)-4-hydroxypiperidine (II) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) in dimethylformamide in the presence of potassium hydrogencarbonate. b) By condensation of 1,4-dioxa-8-azaspiro[4.5]decane (VII) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) and hydrolysis of the acetal to give 1-[4-(4-oxo-1-piperidyl)butyl]-1H-1,2,4-triazole (VIII), followed by addition of 4-fluorophenyllithium or 4-fluorophenyl magnesium bromide in ether or tetrahydrofuran to yield (VI).

参考文献中间体

合成目标

【1】 Merce-Vidal, R.; Frigola-Constansa, J. (Laboratorios del Dr. Esteve, SA); Tetrahydropyridine-(or -4-hydroxypiperidine)alkyla. EP 0721455; FR 2723091; JP 1997503230; US 5731331; WO 9604287 .

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)	23463	4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-1,2,3,6-tetrahydropyridine		C₁₇H₂₁FN₄	详情	详情
(II)	15723	4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine	3888-65-1	C₁₁H₁₄FNO	详情	详情
(III)	23465	4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine	1978-59-2	C₁₁H₁₂FN	详情	详情
(IV)	23466	8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene		C₁₅H₁₉FN	详情	详情
(V)	23467	1-(4-chlorobutyl)-1H-1,2,4-triazole		C₆H₁₀ClN₃	详情	详情
(VI)	23468	4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinol		C₁₇H₂₃FN₄O	详情	详情
(VII)	11338	1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal	177-11-7	C₇H₁₃NO₂	详情	详情
(VIII)	23470	1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinone		C₁₁H₁₈N₄O	详情	详情
(IX)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情

Extended Information