1-benzyl-4-(4-fluorophenyl)-4-piperidinol -Drug Synthesis Database

【结构式】

【分子编号】15722

【品名】1-benzyl-4-(4-fluorophenyl)-4-piperidinol

【CA登记号】

【分子式】C₁₈H₂₀FNO

【分子量】285.3613432

【元素组成】C 75.76% H 7.06% F 6.66% N 4.91% O 5.61%

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：(III)

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：(XIV)

Addition of 4-fluorophenylmagnesium bromide (XIII) to 1-benzyl-4-piperidinone (XII) afforded carbinol (XIV), which was dehydrated to the tetrahydropyridine (XV) by treatment with p-toluenesulfonic acid in refluxing toluene. Hydrogenation of the olefin (XV) with concomitant benzyl group hydrogenolysis gave 4-(4-fluorophenyl)piperidine (XVI) (1). This compound was also obtained by catalytic hydrogenation of the commercially available 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (XVII). Alkylation of piperidine (XVI) with N-(3-bromopropyl)phthalimide (XVIII) provided adduct (XIX), which was subjected to hydrazinolysis in refluxing MeOH to furnish the primary amine (XX). Deprotonation of oxazolidine (IX) with n-butyllithium in THF at -78 C, followed by condensation with p-nitrophenyl chloroformate, gave the p-nitrophenoxycarbonyl derivative (XXI). This was finally coupled with amine (XX) to furnish the title carboxamide.

参考文献中间体

合成目标

【1】 Tian, D.; Jeon, Y.; Lagu, B.; et al.; De novo design of a novel oxazolidinone analogue as a potent and selective alpha1A adrenergic receptor antagonist with high oral bioavailability. J Med Chem 2000, 43, 15, 2775.
【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 .
【3】 Marzabadi, M.R.; Wong, W.C.; Gluchowski, C.; Tian, D.; Nagarathnam, D.; Lagu, B.; Dhar, T.G.M.; Jeon, Y.T. (Synaptic Pharmaceutical Corp.); Heterocyclic substd. piperidines and uses thereof. EP 0988295; WO 9857940 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	43324	(4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one		C₁₀H₉F₂NO₂	详情	详情
(XII)	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
(XIII)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(XIV)	15722	1-benzyl-4-(4-fluorophenyl)-4-piperidinol		C₁₈H₂₀FNO	详情	详情
(XV)	43327	1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine		C₁₈H₁₈FN	详情	详情
(XVI)	39299	4-(4-fluorophenyl)piperidine	37656-48-7	C₁₁H₁₄FN	详情	详情
(XVII)	23465	4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine	1978-59-2	C₁₁H₁₂FN	详情	详情
(XVIII)	15216	N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione	5460-29-7	C₁₁H₁₀BrNO₂	详情	详情
(XIX)	39300	2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione		C₂₂H₂₃FN₂O₂	详情	详情
(XX)	39302	3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine		C₁₄H₂₁FN₂	详情	详情
(XXI)	43328	4-nitrophenyl (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-2-oxo-1,3-oxazolidine-3-carboxylate		C₁₇H₁₂F₂N₂O₆	详情	详情

Extended Information