4-[bis(4-fluorophenyl)methylene]piperidine -Drug Synthesis Database

【结构式】

【分子编号】24706

【品名】4-[bis(4-fluorophenyl)methylene]piperidine

【CA登记号】

【分子式】C₁₈H₁₇F₂N

【分子量】285.3365264

【元素组成】C 75.77% H 6.01% F 13.32% N 4.91%

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：(V)

The Grignard condensation of ethyl 1-benzyl-piperidine-4-carboxylate (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a-bis(4-fluorophenyl)-1-benzylpiperidine-4-methanol (III), which is dehydrated with HCl in refluxing acetic acid yielding 1-benzyl-4-[bis(4 fluorophenyl)methylene]piperidine (IV). Elimination of the benzyl group of (IV) by hydrogenation with H2 over rhodium/carbon in methanol affords 4-[bis(4 fluorophenyl)metlylene] piperidine (V), which is finally condensed with 6-(2-chloroethyl)-7-methyl 5H thiazolo[3,2-a]pyrimidin-5-one (VI) by means of Na2CO3 and KI lo refluxing 4-methyl-2-pentanone. Compound (VI) is obtained by cyclocondensation of 2-thiazolylamine (VII) with 3 acetyl 4,5 dihydro-2(3H)furanone (VIII) by means of aqueous concentrated HCl in refluxing toluene.

参考文献中间体

合成目标

【1】 Kennis, L.E.J.; Mertens, J.C.; Vandenberk, J. (Janssen Pharmaceutica NV); Novel ((bis(aryl)methylene)-1-piperidinyl)alkyl-pyrimidinones. EP 0110435; ES 8601965; US 4485107 .
【2】 Prous, J.; Castaner, J.; Ritanserin. Drugs Fut 1986, 11, 5, 391.

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)	22600	ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine	24228-40-8	C₁₅H₂₁NO₂	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)	22601	(1-benzyl-4-piperidinyl)[bis(4-fluorophenyl)]methanol		C₂₅H₂₅F₂NO	详情	详情
(IV)	24705	1-benzyl-4-[bis(4-fluorophenyl)methylene]piperidine		C₂₅H₂₃F₂N	详情	详情
(V)	24706	4-[bis(4-fluorophenyl)methylene]piperidine		C₁₈H₁₇F₂N	详情	详情
(VI)	24707	6-(2-chloroethyl)-7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one		C₉H₉ClN₂OS	详情	详情
(VIII)	24709	3-acetyldihydro-2(3H)-furanone	517-23-7	C₆H₈O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.

参考文献中间体

合成目标

【1】 Rae, D.R.; Jaap, D.R. (Akzo Nobel N.V.); Diphenylmethylene piperidine derivs.. EP 0842170; JP 1999508907; US 5935974; WO 9703065 .

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)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	33780	ethyl 1-trityl-4-piperidinecarboxylate		C₂₇H₂₉NO₂	详情	详情
(III)	29012	1-bromo-4-fluorobenzene	460-00-4	C₆H₄BrF	详情	详情
(IV)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(V)	33781	bis(4-fluorophenyl)(1-trityl-4-piperidinyl)methanol		C₃₇H₃₃F₂NO	详情	详情
(VI)	24706	4-[bis(4-fluorophenyl)methylene]piperidine		C₁₈H₁₇F₂N	详情	详情
(VII)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(VIII)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(IX)	33782	4-chloro-1-(1-pyrrolidinyl)-1-butanone		C₈H₁₄ClNO	详情	详情

Extended Information