ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine -Drug Synthesis Database

【结构式】

【分子编号】22600

【品名】ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine

【CA登记号】24228-40-8

【分子式】C₁₅H₂₁NO₂

【分子量】247.33728

【元素组成】C 72.84% H 8.56% N 5.66% O 12.94%

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：(I)

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：(III)

AHR-53338 is synthesized in an overall yield of 62% from ethyl isonipecotate (I): Ethyl isonipecotate (I) is protected with benzyl bromide (II) to give (III), which is then treated with 2.5 moles of 4-fluorophenylmagnesium bromide to give the tertiary alcohol (IV). The benzyl group is removed by catalytic hydrogenolysis to give the secondary piperidine (V). The reaction of 1-bromo-3-chloropropane (VI) with acetovanillone (VII) gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (VIII) in excellent yield. A mixture of (V) and (VIII) in 1-butanol and triethylamine heated at reflux yields AHR-53338 isolated as the mandelic acid salt.

参考文献中间体

合成目标

【1】 Yanni, J.M.; Walsh, D.A.; Franzyshen, S.K.; The synthesis and antiallergy activity of 1-[4-[3-. 193rd ACS Natl Meet 1987, Abst MEDI 85.
【2】 Yanni, J.M.; Walsh, D.A.; AHR-5333B. Drugs Fut 1988, 13, 7, 605.

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)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(B)	28161	2-hydroxy-2-phenylacetic acid	611-72-3	C₈H₈O₃	详情	详情
(I)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(II)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(III)	22600	ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine	24228-40-8	C₁₅H₂₁NO₂	详情	详情
(IV)	22601	(1-benzyl-4-piperidinyl)[bis(4-fluorophenyl)]methanol		C₂₅H₂₅F₂NO	详情	详情
(V)	22602	bis(4-fluorophenyl)(4-piperidinyl)methanol	60284-98-2	C₁₈H₁₉F₂NO	详情	详情
(VI)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(VII)	22604	1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone	498-02-2	C₉H₁₀O₃	详情	详情
(VIII)	22605	4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone	58113-30-7	C₁₂H₁₅ClO₃	详情	详情

Extended Information