(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone -Drug Synthesis Database

【结构式】

【分子编号】17409

【品名】(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone

【CA登记号】

【分子式】C₂₂H₂₆FNO₃

【分子量】371.4517832

【元素组成】C 71.14% H 7.06% F 5.11% N 3.77% O 12.92%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XVII)

2) Racemic MDL-100907 (VII) can also be obtained by reaction of piperidine-4-carboxylic acid (X) with di-tert-butyl dicarbonate (XI) by means of NaOH in tert-butanol/ water, giving piperidine-1,4-dicarboxylic acid 1-mono-tert-butyl ester (XII), which is treated with N,O-dimethylhydroxylamine (XIII) and carbonyldiimidazole (CDI) in dichloromethane to afford the methoxy(methyl)amide (XIV). The condensation of (XIV) with veratrole (VI) by means of BuLi in THF gives 4-(2,3-dimethoxybenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (XV), which is decarboxylated by means of trifluoroacetic acid, yielding ketone (XVI). The condensation of (XVI) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in DMF affords 1-(2,3-dimethoxyphenyl)-1-[1-[2-(4-fluorophenyl)-ethyl]piperidin-4-yl]methanone (XVII). Finally, this compound is reduced with NaBH4 in methanol

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; MDL-100907. Drugs Fut 1998, 23, 9, 955.
【2】 Carr, A.A.; Kane, J.M.; Hay, D.A. (Merrell Pharmaceuticals, Inc.); (+)-*-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. EP 0531410; JP 1993507482; US 5134149; WO 9118602 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情
(VI)	17398	2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene	91-16-7	C₈H₁₀O₂	详情	详情
(VII)	17399	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol		C₂₂H₂₈FNO₃	详情	详情
(X)	17402	4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid	498-94-2	C₆H₁₁NO₂	详情	详情
(XI)	13214	Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate	24424-99-5	C₁₀H₁₈O₅	详情	详情
(XII)	17404	1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid	84358-13-4	C₁₁H₁₉NO₄	详情	详情
(XIII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XIV)	17406	tert-butyl 4-[[methoxy(methyl)amino]carbonyl]tetrahydro-1(2H)-pyridinecarboxylate		C₁₃H₂₄N₂O₄	详情	详情
(XV)	17407	tert-butyl 4-(2,3-dimethoxybenzoyl)tetrahydro-1(2H)-pyridinecarboxylate		C₁₉H₂₇NO₅	详情	详情
(XVI)	17408	(2,3-dimethoxyphenyl)(4-piperidinyl)methanone		C₁₄H₁₉NO₃	详情	详情
(XVII)	17409	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone		C₂₂H₂₆FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

3) Racemic MDL-100907 (VII) can also be obtained as follows: The reaction of piperidine-4-carboxylic acid ethyl ester (XVIII) with the previously mentioned bromide (II) by means of K2CO3 as before gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxylic acid ethyl ester (XIX), which is treated with N,O-dimethylhydroxylamine (XIII) to afford carboxamide (XX). The condensation of (XX) with veratrole (VI) by means of BuLi as before yields the ketonic precursor (XVII), which is finally reduced as before. 4) [11C]-Radiolabeled MDL-100907 can be obtained as follows: Racemic MDL-100907 (VII) is treated with L-Selectride in THF, yielding racemic 1-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]-1-(3-hydroxy-2-methoxy-phenyl)methanol (rac-XXI), which is submitted to semi-preparative HPLC separation over Chiracel OD, affording pure (R-XXI). Finally, this compound is methylated with [11C]-methyl iodide and KOH in HMPA. If this methylation is performed with nonlabeled methyl iodide, MDL-100907 is obtained. 5) The radiolabeling of phenol (R-XXI) can also be performed with better yields using [11C]-methyl trifluoromethanesulfonate (XXII) as methylating agent. Triflate (XXII) is obtained by reaction of silver triflate with [11C]-methyl iodide.

参考文献中间体

合成目标

【1】 Mathis, C.A.; Mahmood, K.; Price, J.C.; Huang, Y.; Gerdes, J.M.; Simpson, N.R.; Synthesis and preliminary in vivo evaluation of [11C]MDL 100907: A potent and selective radioligand for the 5-HT2A receptor system. Med Chem Res 1996, 6, 1, 1-10.
【2】 Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; MDL-100907. Drugs Fut 1998, 23, 9, 955.
【3】 Hiyama, T.; Minami, T.; Hanamoto, T.; Reddy, G.B. (Sagami Chemical Research Center); Optically active esters of 7-substd. 3,5-difunctionalized 6-heptenoic acids. EP 0475627 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情
(VI)	17398	2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene	91-16-7	C₈H₁₀O₂	详情	详情
(VII)	17399	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol		C₂₂H₂₈FNO₃	详情	详情
(XIII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XVII)	17409	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone		C₂₂H₂₆FNO₃	详情	详情
(XVIII)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(XIX)	17411	ethyl 1-(4-fluorophenethyl)-4-piperidinecarboxylate		C₁₆H₂₂FNO₂	详情	详情
(XX)	17412	1-(4-fluorophenethyl)-N-methoxy-N-methyl-4-piperidinecarboxamide		C₁₆H₂₃FN₂O₂	详情	详情
(XXI)	17413	3-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-2-methoxyphenol		C₂₁H₂₆FNO₃	详情	详情
(XXII)	17414	methyl trifluoromethane sulfonate; methyl trifluoromethanesulfonate	333-27-7	C₂H₃F₃O₃S	详情	详情
(XXII)	45233	methyl trifluoromethanesulfonate		C₂H₃F₃O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The synthesis of MDL-100907 [11C]-labeled at the 2'-methoxy group has been reported: Condensation of 2-(4-fluorophenyl)ethyl bromide (I) with piperidine-4-carboxylic acid ethyl ester (II) by means of K2CO3 in DMF gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxylic acid ethyl ester (III), which is treated with N,O-dimethylhydroxylamine and ethylmagnesium bromide in THF to yield compound (IV). Condensation of (IV) with veratrole (V) by means of BuLi in THF affords the 4-benzoylpiperidine derivative (VI), which is reduced with NaBH4 in methanol to give the racemic carbinol (VII). Optical resolution of (VII) by esterification with (S)-2-methoxy-2-phenylacetic acid (VIII) by means of DCC and DMAP in chloroform followed by column chromatography yields the diastereomer (IX), which is hydrolyzed with K2CO3 in methanol to afford MDL-100907 (X). Selective demethylation of (X) with L-selectride in THF gives the 2'-hydroxy derivative (XI), which is finally remethylated with [11C]-methyl iodide and K2CO3 in methanol.

参考文献中间体

合成目标

【1】 Mathis, C.A.; Huang, Y.Y.; Mahmood, K.; An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions. J Label Compd Radiopharm 1999, 42, 10, 949.

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)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情
(II)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(III)	17411	ethyl 1-(4-fluorophenethyl)-4-piperidinecarboxylate		C₁₆H₂₂FNO₂	详情	详情
(IV)	17412	1-(4-fluorophenethyl)-N-methoxy-N-methyl-4-piperidinecarboxamide		C₁₆H₂₃FN₂O₂	详情	详情
(V)	40496	tert-butyl(2-methoxyphenoxy)diphenylsilane; tert-butyl(diphenyl)silyl 2-methoxyphenyl ether		C₂₃H₂₆O₂Si	详情	详情
(VI)	17409	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone		C₂₂H₂₆FNO₃	详情	详情
(VII)	17399	(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol		C₂₂H₂₈FNO₃	详情	详情
(VIII)	17400	(2S)-2-methoxy-2-phenylethanoic acid		C₉H₁₀O₃	详情	详情
(IX)	17401	(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate		C₃₁H₃₆FNO₅	详情	详情
(X)	40494	(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol		C₂₂H₂₈FNO₃	详情	详情
(XI)	40495	2-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-6-methoxyphenol		C₂₁H₂₆FNO₃	详情	详情

Extended Information