(2S)-2-methoxy-2-phenylethanoic acid -Drug Synthesis Database

【结构式】

【分子编号】17400

【品名】(2S)-2-methoxy-2-phenylethanoic acid

【CA登记号】

【分子式】C₉H₁₀O₃

【分子量】166.1766

【元素组成】C 65.05% H 6.07% O 28.88%

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：(VIII)

MDL-100907 can be obtained by several different ways: 1) The condensation of piperidine-4-carboxamide (I) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in hot DMF gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide (III), which by reaction with refluxing POCl3 is converted into the nitrile (IV). The reduction of (IV) with diisobutyl aluminum hydride (DIBAL) in THF affords the aldehyde (V), which by condensation with 1,2-dimethoxybenzene (veratrole) (VI) by means of BuLi in THF affords racemic MDL-100907 (VII). The esterification of (VII) with (S)-2-methoxy-2-phenylacetic acid (VIII) by means of dicyclohexylcarbodiimide (DCC) and dimethyl-aminopyridine (DMAP) in refluxing CHCl3 affords a mixture of diastereomers that is submitted to column chromatography over silica gel to afford the pure diastereomer (IX). Finally, (IX) is saponified with K2CO3 in methanol/ water

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
(I)	11762	4-Piperidinecarboxamide; Isonipecotamide	39546-32-2	C₆H₁₂N₂O	详情	详情
(II)	17394	1-(2-bromoethyl)-4-fluorobenzene		C₈H₈BrF	详情	详情
(III)	17395	1-(4-fluorophenethyl)-4-piperidinecarboxamide		C₁₄H₁₉FN₂O	详情	详情
(IV)	17396	1-(4-fluorophenethyl)-4-piperidinecarbonitrile		C₁₄H₁₇FN₂	详情	详情
(V)	17397	1-(4-fluorophenethyl)-4-piperidinecarbaldehyde		C₁₄H₁₈FNO	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
(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

合成路线2

该中间体在本合成路线中的序号：(VIII)

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