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【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

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

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.

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