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【结 构 式】 
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【分子编号】17401 【品名】(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate 【CA登记号】 |
【 分 子 式 】C31H36FNO5 【 分 子 量 】521.6289832 【元素组成】C 71.38% H 6.96% F 3.64% N 2.69% O 15.34% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(IX)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 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The synthesis of MDL-100907 [11C]-labeled at the 3'-methoxy group has been described: 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 yielding the carbohydroxamic ester (IV). The condensation of (IV) with the silylated guaiacole (V) by means of n-BuLi in THF affords the 4-benzoylpiperidine (VI), which is reduced with NaBH4 in methanol giving 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 simultaneously hydrolyzed and desilylated with K2CO3 in methanol affording the chiral carbinol (X). Finally, (X) is methylated 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) | 40497 | (3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone | C37H42FNO3Si | 详情 | 详情 | |
| (VII) | 40498 | (3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol | C37H44FNO3Si | 详情 | 详情 | |
| (VIII) | 17401 | (R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate | C31H36FNO5 | 详情 | 详情 | |
| (IX) | 40499 | (R)-(3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate | C46H52FNO5Si | 详情 | 详情 | |
| (X) | 17413 | 3-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-2-methoxyphenol | C21H26FNO3 | 详情 | 详情 |