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【结 构 式】 
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【分子编号】32034 【品名】4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinecarbaldehyde 【CA登记号】 |
【 分 子 式 】C13H14F2N2O2 【 分 子 量 】268.2632464 【元素组成】C 58.21% H 5.26% F 14.16% N 10.44% O 11.93% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of piperidine-4-carboxylic acid (I) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (II), which is treated with SOCl2 and acetic anhydride to yield the corresponding acyl chloride (III). The Friedel-Crafts condensation of (III) with refluxing 1,3-difluorobenzene (IV) by means of AlCl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (V), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (VI). The cyclization of (VI) by means of NaH in hot THF/DMF yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (VII), which is treated with HCl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (VIII). Finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) by means of K2CO3 in hot DMF. The intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (IX) with 3-chcloropropyl bromide (X) by means of NaH or K2CO3 in DMF.
| 【1】 Corbett, R.; Bordeau, K.J.; Helsley, G.C.; Szewczak, M.R.; Wilmot, C.A.; Chiang, Y.; Hartman, H.B.; Conway, P.G.; Glamkowski, E.J.; Strupczewski, J.T.; 3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: Antipsychotic profile of iloperidone (HP 873). J Med Chem 1995, 38, 7, 1119-31. |
| 【2】 Strupczewski, J.T.; Helsley, G.C.; Chiang, Y.; Bordeau, K.J. (Aventis Pharmaceuticals, Inc.); N-(Aryloxyalkyl)heteroarylpiperidines and-heteroarylpiperazines, a process for their preparation and their use as medicaments. EP 0402644; JP 1991063263 . |
| 【3】 Strupczewski, J.T.; Helsley, G.C.; Chiang, Y.; Bordeau, K.J.; Glamkowski, E.J. (Aventis Pharmaceuticals, Inc.); Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgetics. EP 0542136; EP 0612318; EP 0730452; EP 0957102; EP 0959075; EP 0959076; EP 0963984; JP 1995501055; JP 1997511215; US 5364866; US 5776963; WO 9309102; WO 9511680 . |
| 【4】 Mucke, H.A.M.; Castaner, J.; Iloperidone. Drugs Fut 2000, 25, 1, 29. |
| 【5】 Strupczewski, J.T.; Allen, R.C.; Gardner, B.A. (Aventis Pharmaceuticals, Inc.); 3-(4-Piperidyl)-1,2-benzisoxazoles. US 4355037 . |
| 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) | 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 |
| (II) | 32031 | 1-Formyl-4-piperidinecarboxylic acid | 84163-42-8 | C7H11NO3 | 详情 | 详情 |
| (III) | 32032 | 1-formyl-4-piperidinecarbonyl chloride | C7H10ClNO2 | 详情 | 详情 | |
| (IV) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (V) | 32033 | 4-(2,4-difluorobenzoyl)-1-piperidinecarbaldehyde | C13H13F2NO2 | 详情 | 详情 | |
| (VI) | 32034 | 4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinecarbaldehyde | C13H14F2N2O2 | 详情 | 详情 | |
| (VII) | 32035 | 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinecarbaldehyde | C13H13FN2O2 | 详情 | 详情 | |
| (VIII) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 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 |
| (XI) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)
| 【1】 Strupczewski JT, Allen RC, Gardner BA, et al. 1985. Synthesis and neuroleptic activity of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles. J Med Chem, 28(6) : 761～769. |
| 【2】 Strupczewski JT, Bordeau KJ, Chiang YL, et al. 1995. 3-[[(aryloxy) alkyl] piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone. J Med Chem, 38(7): 1119～1131. |
| 【3】 Walsh DA, Franzyshen SK, Yanni JM. 1989. Synthesis and antiallergy activity of 4-(diarylhydroxymethyl)-1-[3-(aryloxy) propyl] piperidines and structurally related compounds. J Med Chem, 32(1): 105～118. |
| 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) | 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 |
| (X) | 32035 | 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinecarbaldehyde | C13H13FN2O2 | 详情 | 详情 | |
| (I) | 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 |
| (III) | 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 |
| (IV) | 32031 | 1-Formyl-4-piperidinecarboxylic acid | 84163-42-8 | C7H11NO3 | 详情 | 详情 |
| (V) | 32032 | 1-formyl-4-piperidinecarbonyl chloride | C7H10ClNO2 | 详情 | 详情 | |
| (VI) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (VII) | 32033 | 4-(2,4-difluorobenzoyl)-1-piperidinecarbaldehyde | C13H13F2NO2 | 详情 | 详情 | |
| (VIII) | 32034 | 4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinecarbaldehyde | C13H14F2N2O2 | 详情 | 详情 | |
| (IX) | 67149 | （E）-4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinecarbaldehyde | C13H14F2N2O2 | 详情 | 详情 | |
| (XI) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 |