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【结 构 式】 
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【分子编号】26065 【品名】3-isobutylpentanedioic acid 【CA登记号】 |
【 分 子 式 】C9H16O4 【 分 子 量 】188.22364 【元素组成】C 57.43% H 8.57% O 34% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)5) The condensation of 3-methylbutanal (XIX) with cyanoacetic acid ethyl ester (XXXII) or cyanoacetamide (XXXIII) by means of dipropylamine in refluxing hexane, followed by treatment with refluxing 6N HCl, gives 3-isobutylglutaric acid (XXXIV). This compound is converted into the corresponding anhydride (XXXV) by treatment with refluxing acetic anhydride. The reaction of the anhydride (XXXV) with NH4OH affords the glutaramic amide (XXXVI), which is submitted to optical resolution with (R)-(+)-1-phenylethylamine, yielding the (S)-enantiomer (XXXVII). Finally, this compound is submitted to a Hoffmann degradation with Br2/NaOH.
| 【1】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
| 【2】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
| 【3】 Huckabee, B.K.; Sobieray, D.M. (Pfizer Inc.); Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid. WO 9638405 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (XXXII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (XXXIII) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (XXXIV) | 26065 | 3-isobutylpentanedioic acid | C9H16O4 | 详情 | 详情 | |
| (XXXV) | 26066 | 4-isobutyldihydro-2H-pyran-2,6(3H)-dione | C9H14O3 | 详情 | 详情 | |
| (XXXVI) | 26067 | 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid | C9H17NO3 | 详情 | 详情 | |
| (XXXVII) | 26068 | (3R)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid | C9H17NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)
| 【1】 Zhang GS, Yang XP, Ma, YQ, et aL. 2006. Method for preparation of Pregabalin and its intermediate. W0 2006136087．(本专利属于Nhwa Pharma Corporation, Peop Rep China) |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (III) | 66601 | diethyl 3-isobutylpentanedioate | C13H24O4 | 详情 | 详情 | |
| (IV) | 26065 | 3-isobutylpentanedioic acid | C9H16O4 | 详情 | 详情 | |
| (V) | 66602 | 4-isobutylpiperidine-2,6-dione | C9H15NO2 | 详情 | 详情 | |
| (VI) | 26056 | 3-(aminomethyl)-5-methylhexanoic acid | 130912-52-6 | C8H17NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【1】 Chen A, Zhang JJ. 2005. Synthesis of Pregabalin. 中国医药工业杂志，35: 195～196 |
| 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) | 26065 | 3-isobutylpentanedioic acid | C9H16O4 | 详情 | 详情 | |
| (II) | 26066 | 4-isobutyldihydro-2H-pyran-2,6(3H)-dione | C9H14O3 | 详情 | 详情 | |
| (III) | 66612 | 3-(2-(aminooxy)-2-oxoethyl)-5-methylhexanoic acid | C9H17NO4 | 详情 | 详情 | |
| (IV) | 26056 | 3-(aminomethyl)-5-methylhexanoic acid | 130912-52-6 | C8H17NO2 | 详情 | 详情 |