CN110790731A - 4取代-γ丁内酯的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明属于药物化学领域，涉及式Ⅰ所示的(R)‑4‑丙基‑二氢呋喃‑2‑酮的制备。
Description
技术领域
本发明属于药物化学领域，涉及式Ⅰ所示的(R)-4-丙基-二氢呋喃-2-酮的制备。
背景技术
布瓦西坦(Brivaracetam)，化学名为(2S)-2-[(4R)-2-氧代-4-丙基吡咯烷-1-基]丁酰胺，是由比利时UCB公司研发的第三代抗癫痫药物，与上一代药物左乙拉西坦的化学结构和作用机制非常相似。FDA于2016年2月正式批准上市，并将其作为治疗成人和16岁以上青少年癫痫患者的部分发作、伴有或不伴有继发性全身发作的辅助治疗药物。布瓦西坦是一种高选择性、高亲和性的第二代SV2A配体，通过与中枢突触囊泡蛋白2A（SV2A）结合影响突触功能，同时作为一种高亲和性的钠通道抑制剂，显著提高抗癫痫活性。由于其独特的抗癫痫机制、较好的药动学性质、安全、高效的临床效果成为最有前景的新型抗癫痫药物之一。
在制备布瓦西坦过程中，化合物(Ⅰ)的使用极为频繁，但此类化合物的制备方法较为困难，所需反应条件较为苛刻或者溶剂试剂危险性较大，本专利旨在公开一种反应条件温和，试剂选择常规的适合工业化的方法。
发明内容
本发明提供式Ⅰ所示的(R)-4-丙基-二氢呋喃-2-酮制备方法，以保证布瓦西坦终产品有关物质合格及工业化生产的实现。
本发明制备方法，包含以下步骤：
1.在有机溶剂中，富马酸二甲酯（Ⅱ）和硝基丙烷（Ⅲ）反应得到式（Ⅳ）化合物。
2.式（Ⅳ）化合物经过水解反应得到式（Ⅴ）化合物。
3.式（Ⅴ）化合物分别经过单酯化、催化加氢反应、拆分得到式（Ⅶ）化合物。
4.式（Ⅵ）化合物经过还原、酸化后成内酯得到式（Ⅰ）化合物。
本发明具有以下有益效果：第一，原料廉价易得，成本低，绿色环保，为工业化生产提供了条件；第二，操作简便，工艺稳定，产品纯度高，有利于工业化生产。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1本发明布瓦西坦中间体的制备方法：
（1）化合物Ⅳ的制备
将富马酸二甲酯Ⅱ（317 g，2.2mol）、DBU（340g ，2.2mol）、1.60L乙腈加至3L三口烧瓶中，开启搅拌，待其完全溶解后，将硝基丙烷Ⅲ（214 g，2.4mol）缓慢滴加至反应瓶中，搅拌30min。反应结束，旋除溶剂，将所得固体用500mL DCM溶解，分离萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩滤液得375g粗品，经柱层析分离得252g淡黄色油状液体（淋洗剂为石油醚：乙酸乙酯=6:1），收率为61.6%。1H NMR δ(ppm):1.07 (t, 3H),2.15–2.27 (m, 2H), 3.35 (s, 2H), 3.76 (s, 3H), 7.11 (t, 1H)。
（2）化合物Ⅴ的制备
将化合物Ⅳ（252g，1.35mol）、乙醇(2L)加至5L三口烧瓶中，搅拌使其混合均匀，降温至0℃，将300mL 1N NaOH水溶液滴加至反应体系，滴加完毕，加热回流6h，TLC点板检测反应进程。反应结束，滴加1N HCl调节反应液PH至3~4，经EA萃取，取有机相用饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩滤液得192g无色油状液体，收率为90.0%。1H NMR δ(ppm):1.12 (t, 3H),2.19–2.32 (m, 2H), 3.38 (s, 2H), 3.72 (s, 3H), 7.14 (t, 1H)。
（3）化合物Ⅵ的制备
将化合物Ⅴ（192g，1.21mol）、叔丁醇（2L）和Amberylst 15（13.3g）在室温下加至5L三口烧瓶中，搅拌使其混合均匀，加热回流8h。降至室温后，用200ml叔丁醇淋洗Amberylst 15树脂，滤液浓缩，得到黄色油状物，经柱层析分离得181g淡黄色油状液体（淋洗剂为二氯甲烷：甲醇=9:1），收率为70%。1H NMR δ(ppm):1.09 (t, 3H),1.42(s,9H),2.23–2.32 (m,2H), 3.42 (s, 2H), 3.76 (s, 3H), 7.10 (t, 1H)。
（4）化合物Ⅶ的制备
将化合物Ⅵ（181g，0.84mol）溶于2L EtOH中，通N2置换空气5min，后加入10%Pd/C（10g），加入完毕，室温下通H2以开始反应，TLC点板监测反应进程。反应结束，抽滤除去Pd/C，得淡黄色透明滤液，旋除溶剂得172g淡黄色固体，收率为94.7%。
a) 将淡黄色固体（172g，0.80mol）溶于1.7 L甲醇中，搅拌加热使之完全溶解；
b) 将(S)-α-苯乙胺（107g，0.88mol）加至3L三口瓶中，搅拌溶解；
c) 将a)混合液滴加至b)混合液中，滴加完毕，冷却析晶5h，过滤得152g粗品。
将粗品溶于1.2L甲醇中加热回流30min，0-5℃冷却析晶5h，得到产物91g，，收率27％HPLC：光学纯度为98.3%。1H NMR δ(ppm):0.91 (t, 3H), 1.30–1.42 (m, 2H), 1.45(s, 9H),1.47–1.69 (m, 2H), 2.43 (dd, 1H), 2.66–2.92 (m, 2H)。
（5）化合物Ⅰ的制备
将化合物Ⅶ（91g，0.27mol）溶于1N HCl中，用乙酸乙酯萃取、干燥。有机相浓缩后，再用无水THF溶解冷却至0℃，加入硼烷二甲硫醚（10M，30mL）室温下搅拌过夜，后加入1N盐酸淬灭反应，再加入100 mL的TFA，于50℃下搅拌12h。反应液中加入饱和氯化钠，用乙酸乙酯萃取。干燥，浓缩，残余物减压蒸馏得18g无色液体，收率52.0%。1H NMR δ(ppm):0.94 (t,3H), 1.30–1.40 (m, 2H), 1.50-1.44 (m, 1H),2.15-2.21 (m, 1H), 2.52-2.65(m,2H), 3.93 (dd, 2H),4.42 (dd, 2H)。
Claims (5)
1.一种式Ⅰ的制备方法，其特征在于，包含以下步骤：
。
2.根据权利要求1的方法，化合物Ⅵ制备中单酯化选择的醇可为甲醇、乙醇、异丙醇或叔丁醇等，优选叔丁醇。
3.根据权利要求1的方法，化合物Ⅵ制备中酯化催化剂可为Amberlyst 15、DCC、浓硫酸等，优选Amberlyst 15。
4.根据权利要求1的方法，其中化合物Ⅶ制备采用的加氢还原反应为室温和常压；
5.根据权利要求1的方法，其中化合物Ⅷ制备采用的还原剂为硼烷二甲硫醚或硼氢化钠和碘体系。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286504A (zh) * | 2022-08-18 | 2022-11-04 | 上海博氏医药科技有限公司 | 一种合成（r）-2-（2-（叔丁氧基）-2-氧乙基）戊酸的方法 |
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| CN105646319A (zh) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | 一种布瓦西坦的制备方法 |
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| WO2018042393A1 (en) * | 2016-09-05 | 2018-03-08 | Micro Labs Limited | Novel process for the preparation of brivaracetam |
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2018
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Patent Citations (3)
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| CN105646319A (zh) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | 一种布瓦西坦的制备方法 |
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Non-Patent Citations (3)
| Title |
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| ROBERTO BALLINI ET AL.: "Conjugate addition of nitroalkanes to dimethyl maleate. Regioselective formation of both monoesters of 2-alkylsuccinic acids", TETRAHEDRON, vol. 59, pages 7283 - 7289, XP004453326, DOI: 10.1016/S0040-4020(03)01175-X * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286504A (zh) * | 2022-08-18 | 2022-11-04 | 上海博氏医药科技有限公司 | 一种合成（r）-2-（2-（叔丁氧基）-2-氧乙基）戊酸的方法 |
| CN115286504B (zh) * | 2022-08-18 | 2024-01-26 | 上海博氏医药科技有限公司 | 一种合成（r）-2-（2-（叔丁氧基）-2-氧乙基）戊酸的方法 |
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