CN1884251B - 一种盐酸贝凡洛尔的精制方法 - Google Patents
一种盐酸贝凡洛尔的精制方法 Download PDFInfo
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- CN1884251B CN1884251B CN 200510077341 CN200510077341A CN1884251B CN 1884251 B CN1884251 B CN 1884251B CN 200510077341 CN200510077341 CN 200510077341 CN 200510077341 A CN200510077341 A CN 200510077341A CN 1884251 B CN1884251 B CN 1884251B
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- Prior art keywords
- bevantolol hydrochloride
- refining
- water
- bevantolol
- hydrochloride
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- 229960003588 bevantolol Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 17
- HXLAFSUPPDYFEO-UHFFFAOYSA-N bevantolol Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC(O)COC1=CC=CC(C)=C1 HXLAFSUPPDYFEO-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 238000007670 refining Methods 0.000 title abstract description 7
- 239000007787 solid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000036772 blood pressure Effects 0.000 abstract 1
- 238000010276 construction Methods 0.000 abstract 1
- FJTKCFSPYUMXJB-UHFFFAOYSA-N bevantolol hydrochloride Chemical compound [Cl-].C1=C(OC)C(OC)=CC=C1CC[NH2+]CC(O)COC1=CC=CC(C)=C1 FJTKCFSPYUMXJB-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种高效、低成本的盐酸贝凡洛尔的精制方法。盐酸贝凡洛尔的化学结构如式(I)所示。
式(I)盐酸贝凡洛尔为一长效β1-受体阻滞剂，用于降低血压和治疗心绞痛。
Description
所属技术领域
本发明涉及盐酸贝凡洛尔的精制方法，盐酸贝凡洛尔为一长效β1-受体阻滞剂，用于降低血压和治疗心绞痛。
背景技术
盐酸贝凡洛尔(化学名：1-[2-(3，4-二甲氧苯基)乙氨基])-3-(3-甲基苯氧基)-2-异丙醇盐酸盐)，具有如下式结构：
盐酸贝凡洛尔为一长效β1-受体阻滞剂，用于降低血压和治疗心绞痛。
根据现有文献，盐酸贝凡洛尔主要按照如下路线进行合成：
工艺中用到了原料3，4-二甲氧基苯乙胺，其在反应过程中形成盐酸盐结构，很难与终产品用现有方法进行分离。文献中提到的盐酸贝凡洛尔的精制方法，主要是用乙腈、异丙醇对其粗品进行重结晶。但是我们在实验工作中发现：乙腈或异丙醇对本品的颜色和3，4-二甲氧基苯乙胺盐酸盐无明显精制效果，且较难去除无机盐。采用文献提供的精制方法，需要对产品进行多次重结晶，极大的增加了产品的成本，且增加了溶剂的后处理工作。本发明则提供了一种经济、高效且绿色环保的盐酸贝凡洛尔的精制方法。该方法可以只通过一次重结晶过程就可以将的盐酸贝凡洛尔粗品精制合格，符合药用原料药标准。
发明内容
本发明的目的是提供一种经济、高效且绿色环保的盐酸贝凡洛尔的精制方法，通过该方法能够有效的改善产品的颜色，同时也能够有效的去除3，4-二甲氧基苯乙胺的盐酸盐等杂质，能够制得纯度在99.8％以上的高纯度的盐酸贝凡洛尔产品。
本发明方法是用水或一种与水混溶的有机溶剂(如丙酮，乙腈，甲醇，乙醇，异丙醇等)同水以一定比例混合，在加热条件下使固体溶解，热过滤，冷却析晶，得到高纯度的盐酸贝凡洛尔。
本发明的特征是：
①在药物的精制工艺中可以避免使用乙腈等毒性较大的有机溶剂；
②使用了水作为主要精制溶剂，降低了生产成本；
③减少了精制次数，简化操作，降低了成本；
④本发明方法可以制备出纯度大于99.8％的高纯度盐酸贝凡洛尔，且可有效控制无机盐含量；
以下的实施例在于详细说明本发明，而非限制本发明。
实施例1
向反应瓶中加入蒸馏水150ml，50g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：46g，收率：92％，纯度：99.82％(HPLC)，炽灼残渣：0.012％。
实施例2
向反应瓶中加5％的异丙醇水溶液2250ml，300g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：282g，收率：94％，纯度：99.81％(HPLC)，炽灼残渣：0.010％。
实施例3
向反应瓶中加入95％的异丙醇水溶液550ml，100g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：95g，收率：95％，纯度：99.80％(HPLC)，炽灼残渣：0.013％。
实施例4
向反应瓶中加入5％的丙酮水溶液160ml，50g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：46g，收率：92％，纯度：99.85％(HPLC)，炽灼残渣：0.014％。
实施例5
向反应瓶中加入5％的乙醇水溶液200ml，60g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：57g，收率：95％，纯度：99.89％(HPLC)，炽灼残渣：0.010％。
实施例6
向反应瓶中加入95％的乙醇溶液320ml，60g盐酸贝凡洛尔粗品，回流使固体溶解，热过滤，滤液冷却析晶。抽滤，干燥至恒重，得到白色固体粉末：56g，收率：93％，纯度：99.85％(HPLC)，炽灼残渣：0.011％。
Claims (1)
1.一种盐酸贝凡洛尔的精制方法，该方法在于，用水或一种与水混溶的有机溶剂同水以一定比例混合，在加热条件下使固体溶解，热过滤，冷却析晶，得到高纯度的盐酸贝凡洛尔，其中与水混溶的有机溶剂选自丙酮、异丙醇、乙醇。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510077341 CN1884251B (zh) | 2005-06-22 | 2005-06-22 | 一种盐酸贝凡洛尔的精制方法 |
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| CN 200510077341 CN1884251B (zh) | 2005-06-22 | 2005-06-22 | 一种盐酸贝凡洛尔的精制方法 |
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| Publication Number | Publication Date |
|---|---|
| CN1884251A CN1884251A (zh) | 2006-12-27 |
| CN1884251B true CN1884251B (zh) | 2010-06-23 |
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| CN 200510077341 Expired - Fee Related CN1884251B (zh) | 2005-06-22 | 2005-06-22 | 一种盐酸贝凡洛尔的精制方法 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936607A (zh) * | 2013-01-23 | 2014-07-23 | 扬子江药业集团上海海尼药业有限公司 | 盐酸贝凡洛尔制备方法 |
| CN119591511A (zh) * | 2024-12-04 | 2025-03-11 | 北京四环科宝制药股份有限公司 | 盐酸贝凡洛尔晶型及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3857891A (en) * | 1971-12-14 | 1974-12-31 | Parke Davis & Co | New aminoalkanol compounds and methods for their production |
| US4994618A (en) * | 1984-05-15 | 1991-02-19 | Warner-Lambert Company | Bevantolol preparation |
| US5382689A (en) * | 1991-10-03 | 1995-01-17 | Nippon Chemiphar Co., Ltd. | Process for preparation of bevantolol hydrochloride |
-
2005
- 2005-06-22 CN CN 200510077341 patent/CN1884251B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3857891A (en) * | 1971-12-14 | 1974-12-31 | Parke Davis & Co | New aminoalkanol compounds and methods for their production |
| US4994618A (en) * | 1984-05-15 | 1991-02-19 | Warner-Lambert Company | Bevantolol preparation |
| US5382689A (en) * | 1991-10-03 | 1995-01-17 | Nippon Chemiphar Co., Ltd. | Process for preparation of bevantolol hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 陈芬儿.有机药物合成法 1 1.中国医药科技出版社,1999,732-734. * |
| 陈芬儿.有机药物合成法1 1.中国医药科技出版社,1999,732-734. |
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| CN1884251A (zh) | 2006-12-27 |
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