CN102250090A - 一种米诺膦酸中间体的制备方法 - Google Patents
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Abstract
本发明涉及药物合成领域，具体涉及米诺膦酸的中间体2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)的制备方法。其特征是：将3-溴咪唑并[1，2-a]吡啶(II)与丙二酸二乙酯缩合得到2-(咪唑并[1，2-a]吡啶-3-基)丙二酸二乙酯(III)，然后水解脱羧得到(I)。本发明具有原料价廉易得、反应步骤少、操作简单、产品质量优、成本较低、适合工业化生产等优点。
Description
技术领域
本发明涉及药物合成领域，具体涉及米诺膦酸中间体2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)的制备方法。
背景技术
米诺膦酸为第三代氮杂芳基双膦酸盐衍生物，其化学名为[1-羟基-2-(咪唑并[1，2-a]吡啶-3-基)亚乙基]双膦酸一水合物，其抗骨吸收活性较帕米膦酸钠高100～1000倍，且能拮抗骨髓瘤和肿瘤引起的骨质溶解作用。临床用于治疗骨质疏松症。其化学结构如下：
文献报道的米诺膦酸的合成方法较多：
方法一：中国医药工业杂志2004，35(4)：193-194及文献J Med.Chem，1969，12(1)：122-126公开的合成方法如下：
该方法以2-咪唑并[1，2-a]吡啶为原料，与多聚甲醛和二甲胺盐酸盐进行曼尼希反应得到3-[(N，N-二甲胺基)甲基]咪唑并[1，2-a]吡啶，与溴乙烷反应形成季铵盐，再与氰化钠反应得到3-氰乙基咪唑并[1，2-a]吡啶，再在碱性条件下水解得到2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)。此方法用到了剧毒的氰化钠，环境不友好，同时副反应较多，生成的产品较难纯化，反应步骤多，操作繁琐，不适合工业化生产。
方法二：文献Chem Pharm Bull 1998，46(11)：1703的工艺路线为：
该方法通过原料2-氨基吡啶与4-溴乙酰乙酸乙酯环合后经水解得到2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)，再经双磷酸化得到米诺膦酸。此方法原料4-溴乙酰乙酸乙酯不稳定，制备时需要用到大量的溴，环境污染大，产物中以中间体(I)的同分异构体副产物(IV)居多，分离困难。
方法三：杨利民，一种高纯度米诺膦酸及其制备方法，CN101531681A(2009-09-16)的工艺路线为：
该方法采用丁二酸单乙酯酰氯为原料，经还原、溴代，然后与2-氨基吡啶环化，经水解得到中间体(I)。此方法需要-80℃低温反应，溶剂量大，溴代产率低，不适宜工业化生产。
上述三种制备方法均存在不同程度的不足，但工艺中都使用了关键中间体I，因此，寻找一种能够安全且容易控制的合成中间体I的方法十分必要。
发明内容
本发明公开了一种操作简单、后处理方便、成本低、收率较高的制备米诺膦酸中间体(I)的方法。
本发明的中间体(I)的制备方法包括：将3-溴咪唑并[1，2-a]吡啶(II)与丙二酸二甲酯或丙二酸二乙酯缩合得到2-(咪唑并[1，2-a]吡啶-3-基)丙二酸二乙酯(III)，III水解脱羧得到(I)。反应式如下：
其中R代表甲基或乙基；
碱是甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠或氢氧化钾；
酸是10％～37％盐酸、10％～49％氢溴酸或10％～80％硫酸，本发明的百分比均为重量百分比。
其中由II制备III的反应溶剂优选无水乙醇或无水甲醇。更优选无水乙醇。
由III制备I的反应温度优选50℃～130℃。更优选100℃～120℃。
酸优选30％～37％的盐酸。
R代表优选乙基。碱最优选乙醇钠。
其中II与丙二酸二甲酯或丙二酸二乙酯摩尔比为1∶1～1∶2，最优选为1∶1.3。
本发明方法还进一步包括用甲醇精制。
更优选的制备方法如下：
将II与丙二酸乙酯在乙醇钠存在下，于无水乙醇中反应，生成2-(咪唑并[1，2-a]吡啶-3-基)丙二酸二乙酯(III)，III在37％盐酸中水解得到2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)粗品，产品用甲醇重结晶得到精品。
本发明原料易得，原料价廉易得，反应步骤少，操作简单，产品质量优，成本较低，适合工业化生产，收率达53.9％。
具体实施方式
实施例1
2-(咪唑并[1，2-a]吡啶-3-基)丙二酸二乙酯(III)的制备
将50ml丙二酸二乙酯用1L无水乙醇溶解，加入30g乙醇钠室温搅拌反应2h，加入3-溴-咪唑并[1，2-a]吡啶(II)50g，回流反应4h。将反应液倒入大量冰水中，用乙酸乙酯萃取，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩，60℃鼓风干燥得黄色固体58g，收率82.8％。2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)的制备
将中间体(III)58g加入到反应瓶中，加入浓盐酸348ml，升温至120℃搅拌反应6h，反应结束。反应液减压浓缩，得到土黄色固体(I)27.5g，收率75.3％。
实施例2
2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)的重结晶
将27.5g中间体I粗品加入到反应瓶中，加入550ml甲醇，加热溶解，趁热过滤，滤液冷却析晶，抽滤得到类白色固体23.8g，收率86.5％，熔点236℃-238℃。
Claims (8)
1.一种制备2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)的方法，包括：
其中R代表甲基或乙基；
碱是甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠或氢氧化钾；
酸是10％～37％盐酸、10％～49％氢溴酸或10％～80％硫酸，为重量百分比。
2.权利要求1的方法，其中由II制备III的反应溶剂是无水乙醇或无水甲醇。
3.权利要求1的方法，其中由III制备I的反应温度为50℃～130℃。
4.权利要求3的方法，其中由III制备I的反应温度为100℃～120℃。
5.权利要求1的方法，其中酸是30％～37％的盐酸。
6.权利要求1的方法，其中R代表乙基，碱是乙醇钠。
7.权利要求1的方法，其中II与丙二酸二甲酯或丙二酸二乙酯摩尔比为1∶1～1∶2。
8.权利要求1的方法，包括：将II与丙二酸乙酯在乙醇钠存在下，于无水乙醇中反应，生成2-(咪唑并[1，2-a]吡啶-3-基)丙二酸二乙酯(III)，III在37％盐酸中水解得到2-(咪唑并[1，2-a]吡啶-3-基)乙酸(I)粗品，用甲醇重结晶得到精品。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103342639A (zh) * | 2013-07-25 | 2013-10-09 | 南通瑞点化工科技有限公司 | 一种合成2-苯基羧酸酯的方法 |
| CN110964010A (zh) * | 2019-11-29 | 2020-04-07 | 上海应用技术大学 | 一种米诺磷酸中间体的制备方法 |
| CN112390794A (zh) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
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| 《Bioconjugate Chem.》 20070828 Valentino Laquintana 等 N-Benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a New Fluorescent Probe for Peripheral Benzodiazepine Receptor and Microglial Cell Visualization 第1397-1407页 1-8 第18卷, 第5期 * |
| 《中国医药工业杂志》 20041231 皮士卿 等 米诺膦酸二钠的合成 第193-194页 1-8 第35卷, 第4期 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103342639A (zh) * | 2013-07-25 | 2013-10-09 | 南通瑞点化工科技有限公司 | 一种合成2-苯基羧酸酯的方法 |
| CN112390794A (zh) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
| CN112390794B (zh) * | 2019-08-19 | 2023-05-26 | 鲁南制药集团股份有限公司 | 一种米诺膦酸关键中间体的制备方法 |
| CN110964010A (zh) * | 2019-11-29 | 2020-04-07 | 上海应用技术大学 | 一种米诺磷酸中间体的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102250090B (zh) | 2013-01-16 |
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