CN100418962C - 一种厄贝沙坦合成工艺 - Google Patents
一种厄贝沙坦合成工艺 Download PDFInfo
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 title claims abstract description 16
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960002198 irbesartan Drugs 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title 1
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- -1 2'-cyanobiphenyl-4-yl Chemical group 0.000 claims abstract description 5
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- 150000003536 tetrazoles Chemical class 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- 125000003003 spiro group Chemical group 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 2
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 abstract 1
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 abstract 1
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- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 2
- SEXZHJJUKFXNDY-UHFFFAOYSA-N 1-(bromomethyl)-2-phenylbenzene Chemical group BrCC1=CC=CC=C1C1=CC=CC=C1 SEXZHJJUKFXNDY-UHFFFAOYSA-N 0.000 description 1
- KDFQYGBJUYYWDJ-UHFFFAOYSA-N azane;sodium Chemical compound N.[Na] KDFQYGBJUYYWDJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及一种厄贝沙坦的合成工艺，其特征是中间体2-正丁基-3-[(2’-氰基联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮不经纯化直接用于下一步反应的方法，并在氰基转化为四氮唑的反应中，用三正丁基氯化锡和叠氮钠混合投料代替三正丁基叠氮锡。本发明原料易得、且成本较现有技术大大降低，两步收率达到75%。
Description
技术领域
本发明涉及一种制备厄贝沙坦的合成工艺。
背景技术
关于厄贝沙坦的合成工艺，现有公开文献报道均是以2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮(以下简称杂环)与4-溴甲基-2′-氰基-联苯缩合后得2-正丁基-3-[(2′-氰基联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮，该化合物与三正丁基叠氮锡反应而制得。上述工艺中的中间体2-正丁基-3-[(2′-氰基联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮的纯化方法为柱层析分离，不适合工业化生产，且原料三正丁基叠氮锡国内难以购得。
发明内容
本发明要解决的技术问题就是现有的厄贝沙坦合成工艺不适合工业化生产、生产成本高、且原料难得的问题。
为解决上述技术问题，本发明采用如下技术方案：
中间体2-正丁基-3-[(2′-氰基联苯-4-基)甲基]--1，3-二氮杂螺[4，4]-壬-1-烯-4-酮不经纯化直接用于下一步反应的方法，并在氰基转化为四氮唑的反应中，用三正丁基氯化锡和叠氮钠混合投料代替三正丁基叠氮锡。整个工艺过程包括如下步骤：
(1)2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮的制备：
A.在三颈瓶中先加入杂环、无水DMF，搅拌，然后分次加入氢化钠，加完后搅拌0.5小时，滴加2-氰基-4′-溴甲基联苯溶于DMF的溶液，滴完后室温搅拌；
B.薄层跟踪原料反应完全约需3小时，减压蒸出DMF，残留物用乙酸乙酯提取；
C.合并乙酸乙酯层，用水、饱和食盐水洗涤后，经无水硫酸钠干燥，减压浓缩得2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮粗品；
本步的化学反应式如下：
(2)、厄贝沙坦的合成
A.在三颈瓶中依次加入2-正丁基-3-[(-2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮、叠氮钠、二甲苯，搅拌，滴加三正丁基氯化锡，加完后加热、回流；
B.薄层跟踪反应完全约需70小时，停止加热，冷至室温后，用1mol/l的氢氧化钠溶液50ml*3萃取，碱水相用乙醚20ml*2洗涤后，用3mol/L的盐酸调PH＝5，用二氯甲烷200ml*3萃取，合并有机相，用水50ml、饱和食盐水50ml洗涤后，无水硫酸钠干燥减压浓缩得厄贝沙坦粗品。
本步的化学反应式如下：
本发明原料易得、且成本较现有技术大大降低，两步收率达到75％。
具体实施方式
1、2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮的制备。
在三颈瓶中先加入杂环(3.9g，20mmol)、无水DMF20ml，搅拌，分次加入氢化钠(1.25g，42mmol)，加完后搅拌0.5小时，滴加2-氰基-4′-溴甲基联苯(6g，22mmol)溶于40mlDMF的溶液，滴完后室温搅拌。薄层跟踪(展开剂：石油醚∶乙酸乙酯＝2∶1)原料反应完全约需3小时，减压蒸出DMF，残留物用乙酸乙酯100ml*3提取，合并乙酸乙酯层，用水50ml、饱和食盐水50ml洗涤后，经无水硫酸钠干燥，减压浓缩得粗品为黄色粘稠状液体7.2g，收率93.5％。
2、厄贝沙坦的合成
在三颈瓶中依次加入2-正丁基-3-[(2-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮(7.2g，18.7mmol)、叠氨钠(1.63g，25mmol)、二甲苯100ml，搅拌，滴加三正丁基氯化锡(6.8ml，25mmol)，加完后加热、回流。薄层跟踪(展开剂：乙酸乙酯∶甲醇∶6∶1)反应完全约需70小时，停止加热，冷至室温后，用1mol/l的氢氧化钠溶液50ml*3萃取，碱水相用乙醚20ml*2洗涤后，用3mol/L的盐酸调PH＝5，用二氯甲烷200ml*3萃取，合并有机相，用水50ml、饱和食盐水50ml洗涤后，无水硫酸钠干燥减压浓缩得厄贝沙坦粗品6.4g，收率：80％。
Claims (4)
1. 一种以2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮和4-溴甲基-2′-氰基-联苯为原料制备厄贝沙坦的方法，其特征在于中间体2-正丁基-3-[(2′-氰基联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮不经纯化直接用于下一步反应，并在氰基转化为四氮唑的反应中，用三正丁基氯化锡和叠氮钠混合投料代替三正丁基叠氮锡。
2. 如权利要求1所述的以2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮和4-溴甲基-2′-氰基-联苯为原料制备厄贝沙坦的方法，其特征在于包括如下步骤：
(1)2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮的制备：
A.在三颈瓶中先加入2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮、无水DMF，搅拌，然后分次加入氢化钠，加完后搅拌0.5小时，滴加4-溴甲基-2′-氰基-联苯溶于DMF的溶液，滴完后室温搅拌；
B.薄层跟踪原料反应完全约需3小时，减压蒸出DMF，残留物用乙酸乙酯提取；
C.合并乙酸乙酯层，用水、饱和食盐水洗涤后，经无水硫酸钠干燥，减压浓缩得粗品2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮；
(2)、厄贝沙坦的合成
A.在三颈瓶中依次加入2-正丁基-3-[(2′-氰基-联苯-4-基)甲基]-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮、叠氮钠、二甲苯，搅拌，滴加三正丁基氯化锡，加完后加热、回流；
B.薄层跟踪反应完全约需70小时，停止加热，冷至室温后，用1mol/l的氢氧化钠溶液萃取3次，碱水相用乙醚洗涤2次后，用3mol/L的盐酸调PH＝5，用二氯甲烷萃取3次，合并有机相，用水和饱和食盐水洗涤后，无水硫酸钠干燥减压浓缩得厄贝沙坦粗品。
3. 如权利要求2所述的以2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮和4-溴甲基-2′-氰基-联苯为原料制备厄贝沙坦的方法，其特征在于步骤(1)中薄层跟踪反应时所用的展开剂是石油醚∶乙酸乙酯＝2∶1。
4. 如权利要求2所述的以2-正丁基-1，3-二氮杂螺[4，4]-壬-1-烯-4-酮和4-溴甲基-2′-氰基-联苯为原料制备厄贝沙坦的方法，其特征在于步骤(2)中薄层跟踪反应时所用的展开剂是乙酸乙酯∶甲醇＝6∶1。
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
| WO2005122699A2 (en) * | 2004-06-16 | 2005-12-29 | Matrix Laboratories Ltd | An improved process for the preparation of n-substituted hetero cyclic derivatives |
| TWI346108B (en) * | 2004-08-23 | 2011-08-01 | Bristol Myers Squibb Co | A method for preparing irbesartan and intermediates thereof |
| CN104447763B (zh) * | 2014-12-18 | 2017-05-17 | 南京华威医药科技开发有限公司 | 联苯四氮唑类化合物 |
| CN106117146A (zh) * | 2016-06-22 | 2016-11-16 | 浙江华海药业股份有限公司 | 一种制备厄贝沙坦缩合物的方法 |
| CN108276389B (zh) * | 2018-02-09 | 2020-10-16 | 北京化工大学 | 一种厄贝沙坦的合成方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5599943A (en) * | 1992-07-06 | 1997-02-04 | Takeda Chemical Industries, Ltd. | Method for producing tetrazolylbenzene compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599943A (en) * | 1992-07-06 | 1997-02-04 | Takeda Chemical Industries, Ltd. | Method for producing tetrazolylbenzene compound |
Non-Patent Citations (2)
| Title |
|---|
| 伊贝沙坦的合成工艺改进. 沈敬山等人.中国药物化学杂志，第11卷第2期. 2001 |
| 伊贝沙坦的合成工艺改进. 沈敬山等人.中国药物化学杂志，第11卷第2期. 2001 * |
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| C06 | Publication | ||
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| C14 | Grant of patent or utility model | ||
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| ASS | Succession or assignment of patent right |
Owner name: NANJING CHANG AO PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: CHANG'AO PHARMACY TECHNOLOGY CO., LTD., NANJING CITY Effective date: 20081031 |
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| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20081031 Address after: No. eight hundred, No. 2, Liuhe District, Jiangsu, Nanjing Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: Jiangsu province Nanjing city Qinhuai District dajiaochang No. 30 Patentee before: NANJING CHANGAO PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. |
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| C56 | Change in the name or address of the patentee | ||
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Address after: Kexinlu Liuhe District of Nanjing City, Jiangsu Province, No. 63 211500 Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: 211500 No. eight hundred, No. 2, Liuhe District, Jiangsu, Nanjing Patentee before: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. |
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| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 211500 No. 63 Kexin Road, Jiangbei New District, Nanjing City, Jiangsu Province Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: Kexinlu Liuhe District of Nanjing City, Jiangsu Province, No. 63 211500 Patentee before: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. |
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Granted publication date: 20080917 |