CN1415614A - Technique for synthesizing Irbesartan - Google Patents
Technique for synthesizing Irbesartan Download PDFInfo
- Publication number
- CN1415614A CN1415614A CN 02138504 CN02138504A CN1415614A CN 1415614 A CN1415614 A CN 1415614A CN 02138504 CN02138504 CN 02138504 CN 02138504 A CN02138504 A CN 02138504A CN 1415614 A CN1415614 A CN 1415614A
- Authority
- CN
- China
- Prior art keywords
- butyl
- normal
- irbesartan
- methyl
- cyano group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 239000002947 C09CA04 - Irbesartan Substances 0.000 title claims description 15
- 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 description 15
- 229960002198 irbesartan Drugs 0.000 title claims description 15
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- -1 2'-cyanobiphenyl-4- yl Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 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 13
- 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
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 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
- 239000002994 raw material Substances 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
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 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
- 239000000463 material Substances 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 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
- 239000000203 mixture Substances 0.000 abstract 1
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A process for synthesizing Ebeishatan features that the intermediate 2-n-butyl-3-[(2'-cyanobiphenyl-4- yl)methyl]-1,3-diazaspiro [4,4]-nonyl-1-ene-4-one can be directly used in next step without purification, and in the reaction where cyano is converted to tetrazazole, the mixture of tributyl tin chloride and sodium azide is used to replace tributyl tin azide. Its advantage is high output rate up to 75%.
Description
Technical field
The present invention relates to a kind of synthesis technique of irbesartan.
Background technology
Synthesis technique about irbesartan, existing open source literature report all is with 2-normal-butyl-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone (hereinafter to be referred as heterocycle) and 4-brooethyl-2 '-after cyano group-biphenyl condensation 2-normal-butyl-3-[(2 '-cyanobiphenyl-4-yl) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone, this compound and three normal-butyl nitrine tin react and make.Intermediate 2-normal-butyl-3-[(2 '-cyanobiphenyl-4-yl in the above-mentioned technology) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-purification process of 1-alkene-4-ketone is a column chromatography for separation, be not suitable for suitability for industrialized production, and three domestic being difficult to of normal-butyl nitrine tin of raw material buys.
Summary of the invention
The technical problem to be solved in the present invention is exactly that existing irbesartan synthesis technique is not suitable for suitability for industrialized production, production cost height and the rare problem of raw material.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
Intermediate 2-normal-butyl-3-[(2 '-cyanobiphenyl-4-yl) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-the not purified method that is directly used in next step reaction of 1-alkene-4-ketone, and be converted in the reaction of tetrazole at cyano group, replace three normal-butyl nitrine tin with three normal-butyl chlorination tin and sodium azide mixed material feeding.Whole technological process comprises the steps:
(1) methyl 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl)]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-preparation of 1-alkene-4-ketone:
A. add heterocycle, anhydrous earlier in three-necked bottle, stir, gradation adds sodium hydride then, adds the back and stirs 0.5 hour, drips 2-cyano group-4 '-bromomethylbiphenyl and is dissolved in the solution of DMF, drips off the back stirring at room;
B. thin layer is followed the tracks of raw material reaction and is needed 3 hours fully approximately, and decompression steams DMF, residue ethyl acetate extraction;
C. combined ethyl acetate layer, after water, the saturated common salt water washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure gets 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone crude product;
The chemical equation in this step is as follows:
(2), irbesartan is synthetic
A. in three-necked bottle, add 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl successively) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone, sodium azide, dimethylbenzene, stir, drip three normal-butyl chlorination tin, add post-heating, backflow;
B. thin layer is followed the tracks of to react completely needs 70 hours approximately, stop heating, after being chilled to room temperature, with the sodium hydroxide solution 50ml*3 extraction of 1mol/l, buck with after the ether 20ml*2 washing, is transferred PH=5 with the hydrochloric acid of 3mol/L mutually, extract with methylene dichloride 200ml*3, merge organic phase, after water 50ml, the saturated aqueous common salt 50ml washing, the anhydrous sodium sulfate drying concentrating under reduced pressure gets irbesartan crude product 6.4g.
The chemical equation in this step is as follows:
Raw material of the present invention is easy to get and cost reduces greatly than prior art, and two step yields reach 75%.
Embodiment
1, methyl 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl)]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-preparation of 1-alkene-4-ketone.
(3.9g 20mmol), dry DMF 20ml, stirs to add earlier heterocycle in three-necked bottle, gradation adds sodium hydride, and (1.25g 42mmol), adds the back and stirred 0.5 hour, (6g 22mmol) is dissolved in the solution of 40mlDMF, drips off the back stirring at room to drip 2-cyano group-4 '-bromomethylbiphenyl.(developping agent: sherwood oil: ethyl acetate=2: 1) raw material reaction needs 3 hours fully approximately in the thin layer tracking, decompression steams DMF, residue extracts with ethyl acetate 100ml*3, the combined ethyl acetate layer, after water 50ml, the saturated aqueous common salt 50ml washing, through anhydrous sodium sulfate drying, it is yellow viscous liquid 7.2g that concentrating under reduced pressure gets crude product VIII, yield 93.5%.
2, irbesartan is synthetic
In three-necked bottle, add 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl successively) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone (7.2g, 18.7mmol), sodium azide (1.63g, 25mmol), dimethylbenzene 100ml, stir, drip three normal-butyl chlorination tin (6.8ml, 25mmol), add post-heating, backflow.Thin layer is followed the tracks of (developping agent: ethyl acetate: methyl alcohol=6: 1) react completely and need 70 hours approximately, stop heating, after being chilled to room temperature, with the sodium hydroxide solution 50ml*3 extraction of 1mol/l, buck is mutually with after the ether 20ml*2 washing, hydrochloric acid with 3mol/L is transferred PH=5, with methylene dichloride 200ml*3 extraction, merge organic phase, after water 50ml, the saturated aqueous common salt 50ml washing, the anhydrous sodium sulfate drying concentrating under reduced pressure gets irbesartan crude product 6.4g, yield: 80%.
Claims (4)
1, a kind of irbesartan synthesis technique, it is characterized in that intermediate 2-normal-butyl-3-[(2 '-cyanobiphenyl-4-yl) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-the not purified method that is directly used in next step reaction of 1-alkene-4-ketone, and be converted in the reaction of tetrazole at cyano group, replace three normal-butyl nitrine tin with three normal-butyl chlorination tin and sodium azide mixed material feeding.
2, irbesartan synthesis technique as claimed in claim 1 is characterized in that comprising the steps:
(1) methyl 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl)]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-preparation of 1-alkene-4-ketone:
A. add heterocycle, dry DMF earlier in three-necked bottle, stir, gradation adds sodium hydride then, adds the back and stirs 0.5 hour, drips 2-cyano group-4 '-bromomethylbiphenyl and is dissolved in the solution of DMF, drips off the back stirring at room;
B. thin layer is followed the tracks of raw material reaction and is needed 3 hours fully approximately, and decompression steams DMF, residue ethyl acetate extraction;
C. combined ethyl acetate layer, after water, the saturated common salt water washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone;
(2), irbesartan is synthetic
A. in three-necked bottle, add 2-normal-butyl-3-[(-2 '-cyano group-biphenyl-4-yl successively) methyl]-1,3-diaza spiro [4,4]-ninth of the ten Heavenly Stems-1-alkene-4-ketone, sodium azide, dimethylbenzene, stir, drip three normal-butyl chlorination tin, add post-heating, backflow;
B. thin layer is followed the tracks of to react completely needs 70 hours approximately, stop heating, after being chilled to room temperature, with the sodium hydroxide solution 50ml*3 extraction of 1mol/1, buck with after the ether 20ml*2 washing, is transferred PH=5 with the hydrochloric acid of 3mol/L mutually, extract with methylene dichloride 200ml*3, merge organic phase, after water 50ml, the saturated aqueous common salt 50ml washing, the anhydrous sodium sulfate drying concentrating under reduced pressure gets irbesartan crude product 6.4g.
3, irbesartan synthesis technique as claimed in claim 2, used developping agent is a sherwood oil when it is characterized in that the middle thin layer tracking of step (1) reaction: ethyl acetate=2: 1.
4, irbesartan synthesis technique as claimed in claim 2, used developping agent is an ethyl acetate when it is characterized in that the middle thin layer tracking of step (2) reaction: methyl alcohol=6: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385041A CN100418962C (en) | 2002-10-28 | 2002-10-28 | Technique for synthesizing Irbesartan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385041A CN100418962C (en) | 2002-10-28 | 2002-10-28 | Technique for synthesizing Irbesartan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1415614A true CN1415614A (en) | 2003-05-07 |
| CN100418962C CN100418962C (en) | 2008-09-17 |
Family
ID=4749527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021385041A Expired - Lifetime CN100418962C (en) | 2002-10-28 | 2002-10-28 | Technique for synthesizing Irbesartan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100418962C (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
| WO2005122699A3 (en) * | 2004-06-16 | 2007-05-31 | Matrix Lab Ltd | An improved process for the preparation of n-substituted hetero cyclic derivatives |
| CN101006064B (en) * | 2004-08-23 | 2011-01-26 | 布里斯托尔-迈尔斯斯奎布公司 | Method for preparing irbesartan and intermediates thereof |
| CN104447763A (en) * | 2014-12-18 | 2015-03-25 | 南京华威医药科技开发有限公司 | Biphenyl tetrazole compound |
| CN106117146A (en) * | 2016-06-22 | 2016-11-16 | 浙江华海药业股份有限公司 | A kind of method preparing irbesartan condensation substance |
| CN108276389A (en) * | 2018-02-09 | 2018-07-13 | 北京化工大学 | A kind of synthetic method of Irbesartan |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5484955A (en) * | 1992-07-06 | 1996-01-16 | Takeda Chemical Industries, Ltd. | Tri-higher alkyl tin azide and its use |
-
2002
- 2002-10-28 CN CNB021385041A patent/CN100418962C/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
| WO2005122699A3 (en) * | 2004-06-16 | 2007-05-31 | Matrix Lab Ltd | An improved process for the preparation of n-substituted hetero cyclic derivatives |
| CN101006064B (en) * | 2004-08-23 | 2011-01-26 | 布里斯托尔-迈尔斯斯奎布公司 | Method for preparing irbesartan and intermediates thereof |
| CN104447763A (en) * | 2014-12-18 | 2015-03-25 | 南京华威医药科技开发有限公司 | Biphenyl tetrazole compound |
| CN106117146A (en) * | 2016-06-22 | 2016-11-16 | 浙江华海药业股份有限公司 | A kind of method preparing irbesartan condensation substance |
| CN108276389A (en) * | 2018-02-09 | 2018-07-13 | 北京化工大学 | A kind of synthetic method of Irbesartan |
| CN108276389B (en) * | 2018-02-09 | 2020-10-16 | 北京化工大学 | A kind of synthetic method of irbesartan |
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| Publication number | Publication date |
|---|---|
| CN100418962C (en) | 2008-09-17 |
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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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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 |