CN104817546A - Method for recovering olmesartan medoxomil mother solution - Google Patents
Method for recovering olmesartan medoxomil mother solution Download PDFInfo
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- CN104817546A CN104817546A CN201510258319.9A CN201510258319A CN104817546A CN 104817546 A CN104817546 A CN 104817546A CN 201510258319 A CN201510258319 A CN 201510258319A CN 104817546 A CN104817546 A CN 104817546A
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- olmesartan medoxomill
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention provides a recovery method of an olmesartan medoxomil mother solution, which comprises the following steps: concentrating a certain amount of olmesartan medoxomil mother solution under reduced pressure, filtering, pulping, washing, heating until the solution is clear, adding a crystal seed for induction, carrying out vacuum filtration, drying and the like to obtain the olmesartan medoxomil product. The method has the advantages of high recovered product quality, high yield, simple technical operation and the like. Besides, the recovery technique can recycle the solvent, thereby saving the production cost, lowering the energy consumption and being beneficial to environment friendliness.
Description
Technical field
The present invention relates to a kind of method of olmesartan medoxomill disposing mother liquor, belong to pharmaceutical technology sectors.
Technical background
Olmesartan medoxomill (Olmesartan Medoxomil) is novel Angiotensin II 1 receptor (AT1) antagonist of a class, and by Japan three, companies and U.S. Forest Laboratories research and develop (structural formula is as follows) jointly altogether.Have that dosage is little, the advantage such as instant effect, step-down are lasting, curative effect is obviously better than the sartans that losartan etc. comparatively early goes public, and is regarded as a kind of comparatively ideal antihypertensive drug.In addition, Olmesartan all has better effect to arteriosclerosis, myocardial hypertrophy, heart failure, diabetes, ephrosis etc.In May, 2002 goes on the market in the U.S. with trade(brand)name Benicar, and October in the same year goes on the market in Germany, and in July, 2006 smoothly logs in Chinese market so that trade(brand)name is proud.Olmesartan medoxomill wide market, has reached 21.57 hundred million U.S. dollars at global marketing volume in 2008.Along with compound Patent expiry, olmesartan medoxomill has become the major products of each imitation medicine company of world research and development.
According to document and patent report, existing many operational paths of olmesartan medoxomill are applied to industrialized production, although the starting material that these operational paths use and reaction reagent are not quite similar, but every bar operational path all needs the further crystallization purifying through solvent, just can reach the purity needed for API product.Wherein, three totally 2003 annual reports disclose multiple refining solvent, the research in later stage finds: acetone soln has good impurity elimination effect as refining solvent.But use acetone solvent crystallization purifying not only to cause the raising of the decline of overall yield, pre-production cost for the period, and small part olmesartan medoxomill product is dissolved in crystallization mother liquor, for the three-protection design in later stage makes troubles.Therefore, the olmesartan medoxomill in necessary recovery mother liquor.In addition, the olmesartan medoxomill crystalline mother solution impurity that also enrichment is more, is difficult to purify further from mother liquor the olmesartan medoxomill product dissolved.Therefore, be badly in need of the method for a kind of high efficiente callback olmesartan medoxomill mother liquor of exploitation, be conducive to the raising of product yield on the one hand, cost-saving; Be conducive to energy-conserving and environment-protective on the other hand.
We take concentrating under reduced pressure mother liquor, making beating washing, crystallization of lowering the temperature, add the strategies such as crystal seed induction, and from mother liquor, be recovered to olmesartan medoxomill product, the product obtained meets US DMF quality standard.The method refining effect is good, yield is high, and technological operation is easy, is suitable for industrialized production.
Summary of the invention
The object of the invention is a kind of method developing effective olmesartan medoxomill disposing mother liquor, for the recovery of olmesartan medoxomill, be applicable to industrialized production.
The object of the invention is to realize by following technical solution:
By olmesartan medoxomill mother liquor first reclaim under reduced pressure part acetone solution, then filtering filtrate, then wash with organic solvent making beating.After making beating, add recovery acetone soln, heating up, it is clearly molten to stir, and adds the aqueous solution and olmesartan medoxomill crystal seed, cooling crystallization, and suction filtration, drying, reclaim and obtain olmesartan medoxomill product.
Above-mentioned mother liquor is that olmesartan medoxomill crude product treating process in acetone soln produces, and is the filtrate obtained after cooling crystallization filters.
The method can first by a certain amount of olmesartan medoxomill mother liquor reclaim under reduced pressure part acetone solution, and the quality reclaiming acetone soln is 70% ~ 95% of mother liquor quality, and preferably 85% ~ 90%.
The method organic solvent used can be ester class, ethers, alcohols, halogenated hydrocarbon solvent, and wherein esters solvent is ethyl acetate, and ether solvent is methyl tertiary butyl ether, and alcoholic solvent is ethanol, and halogenated hydrocarbon solvent is methylene dichloride.
In the mother liquor that the method is used, the quality of olmesartan medoxomill is 1:10 ~ 1:18 with adding the mass ratio reclaiming acetone soln, and preferred proportion is 1:12 ~ 1:16.
What the method was used add reclaim acetone soln after, molten clear temperature is 40 ~ 60 DEG C, and preferable temperature is 45 ~ 55 DEG C.
What the method was used adds the aqueous solution with the mass ratio of recovery acetone soln is 1:1 ~ 1:5, and preferred proportion is 1:2 ~ 1:4.
The amount of what the method was used add crystal seed is 1% ~ 10% of olmesartan medoxomill quality, and preferred proportion is 3% ~ 5%.
The method cooling recrystallization temperature used is-10 ~ 10 DEG C, and preferable temperature is-5 ~ 5 DEG C.
The method crystallization time used is 3 ~ 20 h, and the preferred time is 5 ~ 15 h.
The invention provides preferred technical scheme as follows:
By 150 g olmesartan medoxomill mother liquors (content is 10 %), the acetone of first reclaim under reduced pressure 90 %, then filtering filtrate, the solid of separating out is pulled an oar in ethanolic soln, filter after making beating, add and reclaim acetone soln 200 g, be warming up to 50 DEG C clearly molten, add the aqueous solution and the 0.6 g olmesartan medoxomill crystal seed of 50 mL, stirring at room temperature 30 min.Then cool the temperature to 0 DEG C, stir 6 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 84 %, HPLC purity is 99.66 %.
In sum, olmesartan medoxomill mother liquor reclaiming method technique provided by the present invention is simple, solvent energy recovery.In addition, the olmesartan medoxomill product yield utilizing this method to reclaim is high, purity good.
Embodiment
The present invention is further described in conjunction with the embodiments.Following examples just illustrate the present invention, and not limit the present invention by any way.
Wherein, olmesartan medoxomill crude product reference method synthesis (East China University of Science's journal, the synthesis of antihypertensive agent Olmesartan, 2005,31 (2), 189-192), and olmesartan medoxomill mother liquor preparation method is as follows: in 2L four-hole boiling flask, add 100g olmesartan medoxomill crude product and 1400g acetone soln, be heated to reflux state, until material complete molten clear after, cool the temperature to 40 DEG C, underpressure distillation goes out 700g acetone, after distillation terminates, reaction solution is cooled to 0 ~ 5 DEG C, separate out solid, feed liquid is filtered, obtains filtrate and be mother liquor.
Embodiment 1:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 70 %, then filtering filtrate, the solid of separating out is pulled an oar in dichloromethane solution, filter after making beating, add and reclaim acetone soln 180 g, be warming up to 40 DEG C clearly molten, add the aqueous solution and the 0.25 g olmesartan medoxomill crystal seed of 180 mL, stirred at ambient temperature 30 min.Then cool the temperature to-10 DEG C, stir 5 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 81 %, HPLC purity is 99.47 %.
Embodiment 2:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 75 %, then filtering filtrate, the solid of separating out is pulled an oar in ethanolic soln, filter after making beating, add and reclaim acetone soln 150 g, be warming up to 45 DEG C clearly molten, add the aqueous solution and the 0.50 g olmesartan medoxomill crystal seed of 75 mL, stirred at ambient temperature 30 min.Then cool the temperature to-5 DEG C, stir 3 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 79 %, HPLC purity is 99.38 %.
Embodiment 3:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 80 %, then filtering filtrate, the solid of separating out is pulled an oar in ethyl acetate solution, filter after making beating, add and reclaim acetone soln 170 g, be warming up to 47 DEG C clearly molten, add the aqueous solution and the 0.15 g olmesartan medoxomill crystal seed of 57 mL, stirred at ambient temperature 30 min.Then cool the temperature to 0 DEG C, stir 7 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 85 %, HPLC purity is 99.52 %.
Embodiment 4:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 85 %, then filtering filtrate, the solid of separating out is pulled an oar in t-butyl methyl ether solution, filter after making beating, add and reclaim acetone soln 220 g, be warming up to 43 DEG C clearly molten, add the aqueous solution and the 0.20 g olmesartan medoxomill crystal seed of 55 mL, stirred at ambient temperature 30 min.Then cool the temperature to 3 DEG C, stir 10 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 86 %, HPLC purity is 99.60 %.
Embodiment 5:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 90 %, then filtering filtrate, the solid of separating out is pulled an oar in ethanolic soln, filter after making beating, add and reclaim acetone soln 200 g, be warming up to 50 DEG C clearly molten, add the aqueous solution and the 0.75 g olmesartan medoxomill crystal seed of 40 mL, stirred at ambient temperature 30 min.Then cool the temperature to 5 DEG C, stir 12 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 87 %, HPLC purity is 99.65 %.
Embodiment 6:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 95 %, then filtering filtrate, the solid of separating out is pulled an oar in dichloromethane solution, filter after making beating, add and reclaim acetone soln 240 g, be warming up to 53 DEG C clearly molten, add the aqueous solution and the 1.0 g olmesartan medoxomill crystal seeds of 60 mL, stirred at ambient temperature 30 min.Then cool the temperature to 7 DEG C, stir 15 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 82 %, HPLC purity is 99.70 %.
Embodiment 7:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 87 %, then filtering filtrate, the solid of separating out is pulled an oar in ethyl acetate solution, filter after making beating, add and reclaim acetone soln 250 g, be warming up to 55 DEG C clearly molten, add the aqueous solution and the 1.1 g olmesartan medoxomill crystal seeds of 50 mL, stirred at ambient temperature 30 min.Then cool the temperature to 10 DEG C, stir 17 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 80 %, HPLC purity is 99.50 %.
Embodiment 8:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 90 %, then filtering filtrate, the solid of separating out is pulled an oar in ethanolic soln, filter after making beating, add and reclaim acetone soln 270 g, be warming up to 57 DEG C clearly molten, add the aqueous solution and the 0.55 g olmesartan medoxomill crystal seed of 90 mL, stirred at ambient temperature 30 min.Then cool the temperature to-7 DEG C, stir 5 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 78 %, HPLC purity is 99.53 %.
Embodiment 9:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 85 %, then filtering filtrate, the solid of separating out is pulled an oar in dichloromethane solution, filter after making beating, add and reclaim acetone soln 190 g, be warming up to 60 DEG C clearly molten, add the aqueous solution and the 0.45 g olmesartan medoxomill crystal seed of 95 mL, stirred at ambient temperature 30 min.Then cool the temperature to 0 DEG C, stir 20 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 81 %, HPLC purity is 99.60 %.
Embodiment 10:
By 150 g olmesartan medoxomill mother liquors (liquid content is 10 %), the acetone of first reclaim under reduced pressure 95 %, then filtering filtrate, the solid of separating out is pulled an oar in t-butyl methyl ether solution, filter after making beating, add and reclaim acetone soln 230 g, be warming up to 50 DEG C clearly molten, add the aqueous solution and the 1.5 g olmesartan medoxomill crystal seeds of 77 mL, stirred at ambient temperature 30 min.Then cool the temperature to 5 DEG C, stir 15 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 84 %, HPLC purity is 99.45 %.
Embodiment 11:
By 150 g olmesartan medoxomill mother liquors (content is 10 %), the acetone of first reclaim under reduced pressure 90 %, then filtering filtrate, the solid of separating out is pulled an oar in ethanolic soln, filter after making beating, add and reclaim acetone soln 200 g, be warming up to 50 DEG C clearly molten, add the aqueous solution and the 0.6 g olmesartan medoxomill crystal seed of 50 mL, stirring at room temperature 30 min.Then cool the temperature to 0 DEG C, stir 6 h at this temperature, suction filtration, vacuum-drying, obtain white solid, and yield is 84 %, HPLC purity is 99.66 %.
Claims (10)
1. an olmesartan medoxomill mother liquor reclaiming method, it is characterized in that: by olmesartan medoxomill mother liquor first reclaim under reduced pressure part acetone solution, then filtering filtrate, then wash, after making beating with organic solvent making beating, add recovery acetone soln, heating up, it is clearly molten to stir, and adds the aqueous solution and olmesartan medoxomill crystal seed, cooling crystallization, suction filtration, drying, reclaim and obtain olmesartan medoxomill product.
2. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that described olmesartan medoxomill mother liquor refers to what olmesartan medoxomill crude product treating process in acetone soln produced, is the filtrate obtained after cooling crystallization filters.
3. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: the quality of olmesartan medoxomill mother liquor reclaim under reduced pressure part acetone solution is 70% ~ 95% of mother liquor quality, preferably 85% ~ 90%.
4. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: organic solvent can be ester class, ethers, alcohols, halogenated hydrocarbon solvent.
5. olmesartan medoxomill mother liquor reclaiming method according to claim 4, is characterized in that: wherein esters solvent is ethyl acetate, and ether solvent is methyl tertiary butyl ether, and alcoholic solvent is ethanol, and halogenated hydrocarbon solvent is methylene dichloride.
6. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: in mother liquor, the quality of olmesartan medoxomill is 1:10 ~ 1:18 with adding the mass ratio reclaiming acetone soln, and preferred proportion is 1:12 ~ 1:16.
7. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: add after reclaiming acetone soln, molten clear temperature is 40 ~ 60 DEG C, and preferable temperature is 45 ~ 55 DEG C.
8. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: adding the aqueous solution with the mass ratio of recovery acetone soln is 1:1 ~ 1:5, and preferred proportion is 1:2 ~ 1:4.
9. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: the amount adding olmesartan medoxomill crystal seed is 1% ~ 10% of olmesartan medoxomill quality, and preferred proportion is 3% ~ 5%.
10. olmesartan medoxomill mother liquor reclaiming method according to claim 1, is characterized in that: cooling recrystallization temperature is-10 ~ 10 DEG C, and preferable temperature is-5 ~ 5 DEG C; The described crystallization time is 3 ~ 20 h, and the preferred time is 5 ~ 15 h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130968A (en) * | 2015-08-25 | 2015-12-09 | 江苏中邦制药有限公司 | Purification method of olmesartan |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070105923A1 (en) * | 2005-09-14 | 2007-05-10 | Glenmark Pharmaceuticals Limited | Substantially pure olmesartan medoxomil and processes for its preparation |
| CN101778843A (en) * | 2007-08-08 | 2010-07-14 | 力奇制药公司 | A process for the preparation of olmesartan medoxomil |
| WO2011013096A1 (en) * | 2009-07-31 | 2011-02-03 | Ranbaxy Laboratories Limited | Polymorphic form of olmesartan medoxomil |
| CN102558161A (en) * | 2011-12-07 | 2012-07-11 | 浙江华海药业股份有限公司 | Process for refining olmesartan medoxomil by adopting mixed solution of acetone and water |
| CN102850333A (en) * | 2011-06-30 | 2013-01-02 | 北京万生药业有限责任公司 | Olmesartan medoxomil crystal and preparation method thereof |
| JP2015074608A (en) * | 2013-10-07 | 2015-04-20 | 株式会社トクヤマ | Method for producing olmesartan medoxomil |
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- 2015-05-20 CN CN201510258319.9A patent/CN104817546B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070105923A1 (en) * | 2005-09-14 | 2007-05-10 | Glenmark Pharmaceuticals Limited | Substantially pure olmesartan medoxomil and processes for its preparation |
| CN101778843A (en) * | 2007-08-08 | 2010-07-14 | 力奇制药公司 | A process for the preparation of olmesartan medoxomil |
| WO2011013096A1 (en) * | 2009-07-31 | 2011-02-03 | Ranbaxy Laboratories Limited | Polymorphic form of olmesartan medoxomil |
| CN102850333A (en) * | 2011-06-30 | 2013-01-02 | 北京万生药业有限责任公司 | Olmesartan medoxomil crystal and preparation method thereof |
| CN102558161A (en) * | 2011-12-07 | 2012-07-11 | 浙江华海药业股份有限公司 | Process for refining olmesartan medoxomil by adopting mixed solution of acetone and water |
| JP2015074608A (en) * | 2013-10-07 | 2015-04-20 | 株式会社トクヤマ | Method for producing olmesartan medoxomil |
Non-Patent Citations (1)
| Title |
|---|
| 吴泰志 等: "抗高血压药奥美沙坦酯合成新路线和相关杂质的研究", 《药学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130968A (en) * | 2015-08-25 | 2015-12-09 | 江苏中邦制药有限公司 | Purification method of olmesartan |
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