CN100396691C - Preparation method of ivermectin - Google Patents
Preparation method of ivermectin Download PDFInfo
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- CN100396691C CN100396691C CNB2004100813959A CN200410081395A CN100396691C CN 100396691 C CN100396691 C CN 100396691C CN B2004100813959 A CNB2004100813959 A CN B2004100813959A CN 200410081395 A CN200410081395 A CN 200410081395A CN 100396691 C CN100396691 C CN 100396691C
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- Prior art keywords
- avrmectin
- phosphine
- product
- ivermectin
- rhx
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Abstract
The present invention provides a method for preparing ivermectin. The present invention is characterized in that 1 wt. % of a rhodium compound or a rhodium phosphine composition catalyst, 1 to 40 wt. % of phosphine ligand, 0.1 to 5 wt. % of surface active agent, 100 to 500 wt. % of water as a solvent, 100 to 500 wt. % of organic solvent and 10 to 200 wt. % of abamectin are put in a reaction kettle with a stirring device, a thermometer and a hydrogen gas outlet. The pH is regulated to 2 to 12. Before reaction, hydrogen gas is introduced in the kettle for displacing air. Then, hydrogen pressure rises from 0.1 to 5MPa. A mixture reacts for 6 to 24 hours at a temperature of 40 to 150 DEG C, and a product is analyzed by HPLC. The conversion rate of abamectin is from 96.0 to 99.8%, and selectivity is from 91.9 to 95.1%.
Description
One, technical field
The present invention relates to a kind of preparation method of ivermectin, belong to the preparation field of bio-pharmaceutical.
Two, background technology
Ivermectin is a kind of novel macrolide antibiotic class insect repellent, has advantages such as efficient, wide spectrum, low toxicity.Be widely used at present human body, animal and plant sterilant, drive mite agent etc., therefore be one of biological pesticide that has the potentiality that develop on a large scale very much.Its anthelmintic activity is by suppressing r-aminobutyric acid (GABA) acceptor, thereby nerve conduction is obstructed reach, can prevent and treat the parasite that those have developed immunity to drugs to General Medicine.
Ivermectin be by the Wilkinson catalyzer under the hydrogen effect with C in the Avrmectin molecule
22And C
23Between the carbon-carbon double bond dihydro product that obtains of hydrogenation optionally, promptly 22,23-dihydroavermectin B1.
In U.S. Pat 4,199,569 to disclose a kind of molecular formula be RhX (PR
3)
3Catalyzer can satisfy and select the hydrogenation requirement, wherein especially with the catalyzer RhCl (PPh of hydrocarbon dissolubility
3)
3The shortening effect is remarkable.U.S. Pat 6,072, the phosphine part of 052 usefulness rhodium salt and hydrocarbon dissolubility is used for Avrmectin hydrogenation system ivermectin at hydrazine or hydrazonium salt reducing in-situ generation catalyzer.And at European patent EP A0,059,616 at catalyzer RhCl (PPh
3)
3After catalysis Avrmectin hydrogenation reaction is finished, proposed a kind of method that reclaims catalyzer, precious metal is separated from reaction product.Now industrial many this legal systems of employing are equipped with the rhodium phosphine catalyst in ivermectin and the separated product.
The shortcoming of the Avrmectin selective hydrogenation reaction in the homogeneous catalysis system is: the Noble Metal Rhodium catalyst consumption is bigger, the relative consumption of catalyzer and Avrmectin is the catalyzer 0.05-0.5 mole of every mole of Avrmectin correspondence, or the mass ratio of catalyzer and substrate was up to 1: 10.After catalyzed reaction is finished through the process of complexity with separation means such as catalyst breakage, precipitations, metal rhodium is separated from product with the phosphine part, cause catalyzer not circulate, simultaneously metal rhodium and phosphine part are difficult to remove to the pollution of product, this not only makes the quality of product ivermectin be affected, and the production cost height.
In existing technology, WO9,838,201 usefulness [RhCl (COD)]
2And the situ catalytic system of TPPMS (single sulfonated triphenylphosphine sodium salt) composition, using the pure homogeneous catalysis system of making solvent, or in the biphasic catalysis system formed of water and organic solvent in the presence of tertiary butyl bromination ammonium, the transformation efficiency of hydrogenation reaction can reach 100%, selectivity is more than 98%.But adopt this method to prepare the used catalytic amount of ivermectin up to 30% of substrate weight, the phosphine part that uses is water-soluble relatively poor, and has a higher hydrocarbon dissolubility, the rhodium complex catalyst that is generated can enter organic layer inevitably, can not fundamentally solve separating of catalyzer and product, and catalyzer is to the pollution problem of product.
Three, summary of the invention
The preparation method that a kind of ivermectin of providing at the deficiencies in the prior art is provided is characterized in Avrmectin hydrogenation system ivermectin is reflected in water-organic biphasic catalysis system and carries out.Select water-soluble good phosphine part trisulfonated triphenylphosphine trisodium salt (TPPTS) or/and two sulfonated triphenylphosphine disodium salt (TPPDS) and RhX
3, RhX (L
1)
3, RhX (L
2)
3And RhX
2 
Water-soluble good rhodium compound or rhodium-and-phosphine composition in the presence of the long chain alkane tensio-active agent, have been realized Avrmectin selection hydrogenation preparing ivermectin as catalyzer.
Purpose of the present invention is realized that by following technical measures wherein said raw material umber is parts by weight except that Special Circumstances.
The preparation method of ivermectin:
With 1 part of rhodium compound or rhodium-and-phosphine composition catalyst and phosphine ligand 1～40 part, 0.1～5 part in tensio-active agent, 100～500 parts of aqueous solvent, 100～500 parts of organic solvents, 10～200 parts of Avrmectins, add and have in the reactor of agitator, thermometer and hydrogen gangway, regulate pH=2～12, in reaction forward direction still, feed the hydrogen exchange air, then hydrogen pressure being risen to 0.1～5Mpa, is 40～150 ℃ of reactions 6～24 hours in temperature, and product is analyzed with HPLC, learn the transformation efficiency 98.8～99.8% of Avrmectin, selectivity is 91.9～95.1%.
Wherein rhodium compound or rhodium-and-phosphine composition catalyst are RhX
3, RhX (L
1)
3, RhX (L
2)
3And RhX
2 In at least a.X is F, Cl, Br, I, L
1Be three-(-the sulfonate phenyl) phosphine, L
2Be two-(-the sulfonate phenyl) phosphine, sulfonate is alkali metal salts or ammonium salt.
The phosphine part is three-in (-sulfonate phenyl) phosphine, two-(-sulfonate phenyl) phosphine or three-(-sulfonate phenyl) phosphine and two-(-sulfonate phenyl) phosphine mixture any.
Tensio-active agent is a cats product: Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, tetradecyl benzyl dimethyl brometo de amonio, cetyl trimethylammonium bromide, dodecyl trimethylammonium bromo-phosphonium, any one in tetradecyl trimethylammonium bromo-phosphonium or the cetyl trimethyl bromo-phosphonium.
The solvent of catalyst-solvent is a water, and the organic solvent of solubilizing reaction thing is any one in hexanaphthene, methylcyclohexane, benzene, toluene or the dimethylbenzene.
The present invention has following advantage:
After the Avrmectin reaction is finished, catalyzer and phosphine part are soluble in the aqueous phase, product is dissolved in organic phase, promptly realize separating of rhodium compound or rhodium-and-phosphine composition catalyst, phosphine part and product by simple standing separation, solved the separation difficulty of above-mentioned catalyzer and product effectively, also solved the pollution problem of heavy metal and phosphine part product.This has not only simplified production process, has reduced production cost, has improved quality product; Adopting water not only safe but also cheap as solvent, is environment amenable " Green Chemistry " process.
Four, embodiment
Below by embodiment the present invention is specifically described; be necessary to be pointed out that at this present embodiment only is used for the present invention is further specified; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment according to the content of the invention described above.
Embodiment
1, with Avrmectin 150mg, rhodium compound RhCl
3.3H
3O 3.0mg, phosphine part TPPTS 39.0mg, cetyl trimethylammonium bromide 5.0mg, hexanaphthene 2.5ml, water 2.5ml add in the autoclave of 60ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 4MPa, heated and stirred was in 80 ℃ of reactions of temperature 6 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 99.2%, and selectivity is 91.9%.
2, with Avrmectin 150mg, rhodium complex RhCl
2 
5.0mg, phosphine part TPPDS 65.0mg, tetradecyl benzyl dimethyl brometo de amonio 2.0mg, methylcyclohexane 2.5ml, water 2.5ml add in the autoclave of 60ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is elevated to 3MPa, heated and stirred was in 90 ℃ of reactions of temperature 6 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 98.8%, and selectivity is 94.0%.
3, with Avrmectin 3.0g, rhodium-and-phosphine composition RhCl (TPPDS)
3160.0mg, the mixture 0.31g of phosphine part TPPTS and TPPDS, tetradecyl benzyl dimethyl brometo de amonio 60.0mg, toluene 15.0ml, water 20.0ml add in the autoclave of 100ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 3.0MPa, heated and stirred was in 60 ℃ of reactions of temperature 12 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 98.3%, and selectivity is 96.1%.
4, with Avrmectin 5.0g, rhodium compound RhCl
3.3H
2O 30mg, phosphine part TPPTS 0.40g, Trimethyllaurylammonium bromide 60.0mg, benzene 15.0ml, pH are 2.0 aqueous hydrochloric acid 30.0ml, add in the autoclave of 100ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 1.0MPa, heated and stirred was in 90 ℃ of reactions of temperature 12 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 98.5%, and selectivity is 94.5%.
5, with Avrmectin 6.0g, rhodium compound RhCl
3.3H
2O 30mg, phosphine part TPPTS 0.40g, Trimethyllaurylammonium bromide 60.0mg, dimethylbenzene 15.0ml, pH are 10.0 aqueous solution 10.0ml, add in the autoclave of 100ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 1.0MPa, heated and stirred was in 90 ℃ of reactions of temperature 6 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 98.0%, and selectivity is 92.5%.
6, with Avrmectin 3.0g, rhodium compound RhCl
3.3H
2O 40mg, phosphine part three-(-the potassium sulfonate phenyl) phosphine 1.50g, cetyl trimethyl bromo-phosphonium 100.0mg, toluene 15.0ml, water 15.0ml add in the autoclave of 100ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 5.0MPa, heated and stirred was in 120 ℃ of reactions of temperature 12 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 96.0%, and selectivity is 95.5%.
7, with Avrmectin 30.0g, rhodium complex RhCl
2 
0.5g, the mixture 4.5g of TPPTS and TPPDS, tetradecyl benzyl bromo-phosphonium 0.15g, toluene 200ml, water 200ml add in the autoclave of 1000ml.In reaction forward direction still, feed the hydrogen exchange air, then hydrogen pressure is risen to 2.0MPa, heated and stirred, 90 ℃ of reactions of sub-temperature 18 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 98.2%, and selectivity is 93.4%.
8, with Avrmectin 50.0g, rhodium-and-phosphine composition RhCl (TPPDS)
31.5g, tetradecyl benzyl brometo de amonio 0.15g, toluene 300ml, water 200ml add in the autoclave of 1000ml.Feed the hydrogen exchange air in reaction forward direction still, then hydrogen pressure is risen to 3.0MPa, heated and stirred was in 90 ℃ of reactions of temperature 24 hours.Product is analyzed with HPLC and is learnt that the transformation efficiency of Avrmectin is 99.2%, and selectivity is 94.6%.
Claims (2)
1. the preparation method of an ivermectin, it is characterized in that composition catalyst 1 weight part and phosphine ligand 1～40 weight parts with rhodium, tensio-active agent 0.1～5 weight part, solvent 100～500 weight parts, organic solvent 100～500 weight parts, Avrmectin 10～200 weight parts, add and have agitator, in the reactor of thermometer and hydrogen gangway, regulate pH=2～12, in reaction forward direction still, feed the hydrogen exchange air, then hydrogen pressure is risen to 0.1～5Mpa, in temperature is 40～150 ℃ of reactions 6～24 hours, product is analyzed with HPLC, learns the transformation efficiency 98.8～99.8% of Avrmectin, and selectivity is 91.9～95.1%;
Wherein, catalyzer is RhX (L
1)
3, RhX (L
2)
3And RhX
2 In at least a, X is Cl, L
1Be TPPTS, L
2Be TPPDS; The phosphine part is any in TPPTS, TPPDS or TPPTS and the TPPDS mixture, and solvent is a water, and organic solvent is any in hexanaphthene, methylcyclohexane, benzene, toluene or the dimethylbenzene.
2. the preparation method of ivermectin according to claim 1, it is characterized in that tensio-active agent is a cats product: Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, tetradecyl benzyl dimethyl brometo de amonio, cetyl trimethylammonium bromide, dodecyl trimethylammonium bromo-phosphonium, any in tetradecyl trimethylammonium bromo-phosphonium or the cetyl trimethyl bromo-phosphonium.
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|---|---|---|---|
| CNB2004100813959A CN100396691C (en) | 2004-12-06 | 2004-12-06 | Preparation method of ivermectin |
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|---|---|---|---|
| CNB2004100813959A CN100396691C (en) | 2004-12-06 | 2004-12-06 | Preparation method of ivermectin |
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|---|---|
| CN1651449A CN1651449A (en) | 2005-08-10 |
| CN100396691C true CN100396691C (en) | 2008-06-25 |
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ID=34869148
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|---|---|---|---|
| CNB2004100813959A Expired - Fee Related CN100396691C (en) | 2004-12-06 | 2004-12-06 | Preparation method of ivermectin |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362786B (en) * | 2008-10-06 | 2011-04-20 | 山东齐发药业有限公司 | Method for preparing ivermectin |
| CN102154168B (en) * | 2011-01-07 | 2012-06-06 | 石家庄市兴柏生物工程有限公司 | Abamectin producing bacterium and preparation method thereof |
| CN103396464B (en) * | 2013-07-16 | 2017-04-05 | 河北威远动物药业有限公司 | A kind of preparation method of ivermectin |
| CN112745367A (en) * | 2020-12-31 | 2021-05-04 | 浙江珲达生物科技有限公司 | Method for reducing content of heavy metal rhodium in ivermectin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998038201A1 (en) * | 1997-02-27 | 1998-09-03 | Antibioticos S.P.A. | Process for the preparation of ivermectin |
| US6072052A (en) * | 1996-10-31 | 2000-06-06 | Bayer Aktiengesellschaft | Method for the production of ivermectin |
-
2004
- 2004-12-06 CN CNB2004100813959A patent/CN100396691C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6072052A (en) * | 1996-10-31 | 2000-06-06 | Bayer Aktiengesellschaft | Method for the production of ivermectin |
| WO1998038201A1 (en) * | 1997-02-27 | 1998-09-03 | Antibioticos S.P.A. | Process for the preparation of ivermectin |
Non-Patent Citations (2)
| Title |
|---|
| 阿维菌素催化选择加氢合成伊维菌素的研究. 范琳玉等人.分子催化，第17卷第1期. 2003 |
| 阿维菌素催化选择加氢合成伊维菌素的研究. 范琳玉等人.分子催化，第17卷第1期. 2003 * |
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| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Hebei Veyon Animal Pharmaceutical Co., Ltd. Assignor: Sichuan University Contract record no.: 2011990000725 Denomination of invention: Preparation method of ivermectin Granted publication date: 20080625 License type: Exclusive License Open date: 20050810 Record date: 20110728 |
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Granted publication date: 20080625 Termination date: 20141206 |
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