CN103601735A - Method for purifying moxidectin - Google Patents
Method for purifying moxidectin Download PDFInfo
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- CN103601735A CN103601735A CN201310557480.7A CN201310557480A CN103601735A CN 103601735 A CN103601735 A CN 103601735A CN 201310557480 A CN201310557480 A CN 201310557480A CN 103601735 A CN103601735 A CN 103601735A
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- mosictin
- moxidectin
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- crude product
- crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a method for purifying moxidectin, and belongs to the field of medicinal chemistry. The moxidectin is a novel, high-efficiency and spectral insecticide macrolide antibiotic which is widely applied to the veterinary clinic. The method comprises the following steps: mixing a moxidectin crude product with an appropriate organic solvent to prepare a solution, and placing moxidectin crystals into the solution to induce the crystallization at an appropriate temperature, thereby obtaining the moxidectin with higher purity. The moxidectin has the advantages of high yield, less solvent consumption and short preparation time. The moxidectin crude product with low initial purity can be repeatedly purified, so that the purity of a final product can be improved.
Description
Technical field
The present invention relates to a kind of method of the mosictin of purifying, belong to pharmaceutical chemistry field.
Background technology
Mosictin is a kind of spectrum of veterinary clinic, efficient, novel macrolide expelling parasite microbiotic of being widely used in, and is mainly used in treating the parasite on the animals such as cattle and sheep and farm crop.Synthetic, production and the morphology of mosictin have further instruction in US Patent No. 4916154A, Chinese patent CN101372492A, US Patent No. 5106994.
Known mosictin method of purification has at present:
1. in mosictin/methylcyclohexane solution, add water, vigorous stirring a couple of days, can obtain white mosictin precipitation.This method length consuming time, productive rate is low, and product purity improves not remarkable.
2. the column chromatography method of purification of mentioning in US Patent No. 4916154A and Chinese patent CN101372492A.This method can obtain the mosictin of 90% above purity, but expends a large amount of organic solvents, length consuming time, and solvent recuperation energy consumption is high simultaneously.
3. disclosed method in US Patent No. 7348417, US7645863 and their Chinese patent families CN1626536A: use methylcyclohexane and normal hexane (or normal heptane) recrystallization purification mosictin.This method can make the mosictin of 94% above purity, but because used the solvents high to mosictin solubleness such as methylcyclohexane, so the yield of this method is lower.
4. in US Patent No. 7348417 and Chinese patent families CN1117969A thereof, disclose a kind of by p-nitrophenyl acyl chlorides to protecting on mosictin, and then the method for being purified by recrystallizing methanol.But the method mainly for be " single assorted L " (referring to European Pharmacopoeia), there is limitation.
Summary of the invention
The invention provides a kind of method with higher yield, more low-cost purification mosictin.
The technical solution used in the present invention is: the step that a kind of method of the mosictin of purifying adopts is:
(1) weight ratio of organic solvent and mosictin crude product is 3:1-5:1,50 ℃ of following stirrings, obtains transparent mosictin solution;
(2) described mosictin solution is cooled to 30 ℃-25 ℃, and cooling rate is per hour is less than 5 ℃, and drops into mosictin crystal as crystal seed induced crystallization, and the weight ratio of described mosictin crystal and described mosictin crude product is 1:20-1:100;
(3) insulation ageing, the temperature of ageing is 30 ℃-10 ℃, digestion time is 6 hours-12 hours;
(4) filter crystal, vacuum-drying, drying temperature is less than 50 ℃, obtains mosictin;
(5) repeating step (1)-(4), obtain the mosictin that purity is greater than 94%.
In aforesaid method, described organic solvent adopts normal hexane or normal heptane.
The invention has the beneficial effects as follows: the method for this purification mosictin adopts mosictin crude product to mix with suitable organic solvent, make solution, under proper temperature, drop into mosictin crystal induced crystallization, can obtain more highly purified mosictin, there is productive rate high simultaneously, consumption solvent is few, the advantage that preparation time is short.For the lower mosictin crude product of those initial purity, can repeat once or repeatedly to improve the purity of its finished product.
Embodiment
By following embodiment, contribute to further to understand the present invention.
Embodiment 1
In 100mL round-bottomed flask, drop into mosictin crude product (10g, purity 90.6%), normal hexane (30g), be warming up to 45 ℃, be stirred to molten clear.Programmed cooling immediately, 5 ℃ of coolings per hour, are cooled to 30 ℃, drop into mosictin crystal (0.1g, purity 97.1%).Continue to be cooled to 25 ℃, ageing 2 hours, during keep soft and stir.Finally be cooled to 10 ℃, 2 ℃～3 ℃ of coolings per hour, and 10 ℃ of ageings 2 hours.Filter 5 ℃ of normal hexane drip washing for filter cake.45 ℃ of vacuum-dryings of filter cake 24 hours, obtain white solid powder 8.1g, and purity is 94.2%.
Embodiment 2
In 100mL round-bottomed flask, drop into mosictin crude product (10g, purity 83.1%), normal hexane (40g), be warming up to 40 ℃, be stirred to molten clear.Programmed cooling immediately, 5 ℃ of coolings per hour, are cooled to 28 ℃, drop into mosictin crystal (0.5g, purity 97.1%).Continue to be cooled to 20 ℃, ageing 12 hours, during keep soft and stir.Filter 10 ℃ of normal hexane drip washing for filter cake.45 ℃ of vacuum-dryings of filter cake 24 hours, obtain white solid powder 6.9g, and purity is 90.1%.
Embodiment 3
In 100mL round-bottomed flask, drop into mosictin crude product (10g, purity 91.1%), normal heptane (50g), be warming up to 40 ℃, be stirred to molten clear.Programmed cooling immediately, 5 ℃ of coolings per hour, are cooled to 30 ℃, drop into mosictin crystal (0.1g, purity 97.1%).Continue to be cooled to 25 ℃, ageing 2 hours, during keep soft and stir.Finally be cooled to 10 ℃, 2 ℃～3 ℃ of coolings per hour, and 10 ℃ of ageings 2 hours.Filter 5 ℃ of normal heptane drip washing for filter cake.45 ℃ of vacuum-dryings of filter cake 24 hours, obtain white solid powder 7.3g, and purity is 94.8%.
Embodiment 4
In 100mL round-bottomed flask, drop into mosictin crude product (10g, purity 79.6%), normal heptane (50g), be warming up to 38 ℃, be stirred to molten clear.Programmed cooling immediately, 5 ℃ of coolings per hour, are cooled to 25 ℃, drop into mosictin crystal (0.5g, purity 97.1%).Continue to be cooled to 20 ℃, ageing 12 hours, during keep soft and stir.Filter 10 ℃ of normal heptane drip washing for filter cake.45 ℃ of vacuum-dryings of filter cake 24 hours, obtain white solid powder 6.3g, and purity is 89.4%.
Above-mentioned purification obtains white solid powder and is dissolved in normal hexane (18.9g), is warming up to 45 ℃, is stirred to molten clear.Programmed cooling immediately, 5 ℃ of coolings per hour, are cooled to 30 ℃, drop into mosictin crystal (0.06g, purity 97.1%).Continue to be cooled to 25 ℃, ageing 2 hours, during keep soft and stir.Finally be cooled to 10 ℃, 2 ℃～3 ℃ of coolings per hour, and 10 ℃ of ageings 2 hours.Filter 5 ℃ of normal hexane drip washing for filter cake.45 ℃ of vacuum-dryings of filter cake 24 hours, obtain white solid powder 5.2g, and purity is 94.0%.
Claims (2)
1. the purify method of mosictin, is characterised in that: the step that described method adopts is:
(1) weight ratio of organic solvent and mosictin crude product is 3:1-5:1,50 ℃ of following stirrings, obtains transparent mosictin solution;
(2) described mosictin solution is cooled to 30 ℃-25 ℃, and cooling rate is per hour is less than 5 ℃, and drops into mosictin crystal as crystal seed induced crystallization, and the weight ratio of described mosictin crystal and described mosictin crude product is 1:20-1:100;
(3) insulation ageing, the temperature of ageing is 30 ℃-10 ℃, digestion time is 6 hours-12 hours;
(4) filter crystal, vacuum-drying, drying temperature is less than 50 ℃, obtains mosictin;
(5) repeating step (1)-(4), obtain the mosictin that purity is greater than 94%.
2. according to the method for a kind of mosictin of purifying described in claims 1, be characterised in that: described organic solvent adopts normal hexane or normal heptane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310557480.7A CN103601735B (en) | 2013-11-08 | 2013-11-08 | A kind of method of mosictin of purifying |
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| CN201310557480.7A CN103601735B (en) | 2013-11-08 | 2013-11-08 | A kind of method of mosictin of purifying |
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| CN103601735A true CN103601735A (en) | 2014-02-26 |
| CN103601735B CN103601735B (en) | 2015-12-09 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356140A (en) * | 2014-09-30 | 2015-02-18 | 大连九信生物化工科技有限公司 | Method for separating and preparing high-purity Moxidectin membrane |
| CN105001232A (en) * | 2015-07-08 | 2015-10-28 | 安徽省皖北药业股份有限公司 | Purification method for moxidectin |
| CN105294729A (en) * | 2015-11-12 | 2016-02-03 | 大连九信生物化工科技有限公司 | Method for eliminating by-product dimethyl sulfide during Moxidectin production process |
| CN105646521A (en) * | 2016-03-28 | 2016-06-08 | 河北圣雪大成制药有限责任公司 | Moxidectin crystallizing method |
| CN107216338A (en) * | 2016-03-21 | 2017-09-29 | 江苏汉邦科技有限公司 | A kind of method for isolating and purifying moxidectin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5106994A (en) * | 1984-06-05 | 1992-04-21 | American Cyanamid Company | Agents and method of production thereof |
| CN1117969A (en) * | 1994-06-22 | 1996-03-06 | 美国氰胺公司 | Method for the purification of 23-E isomers of 23-imino derivatives of LL-F28249 compounds |
| CN1626536A (en) * | 2003-08-07 | 2005-06-15 | 惠氏公司 | Method of purifying moxidectin through crystallization |
| CN101372492A (en) * | 2007-06-29 | 2009-02-25 | 浙江海正药业股份有限公司 | Method for preparing high-purity moxidectin |
-
2013
- 2013-11-08 CN CN201310557480.7A patent/CN103601735B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5106994A (en) * | 1984-06-05 | 1992-04-21 | American Cyanamid Company | Agents and method of production thereof |
| CN1117969A (en) * | 1994-06-22 | 1996-03-06 | 美国氰胺公司 | Method for the purification of 23-E isomers of 23-imino derivatives of LL-F28249 compounds |
| CN1626536A (en) * | 2003-08-07 | 2005-06-15 | 惠氏公司 | Method of purifying moxidectin through crystallization |
| CN101372492A (en) * | 2007-06-29 | 2009-02-25 | 浙江海正药业股份有限公司 | Method for preparing high-purity moxidectin |
Non-Patent Citations (2)
| Title |
|---|
| 刘开永，等: "新一代驱虫抗生素—莫西菌素", 《动物医学进展》, vol. 24, no. 4, 30 April 2003 (2003-04-30), pages 59 - 62 * |
| 魏红，吴秋业: "《化学实验（I）》", 31 August 2006, article "（三）结晶、重结晶", pages: 56 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356140A (en) * | 2014-09-30 | 2015-02-18 | 大连九信生物化工科技有限公司 | Method for separating and preparing high-purity Moxidectin membrane |
| CN104356140B (en) * | 2014-09-30 | 2016-06-08 | 大连九信生物化工科技有限公司 | A kind of membrance separation preparation method of high-purity moxidectin |
| CN105001232A (en) * | 2015-07-08 | 2015-10-28 | 安徽省皖北药业股份有限公司 | Purification method for moxidectin |
| CN105294729A (en) * | 2015-11-12 | 2016-02-03 | 大连九信生物化工科技有限公司 | Method for eliminating by-product dimethyl sulfide during Moxidectin production process |
| CN107216338A (en) * | 2016-03-21 | 2017-09-29 | 江苏汉邦科技有限公司 | A kind of method for isolating and purifying moxidectin |
| CN107216338B (en) * | 2016-03-21 | 2019-04-02 | 江苏汉邦科技有限公司 | A method of isolating and purifying moxidectin |
| CN105646521A (en) * | 2016-03-28 | 2016-06-08 | 河北圣雪大成制药有限责任公司 | Moxidectin crystallizing method |
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| CN103601735B (en) | 2015-12-09 |
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Effective date of registration: 20171124 Address after: 116600 double D five street, double D, Dalian economic and Technological Development Zone, 18 Patentee after: Dalian nine Fine Chemical Co., Ltd. Address before: 116600 Dalian economic and Technological Development Zone, Liaoning D double D Double Street, No. 18, No. five Patentee before: Dalian Join King Biological Chemical Technology Co., Ltd. |
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