CN101891779A - Process for synthesizing clindamycin phosphate - Google Patents
Process for synthesizing clindamycin phosphate Download PDFInfo
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- CN101891779A CN101891779A CN 201010201899 CN201010201899A CN101891779A CN 101891779 A CN101891779 A CN 101891779A CN 201010201899 CN201010201899 CN 201010201899 CN 201010201899 A CN201010201899 A CN 201010201899A CN 101891779 A CN101891779 A CN 101891779A
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Abstract
The invention relates to a process for synthesizing clindamycin phosphate. The process comprises the following steps: 1) ketal reaction, wherein clindamycin hydrochloride alcoholate is used as a basic raw material to prepare a 3.4-clindamycin condensation compound through selective hydroxyl protection; and 2) phosphatidic reaction, wherein the 3.4-clindamycin condensation compound is used as a raw material, phosphorus oxychloride is used as a phosphatidic agent, and anhydrous potassium carbonate is used as an acid binding agent to complete the phosphatidic reaction under double actions of esterification catalyst dimethylamino pyridine and phase-transfer catalyst benzyl triethyl ammonium chloride, and a target compound, namely the clindamycin phosphate, can be obtained through hydrolysis deprotection. The process has the advantages that: 1, the process has simple method and practical application; 2, the content of pyridine/triethylamine in wastewater of phosphatidic reacting process can be controlled, so that the pressure of high COD wastewater drainage can be greatly reduced; and 3, the weight yield reaches over 95 percent, and the product quality fulfills the requirement of WS1-(X-322)-2003Z.
Description
Technical field
The present invention relates to a kind of synthesis technique of new Clindamycin Phosphate.
Background technology
Clindamycin Phosphate is as the broad-spectrum antibiotics bulk drug, and application clinically is very extensive, and it is the semi-synthetic derivative of lincomycin, and mechanism of action is synthetic for suppressing bacterioprotein.This product antimicrobial spectrum is identical with lincomycin, and anerobes such as gram-positive microorganisms such as streptococcus aureus, staphylococcus epidermidis, Hemolytic streptococcus, Streptococcus viridans, streptococcus pneumoniae, diphtheria corynebacterium and dyspepsiacoccus, peptostreptococcus, bacteroides fragilis, Fusobacterium, Eubacterium, propionibacterium are had anti-microbial effect.The synthesis technique that Clindamycin Phosphate is commonly used is at present: with 3.4-clindamycin condenses (protection thing) is raw material; do the phosphotidic agent with phosphorus oxychloride; make acid binding agent with single pyridine (or combination of pyridine and triethylamine); finish the phosphotidic reaction; through the hydrolysis deprotection, obtain target compound-Clindamycin Phosphate again.
There is following shortcoming in above-mentioned process program: (1) uses a large amount of pyridines (or pyridine and triethylamine), and owing to pyridine costs an arm and a leg, so production cost is very high; (2) because pyridine (or pyridine and triethylamine) wouldn't reclaim, all enter the phosphotidic processing wastewater, cause very big pressure to wastewater treatment.
Summary of the invention
Technical problem to be solved by this invention is the shortcoming and defect that overcomes existing synthesis technique, and the synthesis technique of the Clindamycin Phosphate of a kind of environmental protection, lower production cost is provided.
The present invention for the solution that problem adopts of the above-mentioned proposition of solution is: the synthesis technique of Clindamycin Phosphate, it is characterized in that including following steps: 1) ketal reaction: with the Dalacina alcoholate is basic raw material, by the selectivity hydroxyl protection, obtain 3.4-clindamycin condenses; 2) phosphotidic reaction: with 3.4-clindamycin condenses is raw material; do the phosphotidic agent with phosphorus oxychloride; Anhydrous potassium carbonate is made acid binding agent; under the dual function of esterifying catalyst Dimethylamino pyridine and phase-transfer catalyst benzyltriethylammoinium chloride; finish the phosphotidic reaction; through the hydrolysis deprotection, obtain target compound again: Clindamycin Phosphate.
Press such scheme, the ketal reaction concrete operation method of step 1) is: 1. press the Dalacina alcoholate: acetone: phosphorus oxychloride=1: 3～4: 0.6～0.8, and the weight ratio meter is got above-mentioned three kinds of materials and is mixed, under-10～20 ℃, insulation reaction 4～6 hours; 2. press the Dalacina alcoholate: yellow soda ash: water=1: 1～1.5: 10～15, the weight ratio meter is got yellow soda ash, water mixes, and then it is added to step 1. in the product of gained, and stirred crystallization obtains 3.4-clindamycin condenses.
Press such scheme, step 2) phosphotidic reaction concrete operation method is: 1. press 3.4-clindamycin condenses: acetone: phosphorus oxychloride: salt of wormwood: Dimethylamino pyridine: benzyltriethylammoinium chloride=1: 5～6: 1.2～1.8: 0.8～1.2: 0.1～0.15: 0.1～0.15, the weight ratio meter, getting above-mentioned substance mixes, under-10～20 ℃, insulation reaction 8～12 hours obtains reaction product; 2. in the gained reaction product, add 40～50 times of water by weight to 3.4-clindamycin condenses, under-10～20 ℃, insulation reaction 4～8 hours; 3) absorption, crystallization: according to a conventional method the product with gained adsorb, crystallization, promptly obtain target compound: Clindamycin Phosphate.
Beneficial effect of the present invention is:
1. the present invention mainly is phosphotidic reaction link, substitute organic bases (pyridine/triethylamine) with mineral alkali (salt of wormwood), under the dual function of esterifying catalyst DMAP (Dimethylamino pyridine) and phase-transfer catalyst TEBA-C1 (benzyltriethylammoinium chloride), finish the phosphotidic reaction, processing method is simple, has practical application;
2. the present invention only uses salt of wormwood because phosphotidic reaction process system is not used pyridine/triethylamine, has controlled the content of pyridine/triethylamine the phosphotidic reaction process waste water from the source, alleviates the pressure of high-COD waste water discharging greatly;
3. Technology has high yield, and product reaches more than 95% the weight yield of 3.4-clindamycin condenses (protection thing), and quality product reaches the requirement of WS1-(X-322)-2003Z.
Embodiment
In order to understand the present invention better, further set forth content of the present invention below in conjunction with the test example, but content of the present invention not only is confined to the following examples.
Embodiment 1
3.4-clindamycin condenses (protection thing) is synthetic
(1) get Dalacina alcoholate, acetone, each 40Kg of phosphorus oxychloride, 150Kg, 25Kg respectively, above-mentioned three kinds of materials are mixed, under-10～20 ℃, insulated and stirred reaction 4 hours;
(2) get yellow soda ash, each 60Kg of water, 500Kg respectively, carry out mixed dissolution, then it is added in the product of step (1) gained, stirred crystallization, the centrifugal wet product of 3.4-clindamycin condenses (protection thing) that obtain;
(3) dry dry product: 35.5Kg, weight yield 88.75%.
Embodiment 2
3.4-clindamycin condenses (protection thing) is synthetic
(1) get Dalacina alcoholate, acetone, each 80Kg of phosphorus oxychloride, 250Kg, 50Kg respectively, above-mentioned three kinds of materials are mixed, under-10～20 ℃, insulated and stirred reaction 6 hours;
(2) get yellow soda ash, each 100Kg of water, 1000Kg respectively, carry out mixed dissolution, then it is added in the product of step (1) gained, stirred crystallization, the centrifugal wet product of 3.4-clindamycin condenses (protection thing) that obtain.
(3) dry dry product: 72.5Kg, weight yield 90.63%.
Embodiment 3
Synthesizing of Clindamycin Phosphate
(1) gets 3.4-clindamycin condenses (protection thing) that embodiment 1 obtains and acetone, phosphorus oxychloride, salt of wormwood, each 40Kg of DMAP, TEBA-C1,240Kg, 50Kg, 30Kg, 5Kg, 5Kg respectively, above-mentioned substance is mixed, under-10～20 ℃, insulation reaction 8 hours;
(2) in step (1) products therefrom, add the water of 2000Kg, under-10～20 ℃, insulation reaction 4 hours;
(3) absorption, crystallization: according to a conventional method to the product of step (2) gained, adsorb, crystallization the centrifugal wet product of Clindamycin Phosphate that obtain.
(4) dry dry product: 39.1Kg, weight yield 97.75%.
Embodiment 4
Synthesizing of Clindamycin Phosphate
(1) gets 3.4-clindamycin condenses (protection thing) that embodiment 1 obtains and acetone, phosphorus oxychloride, salt of wormwood, each 80Kg of DMAP, TEBA-C1,440Kg, 100Kg, 60Kg, 10Kg, 10Kg respectively, above-mentioned five kinds of materials are mixed, under-10～20 ℃, insulation reaction 10 hours;
(2) in the product of step (1), add the water of 3500Kg, under-10～20 ℃, insulation reaction 6 hours;
(3) absorption, crystallization; According to a conventional method to the product of step (4), adsorb, crystallization the centrifugal wet product of Clindamycin Phosphate that obtain.
(4) dry dry product: 76.5Kg, weight yield 95.63%.
Embodiment 5
Synthesizing of Clindamycin Phosphate
(1) gets 3.4-clindamycin condenses (protection thing), acetone, phosphorus oxychloride, salt of wormwood, each 120Kg of DMAP, TEBA-Cl, 600Kg, 150Kg, 120Kg, 12Kg, the 12Kg that embodiment 2 obtains respectively; above-mentioned five kinds of materials are mixed; under-10～20 ℃, insulation reaction 12 hours.
(2) in the product of step (1), add the water of 5000Kg, under-10～20 ℃, insulation reaction 8 hours.
(3) absorption, crystallization; According to a conventional method to the product of step (4), adsorb, crystallization the centrifugal wet product of Clindamycin Phosphate that obtain.
(4) dry dry product: 114.3Kg, weight yield 95.25%.
Embodiment 6
Synthetic (current technology) of Clindamycin Phosphate
(1) get Dalacina alcoholate, acetone, each 40Kg of phosphorus oxychloride, 200L, 15L respectively, above-mentioned three kinds of materials are mixed, under-10～20 ℃, stirring reaction 6 hours;
(2) in the product of step (1), the pyridine of phosphorus oxychloride, 60L that adds 30L under-10～20 ℃, insulation reaction 6 hours.
(3) in the product of step (2), add the water of 2000Kg, under-10～20 ℃, insulation reaction 8 hours.
(4) absorption, crystallization; According to a conventional method to the product of step (3), adsorb, crystallization the centrifugal wet product of Clindamycin Phosphate that obtain.
(5) dry dry product: 32.4Kg, weight yield 81.0%.
Embodiment 7
Synthetic (current technology) of Clindamycin Phosphate
(1) get Dalacina alcoholate, acetone, each 80Kg of phosphorus oxychloride, 400L, 30L respectively, above-mentioned three kinds of materials are mixed, under-10～20 ℃, stirring reaction 6 hours;
(2) in the product of step (1), add the phosphorus oxychloride of 60L, the pyridine of 60L, the triethylamine of 60L, under-10～20 ℃, insulation reaction 6 hours.
(3) in the product of step (2), add the water of 4000Kg, under-10～20 ℃, insulation reaction 8 hours.
(4) absorption, crystallization; According to a conventional method to the product of step (3), adsorb, crystallization the centrifugal wet product of Clindamycin Phosphate that obtain.
(5) dry dry product: 63.6Kg, weight yield 79.5%.
Claims (3)
1. the synthesis technique of Clindamycin Phosphate, it is characterized in that: include following steps: 1) ketal reaction: with the Dalacina alcoholate is basic raw material, by the selectivity hydroxyl protection, obtains 3.4-clindamycin condenses; 2) phosphotidic reaction: with 3.4-clindamycin condenses is raw material; do the phosphotidic agent with phosphorus oxychloride; Anhydrous potassium carbonate is made acid binding agent; under the dual function of esterifying catalyst Dimethylamino pyridine and phase-transfer catalyst benzyltriethylammoinium chloride; finish the phosphotidic reaction; through the hydrolysis deprotection, obtain target compound again: Clindamycin Phosphate.
2. press the synthesis technique of the described Clindamycin Phosphate of claim 1, it is characterized in that: the ketal reaction concrete operation method of step 1) is: 1. press the Dalacina alcoholate: acetone: phosphorus oxychloride=1: 3～4: 0.6～0.8, the weight ratio meter, getting above-mentioned three kinds of materials mixes, under-10～20 ℃, insulation reaction 4～6 hours; 2. press the Dalacina alcoholate: yellow soda ash: water=1: 1～1.5: 10～15, the weight ratio meter is got yellow soda ash, water mixes, and then it is added to step 1. in the product of gained, and stirred crystallization obtains 3.4-clindamycin condenses.
3. press the synthesis technique of the described Clindamycin Phosphate of claim 1, it is characterized in that: step 2) phosphotidic reaction concrete operation method be: 1. press 3.4-clindamycin condenses: acetone: phosphorus oxychloride: salt of wormwood: Dimethylamino pyridine: benzyltriethylammoinium chloride=1: 5～6: 1.2～1.8: 0.8～1.2: 0.1～0.15: 0.1～0.15, the weight ratio meter, getting above-mentioned substance mixes, under-10～20 ℃, insulation reaction 8～12 hours obtains reaction product; 2. in the gained reaction product, add 40～50 times of water by weight to 3.4-clindamycin condenses, under-10～20 ℃, insulation reaction 4～8 hours; 3. absorption, crystallization: according to a conventional method the product with gained adsorb, crystallization, promptly obtain target compound: Clindamycin Phosphate.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964402A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof |
| CN103483399A (en) * | 2013-08-27 | 2014-01-01 | 河南天方药业股份有限公司 | Synthetic method of clindamycin phosphate |
| CN105037457A (en) * | 2015-07-27 | 2015-11-11 | 天方药业有限公司 | Application of tolyltriazole in clindamycin phosphate synthesis |
| CN107652332A (en) * | 2017-10-11 | 2018-02-02 | 福安药业集团重庆博圣制药有限公司 | A kind of preparation method of clindamycin phosphate |
| CN109111492A (en) * | 2018-10-18 | 2019-01-01 | 新宇药业股份有限公司 | A kind of preparation method of propylidene clindamycin B reference substance |
| CN110066301A (en) * | 2018-01-23 | 2019-07-30 | 天方药业有限公司 | A kind of synthetic method of clindamycin phosphate |
| CN115141234A (en) * | 2022-07-14 | 2022-10-04 | 湖南恒生制药股份有限公司 | Synthesis process of clindamycin phosphate raw material medicine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298463A (en) * | 2007-09-19 | 2008-11-05 | 浙江天台药业有限公司 | Preparation of clindamycinum phosphoester |
-
2010
- 2010-06-17 CN CN 201010201899 patent/CN101891779A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298463A (en) * | 2007-09-19 | 2008-11-05 | 浙江天台药业有限公司 | Preparation of clindamycinum phosphoester |
Non-Patent Citations (1)
| Title |
|---|
| 《中国抗生素杂志》 20030831 胡国强等 相转移催化法合成克林霉素磷酸酯 463-464 1-3 第28卷, 第8期 2 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964402A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof |
| CN102964402B (en) * | 2012-11-20 | 2015-07-22 | 广州白云山天心制药股份有限公司 | Preparation method for dehydro-clindamycin-free clindamycin hydrochloride |
| CN103483399A (en) * | 2013-08-27 | 2014-01-01 | 河南天方药业股份有限公司 | Synthetic method of clindamycin phosphate |
| CN103483399B (en) * | 2013-08-27 | 2016-04-20 | 河南天方药业股份有限公司 | A kind of synthetic method of Clindamycin Phosphate |
| CN105037457A (en) * | 2015-07-27 | 2015-11-11 | 天方药业有限公司 | Application of tolyltriazole in clindamycin phosphate synthesis |
| CN105037457B (en) * | 2015-07-27 | 2017-10-31 | 天方药业有限公司 | Application of the triazole in synthesis clindamycin phosphate |
| CN107652332A (en) * | 2017-10-11 | 2018-02-02 | 福安药业集团重庆博圣制药有限公司 | A kind of preparation method of clindamycin phosphate |
| CN110066301A (en) * | 2018-01-23 | 2019-07-30 | 天方药业有限公司 | A kind of synthetic method of clindamycin phosphate |
| CN109111492A (en) * | 2018-10-18 | 2019-01-01 | 新宇药业股份有限公司 | A kind of preparation method of propylidene clindamycin B reference substance |
| CN115141234A (en) * | 2022-07-14 | 2022-10-04 | 湖南恒生制药股份有限公司 | Synthesis process of clindamycin phosphate raw material medicine |
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Application publication date: 20101124 |