CN103483399B - A kind of synthetic method of Clindamycin Phosphate - Google Patents
A kind of synthetic method of Clindamycin Phosphate Download PDFInfo
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- CN103483399B CN103483399B CN201310375150.6A CN201310375150A CN103483399B CN 103483399 B CN103483399 B CN 103483399B CN 201310375150 A CN201310375150 A CN 201310375150A CN 103483399 B CN103483399 B CN 103483399B
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Abstract
The invention belongs to chemosynthesis technical field, be specifically related to a kind of synthetic method of Clindamycin Phosphate.The method obtains through the synthesis-oneization reaction-phosphorus acylation reaction-aftertreatment of clindamycin free alkali.The present invention, by changing order of addition(of ingredients), step and catalyzer, makes the weight yield of Clindamycin Phosphate to reach more than 80%.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of synthetic method of Clindamycin Phosphate.
Background technology
Clindamycin Phosphate is Broad spectrum antibiotics, applies very extensive clinically.It is the semi-synthetic derivative of U 10149a, and mechanism of action is the synthesis of anti-bacteria albumen.Its antimicrobial spectrum is identical with lincomycin, to streptococcus aureus, staphylococcus epidermidis, Hemolytic streptococcus, the anerobes such as the gram-positive microorganisms such as Streptococcus viridans, streptococcus pneumoniae, diphtheria corynebacterium and dyspepsiacoccus, peptostreptococcus, bacteroides fragilis, Fusobacterium, Eubacterium, propionibacterium have anti-microbial effect.The good water solubility of Clindamycin Phosphate, with the antimicrobial characteristic of efficient, spectrum, low toxicity, few side effects and being widely used at home and abroad.
Clindamycin Phosphate, its chemical name is: (2S-is trans)-6-(1-methyl-4-propyl group-2-tetramethyleneimine carbonic acid amido)-1-sulfo--methyl-7-chloro-6,7,8-tri-deoxidation-L-Su Shi-α-D-noside-2-dihydrogen phosphoric acid ester, English name: ClindamycinPhosphate, molecular formula: C
18h
34clN
2o
8pS, molecular weight: 504.97, structural formula is:
The synthesis of Clindamycin Phosphate, the route of bibliographical information mainly contains following three kinds:
1, triphenylphosphine or Rydon reagent method: be take U 10149a as raw material, through cyclisation, chlorination, hydrolysis, open loop, alcohol and, obtain clindamycin alcoholate, after ketonize, esterification, hydrolysis, absorption, crystallization, obtaining Clindamycin Phosphate.But this technique, because using the raw materials such as triphenylphosphine, acetonitrile, methyl alcohol, causes seriously polluted, labour protection requires high, and triphenylphosphine and by product triphen phosphine oxide are difficult to thoroughly remove in technological process; Have impact on quality product to a certain extent.The later stage eighties 20th century, people did not re-use this technique.
2, phosphorus oxychloride chloro technique: enter the middle and later periods eighties, the domestic and international novel process having occurred some synthesis Clindamycin Phosphates, this technique first generates Vilsmeier reagent by DMF and phosphorus oxychloride, direct and U 10149a adduction again, make chlorine substituted hydroxy, adducts obtains clindamycin free alkali through basic hydrolysis, further concentratedly add hydrochloric acid alcohol crystal and obtain Dalacina alcoholate, ketonize is then under the katalysis of pyridine again, in acetone solvent, carry out esterification with phosphorus oxychloride, after hydrolysis, absorption, crystallization, obtain Clindamycin Phosphate.
This handicraft product steady quality, environmental influence also comparatively triphenylphosphine method decline, but phosphorus oxychloride is unstable, presents the colors such as dark red black and lays particular stress on, the phenomenon that yield is on the low side even there will be chlorated liquid appearance color when carrying out chlorination reaction.And after basic hydrolysis, produce a large amount of sodium phosphate salts, thus cause in waste liquid phosphorous too high, environmental protection treatment pressure is large; Meanwhile, because temperature of reaction is high, make finished product contain table crin too high, be difficult to the needs meeting high-end customer.
3, solid phosgene chloro technique: bibliographical information, replaces phosphorus oxychloride to participate in the environmental influence that obviously can reduce the initiation of phosphorus oxychloride technique of chlorination reaction with solid phosgene.Solid phosgene is solids, keeps in Dark Place, and when not contacting water and alcohols material, does not have danger, and in the processes such as whole production, transport, storage stable in properties.But solid phosgene DMF point to take off generated phosgene be highly toxic product, China there occurs a lot of use solid phosgene enterprise and produces the serious accident that phosgene leaks causing death.The reason revealed just is the flow process preparing solid phosgene solution, the technique that manufacturing enterprise uses solid phosgene is first dissolved in trichloromethane by vacant lot in the wild, after abundant dissolving, the chloroform soln solvent pipe being dissolved with solid phosgene is transferred in solvent barrel and is transported to production plant, and then will the chloroform soln vacuum filtration of solid phosgene be dissolved with in header tank, by pipeline the chloroform soln being dissolved with solid phosgene is added drop-wise to fill in DMF reactor and forms chlorination reagent, the turning material and drip many and frequent of whole process, and the chloroform soln being dissolved with solid phosgene is being heated in the process of transhipment, easily decompose under the states such as chance is wet and produce phosgene, easily cause leakage to cause phosgene to volatilize and cause poisoning, operationally there is very large potential safety hazard.
Therefore, industry is needed to find the preparation method of Clindamycin Phosphate of a kind of more stable, safety, environmental protection.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of Clindamycin Phosphate of Environmental Safety.
The present invention is by the following technical solutions:
A synthetic method for Clindamycin Phosphate, comprises the steps:
(1) synthesis of clindamycin free alkali: first solid phosgene is dissolved in after dripping DMF formation chlorination reagent in trichloromethane, below 10 DEG C, add U 10149a, backflow is warmed up to 65-71 DEG C, insulation reaction 2 ~ 10h, cooling alkaline hydrolysis, distillation removing trichloromethane, obtains clindamycin free alkali;
(2) ketonize reaction: mixed with acetone, triethyl orthoformate, tosic acid by the clindamycin free alkali of step (1) gained, reacts 3 ~ 10h between 20 ~ 50 DEG C, after reaction terminates, obtains the acetone soln of propylidene free alkali;
(3) phosphorus acylation reaction: add triethylamine, phosphorus oxychloride, imidazoles in the acetone soln of step (2) gained propylidene free alkali, at 20 ~ 25 DEG C of reaction 1-5h, obtains phosphorus acylation reaction liquid;
(4) aftertreatment obtains Clindamycin Phosphate finished product.
In step (1), the mass ratio of U 10149a, trichloromethane, solid phosgene and DMF is: 1:5 ~ 7:1.3 ~ 1.5:1.0 ~ 1.4.
In step (2), the mass ratio of clindamycin free alkali, acetone, triethyl orthoformate, tosic acid is 1:3 ~ 9:1.5 ~ 3.5:0.01 ~ 0.05.
In step (3), the mass ratio of triethylamine, phosphorus oxychloride, imidazoles and clindamycin free alkali is respectively 1.0 ~ 1.3,0.5 ~ 0.7,0.9 ~ 1.1.
Speed when step (1) heats up is 4-6 DEG C/h.
Ordinary method is adopted during aftertreatment.
Synthetic route is as follows:
Beneficial effect of the present invention is:
1, step (1) changes order of addition(of ingredients), have employed first that solid phosgene is directly molten in reactor, then the working method in the chloroform soln of solid phosgene is entered by dropping DMF, this avoid the packing after solid phosgene dissolving, transport, take out the processes such as material, eliminate the potential safety hazard existed in solid phosgene use procedure; Meanwhile, the inorganic salt that such process operations produces are less, and layering is simple, are easy to process; This dropping process temperature is low simultaneously, speed fast, because this reducing the generation of difference to crin, reducing impurity, improve yield;
2. step (2) adopts one pot process propylidene free alkali, direct for clindamycin free alkali ketonize is obtained propylidene free alkali, eliminate the first alcohol of clindamycin free alkali to turn to Dalacina alcoholate, alcoholate is separated the operating process such as dry being separated with propylidene hydrochloride, alkalization, extraction again, propylidene free alkali is directly synthesized by clindamycin free alkali one kettle way, decrease the raw material consumption of operation link, solvent discharge, energy consumption, material loss, thus reduce cost;
3., in phosphorus acylation reaction process, catalyzer adopts imidazoles to replace pyridine, improves the transformation efficiency of phosphorus acylation reaction, improves yield, reduces production cost.
The present invention is optimized by this three step process, makes the weight yield of Clindamycin Phosphate to reach more than 80%, improves more than 10% than current enterprise production level.
Accompanying drawing explanation
Fig. 1 is the infrared Absorption collection of illustrative plates of the finished product that the present invention obtains.
Embodiment
Embodiment 1
(1) 287kg solid phosgene is thrown in 1250kg trichloromethane by chlorination reaction, after stirring and dissolving, the anti-DMF dripping 225kg below 10 DEG C, drip to finish and stir 4h below 10 DEG C, then add U 10149a 205kg in batches, be warmed up to 68 DEG C by slow heating mode (5 DEG C/h) backflow, insulation reaction 8h, then cool to less than 10 DEG C alkaline hydrolysis, distillation and concentration removes most of trichloromethane, obtains clindamycin free base solution (about containing 200kg clindamycin free alkali);
(2) the clindamycin free base solution of step (1) gained and 1640kg acetone, 615kg triethyl orthoformate, 5kg tosic acid join in retort and react 10h at 20 DEG C by ketonize reaction, obtain the acetone soln (about containing 210kg propylidene free alkali) of propylidene free alkali;
(3) phosphorus acylation reaction adds 225kg triethylamine, 123kg phosphorus oxychloride, 205kg imidazoles successively in the acetone soln of the propylidene free alkali of step (2), then at 20 DEG C of reaction 4h;
(4) hydrolysis, absorption, crystallization: add 1500L water hydrolysis reaction at 30 DEG C again, after concentrating out about 250L acetone again at 60 DEG C, dilution, on resin absorption carry out adsorbing, washing, then methyl alcohol desorb is used, carry out when being concentrated in the pasty state under 70 degree, being considered as concentrated end to stripping liquid, carry out crystallization with 2000L ethanol and obtain finished product.Weight yield is 80%.
Embodiment 2
(1) chlorination reaction: 62kg solid phosgene is thrown in 250kg trichloromethane, after stirring and dissolving, the anti-DMF dripping 57kg below 10 DEG C, drip to finish and stir 4h below 10 DEG C, add U 10149a 41kg in batches, be warmed up to 65 DEG C by slow heating mode (4 DEG C/h) backflow, insulation reaction 10h, then cool to less than 10 DEG C alkaline hydrolysis, distillation and concentration removes most of trichloromethane, obtains clindamycin free base solution (about containing 42kg clindamycin free alkali);
(2) the clindamycin free base solution of step (1) gained and 328kg acetone, 123g triethyl orthoformate, 1kg tosic acid join in retort and react 3h at 50 DEG C by ketonize reaction, obtain the acetone soln (about containing 44kg propylidene free alkali) of propylidene free alkali;
(3) phosphorus acylation reaction adds 45kg triethylamine, 25kg phosphorus oxychloride, 41kg imidazoles successively in the acetone soln of the propylidene free alkali of step (2), then at 25 DEG C of reaction 4h;
(4) hydrolysis, absorption, crystallization: add 300L water hydrolysis reaction at 30 DEG C again, after concentrating out about 50L acetone again at 60 DEG C, dilution, on resin absorption carry out adsorbing, washing, then methyl alcohol desorb is used, carry out when being concentrated in the pasty state at 70 DEG C, being considered as concentrated end to stripping liquid, carry out crystallization with 400L ethanol and obtain finished product.Weight yield is 81%.
Embodiment 3
(1) chlorination reaction: 370kg solid phosgene is thrown in 1750kg trichloromethane, after stirring and dissolving, the DMF instead dripping 345kg at 5 DEG C drips complete, stir 4h at 5 DEG C, add U 10149a 287kg in batches, be warmed up to 71 DEG C by heating mode (6 DEG C/h) backflow slowly, insulation reaction 2h, then cool to less than 10 DEG C alkaline hydrolysis, distillation and concentration removes most of trichloromethane, obtains clindamycin free base solution (about containing 290kg clindamycin free alkali);
(2) the clindamycin free base solution of step (1) gained and 1150kg acetone, 560kg triethyl orthoformate, 5.7kg tosic acid join in retort and react 6h at 35 DEG C by ketonize reaction, obtain the acetone soln (about containing 300kg propylidene free alkali) of propylidene free alkali;
(3) phosphorus acylation reaction adds 315kg triethylamine, 175kg phosphorus oxychloride, 287kg imidazoles successively in the acetone soln of the propylidene free alkali of step (2), then at 22 DEG C of reaction 4h;
(4) hydrolysis, absorption, crystallization: add 2100L water hydrolysis reaction at 30 DEG C again, after concentrating out about 350L acetone again at 60 DEG C, dilution, on resin absorption carry out adsorbing, washing, then methyl alcohol desorb is used, carry out when being concentrated in the pasty state at 70 DEG C, being considered as concentrated end to stripping liquid, carry out crystallization with 2800L ethanol and obtain finished product.Weight yield is 82%.
According to the national drug standards (WS
1-(X-020)-2003Z) regulation, respectively to the content such as proterties, specific optical rotation, infrared Absorption spectral contrast, the contrast of liquid phase retention time discriminating, crystallinity, acidity of above embodiment finished product, novel process product is differentiated, Fig. 1 is shown in by infrared Absorption collection of illustrative plates, and other detailed datas are as following table:
Above data validation gained finished product is target product Clindamycin Phosphate.
Comparative example
(1) chlorination reaction
113.6kg solid phosgene is thrown in 350kg trichloromethane, after stirring and dissolving, cool to less than 10 DEG C, suction filtration is in polyacrylic solvent barrel, then solvent barrel is transported in the reactor in the header tank of output zone, by vacuum filtration in the reactor of header tank, DMF, 0.5kg oxidation inhibitor AT-10 that 115kg is housed is added drop-wise to below 10 DEG C, in the reactor of 350kg trichloromethane, then add U 10149a 90kg in batches, at 70 DEG C, insulation reaction 25 hours, then be cooled to 10 DEG C;
(2) the alcoholization reaction 400L and 30% liquid caustic soda (aqueous sodium hydroxide solution) 200L that adds water in the solution of step (1) gained is hydrolyzed at 20 DEG C, layering, there are layer, washing with trichloromethane twice extraction of 136L, at 50 DEG C, concentrate out 500L trichloromethane, add dehydrated alcohol 80L again and carry out crystallization, obtain alcoholate, its alcoholate yield is 85%;
(3) ketonize reacts the alcoholate 40kg of step (2) gained and acetone 160L, phosphorus oxychloride 14.5L insulation reaction 10h at 20 DEG C;
(4) esterification again with phosphorus oxychloride 28L, acetone 40L, pyridine 30L, triethylamine 35L 20 times insulation reaction 10 hours;
(5) hydrolysis, absorption, crystallization: in step (4) gained solution, add 400L tap water at 10 times hydrolysis reaction, concentrate out about 125L acetone again at 50 DEG C after, dilute, upper resin absorption carries out adsorbing, washing, then methyl alcohol desorb is used, carry out when being concentrated in the pasty state at 50 DEG C, being considered as concentrated end to stripping liquid, carry out crystallization with 500L ethanol and obtain finished product.Weight yield from lincomycin to Clindamycin Phosphate is 70%.
Embodiments of the invention are compared with comparative example, and yield of the present invention brings up to more than 80% by existing 70%.
Claims (1)
1. a synthetic method for Clindamycin Phosphate, is characterized in that comprising the steps:
(1) synthesis of clindamycin free alkali: first solid phosgene is dissolved in after dripping DMF formation chlorination reagent in trichloromethane, below 10 DEG C, add U 10149a, backflow is warmed up to 65-71 DEG C, speed during intensification is 4-6 DEG C/h, insulation reaction 2 ~ 10h, cooling hydrolysis, distillation removing trichloromethane, obtains clindamycin free alkali; The mass ratio of U 10149a, trichloromethane, solid phosgene and DMF is: 1:5 ~ 7:1.3 ~ 1.5:1.0 ~ 1.4;
(2) ketonize reaction: mixed with acetone, triethyl orthoformate, tosic acid by the clindamycin free alkali of step (1) gained, reacts 3 ~ 10h between 20 ~ 50 DEG C, after reaction terminates, obtains the acetone soln of propylidene free alkali; The mass ratio of clindamycin free alkali, acetone, triethyl orthoformate, tosic acid is 1:3 ~ 9:1.5 ~ 3.5:0.01 ~ 0.05;
(3) phosphorus acylation reaction: add triethylamine, phosphorus oxychloride, imidazoles in the acetone soln of step (2) gained propylidene free alkali, at 20 ~ 25 DEG C of reaction 1-5h, obtains phosphorus acylation reaction liquid; The mass ratio of triethylamine, phosphorus oxychloride, imidazoles and clindamycin free alkali is respectively 1.0 ~ 1.3,0.5 ~ 0.7,0.9 ~ 1.1;
(4) aftertreatment obtains Clindamycin Phosphate finished product.
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| CN104138358A (en) * | 2014-05-22 | 2014-11-12 | 浙江磐谷药源有限公司 | Specific clindamycin hydrochloride superfine powdered lyophilized preparation and preparation method thereof |
| CN105037457B (en) * | 2015-07-27 | 2017-10-31 | 天方药业有限公司 | Application of the triazole in synthesis clindamycin phosphate |
| CN107652332B (en) * | 2017-10-11 | 2021-02-19 | 福安药业集团重庆博圣制药有限公司 | Preparation method of clindamycin phosphate |
| CN111825729B (en) * | 2020-07-14 | 2023-08-29 | 天方药业有限公司 | Purification method of clindamycin phosphate |
| CN114920786A (en) * | 2022-05-31 | 2022-08-19 | 新宇药业股份有限公司 | Preparation method of clindamycin amide isomer |
| 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 (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3487068A (en) * | 1966-12-16 | 1969-12-30 | Upjohn Co | Lincomycin-2-phosphates,7-substituted compounds and salts thereof |
| US4849515A (en) * | 1988-08-22 | 1989-07-18 | E. I. Du Pont De Nemours And Company | Clindamycin-2-phosphoryl benzylate |
| US5182374A (en) * | 1990-03-21 | 1993-01-26 | American Cyanamid Company | Clindamycin phosphate synthesis |
| CN101298463A (en) * | 2007-09-19 | 2008-11-05 | 浙江天台药业有限公司 | Preparation of clindamycinum phosphoester |
| CN101704852A (en) * | 2009-11-17 | 2010-05-12 | 海南美兰史克制药有限公司 | Novel route for clindamycin phosphate compounds |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN101891779A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin phosphate |
| CN102964400A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Preparation method and applications of dehydro-lincomycin-free lincomycin hydrochloride |
-
2013
- 2013-08-27 CN CN201310375150.6A patent/CN103483399B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3487068A (en) * | 1966-12-16 | 1969-12-30 | Upjohn Co | Lincomycin-2-phosphates,7-substituted compounds and salts thereof |
| US4849515A (en) * | 1988-08-22 | 1989-07-18 | E. I. Du Pont De Nemours And Company | Clindamycin-2-phosphoryl benzylate |
| US5182374A (en) * | 1990-03-21 | 1993-01-26 | American Cyanamid Company | Clindamycin phosphate synthesis |
| CN101298463A (en) * | 2007-09-19 | 2008-11-05 | 浙江天台药业有限公司 | Preparation of clindamycinum phosphoester |
| CN101704852A (en) * | 2009-11-17 | 2010-05-12 | 海南美兰史克制药有限公司 | Novel route for clindamycin phosphate compounds |
| CN101830946A (en) * | 2010-05-05 | 2010-09-15 | 南阳普康药业有限公司 | Method for synthesizing clindamycin phosphate |
| CN101891779A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin phosphate |
| CN102964400A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Preparation method and applications of dehydro-lincomycin-free lincomycin hydrochloride |
Non-Patent Citations (3)
| Title |
|---|
| 克林霉素磷酸酯的合成;李有桂，等;《广州化工》;20120630;第40卷(第11期);第87-88,94页 * |
| 克林霉素磷酸酯的合成工艺研究;陈树红，等;《山西医科大学学报》;20020430;第33卷(第2期);第116-117页 * |
| 相转移催化法合成克林霉素磷酸酯;胡国强，等;《中国抗生素杂质》;20030831;第28卷(第8期);第463-464页 * |
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Effective date of registration: 20160518 Address after: Zhumadian City, Henan province 463000 Guangming Road Yicheng District No. 2 Patentee after: TIANFANG PHARMACEUTICAL CO., LTD. Address before: 463000 No. 2 Guangming Road, Henan, Zhumadian Patentee before: Tianfang Pharmaceutical Co., Ltd., Henan |