CN101830946A - Method for synthesizing clindamycin phosphate - Google Patents
Method for synthesizing clindamycin phosphate Download PDFInfo
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Abstract
The invention discloses a method for synthesizing clindamycin phosphate, which comprises the following steps of: performing ketal protection reaction on clindamycin hydrochloride alcoholate at the temperature of between 2.0 below zero and 2.0 DEG C under the action of acetone and phosphorus oxychloride to form propylidene clindamycin; and performing esterification, hydrolysis, adsorption, washing, deabsorption, concentration, coarse crystallization, decoloration, refining and drying to obtain the finished product of clindamycin phosphate. Because a new catalyst 4-dimethylaminopyridine participates in the esterification in the rection system, the phosphorylating reaction is performed completely, and the conversion rate of raw materials is improved. Meanwhile, due to the secondary crystallization method, the problems of poor color grade and poor powder solubility are solved, and the operating conditions are mild and simple. By adopting triethylamine to replace partial pyridine, the esterification is pushed forwards; the reaction period is shortened; and importantly, related impurities in the finished product and the production cost are reduced, and the content is improved.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly relate to a kind of synthetic method of Clindamycin Phosphate.
Background technology
Clindamycin Phosphate is the derivative of clindamycin, and it is widely used in treating gram-positive microorganism, the microbial various infectious diseases of anaerobism.At present; produce in the building-up process of Clindamycin Phosphate phosphorus, its preparation method is: Dalacina alcoholate and phosphorus oxychloride are carried out the ketal protective reaction under the effect of acetone solvent; again through esterification; hydrolysis, absorption, washing; desorb; concentrate, after crystallization and the oven dry, obtained the Clindamycin Phosphate finished product.There is following shortcoming in this method: the one, and the finished product related substances is unstable and higher, and productive rate is lower, severe reaction conditions, reaction time is long, is difficult to satisfy high-end demand of opening an account; The 2nd, in the phosphorus acylation reaction process, used a large amount of acetone, pyridine, caused cost higher.The 3rd, in the process of hydrolysis reaction, used a large amount of liquid caustic soda, caused unnecessary waste.The 4th, because the crystallization of using belongs to the primary crystallization method, caused the crystallization look differential, problem such as powder solubleness is bad.
Summary of the invention
Technical problem to be solved by this invention is exactly the above-mentioned shortcoming and defect that overcomes existing preparation method, and a kind of novel method of synthetic Clindamycin Phosphate is provided.
The technical scheme that the present invention solves the problems of the technologies described above is: of the present invention from the Clindamycin Phosphate method, be may further comprise the steps:
1., ketal protective reaction: acetone, Dalacina alcoholate, phosphorus oxychloride are joined respectively in the phosphorus acylation reaction device by weight 2.8～3.4: 1.0: 1.6～2.0, and lower the temperature-2.0～2.0 ℃ and reacted 4.5～5 hours down, get the propylidene clindamycin;
2., phosphorus acylation reaction: more respectively in order with the catalyzer of phosphorus oxychloride, superpower nucleophilic esterification, pyridine, triethylamine by weight 0.5～0.7: 0.04～0.08: also join reactor at 0.6～0.8: 0.4～0.6, temperature was reacted 5.0～5.5 hours down at-2.5～2.5 ℃, got propylidene clindamycin phosphorylated compound;
3., hydrolysis reaction: in hydrolysis reactor, add 15～20BV purified water, lower the temperature 0～5.0 ℃, stir, again with above-mentioned reaction solution, the suction reactor, take out complete, the reaction 1.0～2.0 hours down of 35～45 ℃ of temperature, hydrolyzed solution;
4., dilution: in hydrolysis reactor, add 15～20BV purified water dilution feed liquid, mix, wait to adsorb;
5., absorption, washing: during resin absorption, absorption flow 3～5BV after absorption finishes, with the washing of 6～8BV purified water, washes flow 1～2BV, ends to flow out waste liquor PH 4.5～6.0, treats desorb;
6., desorb: after washing finished, to its desorb, flow was 4～6BV with 30～50BV methyl alcohol, and effluent liquid contains methanol content and reaches at 20～30% o'clock, collected, and got stripping liquid;
7., concentrate: stripping liquid is evacuated to the concentration response device,, in the time of extremely in the pasty state, looks to concentrate and finish, get concentrated solution at 60～70 ℃ of concentrating under reduced pressure;
8., coarse crystallization: in the concentration response device, 4.0～5.0BV ethanol is added in the concentrated solution, stir, be cooled to 38～42 ℃, crystal is separated out, and is cooled to 0～5 ℃ again, growing the grain 10～12h, suction filtration, to doing, coarse crystallization;
9., refining decolouring, oven dry: in the 0.8～1.1BV purified water and 6～8BV ethanol suction feeder with meal weight, heat 60～70 ℃, stir, after the dissolving, 0.03～0.05BV activated carbon decolorizing of humidification grain weight amount, insulation is filtered, be pressed into thick knot device, stir, lower the temperature-5.0～5.0 ℃, crystallization, and growing the grain 10～12h, suction filtration, drying, oven dry 4～5h gets finished product.
The present invention has adopted the catalyzer-4-dimethylamino pyridine of new superpower nucleophilic esterification to participate in esterification in reaction system, and phosphorus acylation reaction is carried out fully, improves conversion of raw material; Use the secondary crystal method simultaneously, solved the look differential and bad problem of powder solubleness, and operational condition gentleness, simple; And adopted triethylamine to substitute the part pyridine, also promoted the esterification forward and carried out, shorten reaction time, importantly reduced related impurities and the production cost in the finished product, improved content.
Embodiment
Below enumerate some embodiments of the present invention, understand the present invention to help further, but protection scope of the present invention is not limited in this.
Embodiment 1
1., ketal protective reaction: get acetone 30kg, Dalacina alcoholate 10kg, phosphorus oxychloride 17kg join respectively in the phosphorus acylation reaction device, and lower the temperature 0 ℃, reacted 5 hours.
2., phosphorus acylation reaction: respectively in order with phosphorus oxychloride 6.5kg, 4-dimethylamino pyridine 0.6kg, pyridine 7kg, triethylamine 6kg, also join in the reactor, temperature-2.0 ℃ was reacted 5.5 hours again;
3., hydrolysis reaction: in hydrolysis reactor, add the 180kg purified water, be cooled to 3.0 ℃, open stirring, again with above-mentioned reaction solution, the suction reactor is taken out completely, and temperature is 40 ℃ of down reactions 1.5 hours,
4., dilution: in diluter, add purified water 180kg dilution feed liquid, mix, wait to adsorb;
5., absorption, washing: during resin absorption, absorption flow 40kg/L, absorption finishes, with the washing of 70kg purified water, washing flow 20kg/L ends to pH5.5;
6., desorb: after washing finished, to its desorb, flow was 50kg/L with 400kg methyl alcohol.Methanol content reaches at 20% o'clock, collects;
7., concentrate: stripping liquid is evacuated to the concentration response device,, in the time of extremely in the pasty state, looks to concentrate and finish at 70 ℃ of following concentrating under reduced pressure;
8., coarse crystallization: in the concentration response device, 400kg ethanol is added in the concentrated solution, mixes, cooling, crystallization, 0～5 ℃ of temperature, growing the grain 11.5h, suction filtration is to doing;
9., refining decolouring, oven dry: in 10kg purified water and 70kg ethanol suction feeder.Heat 65 ℃, stir, after the dissolving, the 0.5kg activated carbon decolorizing of humidification grain weight amount, insulation is filtered, and is pressed into thick knot device, stirs, and lowers the temperature 0 ℃ crystallization; And leave standstill growing the grain 12h.Suction filtration, drying, oven dry 5h gets finished product.Yield is 95.4%.
3. above-mentioned～8. all BV calculate with the weight of Dalacina alcoholate relatively in the step.
Embodiment 2
1., ketal protective reaction: get acetone 34kg, Dalacina alcoholate 10kg, phosphorus oxychloride 20kg join respectively in the phosphorus acylation reaction device, and-1.0 ℃ of coolings, reacted 5.5 hours;
2., phosphorus acylation reaction: respectively in order with phosphorus oxychloride 5.5kg, 4-dimethylamino pyridine 0.7kg, pyridine 8kg, triethylamine 5.5kg, also join in the reactor, temperature-1.0 ℃ was reacted 5.5 hours again;
3., hydrolysis reaction: in hydrolysis reactor, add the 180kg purified water, be cooled to 1.0 ℃, open stirring, again with above-mentioned reaction solution, the suction reactor is taken out completely, and temperature is 40 ℃ of down reactions 2.0 hours;
4., dilution: in diluter, add purified water 200kg dilution feed liquid, mix, wait to adsorb.
5., absorption, washing: during resin absorption, absorption flow 40kg/L, absorption finishes, with the washing of 65kg purified water, washing flow 20kg/L ends to pH5.5;
6., desorb: after washing finished, to its desorb, flow was 45kg/L with 350kg methyl alcohol, and methanol content reaches at 20% o'clock, collected;
7., concentrate: stripping liquid is evacuated to the concentration response device,,, concentrates and finish in the pasty state at 75 ℃ of following concentrating under reduced pressure;
8., coarse crystallization: in the concentration response device, 450kg ethanol is added in the concentrated solution, mix cooling, crystallization, 3.0 ℃ of temperature, growing the grain 11h.Suction filtration is to doing;
9., refining decolouring, oven dry: in 10kg purified water and 80kg ethanol suction feeder.Heat 60 ℃, stir, after the dissolving, the 0.35kg activated carbon decolorizing of humidification grain weight amount, insulation is filtered, and is pressed into thick knot device, stirs, and lowers the temperature-5.0 ℃ crystallization; And leave standstill growing the grain 11h; Suction filtration, drying, oven dry 4.5h gets finished product.Yield is 93.8%.
3. above-mentioned～8. all BV calculate with the weight of Dalacina alcoholate relatively in the step.
Embodiment 3
1., ketal protective reaction: get acetone 28kg, Dalacina alcoholate 10kg, phosphorus oxychloride 16kg join respectively in the phosphorus acylation reaction device, and lower the temperature 0 ℃, reacted 5 hours;
2., phosphorus acylation reaction: respectively in order with phosphorus oxychloride 5.5kg, 4-dimethylamino pyridine 0.35kg, pyridine 6.5kg, triethylamine 4.5kg, also join in the reactor, 0 ℃ of temperature was reacted 5 hours again;
3., hydrolysis reaction: in hydrolysis reactor, add the 200kg purified water, be cooled to 1.0 ℃, open stirring, again with above-mentioned reaction solution, the suction reactor is taken out completely, and temperature is 38 ℃ of down reactions 2 hours;
4., dilution: in diluter, add purified water 220kg dilution feed liquid, mix, wait to adsorb;
5., absorption, washing: during resin absorption, absorption flow 35kg/L, absorption finishes, and with the washing of 80kg purified water, flows out waste liquor PH 5.0 and ends, washing flow 30kg/L treats desorb;
6., desorb: after washing finishes, with 450kg methyl alcohol it is carried out desorb, flow is 60kg/L.Methanol content reaches at 20% o'clock, collects;
7., concentrate: stripping liquid is evacuated to the concentration response device, at 65 ℃ of following concentrating under reduced pressure, to finishing in the pasty state;
8., coarse crystallization: in the concentration response device, 500kg ethanol is added in the concentrated solution, mix cooling, crystallization, 2.0 ℃ of temperature, growing the grain 10h.Suction filtration is to doing;
9., refining decolouring, oven dry: in 8kg purified water and 80kg ethanol suction feeder.Heat 70 ℃, stir, after the dissolving, the 0.4kg activated carbon decolorizing of humidification grain weight amount, insulation is filtered, and is pressed into thick knot device, stirs, and lowers the temperature-4.0 ℃ crystallization; And leave standstill growing the grain 12h; Suction filtration, drying, oven dry 5h gets finished product.Yield is 92.2%.
3. above-mentioned～8. all BV calculate with the weight of Dalacina alcoholate relatively in the step.
1.0～1.4 part the phosphorus oxychloride of described step in 1. adds fashionable, should slowly drip, and drips process temperature control and is as the criterion for-2.0～2.0 ℃.
The catalyzer of the selected new superpower nucleophilic esterification of described step in 2. is the 4-dimethylamino pyridine preferably.
The phosphorylated catalyzer of described step in 2. introduced the 4-dimethylamino pyridine, and triethylamine substitutes the part pyridine, greatly reduces cost and foreign matter content; Added phosphorus oxychloride, 4-dimethylamino pyridine, triethylamine, pyridine should guarantee that temperature reacts under-2.5～2.5 ℃.
Described step 3. or in the feed liquid 5. acetone reclaim, after hydrolysis, reclaim in the feed liquid or the waste liquid after absorption in reclaim.
Described step 6. or its hydrolyzed solution 7. or diluent can uncomfortable pH, directly upper prop absorption.
Described step 8. or the crystallization 9. belong to the alternating temperature crystallization process twice, improve look level, content, the solubleness of product, and reduced the content of related substances.
The mother liquor of the crystallization waste liquid of described step in 9. after reclaiming solvent can be applied mechanically upper prop absorption, also can concentrate individual curing.
Claims (8)
1. the synthetic method of a Clindamycin Phosphate is characterized in that being realized by following steps:
1., ketal protective reaction: acetone, Dalacina alcoholate, phosphorus oxychloride are joined respectively in the phosphorus acylation reaction device by weight 2.8～3.4: 1.0: 1.6～2.0, and lower the temperature-2.0～2.0 ℃ and reacted 4.5～5 hours down, get the propylidene clindamycin;
2., phosphorus acylation reaction: more respectively in order with the catalyzer of phosphorus oxychloride, superpower nucleophilic esterification, pyridine, triethylamine by weight 0.5～0.7: 0.04～0.08: also join reactor at 0.6～0.8: 0.4～0.6, temperature was reacted 5.0～5.5 hours down at-2.5～2.5 ℃, got propylidene clindamycin phosphorylated compound;
3., hydrolysis reaction: in hydrolysis reactor, add 15～20BV purified water, lower the temperature 0～5.0 ℃, stir, again with above-mentioned reaction solution, the suction reactor, take out complete, the reaction 1.0～2.0 hours down of 35～45 ℃ of temperature, hydrolyzed solution;
4., dilution: in hydrolysis reactor, add 15～20BV purified water dilution feed liquid, mix, wait to adsorb;
5., absorption, washing: resin column adsorbs, and absorption flow 3～5BV after absorption finishes, washes with 6～8BV purified water, and washing flow 1～2BV only to flow out waste liquor PH 4.5～6.0, treats desorb;
6., desorb: after washing finished, to its desorb, flow was 4～6BV with 30～50BV methyl alcohol.Effluent liquid contains methanol content and reaches at 20～30% o'clock, collects, and gets stripping liquid;
7., concentrate: stripping liquid is evacuated to the concentration response device,, in the time of extremely in the pasty state, looks to concentrate and finish, get concentrated solution at 60～70 ℃ of concentrating under reduced pressure;
8., coarse crystallization: in the concentration response device, 4.0～5.0BV ethanol is added in the concentrated solution, stir, be cooled to 38～42 ℃, crystal is separated out, and is cooled to 0～5 ℃ again, growing the grain 10～12h, suction filtration, to doing, coarse crystallization;
9., refining decolouring, oven dry: in the 0.8～1.1BV purified water and 6～8BV ethanol suction feeder with meal weight, heat 60～70 ℃, stir, after the dissolving, 0.03～0.05BV activated carbon decolorizing of humidification grain weight amount, insulation is filtered, be pressed into thick knot device, stir, lower the temperature-5.0～5.0 ℃, crystallization, and growing the grain 10～12h, suction filtration, drying, oven dry 4～5h gets finished product.
2. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is fashionable to it is characterized in that 1.0～1.4 parts phosphorus oxychloride during described step 1. adds, and should slowly drip, and drips process temperature control and is as the criterion for-2.0～2.0 ℃.
3. according to the synthetic method of the described Clindamycin Phosphate of claim 1, the catalyzer that it is characterized in that the selected new superpower nucleophilic esterification during described step 2. is the 4-dimethylamino pyridine preferably.
4. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is characterized in that the phosphorylated catalyzer during described step is has 2. been introduced the 4-dimethylamino pyridine, and the alternative part pyridine of triethylamine, greatly reduce cost and foreign matter content; Added phosphorus oxychloride, 4-dimethylamino pyridine, triethylamine, pyridine should guarantee that temperature reacts under-2.5～2.5 ℃.
5. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is characterized in that described step 3. or in the feed liquid 5. acetone reclaim, after hydrolysis, reclaim in the feed liquid or the waste liquid after absorption in reclaim.
6. or its hydrolyzed solution 7. or the uncomfortable pH of diluent 6. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is characterized in that described step, directly upper prop absorption.
7. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is characterized in that described step 8. or the crystallization 9. belong to the alternating temperature crystallization process twice, improve look level, content, the solubleness of product, and reduced the content of related substances.
8. according to the synthetic method of the described Clindamycin Phosphate of claim 1, it is characterized in that the mother liquor of crystallization waste liquid after reclaiming solvent during described step 9., apply mechanically upper prop absorption or concentrate individual curing.
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Cited By (9)
| 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 |
| 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 |
| CN103275143A (en) * | 2013-06-05 | 2013-09-04 | 天津大学 | Novel crystal form (beta) of clindamycin phosphate, and preparation method |
| 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 |
| CN103554137A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefdinir micropowder |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| CN105037457A (en) * | 2015-07-27 | 2015-11-11 | 天方药业有限公司 | Application of tolyltriazole in clindamycin phosphate synthesis |
| CN110066301A (en) * | 2018-01-23 | 2019-07-30 | 天方药业有限公司 | A kind of synthetic method of clindamycin phosphate |
| CN111825729A (en) * | 2020-07-14 | 2020-10-27 | 天方药业有限公司 | Purification method of clindamycin phosphate |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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 |
| 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 |
| CN103275143B (en) * | 2013-06-05 | 2016-06-08 | 天津大学 | The new crystal �� of Clindamycin Phosphate and preparation method |
| CN103275143A (en) * | 2013-06-05 | 2013-09-04 | 天津大学 | Novel crystal form (beta) of clindamycin phosphate, and preparation method |
| 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 |
| CN103554137A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefdinir micropowder |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| 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 |
| CN110066301A (en) * | 2018-01-23 | 2019-07-30 | 天方药业有限公司 | A kind of synthetic method of clindamycin phosphate |
| CN111825729A (en) * | 2020-07-14 | 2020-10-27 | 天方药业有限公司 | Purification 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 |
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