CN105566349A - Synthesis process of o-chloro-benzathine penicillin - Google Patents
Synthesis process of o-chloro-benzathine penicillin Download PDFInfo
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- CN105566349A CN105566349A CN201410626311.9A CN201410626311A CN105566349A CN 105566349 A CN105566349 A CN 105566349A CN 201410626311 A CN201410626311 A CN 201410626311A CN 105566349 A CN105566349 A CN 105566349A
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Abstract
The invention discloses a synthesis process of o-chloro-benzathine penicillin. 6-aminopenicillanic acid is firstly dissolved in a dilute alkali solution to be prepared into sodium salt in an aqueous solution of an organic solvent, then subjected to condensation with isoxazolyl o-chlorobenzoyl chloride to directly obtain a cloxacillin sodium solution, and the cloxacillin sodium solution is subjected to double decomposition reaction with N, N-dibenzyl ethylenediamine diacetate to obtain the o-chloro-benzathine penicillin. The synthesis process of the o-chloro-benzathine penicillin disclosed by the invention has benefits of simple process, simple and convenient operation, low cost and easy industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to a kind of Ortho-chlorine Bicillin Synsis Technology.
Background technology
Ortho-chlorine Bicillin Synsis Technology process at least comprises the primary processes such as esterification, salt-forming reaction, stirring.In the preparation process method of current adjacent chlorine dibenzylethylenediamine dipenicillin G, technical process is not easy to implement, and the adjacent chlorine dibenzylethylenediamine dipenicillin G purity of generation is low, and reactant per pass conversion is low, and production process is complicated and environmental pollution is comparatively large, and production efficiency is low and cost is high.
Summary of the invention
In order to overcome the above-mentioned technical problem that prior art field exists, the object of the invention is to, a kind of Ortho-chlorine Bicillin Synsis Technology is provided, the present invention not only production process simple, increase work efficiency, and the adjacent chlorine dibenzylethylenediamine dipenicillin G quality generated is good.
Ortho-chlorine Bicillin Synsis Technology provided by the invention, comprises the following steps:
(1) be (1-3) by the ratio of organic solvent and water: the aqueous solution of the proportions organic solvent of 1, and add in condensation tank, open and stir and chuck water coolant, add 6-amino-penicillanic acid by 99-210 gram/often liter aqueous solutions of organic solvent; When temperature is down to below 16 DEG C, start in tank, add the NaOH solution that concentration is 12%, maintenance pH value is 8-9, till 6-amino-penicillanic acid is dissolved gradually;
(2) be 1 in the mol ratio of 6-amino-penicillanic acid and adjacent chlorobenzene Jia isoxazole acyl chlorides: the ratio of (0.95-1.15) takes adjacent chlorobenzene Jia isoxazole acyl chlorides, when the temperature of the sodium salt solution in above-mentioned (1) step is cooled to below 10 DEG C, start in tank, add load weighted adjacent chlorobenzene Jia isoxazole acyl chlorides, then start to add the NaOH solution that concentration is 13%, and the pH value controlled in tank is 6-8, temperature is no more than 26 DEG C, till pH value is stabilized in 6.5 and reaction solution is clarified;
(3) the clarifying reaction liquid in above-mentioned (2) is pressed into by sterilization filter in the crystallizer of sterilisable chamber;
(4) in preparing tank, add the N of theoretical amount, N-dibenzyl-ethylenediamin two acetic acid, and thin up makes its concentration control at 0.4-0.5g/ml, stir and use chuck hot water heating to make N, N-dibenzyl-ethylenediamin two acetate dissolution, then puts into gac and stirs, to decolour and absorption impurity; The content of sampling and measuring N, N-dibenzyl-ethylenediamin two acetic acid, is pressed into sterilisable chamber by sterilization filter after qualified, stand-by;
(5) make feed temperature reach 10-40 DEG C the feed liquid jacket water (J.W.) in crystallizer, open and stir, then in tank, slowly, evenly add N, N-dibenzyl-ethylenediamin two acetum, after adding, continue stirring 30 minutes again;
(6) open crystallizer baiting valve, make crystallization feed liquid put into suction filtration tank, open vacuum filtration simultaneously, drain to obtain wet cake; The filter cake solution washing three times of organic solvent in above-mentioned (1) step, each washing aqueous solution of 40L organic solvent, and the concentration of the aqueous solution of organic solvent is 30-100%, drains to obtain wet-milling;
(7) sieved by wet-milling, be transferred in double cone dryer, open bipyramid jacket steam valve, controlling bake out temperature is 80 ± 5 DEG C, and vacuum-drying is less than 5% to moisture.
Ortho-chlorine Bicillin Synsis Technology provided by the invention, its beneficial effect is, overcoming prior art, to prepare operation in the technological process of adjacent chlorine dibenzylethylenediamine dipenicillin G more, and workload is large, and the problem that environmental pollution is serious, improves working efficiency; Improve the per pass conversion of reactant and the productive rate of resultant.
Embodiment
Below in conjunction with an embodiment, Ortho-chlorine Bicillin Synsis Technology provided by the invention is described in detail.
Embodiment
The Ortho-chlorine Bicillin Synsis Technology of the present embodiment, comprises the following steps:
(1) be (1-3) by the ratio of organic solvent and water: the aqueous solution of the proportions organic solvent of 1, and add in condensation tank, open and stir and chuck water coolant, add 6-amino-penicillanic acid by 99-210 gram/often liter aqueous solutions of organic solvent; When temperature is down to below 16 DEG C, start in tank, add the NaOH solution that concentration is 12%, maintenance pH value is 8-9, till 6-amino-penicillanic acid is dissolved gradually;
(2) be 1 in the mol ratio of 6-amino-penicillanic acid and adjacent chlorobenzene Jia isoxazole acyl chlorides: the ratio of (0.95-1.15) takes adjacent chlorobenzene Jia isoxazole acyl chlorides, when the temperature of the sodium salt solution in above-mentioned (1) step is cooled to below 10 DEG C, start in tank, add load weighted adjacent chlorobenzene Jia isoxazole acyl chlorides, then start to add the NaOH solution that concentration is 13%, and the pH value controlled in tank is 6-8, temperature is no more than 26 DEG C, till pH value is stabilized in 6.5 and reaction solution is clarified;
(3) the clarifying reaction liquid in above-mentioned (2) is pressed into by sterilization filter in the crystallizer of sterilisable chamber;
(4) in preparing tank, add the N of theoretical amount, N-dibenzyl-ethylenediamin two acetic acid, and thin up makes its concentration control at 0.4-0.5g/ml, stir and use chuck hot water heating to make N, N-dibenzyl-ethylenediamin two acetate dissolution, then puts into gac and stirs, to decolour and absorption impurity; The content of sampling and measuring N, N-dibenzyl-ethylenediamin two acetic acid, is pressed into sterilisable chamber by sterilization filter after qualified, stand-by;
(5) make feed temperature reach 10-40 DEG C the feed liquid jacket water (J.W.) in crystallizer, open and stir, then in tank, slowly, evenly add N, N-dibenzyl-ethylenediamin two acetum, after adding, continue stirring 30 minutes again;
(6) open crystallizer baiting valve, make crystallization feed liquid put into suction filtration tank, open vacuum filtration simultaneously, drain to obtain wet cake; The filter cake solution washing three times of organic solvent in above-mentioned (1) step, each washing aqueous solution of 40L organic solvent, and the concentration of the aqueous solution of organic solvent is 30-100%, drains to obtain wet-milling;
(7) sieved by wet-milling, be transferred in double cone dryer, open bipyramid jacket steam valve, controlling bake out temperature is 80 ± 5 DEG C, and vacuum-drying is less than 5% to moisture.
Ortho-chlorine Bicillin Synsis Technology, without the need to further processing, operation is simple, and data are accurately easy to measure, and technical process is easy to implement.
Claims (1)
1. an Ortho-chlorine Bicillin Synsis Technology, is characterized in that: said method comprising the steps of:
(1) be (1-3) by the ratio of organic solvent and water: the aqueous solution of the proportions organic solvent of 1, and add in condensation tank, open and stir and chuck water coolant, add 6-amino-penicillanic acid by 99-210 gram/often liter aqueous solutions of organic solvent; When temperature is down to below 16 DEG C, start in tank, add the NaOH solution that concentration is 12%, maintenance pH value is 8-9, till 6-amino-penicillanic acid is dissolved gradually;
(2) be 1 in the mol ratio of 6-amino-penicillanic acid and adjacent chlorobenzene Jia isoxazole acyl chlorides: the ratio of (0.95-1.15) takes adjacent chlorobenzene Jia isoxazole acyl chlorides, when the temperature of the sodium salt solution in above-mentioned (1) step is cooled to below 10 DEG C, start in tank, add load weighted adjacent chlorobenzene Jia isoxazole acyl chlorides, then start to add the NaOH solution that concentration is 13%, and the pH value controlled in tank is 6-8, temperature is no more than 26 DEG C, till pH value is stabilized in 6.5 and reaction solution is clarified;
(3) the clarifying reaction liquid in above-mentioned (2) is pressed into by sterilization filter in the crystallizer of sterilisable chamber;
(4) in preparing tank, add the N of theoretical amount, N-dibenzyl-ethylenediamin two acetic acid, and thin up makes its concentration control at 0.4-0.5g/ml, stir and use chuck hot water heating to make N, N-dibenzyl-ethylenediamin two acetate dissolution, then puts into gac and stirs, to decolour and absorption impurity; The content of sampling and measuring N, N-dibenzyl-ethylenediamin two acetic acid, is pressed into sterilisable chamber by sterilization filter after qualified, stand-by;
(5) make feed temperature reach 10-40 DEG C the feed liquid jacket water (J.W.) in crystallizer, open and stir, then in tank, slowly, evenly add N, N-dibenzyl-ethylenediamin two acetum, after adding, continue stirring 30 minutes again;
(6) open crystallizer baiting valve, make crystallization feed liquid put into suction filtration tank, open vacuum filtration simultaneously, drain to obtain wet cake; The filter cake solution washing three times of organic solvent in above-mentioned (1) step, each washing aqueous solution of 40L organic solvent, and the concentration of the aqueous solution of organic solvent is 30-100%, drains to obtain wet-milling;
(7) sieved by wet-milling, be transferred in double cone dryer, open bipyramid jacket steam valve, controlling bake out temperature is 80 ± 5 DEG C, and vacuum-drying is less than 5% to moisture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410626311.9A CN105566349A (en) | 2014-11-10 | 2014-11-10 | Synthesis process of o-chloro-benzathine penicillin |
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| CN201410626311.9A CN105566349A (en) | 2014-11-10 | 2014-11-10 | Synthesis process of o-chloro-benzathine penicillin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883249A (en) * | 2017-01-10 | 2017-06-23 | 华北制药集团先泰药业有限公司 | A kind of preparation method of penicillin V benzathine |
| CN110452254A (en) * | 2019-08-07 | 2019-11-15 | 瑞阳制药有限公司 | The method for crystallising of Cloxacillin Sodium |
-
2014
- 2014-11-10 CN CN201410626311.9A patent/CN105566349A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883249A (en) * | 2017-01-10 | 2017-06-23 | 华北制药集团先泰药业有限公司 | A kind of preparation method of penicillin V benzathine |
| CN110452254A (en) * | 2019-08-07 | 2019-11-15 | 瑞阳制药有限公司 | The method for crystallising of Cloxacillin Sodium |
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Application publication date: 20160511 |