CN101723979B - Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate - Google Patents
Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate Download PDFInfo
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- CN101723979B CN101723979B CN2009102499583A CN200910249958A CN101723979B CN 101723979 B CN101723979 B CN 101723979B CN 2009102499583 A CN2009102499583 A CN 2009102499583A CN 200910249958 A CN200910249958 A CN 200910249958A CN 101723979 B CN101723979 B CN 101723979B
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Abstract
This invention relates to a refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate, comprising the steps of (1) heating up distilled water or purified water to the temperature between 30 DEG C and 35 DEG C; adding crude R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate during stirring, wherein the mass ratio of the fried crude R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate and the distilled water or purified water is 1:4.2135 to 5.3571; (2) heating up continually to the temperature between 40 DEG C to 45 DEG C; adding active carbon; heating up continually to the temperature between 65 DEG C to 75 DEG C; preserving the temperature, wherein the mass ratio of the fried crude R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate to the active carbon is 1:0.0169 to 0.0214; (3) filtrating to remove carbon; washing carbon cake with the distilled water or purified water to obtain filtrate; and (4) cooling the filtrate obtained in step (3) to the temperature between minus 8 DEG C to minus 2 DEG C; separating crystal; filtrating to obtain wet R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate; drying to obtain fine R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate; or drying the filtrate obtained in step (3) with spray drying device to get fine R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate. The method provided by the invention has the advantages of simple technique, easy operation and good security and is beneficial for business health, low material consumption, less pollution and low cost.
Description
Technical field
The present invention relates to field of fine chemical, be specifically related to a kind of process for purification of fosfomycin phenylethylamine calt.
Background technology
Fosfomycin sodium [(-)-suitable-1; 2-phosphate epoxypropyl sodium] (hereinafter to be referred as fosfomycin sodium) be a kind of New-type wide-spectrum microbiotic; IR2S-(-)-suitable-1,2-phosphate epoxypropyl-R-(+)-α-Ben Yian salt (hereinafter to be referred as fosfomycin phenylethylamine calt or left salt) are a kind of important midbodys in the synthetic fosfomycin sodium process of Glamkowski forensic chemistry.The main production stage of fosfomycin phenylethylamine calt is in the synthetic fosfomycin sodium route of Glamkowski forensic chemistry: be starting raw material with the propiolic alcohol; After esterification, hydrolysis, hydrogenation, epoxidation, fractionation, obtain the bullion fosfomycin phenylethylamine calt, will obtain the bullion fosfomycin phenylethylamine calt then and make with extra care to obtain the elaboration fosfomycin phenylethylamine calt, detailed process is that the bullion fosfomycin phenylethylamine calt is dissolved in the ethanol; Add gac at a certain temperature; With the impurity in the charcoal absorption solution, reach the decolouring purpose, remove by filter the gac that has adsorbed impurity then; Obtain clarifying feed liquid; Separate out the fosfomycin phenylethylamine calt crystallization through cooling, filtering separation obtains the wet article of fosfomycin phenylethylamine calt, and drying obtains the elaboration fosfomycin phenylethylamine calt; Filtrating (being mother liquor) is used further to dissolve the bullion fosfomycin phenylethylamine calt; Repeat decolouring, filtration, cooling, crystallization, filtration, drying process; Foreign matter content in the elaboration fosfomycin phenylethylamine calt is reused number of times with mother liquor and is increased; For guaranteeing elaboration fosfomycin phenylethylamine calt quality, mother liquor generally is repeated to use 2～5 times; Owing to still be dissolved with a certain amount of fosfomycin phenylethylamine calt in the final mother liquor, therefore from opening batch refining yield that mother liquid recycle finishes fosfomycin phenylethylamine calt on average 75%～85%.
There is the defective of following 5 aspects in aforesaid method: (1) device resource effective rate of utilization is low: because of the solubleness of left salt in ethanol less; Dissolved bullion left side salt amount is few in the single devices; Cause single batch of elaboration left side salt amount of producing few, cause the effective rate of utilization of device resource low; (2) environment is had the pollution of certain degree: in dissolving, decolorization, temperature of charge will reach 68～72 ℃, and the ethanol that has a great deal of evaporate in the air; Freezing and crystallizing obtains also having in the sepn process behind the solidliquid mixture ethanol and evaporate in the air, has liquid ethanol to run off simultaneously; Have alcohol gas in the drying process with vacuum loss.These all cause the severe contamination of air and discharge water; (3) production environment is abominable, and the harm Occupational health: to evaporate into airborne amount more because of ethanol, and the operator is in the air ambient that is filling the air alcohol gas for a long time, and there are certain harm in respiratory system and liver; (4) have potential safety hazard: to evaporate into airborne amount more because of ethanol equally, and alcohol concn is excessive in the local air environment, in case electrical system goes wrong, will cause fire and explosion hazard; (5) restriction production cost of products: general left salt refining step alcoholic acid unit consumption accounts for certain ratio in the raw materials cost of left salt between 0.6～0.9kg/kg.
Summary of the invention
The process for purification that the purpose of this invention is to provide a kind of fosfomycin phenylethylamine calt; Replace ethanol as fosfomycin phenylethylamine calt purified solvent with zero(ppm) water or purified water, the advantage that this method has that technology is simple, easy to operate, security is good, helps Occupational health, material consumption is low, blowdown is few, cost is low.
The objective of the invention is to realize through following technical scheme:
The process for purification of a kind of fosfomycin phenylethylamine calt of the present invention may further comprise the steps:
1) zero(ppm) water or purified water are warmed up to 30～35 ℃, under stirring state, add bullion left side salt, the mass ratio that wherein said bullion left side salt is given money as a gift with said zero(ppm) water or purified water is 1: 4.2135～5.3571;
2) continue to be warmed up to 40～45 ℃, add gac, continue to be warmed up to 65～75 ℃, insulation, the mass ratio that wherein said bullion left side salt is given money as a gift with gac is 1: 0.0169～0.0214;
3) filter carbon removal,, obtain filtrating with zero(ppm) water or purified water washing charcoal cake;
4) the said filtrating that step 3) is obtained cools to-8～-2 ℃, has crystallization to separate out, the filtering separation solidliquid mixture, and the left salt of article that must wet, the dry elaboration left side salt that gets, the mother liquor that wherein the separation solidliquid mixture is obtained can be used for dissolving once more bullion left side salt, continues use; The said filtrating that perhaps step 3) is obtained is handled with spray drying unit, obtains elaboration left side salt.
The present invention has the following advantages:
1, the device resource effective rate of utilization is high: because of the solubleness of left salt in water is 2 times of solubleness in volume ethanol approximately, so the solvent that adopts water to use as left salt refining can make the throughput of single devices improve 1 times.
2, environmentally safe: the solvent that adopts water to use, environmentally safe as left salt refining.
3, improve production environment, eliminate the factor of harm Occupational health: the solvent that adopts water to use as left salt refining, production environment there is not influence, Occupational health there is not harm.
4, realize safety in production: the solvent that adopts water to use as left salt refining, eliminated the hidden danger of fire, explosion hazard, guaranteed safety in production.
5, reduce production costs: adopt water to replace ethanol to use solvent, because the price of water is significantly less than ethanol, so can reduce production costs as left salt refining.
Embodiment
Embodiment 1:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 35.6g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.761g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is cooled to-8～-2 ℃, there is crystallization to separate out; The filtering separation solidliquid mixture, the left salt of article that must wet, the dry elaboration left side salt that gets.Filter the mother liquid obtained bullion left side salt that is used for dissolving once more, continue to use.
Embodiment 2:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 28.0g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.473g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is cooled to-8～-2 ℃, there is crystallization to separate out; The filtering separation solidliquid mixture, the left salt of article that must wet, the dry elaboration left side salt that gets.Filter the mother liquid obtained bullion left side salt that is used for dissolving once more, continue to use.
Embodiment 3:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 31.35g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.60g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is cooled to-8～-2 ℃, there is crystallization to separate out; The filtering separation solidliquid mixture, the left salt of article that must wet, the dry elaboration left side salt that gets.Filter the mother liquid obtained bullion left side salt that is used for dissolving once more, continue to use.
Embodiment 4:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 28.0g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.60g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is cooled to-8～-2 ℃, there is crystallization to separate out; The filtering separation solidliquid mixture, the left salt of article that must wet, the dry elaboration left side salt that gets.Filter the mother liquid obtained bullion left side salt that is used for dissolving once more, continue to use.
Embodiment 5:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 35.6g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.601g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is cooled to-8～-2 ℃, there is crystallization to separate out; The filtering separation solidliquid mixture, the left salt of article that must wet, the dry elaboration left side salt that gets.Filter the mother liquid obtained bullion left side salt that is used for dissolving once more, continue to use.
Embodiment 6:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 35.6g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.761g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is handled with spray drying unit, obtain elaboration left side salt.
Embodiment 7:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 28.0g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.473g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is handled with spray drying unit, obtain elaboration left side salt.
Embodiment 8:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 31.35g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.60g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is handled with spray drying unit, obtain elaboration left side salt.
Embodiment 9:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 28.0g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.60g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is handled with spray drying unit, obtain elaboration left side salt.
Embodiment 10:
In the three-necked bottle that whisking appliance, TM are housed, add 150g zero(ppm) water or purified water, start stirring, be warmed up to 30～35 ℃; In bottle, add bullion left side salt 35.6g (for the back amount of giving money as a gift), continue to be warmed up to 40～45 ℃, add the 0.601g gac then; Continue to be warmed up to 65～75 ℃, be incubated 10 minutes, filter carbon removal; With 10g zero(ppm) water or purified water washing charcoal cake, the clear filtrate that obtains is handled with spray drying unit, obtain elaboration left side salt.
The process for purification of fosfomycin phenylethylamine calt of the present invention is owing to adopt water as solvent; Environmentally safe; Because of the solubleness of left salt in water is 2 times of solubleness in volume ethanol approximately, so the solvent that adopts water to use as left salt refining can make the throughput of single devices improve 1 times; This process for purification is used in fosfomycin phenylethylamine calt is produced, and makes single batch of throughput improve 95%, and save energy is about 1/3, and 45 tons of ethanol month are practiced thrift in no organic solvent consumption, month reduces 90 tons of COD dischargings, products material cost reduction by 13%.
Claims (1)
1. the process for purification of a fosfomycin phenylethylamine calt is characterized in that, may further comprise the steps:
1) zero(ppm) water or purified water are warmed up to 30～35 ℃, under stirring state, add the bullion fosfomycin phenylethylamine calt, the mass ratio that described bullion fosfomycin phenylethylamine calt is given money as a gift with said zero(ppm) water or purified water is 1: 4.2135～5.3571;
2) continue to be warmed up to 40～45 ℃, add gac, continue to be warmed up to 65～75 ℃, insulation, said soaking time is 10 minutes, the mass ratio that described bullion fosfomycin phenylethylamine calt is given money as a gift with gac is 1: 0.0169～0.0214;
3) filter carbon removal, with zero(ppm) water or purified water washing charcoal cake, obtain filtrating, the said filtrating of acquisition cools to-8～-2 ℃, has crystallization to separate out, filtering separation solidliquid mixture, the article fosfomycin phenylethylamine calt that must wet, the dry elaboration fosfomycin phenylethylamine calt that gets.
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|---|---|---|---|
| CN2009102499583A CN101723979B (en) | 2009-12-08 | 2009-12-08 | Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate |
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| CN2009102499583A CN101723979B (en) | 2009-12-08 | 2009-12-08 | Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate |
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| CN101723979A CN101723979A (en) | 2010-06-09 |
| CN101723979B true CN101723979B (en) | 2012-05-02 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372742B (en) * | 2010-08-13 | 2015-09-23 | 王彦明 | A kind of production technique adopting spray-drying process to make fosfomycin sodium |
| CN103113408B (en) * | 2012-12-10 | 2015-11-18 | 安徽赛诺制药有限公司 | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4222970A (en) * | 1976-08-04 | 1980-09-16 | Roberto Montanari | Process for producing phosphonomycin |
| CN1099036A (en) * | 1994-07-28 | 1995-02-22 | 浙江九洲制药厂 | 2,2'-ethylidene diphenylamine bisphosphate and the prepn. method |
| CN1854146A (en) * | 2005-04-25 | 2006-11-01 | 北京科莱博医药开发有限责任公司 | Synthesis for producing levo phosphomycin by dextro phosphomycin |
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2009
- 2009-12-08 CN CN2009102499583A patent/CN101723979B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4222970A (en) * | 1976-08-04 | 1980-09-16 | Roberto Montanari | Process for producing phosphonomycin |
| CN1099036A (en) * | 1994-07-28 | 1995-02-22 | 浙江九洲制药厂 | 2,2'-ethylidene diphenylamine bisphosphate and the prepn. method |
| CN1854146A (en) * | 2005-04-25 | 2006-11-01 | 北京科莱博医药开发有限责任公司 | Synthesis for producing levo phosphomycin by dextro phosphomycin |
Non-Patent Citations (3)
| Title |
|---|
| 冯晓玲等.(1R，2S)-cis-1 2-环氧丙基膦酸(R)-(+)-α-苯乙胺盐的合成.《中国医药工业杂志》.2009 |
| 冯晓玲等.(1R,2S)-cis-1,2-环氧丙基膦酸(R)-(+)-α-苯乙胺盐的合成.《中国医药工业杂志》.2009,第40卷(第4期),255-257. * |
| 张庆武等.左磷右胺盐精制工艺的改进研究及应用.《当代化工》.2006,第35卷(第5期),第307-308、365页. * |
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