CN104910183A - Method for compounding flucloxacillin sodium-hydrate - Google Patents
Method for compounding flucloxacillin sodium-hydrate Download PDFInfo
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- CN104910183A CN104910183A CN201510380228.2A CN201510380228A CN104910183A CN 104910183 A CN104910183 A CN 104910183A CN 201510380228 A CN201510380228 A CN 201510380228A CN 104910183 A CN104910183 A CN 104910183A
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- flucloxacillin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/76—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with hetero rings directly attached to the carboxamido radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
- C07D499/12—Acylation
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a method for compounding flucloxacillin sodium-hydrate, which belongs to the technical field of drug synthesis, and comprises the steps: 6-aminopenicillanic acid (6-APA) is salified, then 3-(2-chloro-6-fluorophenyl)-5- methyl isoxazole-4-formyl chloride or equivalents thereof are added to do an acylation reaction, and then acids are added drop by drop to adjust a potential of hydrogen (pH) value to obtain flucloxacillin acid aqueous solutions. Organic solution is used to extract, and organic phases are washed, dried and filtered to obtain flucloxacillin acid solutions through saturated salt water, then white solids are dissolved out in the flucloxacillin acid solutions which are added with sodium iso-octoate solutions, and products are obtained by controlling temperature and crystallizing. The method for compounding the flucloxacillin sodium-hydrate does not separate intermediate flucloxacillin acids, obtained flucloxacillin acids are directly salified with sodium iso-octoate after being extracted trough the organic solution, reduces separation steps and operation process, also reduces usage amount and times of organic solution simultaneously, greatly reduces discharge amount of organic solution relative to patent documentation CN 102964356A, reduces production cost above 20%, and obviously improves economic and environmental values.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly the synthetic method of a kind of Flucloxacillin sodium-hydrate.
Background technology
Sodium flucloxacillin (Flucloxacillin, Sodium), chemistry (2S by name, 5R, 6R)-6-[[3-(the chloro-6-fluorophenyl of 2-)-5-methyl isophthalic acid, 2-oxazole-4-formyl] amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-sodium formiate monohydrates, molecular formula is C
19h
16clFN
3naO
5sH
2o, molecular weight 493.9, structural formula is:
Sodium flucloxacillin is a kind of isoxazole class penicillin of semisynthetic penicillin resistant enzyme, reach anti-microbial effect by the biosynthesizing of interference bacteria cell wall mucopeptide, effectively can resist penicillin-fast infection of staphylococcus aureus and infect the streptococcus aureus, Hemolytic streptococcus (streptococcus pyogenes), pneumococcus etc. of penicillin-susceptible are caused.Current preparation method used is with 6-APA(and 6-amino-penicillanic acid) for raw material and fluorine chlorine acyl chlorides or (its Equivalent) are condensed into Flucloxacillin acid, obtain sodium salt in the basic conditions further.
Patent documentation CN101475578A discloses a kind of Sodium flucloxacillin and preparation method thereof, first by N, N ' the sour salify of-dibenzyl ethylenediamine salt and Flucloxacillin, and then spent ion exchange resin obtains Sodium flucloxacillin.The method uses resin cation (R.C.), there is production efficiency low, not easily the problem such as heavy industrialization.Patent documentation CN102351882 discloses the purification process of another kind of Sodium flucloxacillin, first that Sodium flucloxacillin is water-soluble, after adding organic solvent extraction impurity, aqueous phase adds alkaline-earth metal alkyl oxide (as sodium methylate or sodium ethylate) and processes, again through neutral alumina column purification, the crystallization of elutriant concentrating under reduced pressure obtains Sodium flucloxacillin, and the method operating process is complicated, needs column chromatography purification, production cost is high, production efficiency is low, and technology stability is poor, not easily heavy industrialization.Patent documentation CN102702227A discloses the synthetic method of Sodium flucloxacillin, first 6-APA and side chain fluorine chlorine acyl chlorides are reacted in acetone soln, then by reaction system acidifying, Flucloxacillin acid organic solvent extraction, then adds Sodium isooctanoate salify, crystallization obtains Sodium flucloxacillin, this technique needs to use a large amount of organic solvents, causes environmental pollution, and production cost is high simultaneously, and technology stability is poor, quality product is difficult to ensure.CN104402904 discloses the method for a kind of mixed anhydride legal system for Sodium flucloxacillin.The synthetic method of Sodium flucloxacillin disclosed in patent documentation CN102964356A, 6-APA is dissolved in inorganic base aqueous solution and existing system (with POCl under organic amine catalysis
3reaction generate acyl chlorides) fluorine chlorine acyl chloride reaction, reaction terminate after, adjust pH obtain Flucloxacillin acid, this patent application first takes out Flucloxacillin acid with organic solvent extracting, then remove organic solvent, then under alcohol/water condition crystallize out, then add the water thing that organic solvent and Sodium isooctanoate salify obtain Sodium flucloxacillin, this patent application complex operation step, consumption of organic solvent is large, and be unfavorable for environmental protection, cost is high, and yield is only about 80% (the whole yield of two steps), needs to be improved further; And the embodiment of this patent is all laboratory lab scale rank, amplify in production in actual industrial, its product purity, yield etc. are lower.
In a word, there is the problems such as organic solvent uses in a large number, cost is high, pollution is large, complex operation, and yield is not high in the synthetic method of current bibliographical information.
Summary of the invention
The object of the invention is to, for the problems referred to above, provide the synthetic method of a kind of Flucloxacillin sodium-hydrate, solve the deficiency that consumption of organic solvent is large, cost is high, it is high to pollute, yield is low that existing method exists.
The technical solution used in the present invention is: the synthetic method of a kind of Flucloxacillin sodium-hydrate, comprises the following steps:
(1) 6-APA is added to the water, drips alkali lye, regulate pH to 8.0 ~ 9.0, obtain the first reaction solution of the salt containing 6-APA;
(2) 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride or its Equivalent are added in the first reaction solution that step (1) obtains in batches and carry out acylation reaction, after reaction terminates, obtain the second reaction solution, acid is dripped in described second reaction solution, regulate pH to 1.5 ~ 3.0, obtain Flucloxacillin aqueous acid; The Flucloxacillin aqueous acid organic solvent extraction of gained, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filters, obtains Flucloxacillin acid solution;
(3) Sodium isooctanoate is dissolved in organic solvent, be made into sodium iso-octoate solution, the sodium iso-octoate solution obtained is added drop-wise in the Flucloxacillin acid solution of gained in step (2), separate out white solid, temperature control crystallization, filter, drying, obtains Flucloxacillin sodium-hydrate.
Wherein, the Equivalent in step (2) refers to acid anhydrides etc.;
Synthetic route of the present invention is as follows:
；
The present invention is with 6-APA (6-amino-penicillanic acid) for starting raw material, and acidylate after 6-APA salify, separation of intermediates Flucloxacillin is not sour, but extraction is directly rear and Sodium isooctanoate salify.
As preferred technical scheme, in step (1):
Described alkali lye is the aqueous solution of sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus; Described concentration of lye is 0.5 ~ 1.5mol/L, and the temperature dripping alkali lye is 0 ~ 20 DEG C.
As further preferred technical scheme, described alkali lye is the aqueous solution of sodium carbonate.
As further preferred technical scheme, the mol ratio of 6-APA and sodium carbonate is 1:1.0 ~ 1:1.5.
As preferred technical scheme, in step (2):
Described acid is hydrochloric acid or dilute sulphuric acid, and volumetric molar concentration concentration is 1 ~ 2mol/L.
As preferred technical scheme, in step (2):
The organic solvent adopted during extraction Flucloxacillin aqueous acid is the one in ether, methyl tertiary butyl ether, methylene dichloride, ethyl acetate, butylacetate, and the weight ratio of 6-APA and organic solvent is 1:10 ~ 30.
As further preferred technical scheme, the organic solvent adopted during extraction Flucloxacillin aqueous acid is ethyl acetate.
As preferred technical scheme, in step (3): the machine solvent dissolving Sodium isooctanoate is identical for the organic solvent extracting Flucloxacillin aqueous acid with step (2).
As preferred technical scheme, in step (3): the mol ratio of 6-APA and Sodium isooctanoate is 1:1.0 ~ 1:1.3, and Sodium isooctanoate volumetric molar concentration is 1 ~ 2 mol/L.
As preferred technical scheme, in step (3): described recrystallization temperature is 0 ~ 20 DEG C, the crystallization time is 2 ~ 5h.
In sum, owing to have employed technique scheme, the invention has the beneficial effects as follows: adopt water as solvent, and use compared with mixed solvent in traditional technology, easy to operate, reaction conditions is gentle, cost is low, while effectively improving yield, greatly reduces the pollution to environment, energy-conserving and environment-protective, meet the requirement of industrialized production more.Simultaneously, the present invention's not separation of intermediates Flucloxacillin acid, the acid of gained Flucloxacillin is after organic solvent extraction, and direct and Sodium isooctanoate salify, decreases separating step and operating procedure, decrease usage quantity and the number of times of organic solvent simultaneously, relative to patent documentation CN102964356A, greatly reduce the quantity discharged of organic solvent, reduce production cost more than 20%, yield can reach more than 90% (improving more than 10%), considerably improves economic benefit and the value of environmental protection.
Embodiment
The present invention is described in detail below.
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
The preparation of embodiment 1 Flucloxacillin sodium-hydrate
In reaction flask, add 100 g water, add 20.0 g 6-APA under stirring, be cooled to 0 ~ 5 DEG C.Take 10.6 g sodium carbonate to be dissolved in 100 mL water, be made into 1 mol/L sodium carbonate solution; Temperature control less than 10 DEG C, is added drop-wise to sodium carbonate solution in reaction flask, obtains 6-APA sodium-salt aqueous solution;
Divide 4 batches to join in reaction flask 28.0 g 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride, it is 1 hour that feed time controls.Be incubated 20 ~ 25 DEG C of reactions 4 hours; 1 mol/L dilute hydrochloric acid is added drop-wise in above-mentioned reaction solution, regulates pH to 2.5;
Join in reaction flask by 400 g ethyl acetate, stir, separatory, separates ethyl acetate phase.Ethyl acetate uses the water washing of 200g saturated common salt mutually, separatory, then uses 20 g anhydrous sodium sulfate drying 30 minutes; Filter, obtain the ethyl acetate solution of Flucloxacillin acid;
Take 18.0 g Sodium isooctanoates to be dissolved in 108 mL ethyl acetate, be made into 1 mol/L sodium iso-octoate solution; Sodium iso-octoate solution is added drop-wise in the ethyl acetate solution of Flucloxacillin acid, drips and finish, separate out white solid; Be cooled to 5 ~ 10 DEG C of crystallizatioies 3 hours, filter, filter cake ethyl acetate washes twice, 50 DEG C of vacuum-dryings, obtains Flucloxacillin sodium-hydrate 41.3g, product purity 99.8%(HPLC), yield 90.6%.
The present embodiment is compared with the embodiment 2 of patent documentation CN102964356A, obtain the Flucloxacillin sodium-hydrate of equal in quality, the amount of the organic solvent consumed is respectively: the present embodiment obtains 1g product needed and consumes about 12ml ethyl acetate, and the embodiment 2 of patent documentation CN102964356A obtains 1g product needed consumes about 27ml ethyl acetate, and more than a kind of organic solvent that the embodiment 2 of patent documentation CN102964356A is used, and the present embodiment only uses ethyl acetate as single solvent, more convenient recycling, significantly improve on cost savings and recovery process.
The preparation of embodiment 2 Flucloxacillin sodium-hydrate
In reaction flask, add 100g water, add 20.0 g 6-APA under stirring, be cooled to 0 ~ 5 DEG C.Take 12.8 g sodium carbonate to be dissolved in 80 mL water, be made into 1.5 mol/L sodium carbonate solutions; Temperature control less than 10 DEG C, is added drop-wise to sodium carbonate solution in reaction flask, obtains 6-APA sodium-salt aqueous solution;
Divide 4 batches to join in reaction flask 30.0 g 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride, it is 1.5 hours that feed time controls; Be incubated 20 ~ 25 DEG C of reactions 3 hours; 1 mol/L dilute hydrochloric acid is added drop-wise in above-mentioned reaction solution, regulates pH to 3.0;
Join in reaction flask by 300 g methyl tertiary butyl ethers, stir, separatory, separates organic phase.Organic phase 200 g saturated common salt water washings, separatory, then use 20 g anhydrous sodium sulfate drying 30 minutes; Filter, obtain the t-butyl methyl ether solution of Flucloxacillin acid;
Take 18.0 g Sodium isooctanoates to be dissolved in 108 mL methyl tertiary butyl ethers, be made into 1 mol/L sodium iso-octoate solution.Sodium iso-octoate solution is added drop-wise in the t-butyl methyl ether solution of Flucloxacillin acid, drips and finish, separate out white solid.Be cooled to 15 ~ 20 DEG C of crystallizatioies 4 hours, filter, filter cake methyl tertiary butyl ether washes twice, 50 DEG C of vacuum-dryings, obtains Flucloxacillin sodium-hydrate 41g, product content 99.7%(HPLC), yield 90.0%.
The preparation of embodiment 3 Flucloxacillin sodium-hydrate
In reaction flask, add 100 g water, add 20.0 g 6-APA under stirring, be cooled to 15 ~ 20 DEG C; Take 13.8 g saleratus to be dissolved in 150 mL water, be made into 0.93 mol/L potassium bicarbonate solution.Temperature control less than 10 DEG C, is added drop-wise to potassium bicarbonate solution in reaction flask, obtains 6-APA sodium-salt aqueous solution;
Divide 4 batches to join in reaction flask 27.0 g 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride, it is 1 hour that feed time controls; Be incubated 15 ~ 20 DEG C of reactions 4 hours; 2 mol/L dilute sulphuric acids are added drop-wise in above-mentioned reaction solution, regulate pH to 3.0;
Join in reaction flask by 200 g methylene dichloride, stir, separatory, separates ethyl acetate phase.Methylene dichloride uses the water washing of 200g saturated common salt mutually, separatory, then uses 20 g anhydrous sodium sulfate drying 30 minutes; Filter, obtain the dichloromethane solution of Flucloxacillin acid;
Take 17.0 g Sodium isooctanoates to be dissolved in 60 mL methylene dichloride, be made into 2 mol/L sodium iso-octoate solution; Sodium iso-octoate solution is added drop-wise in the dichloromethane solution of Flucloxacillin acid, drips and finish, separate out white solid; Be cooled to 0 ~ 5 DEG C of crystallization 5 hours, filter, filter cake methylene dichloride washes twice, 50 DEG C of vacuum-dryings, obtains Flucloxacillin sodium-hydrate 41.1 g, product content 99.6%, yield 90.1%.
The preparation of embodiment 4 Flucloxacillin sodium-hydrate
Add 150 kg water in a kettle., add 30 kg 6-APA under stirring, be cooled to 0 ~ 5 DEG C.Take 15.9kg sodium carbonate to be dissolved in 150 kg water, be made into 1 mol/L sodium carbonate solution and proceed in header tank; Temperature of reaction kettle temperature control less than 10 DEG C, is added drop-wise to sodium carbonate solution in reaction flask, obtains 6-APA sodium-salt aqueous solution;
Divide 4 batches to join in reactor 42 kg 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride, it is 2 hours that feed time controls; Be incubated 20 ~ 25 DEG C of reactions 5 hours; 1 mol/L dilute hydrochloric acid is added drop-wise in above-mentioned reaction solution, regulates pH to 2.5;
Join in reactor by 600 kg ethyl acetate, stir, separatory, separates ethyl acetate phase.27 kg Sodium isooctanoates are dissolved in 162 kg ethyl acetate, are made into 1 mol/L sodium iso-octoate solution; Sodium iso-octoate solution is added drop-wise in the ethyl acetate solution of Flucloxacillin acid, drips and finish, separate out white solid; Be cooled to 5 ~ 10 DEG C of crystallizatioies 5 hours, filter, solid with ethyl acetate washes twice, 50 DEG C of vacuum-dryings, obtains Flucloxacillin sodium-hydrate 62 kg, product purity 99.6%(HPLC), yield 90.5%.
Claims (10)
1. a synthetic method for Flucloxacillin sodium-hydrate, is characterized in that, comprises the following steps:
(1) 6-APA is added to the water, drips alkali lye, regulate pH to 8.0 ~ 9.0, obtain the first reaction solution of the salt containing 6-APA;
(2) 3-(the chloro-6-fluorophenyl of 2-)-5-methyl isoxazole-4-formyl chloride or its Equivalent are added in the first reaction solution that step (1) obtains in batches and carry out acylation reaction, after reaction terminates, obtain the second reaction solution, acid is dripped in described second reaction solution, regulate pH to 1.5 ~ 3.0, obtain Flucloxacillin aqueous acid; The Flucloxacillin aqueous acid organic solvent extraction of gained, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filters, obtains Flucloxacillin acid solution;
(3) Sodium isooctanoate is dissolved in organic solvent, be made into sodium iso-octoate solution, the sodium iso-octoate solution obtained is added drop-wise in the Flucloxacillin acid solution of gained in step (2), separate out white solid, temperature control crystallization, filter, drying, obtains Flucloxacillin sodium-hydrate.
2. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (1):
Described alkali lye is the aqueous solution of sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus; Described concentration of lye is 0.5 ~ 1.5mol/L, and the temperature dripping alkali lye is 0 ~ 20 DEG C.
3. the synthetic method of a kind of Flucloxacillin according to claim 2 sodium-hydrate, is characterized in that, described alkali lye is the aqueous solution of sodium carbonate.
4. the synthetic method of a kind of Flucloxacillin according to claim 3 sodium-hydrate, is characterized in that, the mol ratio of 6-APA and sodium carbonate is 1:1.0 ~ 1:1.5.
5. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (2):
Described acid is hydrochloric acid or dilute sulphuric acid, and volumetric molar concentration concentration is 1 ~ 2mol/L.
6. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (2):
The organic solvent adopted during extraction Flucloxacillin aqueous acid is the one in ether, methyl tertiary butyl ether, methylene dichloride, ethyl acetate, butylacetate, and the weight ratio of 6-APA and organic solvent is 1:10 ~ 30.
7. the synthetic method of a kind of Flucloxacillin according to claim 6 sodium-hydrate, is characterized in that, the organic solvent adopted during extraction Flucloxacillin aqueous acid is ethyl acetate.
8. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (3): the machine solvent dissolving Sodium isooctanoate is identical for the organic solvent extracting Flucloxacillin aqueous acid with step (2).
9. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (3): the mol ratio of 6-APA and Sodium isooctanoate is 1:1.0 ~ 1:1.3, and Sodium isooctanoate volumetric molar concentration is 1 ~ 2 mol/L.
10. the synthetic method of a kind of Flucloxacillin according to claim 1 sodium-hydrate, is characterized in that, in step (3): described recrystallization temperature is 0 ~ 20 DEG C, and the crystallization time is 2 ~ 5h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110777178A (en) * | 2019-12-02 | 2020-02-11 | 河北慧林生物科技有限公司 | Application of immobilized carboxyl ester hydrolase in synthesis of side chains of cloxacillin, dicloxacillin, flucloxacillin and oxacillin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1406239A (en) * | 1971-10-12 | 1975-09-17 | Beecham Group Ltd | Penicillins |
| CN102702227A (en) * | 2012-06-12 | 2012-10-03 | 河北华日药业有限公司 | Preparation method for flucloxacillin sodium |
| CN102964356A (en) * | 2012-12-25 | 2013-03-13 | 菏泽睿智科技开发有限公司 | Synthesis method of flucloxacillin sodium |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
-
2015
- 2015-07-02 CN CN201510380228.2A patent/CN104910183B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1406239A (en) * | 1971-10-12 | 1975-09-17 | Beecham Group Ltd | Penicillins |
| CN102702227A (en) * | 2012-06-12 | 2012-10-03 | 河北华日药业有限公司 | Preparation method for flucloxacillin sodium |
| CN102964356A (en) * | 2012-12-25 | 2013-03-13 | 菏泽睿智科技开发有限公司 | Synthesis method of flucloxacillin sodium |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
Non-Patent Citations (1)
| Title |
|---|
| 周改平: "氟氯西林钠的合成工艺", 《山西医药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110777178A (en) * | 2019-12-02 | 2020-02-11 | 河北慧林生物科技有限公司 | Application of immobilized carboxyl ester hydrolase in synthesis of side chains of cloxacillin, dicloxacillin, flucloxacillin and oxacillin |
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