CN103319502B - Sulbenicillin sodium preparation method - Google Patents
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- CN103319502B CN103319502B CN201310144115.3A CN201310144115A CN103319502B CN 103319502 B CN103319502 B CN 103319502B CN 201310144115 A CN201310144115 A CN 201310144115A CN 103319502 B CN103319502 B CN 103319502B
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- 0 CC(C)(C1*=C)SC(C2*C(C(*=C)c3ccccc3)=O)N1C2=O Chemical compound CC(C)(C1*=C)SC(C2*C(C(*=C)c3ccccc3)=O)N1C2=O 0.000 description 2
- YFBOJKSIAQAJIM-UHFFFAOYSA-N CC(C(NC(C1SC(C)(C)C(C(O)=O)N11)C1=O)=O)c1ccccc1 Chemical compound CC(C(NC(C1SC(C)(C)C(C(O)=O)N11)C1=O)=O)c1ccccc1 YFBOJKSIAQAJIM-UHFFFAOYSA-N 0.000 description 1
- USNMCXDGQQVYSW-UHFFFAOYSA-N OC(C(c1ccccc1)S(O)(=O)=O)=O Chemical compound OC(C(c1ccccc1)S(O)(=O)=O)=O USNMCXDGQQVYSW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a sulbenicillin sodium preparation method, and belongs to the technical field of medicine. According to the preparation method, alpha-sulfophenylacetic acid reacts with chloroformate to produce a mixed anhydride, 6-APA and an organic alkali are subjected to salt formation, and then dissolved in an organic solvent, the obtained material is subjected to a condensation reaction in the mixed anhydride solution, acidification liquid separation is performed after completing the reaction, the organic phase is retained, and sodium2-ethylhexanoate is added to the organic phase to carry out salt formation to obtain the sulbenicillin sodium, wherein the sulbenicillin sodium is further subjected to sterile crystallization through a system comprising water, ethanol and acetone to obtain sulbenicillin sodium for injection. The preparation method has characteristics of low cost, good quality and easy operation, and is suitable for industrialization.
Description
Technical field
The present invention relates to a kind of preparation method of Sulfocillin, belong to medical art.
Background technology
Sulfocillin is a kind of semisynthetic penicillin being researched and developed synthesis by Japanese Wu Tian company.Wu Tian company obtains license in August, 1972 with the trade(brand)name of Lilacillin, from January, 1973, sell injection.It is mainly used in Pseudomonas aeruginosa, Bacillus proteus, the responsive microbial infection such as colibacillary clinically.
1, synthetic method technical background
The synthetic method of the relevant Sulfocillin of current domestic and foreign literature report is mainly with chloride method and mixed anhydride method.
1) chloride method (typical reaction equation as shown in Scheme 1)
US3660379(1972) report: dissolve 6-APA with aqueous sodium carbonate, alpha-sulfo phenyllacetyl chloride is dissolved in ether, 6-APA solution and the condensation reaction of alpha-sulfo phenyllacetyl chloride in 0 DEG C of environment, reaction solution is through acidifying separatory and alkalization separatory, obtain sulbenicillin sodium water solution, obtain Sulfocillin solid through freeze-drying.The document does not describe the synthetic method of acyl chlorides.Document (J.Med Chem, 1972,15 (11), 1105-1108) according to α-sulfosalicylicacid: the mol ratio of sulfur oxychloride=1:13.6, be dissolved in 8 times of volume ether, DMF makes catalyzer, and 40 DEG C of reaction 4h synthesize alpha-sulfo phenyllacetyl chloride, then add in acyl chloride reaction liquid and measure hexanaphthene with ether equal-volume, be cooled to-25 DEG C of crystallization 8h and obtain alpha-sulfo phenyllacetyl chloride solid.The condition of 6-APA dissolution mechanism and synthesis Sulfocillin and the same US3660379 of route.The method of freezing and crystallizing in the method-sulphophenyl Acetyl Chloride 98Min. is difficult to realize in the industrial production, is only suitable for laboratory synthesis in this way and is not suitable for suitability for industrialized production.
US3925362(1975) and US4057544(1977) report: according to 6-APA: hexamethyldisilazane: the mass ratio of triethylamine=1:1.08:0.5, hexamethyldisilazane and 6-APA reflux 1h in chloroformic solution, be evaporated to dry, add methylene dichloride again and be cooled to 0 DEG C and add triethylamine stirring and dissolving, with alpha-sulfo phenyllacetyl chloride Reactive Synthesis Sulfocillin.The method dissolving 6-APA method is too loaded down with trivial details and solvent temperature is too high (chloroform backflow), and hexamethyldisilazane raw material is not easy to obtain, and seldom uses so this technique is basic at present.
Chinese patent CN101914103A, CN101805356A etc., all adopt α-sulfosalicylicacid and the reaction of excessive sulfur oxychloride to make corresponding acyl chlorides, excess thionyl chloride is removed by concentrating under reduced pressure, and organic solvent adds organic alkali dissolution 6-APA method.
In aforesaid method, acyl chlorides obtains by excessive sulfur oxychloride and sulphophenyl acetic acidreaction, and due in synthesis acyl chlorides process, sulfur oxychloride large usage quantity, causes system side reaction more, and quality product is difficult to improve; Two be removing and reclaim excessive sulfur oxychloride process in bring larger disadvantageous effect to environment and production operation personnel.
2) mixed anhydride method
Patent CN102161667 reports 6-APA and BSA(N, the two trimethylsilyl ethanamide of O-) become organic salt to be dissolved in methylene dichloride, α-sulfosalicylicacid triethylamine salt and pivaloyl chloride make mixed acid anhydride, and both carry out anhydrous condensation reaction and become sodium salt to obtain Sulfocillin (reaction equation as shown in Scheme 2) again in methylene dichloride.This route raw material employs the higher raw material of the price such as pivaloyl chloride and BSA, and production cost is higher.
Patent CN102924480 reports D(-)-α-sulfosalicylicacid and chlorsulfonic acid reacting generating compound a, compound a generates mixed acid anhydride with anhydride reaction again, mixed acid anhydride and the obtained D(-of 6-APA reaction)-sulbenicillin (as shown in Scheme 3).This route shortcoming: transformation efficiency that is loaded down with trivial details, mixed acid anhydride is lower, and 6-APA is poorly soluble in mixed anhydride reaction liquid, forms solid-liquid two phase reaction, causes the sulbenicillin productive rate of generation low, of poor quality.
2, organic solvent crystallization technique background
The equal superstate standards of pharmacopoeia of Sulfocillin organic solvent residual that the organic solvent crystallization that current domestic and foreign literature is reported obtains.So listing sulbenicillin sodium for injection is aseptic freeze-dried powder at present.We find through lot of experiments, and Sulfocillin adopts the organic solvent crystal of mixing better, and the residual quantity of organic solvent is closely related with blending ratio.
Summary of the invention
In order to overcome the deficiency of prior art condition, the invention provides one production process is simple, cost is low, productive rate is high, the method for steady quality and the good Sulfocillin of purity.
Technical scheme of the present invention is: a kind of preparation method of Sulfocillin, is characterized in that,
1) in the presence of an organic base, α-sulfosalicylicacid and chloro-formic ester react, and prepare mixed acid anhydride solution a;
2) by 6-APA(6-aminopenicillanic acid) add in organic solvent, then add organic bases and fully stir and make it dissolve, after solution clarification, obtain solution b;
3) by step 2) the b solution prepared is added to condensation reaction in mixed acid anhydride solution a; After reaction terminates, acidifying separatory, aqueous phase discarded retains organic phase;
4) drip sodium iso-octoate solution in the organic phase prepared to step 3), obtain Sulfocillin.
Concrete steps are:
1) α-sulfosalicylicacid is added in organic solvent, then add organic bases, fully stir and solution is clarified; Be cooled to-20 ~ 10 DEG C (preferably-15 ~-5 DEG C) and drip chloro-formic ester, dropwise rear insulation reaction 1.0 ~ 4.0h(preferably 1.5 ~ 3h), obtain mixed acid anhydride solution a, be cooled to-30 ~ 0 DEG C of heat preservation for standby use; Described ratio, α-sulfosalicylicacid: chloro-formic ester: organic bases=1:1.0 ~ 1.5:1.0 ~ 4.0;
2) 6-APA is added in organic solvent, stir and be cooled to-10 ~ 15 DEG C (preferably-5 ~ 5 DEG C), then add organic bases stirring and make it dissolve, after solution clarification, obtain solution b; Described ratio, 6-APA: organic bases=1.0:1.0 ~ 4.0;
3) solution b is joined in mixed acid anhydride solution a; In-50 ~ 0 DEG C of (preferably-30 ~-10 DEG C) insulation reaction 1 ~ 4h(preferably 1.5 ~ 2.5h), after reaction terminates, be 5 ~ 37 wt %(preferably 10 ~ 20% with concentration) hcl acidifying, separatory, aqueous phase discarded, retains organic phase; Described ratio, 6-APA: α-sulfosalicylicacid=1.0:1.0 ~ 1.5, preferred 1.0:1.2;
4) step 3) gained organic phase is proceeded to crystallization kettle, be incubated 15 ~ 20 DEG C, slowly drip the sodium iso-octoate solution of 5 ~ 10wt%, crystallization, drying obtain Sulfocillin; Described ratio, 6-APA: Sodium isooctanoate=1.0:1.0 ~ 4.0, preferred 1.0:2.0 ~ 3.0.
In above-mentioned preparation method:
Chloro-formic ester in described step 1) is R=C
1~ C
10alkyl, one or more in chloroformic acid benzyl ester or chloroformic acid m-tolyl ester.Its consumption is preferably 1.0 ~ 1.2 times of α-sulfosalicylicacid amount of substance.
Organic solvent in described step 1) is one or more in methylene dichloride, ethylene dichloride, chloroform, trichloroethane and toluene etc., and its consumption is 1 ~ 15 times of the quality of α-sulfosalicylicacid, preferably 5 ~ 10 times.
Described step 1) and 2) in organic bases be one or more in triethylamine, diisopropylamine, N-methylmorpholine, tri-n-butylamine and tetramethyl guanidine etc.Described its consumption of step 1) organic bases is preferably 1.5 ~ 2.5 times of α-sulfosalicylicacid amount of substance; Described step 2) in organic bases consumption be 1.0 ~ 2.5 times of 6-APA molar weight.
Described step 2) in organic solvent be that methylene dichloride, ethylene dichloride, chloroform, trichloroethane and acetonitrile are medium, wherein one or more, its consumption is 3 ~ 15 times of 6-APA quality, preferably 5 ~ 10 times.
The solvent of the dissolving Sodium isooctanoate of described step 3) is wherein one or more such as ethyl acetate, butylacetate, acetone, Virahol.
The method that the present invention prepares sulbenicillin sodium for injection is further: be dissolved in water by Sulfocillin obtained above, then add activated carbon decolorizing, sterile filtration; Then in filtrate, pharmaceutical grade ethanol is dripped and acetone crystallization obtains sulbenicillin sodium for injection sterilized powder; Describedly to count in mass ratio, Sulfocillin: water=1.0:1.5 ~ 2.5; Describedly to count by volume, water: ethanol: acetone=1.0:2.0 ~ 3.0:4.0 ~ 9.0, be preferably 1.0:2.5:7.5.
Compared with prior art, the inventive method has the following advantages:
1) chloro-formic ester and α-sulfosalicylicacid organic bases reactant salt synthesis mixed acid anhydride, the by product that chloro-formic ester is introduced becomes CO through acidification hydrolization
2and alcohol, be easier to removing; Vinyl chloroformate cost is low and be easy to get.
2) in the reaction solution after acidifying, drip sodium iso-octoate solution salify, obtain Sulfocillin crude product, simplify production operation step, shorten the production cycle.Reduce production cost.
3) sulbenicillin sodium solvent crystal adopts the mixed solution of water, ethanol and acetone, and the Sulfocillin crystalline powder quality obtained is good, and yield is high.
Embodiment
Following examples are only for illustration of the present invention, and scope is not by the restriction of embodiment.
Embodiment 1
(1) in 200L reactor, 126kg methylene dichloride is added, 10kg(46.3mol is added under rapid stirring) α-sulfosalicylicacid, add diisopropylamine 9.37kg(92.6mol again), be stirred to solution clarification, be cooled to-10 DEG C, at the uniform velocity add 4.49kg(48.7mol) Vinyl chloroformate ,-10 DEG C of insulation reaction 1.5h, obtained solution a ,-15 DEG C save backup.
(2) in clean 1000L reactor, add 10kg(46.3mol) 6-APA(6-aminopenicillanic acid), 101kg methylene dichloride, abundant stirring, after being cooled to 0 DEG C, slowly drip diisopropylamine 9.37kg (92.6mol), after dropwising, maintaining the temperature at-5 ~ 5 DEG C of stirrings makes 6-APA dissolve completely, obtained solution b.
(3) be incubated-15 DEG C and slowly drip b solution in a solution, after dropwising, continue-15 DEG C of insulation reaction 2h, reaction terminates.In reaction solution, add 40kg propyl carbinol, then slowly drip the hydrochloric acid soln of cold 17%, adjust below PH to 2.0, after stirring 10min, separatory, standing 10min gets organic layer, with 10kg*2 cold water washing organic layer.
(4) in step 3), gained organic phase proceeds in 1000L crystallization kettle, be incubated 15 ~ 20 DEG C, slow dropping sodium iso-octoate solution (19.2kg Sodium isooctanoate is dissolved into 200kg ethyl acetate), drop to PH=5.0, add appropriate crystal seed growing the grain 30min, continuing to drip sodium iso-octoate solution is terminal to PH=7.0.Continue insulated and stirred 60min, filter, vacuum-drying obtains Sulfocillin crude product 15.8kg, purity 98.2%.
(5) 15.0kg Sulfocillin crude product is dissolved in 25kg water for injection, molten clear after add 0.75kg needle-use activated carbon and stir decolouring 20min, 0.22 μm of membrane filtration, with 5.0kg water for injection washing leaching cake, filtrate proceeds in the 500L crystallization kettle of aseptic area, be incubated 15 ~ 20 DEG C, first drip pharmaceutical grade ethanol: pharmaceutical grade acetone=1:1(volume ratio) mixed solution 150L, dropwise rear growing the grain 30min. and add 150L pharmaceutical grade acetone again, after stir 30min filter, dry 14.5kg finished product, purity 99.3%.
Embodiment 2
(1) in 200L reactor, 126kg methylene dichloride is added, 10kg(46.3mol is added under rapid stirring) α-sulfosalicylicacid, add tetramethyl guanidine 8.0kg(69.5mol again), be stirred well to solution clarification and be cooled to-10 DEG C, at the uniform velocity add 6.65kg(48.7mol) butyl chlorocarbonate,-10 DEG C of insulation reaction 2h obtained solution a after completion of the reaction ,-15 DEG C save backup.
(2) in the reactor of 1000L, add 10kg(46.3mol) 6-APA(6-aminopenicillanic acid), 101kg methylene dichloride, abundant stirring, after being cooled to 0 DEG C, slowly drip tetramethyl guanidine 5.86kg (50.9mol), after tetramethyl guanidine dropwises, maintaining the temperature at-5 ~ 5 DEG C of stirrings makes 6-APA dissolve, and cryopreservation is for subsequent use.
(3) be incubated-15 DEG C, in a solution, slowly drip b solution, after dropwising ,-15 DEG C of insulation reaction 2h, reaction terminates.Add 40kg propyl carbinol to reaction solution, then slowly drip the hydrochloric acid soln of cold 17%, adjust below PH to 2.0, after stirring 10min, separatory, standing 10min gets organic layer, with 10kg*2 cold water washing organic layer.
(4) in step 3), gained organic phase proceeds in 1000L crystallization kettle, be incubated 15 ~ 20 DEG C, slow dropping sodium iso-octoate solution (18.5kg Sodium isooctanoate is dissolved into 200kg acetone), drop to PH=5.0, add appropriate crystal seed growing the grain 30min, continuing to drip sodium iso-octoate solution is terminal to PH=7.0.Continue insulated and stirred 60min, filter, vacuum-drying obtains Sulfocillin crude product 15.0kg, purity 98.2%.
(5) 15.0kg Sulfocillin crude product is dissolved in 25kg water for injection, molten clear after add 0.75kg needle-use activated carbon and stir decolouring 20min, 0.22 μm of membrane filtration, with 5.0kg water for injection washing leaching cake, filtrate proceeds in the 500L crystallization kettle of aseptic area, be incubated 15 ~ 20 DEG C, first drip pharmaceutical grade ethanol: pharmaceutical grade acetone=1:1(volume ratio) mixed solution 150L, dropwise rear growing the grain 30min. and add 150L pharmaceutical grade acetone again, after stir 30min filter, dry 14.2kg finished product, purity 99.5%.
Claims (5)
1. a preparation method for Sulfocillin, is characterized in that,
1) α-sulfosalicylicacid is added in methylene dichloride, then add organic bases, fully stir and solution is clarified; Be cooled to-20 ~-10 DEG C and drip chloro-formic ester, dropwise rear insulation reaction 1.0 ~ 4.0h, obtain mixed acid anhydride solution a, be cooled to-30 ~ 0 DEG C of heat preservation for standby use; Described ratio, α-sulfosalicylicacid: chloro-formic ester: organic bases=1:1.0 ~ 1.5:1.5 ~ 2.5; Described organic bases is diisopropylamine or tetramethyl guanidine; Described chloro-formic ester is:
, wherein R=C
1~ C
10alkyl;
2) 6-APA is added in methylene dichloride, stir and be cooled to-10 ~ 15 DEG C, then add organic bases stirring and make it dissolve, after solution clarification, obtain solution b; Described ratio, 6-APA: organic bases=1.0:1.0 ~ 4.0; Described organic bases is diisopropylamine or tetramethyl guanidine;
3) solution b is joined in mixed acid anhydride solution a; In-50 ~-15 DEG C of insulation reaction 1 ~ 4h, after reaction terminates, take concentration as the hcl acidifying of 5 ~ 37 wt %, separatory, aqueous phase discarded, retains organic phase; Described ratio, 6-APA: α-sulfosalicylicacid=1.0:1.0 ~ 1.5;
4) step 3) gained organic phase is proceeded to crystallization kettle, be incubated 15 ~ 20 DEG C, drip the sodium iso-octoate solution of 5 ~ 10wt%, obtain Sulfocillin through crystallization, drying; Described ratio, 6-APA: Sodium isooctanoate=1.0:1.0 ~ 4.0.
2. the preparation method of a kind of Sulfocillin as claimed in claim 1, is characterized in that, described step 2) in organic bases consumption be 1.0 ~ 2.5 times of 6-APA molar weight.
3. the preparation method of a kind of Sulfocillin as claimed in claim 1, is characterized in that, the methylene chloride in described step 1) is 1 ~ 15 times of the quality of α-sulfosalicylicacid.
4. the preparation method of a kind of Sulfocillin as claimed in claim 1, is characterized in that, described step 2) in methylene chloride be 3 ~ 15 times of 6-APA quality.
5. the preparation method of a kind of Sulfocillin as claimed in claim 1, is characterized in that, the solvent of the dissolving Sodium isooctanoate of described step 3) is one or more in ethyl acetate, butylacetate, acetone and Virahol.
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| CN104230955B (en) * | 2013-06-17 | 2016-06-22 | 华北制药集团新药研究开发有限责任公司 | A kind of preparation method to the acid of hydroxyl penicillin V and salt thereof |
| CN103787929B (en) * | 2014-03-03 | 2015-04-15 | 济南盛弘医药科技有限公司 | D,L-sulfophenylacetic acid resolution method |
| CN104910179A (en) * | 2015-05-04 | 2015-09-16 | 湖南尔康湘药制药有限公司 | Preparation method of sulbenicillin sodium for injection |
| CN104945417A (en) * | 2015-05-28 | 2015-09-30 | 浙江长典医药有限公司 | Children sulbenicillin sodium compound entity and pharmaceutical preparation thereof |
| CN104940129A (en) * | 2015-05-28 | 2015-09-30 | 浙江长典医药有限公司 | Children type sulbenicillin sodium and low-sodium carrier pharmaceutical composition |
| CN108752311A (en) * | 2018-07-12 | 2018-11-06 | 福安药业集团重庆博圣制药有限公司 | A kind of sulbenicillin sodium intermediate and its method for being used to prepare sulbenicillin sodium |
| CN113980033B (en) * | 2021-11-03 | 2023-02-28 | 海南海灵化学制药有限公司 | Synthesis process of D-sulbenicillin sodium |
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Effective date of registration: 20151102 Address after: 256100 Zibo Province, Yiyuan County, Yang Rui Road, No. 1, No. Patentee after: Reyoung Pharmaceutical Co., Ltd. Address before: 8, 250110 floor, No. 2766, Sau Sau Road, Ji'nan hi tech Zone, Shandong, 801 Patentee before: Jinan Kanghe Medical Technology Co., Ltd. |
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Address after: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Patentee after: Ruiyang Pharmaceutical Co., Ltd Address before: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |