CN103601737B - A kind of preparation method of cefotiam hydrochloride - Google Patents
A kind of preparation method of cefotiam hydrochloride Download PDFInfo
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- CN103601737B CN103601737B CN201310640766.1A CN201310640766A CN103601737B CN 103601737 B CN103601737 B CN 103601737B CN 201310640766 A CN201310640766 A CN 201310640766A CN 103601737 B CN103601737 B CN 103601737B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Abstract
The invention discloses a kind of preparation method of cefotiam hydrochloride, in the method, processed by the mother liquor produced cefotiam hydrochloride crude product in reaction process and refining two-step reaction, after process, mother liquor recycles in the synthesis of cefotiam hydrochloride crude product respectively and refines in two-step reaction process, cefotiam hydrochloride product yield is significantly improved, quality product conformance with standard.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, relate to a kind of preparation method of high yield cefotiam hydrochloride.
Background technology
Cefotiam hydrochloride; chemical name (6R; 7R)-7-[[(2-amino-4-thiazolyl) ethanoyl] is amino]-3-[[1-[2-(dimethylamino) ethyl]-1H-TETRAZOLE-5-base] sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride, is second generation cephalosporin class microbiotic.Anti-microbial effect is widely had to gram-negative bacteria and positive bacteria; The effect of gram positive organism and Cephazolin are close, and to gram-negative bacteria, as more excellent in effects such as influenzae, escherichia coli, klebsiella spp, Proteus mirabilises, also there is anti-microbial effect to enterobacteria, citrobacter, indole-positive Bacillus proteus etc.
The cefotiam hydrochloride that prior art is produced all needs just can reach medicinal requirements through refining or purge process, report that is refining or purifying about cefotiam hydrochloride also has many, such as patent CN101787037B, CN102190667B, CN102746324A are all the technique about cefotiam hydrochloride purifying, but all impact is in various degree caused on yield after purifying, finally cause the cefotiam hydrochloride yield of acquisition lower.In sum, seeking one can either reach medicinal requirements, and the preparation method that can improve again the cefotiam hydrochloride of yield is current problem demanding prompt solution.
Summary of the invention
In order to solve the defect existed in prior art, the invention provides a kind of preparation method of cefotiam hydrochloride, the mother liquor produced by synthesizing and refine two-step reaction to cefotiam hydrochloride crude product in reaction process processes, and recycle in the synthesis of cefotiam hydrochloride crude product respectively and refine in two-step reaction process, product yield is significantly improved, guarantees quality product conformance with standard simultaneously.
The present invention relates to a kind of preparation method of cefotiam, be achieved through the following technical solutions:
A preparation method for cefotiam, comprises following processing step:
(1) synthesis of cefotiam hydrochloride crude product
Purified water, acetonitrile is added to reactor, add 7-ACTM again, and add triethylamine and all dissolve to 7-ACTM, then add ATC-HCl under cryostat to react, until it is 0.8 ~ 1.0% end reaction that 7-ACTM remains, then add inconsistent organic solvent, concentrated hydrochloric acid with water, stirring, static layering, obtain aqueous phase; In aqueous phase, add concentrated hydrochloric acid, then add acetone to reaction solution change muddiness, be cooled to 4 ~ 6 DEG C of insulated and stirred 1 hour, and then dropping acetone, 0 ~ 2 DEG C is stirred growing the grain 3 hours, suction strainer, must reclaim mother liquor (1), filter cake uses washing with acetone twice, dry, acquisition cefotiam hydrochloride crude product;
(2) cefotiam hydrochloride crude product is refining
Purified water dissolves cefotiam hydrochloride crude product, add activated carbon decolorizing, suction filtration, in filtrate, add concentrated hydrochloric acid, add acetone to reaction solution again and become muddy, be cooled to 6 ~ 8 DEG C of insulated and stirred 1 hour, and then drip acetone, 0 ~ 5 DEG C of insulated and stirred 2 hours, suction strainer, must reclaim mother liquor (1), filter cake acetone foam washing is filtered dry, and obtains cefotiam hydrochloride;
(3) mother liquor (1) process is reclaimed
Use and reclaim mother liquor (1) with the inconsistent organic solvent extraction of water, obtain aqueous phase, namely reclaim mother liquor (2);
(4) synthesis of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Add to reactor and reclaim mother liquor (2), purified water, acetonitrile, add 7-ACTM again, and add triethylamine and all dissolve to 7-ACTM, then add ATC-HCl under cryostat to react, until it is 0.8 ~ 1.0% end reaction that 7-ACTM remains, then add inconsistent organic solvent, concentrated hydrochloric acid with water, stirring, static layering, obtain aqueous phase; Add successively in aqueous phase and reclaim mother liquor (2), concentrated hydrochloric acid, add acetone to reaction solution again and become muddy, be cooled to 4 ~ 6 DEG C of insulated and stirred 1 hour, and then dropping acetone, 0 ~ 2 DEG C is stirred growing the grain 3 hours, suction strainer, mother liquor (1) must be reclaimed, filter cake makes washing with acetone twice, dry, acquisition cefotiam hydrochloride crude product, reclaims mother liquor (1) according to stand-by after step (3) process;
(5) primary purification of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Reclaim mother liquor (2) and dissolve cefotiam crude product, add activated carbon decolorizing, suction filtration, concentrated hydrochloric acid is added in filtrate, add acetone to reaction solution again and become muddy, be cooled to 6 ~ 8 DEG C of insulated and stirred 1 hour, and then drip acetone, 0 ~ 5 DEG C of insulated and stirred 2 hours, suction strainer, must reclaim mother liquor (1), and filter cake acetone foam washing is filtered dry, obtain cefotiam hydrochloride, reclaim mother liquor (1) according to stand-by after step (3) process.
Described cryostat temperature is-15 ~-17 DEG C.
Described is methylene dichloride, ethyl acetate or propyl carbinol with the inconsistent organic solvent of water.
Compared with prior art, the mother liquor that the present invention passes through to synthesize cefotiam hydrochloride crude product in reaction process and refine two-step reaction generation processes, and recycle in the synthesis of cefotiam hydrochloride crude product respectively and refine in two-step reaction process, the yield of cefotiam is significantly improved, more do not use before reclaiming mother liquor and improve nearly 15.9% percentage point, guarantee quality product conformance with standard, purity reaches 99.9% simultaneously, be applicable to industrialization, and significantly can reduce production cost.
Embodiment
Further describe the present invention by following examples, but scope of the present invention should be noted not by any restriction of these embodiments.
embodiment 1
(1) synthesis of cefotiam hydrochloride crude product
Purified water 60g, acetonitrile 142g is added to clean reactor, start stirring, mixed solution is cooled to 0 DEG C, drops into 7-ACTM(7-amino-3-[1-(2-methylamino-) ethyl-1H-TETRAZOLE-5-sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid) 26.4g.Keep 0 DEG C of dropping triethylamine to be about 18g to 7-ACTM all to dissolve, now pH value 9.4, reaction solution is cooled to-15 DEG C.In reactor, slowly drop into ATC-HCl(2-(thiazolamine-4-base) Acetyl Chloride 98Min.) 12.4g, reacting liquid pH value about 3.5 samples and uses high performance liquid chromatography to detect 7-ACTM, until it is 1% namely reach reaction end that 7-ACTM remains.Shift out cryostat after completion of the reaction, in reactor, add methylene dichloride 80g, concentrated hydrochloric acid 12g, stir 10 minutes, leave standstill layering after 30 minutes.Lower floor's aqueous phase divides to clean reactor, and upper organic phase recycles.Start aqueous phase to stir, concentrated hydrochloric acid 24g.Reaction solution heats up 25 DEG C.When temperature rises to 16 DEG C, start in reactor, drip acetone and be about 280g to its state that reaches capacity.After dropwising, reaction solution is cooled to 4 DEG C, insulated and stirred 1 hour.Continue to drip acetone 300g, after dropwising, 0 DEG C is stirred growing the grain 3 hours.Suction strainer, obtains and reclaims mother liquor (1) 380g, filter cake acetone 95g foam washing 10min, suction filtration, and filter cake is used acetone 130g washing, drying again, obtained cefotiam hydrochloride crude product 36g, molar yield 85.6%, purity 99.1%.
(2) cefotiam hydrochloride crude product is refining
Suction purified water 90g in clean reactor, starts stirring, temperature is adjusted to 20 DEG C, drops into cefotiam hydrochloride crude product 36g, stirring and dissolving.Drop into gac 0.9g, 20 DEG C are stirred decolouring 20 minutes, and suction filtration, with water 45g foam washing gac filter cake.Filtrate is mixed to new reactor, adds concentrated hydrochloric acid 19g, and adjustment temperature is 20 DEG C, drips acetone and is about 250g to reaction solution change muddiness.Be cooled to 6 DEG C of insulated and stirred 1 hour.Acetone 130g is again dripped with the time of 1 hours.After dropwising, 0 DEG C of insulated and stirred 2 hours.Suction strainer, obtains recovery mother liquor (1) 540g, filter cake acetone 95g foam washing and is filtered dry, obtain cefotiam hydrochloride 30g, weight yield 83.3%, purity 99.9%, content 87.5%.
(3) process of mother liquor (1) is reclaimed
To reclaim mother liquor (1) 920g joins in four-hole bottle, and add 180g methylene dichloride and stir 5min, separatory 10min, discards upper organic phase, and namely aqueous phase reclaims mother liquor (2) 180g.
(4) synthesis of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Add to clean reactor and reclaim mother liquor (2) 30g, purified water 60g, acetonitrile 142g, start stirring, mixed solution is cooled to 5 DEG C, drops into 7-ACTM(7-amino-3-[1-(2-methylamino-) ethyl-1H-TETRAZOLE-5-sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid) 26.4g.Keep 5 DEG C of dropping triethylamines to be about 18g to 7-ACTM all to dissolve, now pH value is 9.3, and reaction solution is cooled to-17 DEG C.In reactor, slowly drop into ATC-HCl(2-(thiazolamine-4-base) Acetyl Chloride 98Min.) 12.4g, reacting liquid pH value about 3.5 samples and uses high performance liquid chromatography to detect 7-ACTM, until it is 0.8% that 7-ACTM remains, namely reaches reaction end.Shift out cryostat after completion of the reaction, in reactor, add methylene dichloride 80g, concentrated hydrochloric acid 12g, stir 10 minutes, leave standstill layering after 30 minutes.Lower floor's aqueous phase divides to clean reactor, and upper organic phase recycles.Start aqueous phase to stir, add successively and reclaim mother liquor (2) 60g, concentrated hydrochloric acid 24g.Reaction solution is warming up to 27 DEG C.When temperature rises to 16 DEG C, start in reactor, drip acetone and be about 280g to its state that reaches capacity.After dropwising, reaction solution is cooled to 6 DEG C, insulated and stirred 1 hour.Continue to drip acetone 300g, after dropwising, 2 DEG C are stirred growing the grain 3 hours.Suction strainer, must reclaim mother liquor (1) 370g, filter cake acetone 95g foam washing 10min, suction filtration.Filter cake is again with acetone 130g washing, dry, acquisition cefotiam hydrochloride crude product 36g.Molar yield 85.6%, purity 99.0%.Reclaim mother liquor (1) according to stand-by after step (3) process.
(5) primary purification of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
In clean reactor, mother liquor (2) 120g is reclaimed in suction, starts stirring, temperature is adjusted to 25 DEG C, drops into for peace crude product 36g, stirring and dissolving.Drop into gac 0.9g, 22 DEG C are stirred decolouring 20 minutes, suction filtration, gac filter cake use water 45g foam washing carbon cake.Filtrate is mixed to new reactor, adds concentrated hydrochloric acid 19g, and adjustment temperature is 20 DEG C, drips acetone and is about 250g to reaction solution change muddiness.Be cooled to 10 DEG C, add a small amount of cefotiam hydrochloride as crystal seed, continue to be cooled to 8 DEG C of insulated and stirred 1 hour.Acetone 130g is again dripped with the time of 1 hours.After dropwising, 5 DEG C of insulated and stirred 2 hours.Suction strainer, must reclaim mother liquor (1) 550g, and filter cake acetone 95g foam washing is filtered dry.Dry solid 35.7g, weight yield 99.2%, purity 99.9%, content 87%.Reclaim mother liquor (1) according to stand-by after step (3) process.
embodiment 2
(1) synthesis of cefotiam hydrochloride crude product
Purified water 60g, acetonitrile 142g is added to clean reactor, start stirring, mixed solution is cooled to 2 DEG C, drops into 7-ACTM(7-amino-3-[1-(2-methylamino-) ethyl-1H-TETRAZOLE-5-sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid) 26.4g.Keep 3 DEG C of dropping triethylamines to be about 19g to 7-ACTM all to dissolve, now pH value is 9.2, and reaction solution is cooled to-16 DEG C.In reactor, slowly drop into ATC-HCl(2-(thiazolamine-4-base) Acetyl Chloride 98Min.) 13g, reacting liquid pH value about 3.5 samples and uses high performance liquid chromatography to detect 7-ACTM, until it is 0.8% stopped reaction that 7-ACTM remains.Shift out cryostat after completion of the reaction, in reactor, add methylene dichloride 80g, concentrated hydrochloric acid 12g, stir 10 minutes, leave standstill layering after 30 minutes.Lower floor's aqueous phase divides to clean reactor, and upper organic phase recycles.Start aqueous phase to stir, concentrated hydrochloric acid 24g.Reaction solution is warming up to 26 DEG C.When temperature rises to 16 DEG C, start in reactor, drip acetone and be about 280g to its state that reaches capacity.After dropwising, reaction solution is cooled to 5 DEG C, insulated and stirred 1 hour.Continue to drip acetone 300g, after dropwising, 1 DEG C is stirred growing the grain 3 hours.Suction strainer, obtains and reclaims mother liquor (1) 370g, filter cake acetone 95g foam washing 10min, suction filtration, and filter cake is used acetone 130g washing, drying again, obtained cefotiam hydrochloride crude product 36.5g, molar yield 86.77%, purity 99.2%.
(2) cefotiam hydrochloride crude product is refining
Suction purified water 90g in clean reactor, starts stirring, temperature is adjusted 25 DEG C, drops into cefotiam hydrochloride crude product 35g, stirring and dissolving.Drop into gac 0.9g, 20 DEG C are stirred decolouring 20 minutes, and suction filtration, with water 45g foam washing gac filter cake.Filtrate is mixed to new reactor, adds concentrated hydrochloric acid 19g, adjustment temperature 24 DEG C, drips acetone and is about 250g to reaction solution change muddiness.Be cooled to 6 DEG C of insulated and stirred 1 hour.Acetone 130g is again dripped with the time of 1 hours.After dropwising, 3 DEG C of insulated and stirred 2 hours.Suction strainer, obtains recovery mother liquor (1) 530g, filter cake acetone 95g foam washing and is filtered dry, obtain cefotiam hydrochloride 30g, weight yield 85.7%, purity 99.9%, content 87.6%.
(3) process of mother liquor (1) is reclaimed
To reclaim mother liquor (1) 900g joins in four-hole bottle, and add 180g ethyl acetate and stir 5min, separatory 10min, discards upper organic phase, and namely aqueous phase reclaims mother liquor (2) 185g.
(4) synthesis of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Add to clean reactor and reclaim mother liquor (2) 30g, purified water 60g, acetonitrile 142g, start stirring, mixed solution is cooled to 4 DEG C, drops into 7-ACTM(7-amino-3-[1-(2-methylamino-) ethyl-1H-TETRAZOLE-5-sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid) 26.4g.Keep 3 DEG C of dropping triethylamines to be about 18g to 7-ACTM all to dissolve, now pH value 9.5.Reaction solution is cooled to-16 DEG C.In reactor, slowly drop into ATC-HCl(2-(thiazolamine-4-base) Acetyl Chloride 98Min.) 12.4g, reacting liquid pH value about 3.5 samples and uses high performance liquid chromatography to detect 7-ACTM, until it is 0.9% that 7-ACTM remains, namely reaches reaction end.Shift out cryostat after completion of the reaction, in reactor, add methylene dichloride 80g, concentrated hydrochloric acid 12g, stir 10 minutes, leave standstill layering after 30 minutes.Lower floor's aqueous phase divides to clean reactor, and upper organic phase recycles.Start aqueous phase to stir, add successively and reclaim mother liquor (2) 60g, concentrated hydrochloric acid 24g.Reaction solution heats up 26 DEG C.When temperature rises to 16 DEG C, start in reactor, drip acetone and be about 280g to its state that reaches capacity.After dropwising, reaction solution is cooled to 5 DEG C, insulated and stirred 1 hour.Continue to drip acetone 300g, after dropwising, 1 DEG C is stirred growing the grain 3 hours.Suction strainer, must reclaim mother liquor (1) 370g, filter cake acetone 95g foam washing 10min, suction filtration.Filter cake is again with acetone 130g washing, dry, acquisition cefotiam hydrochloride crude product 36.2g.Molar yield 86.1%, purity 99.3%.Reclaim mother liquor (1) according to stand-by after step (3) process.
(5) primary purification of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
In clean reactor, mother liquor (2) 120g is reclaimed in suction, starts stirring, temperature is adjusted to 22 DEG C, drops into for peace crude product 36g, stirring and dissolving.Drop into gac 0.9g, 21 DEG C are stirred decolouring 20 minutes, suction filtration, gac filter cake use water 45g foam washing carbon cake.Filtrate is mixed to new reactor, adds concentrated hydrochloric acid 19g, and adjustment temperature is 21 DEG C, drips acetone and is about 250g to reaction solution change muddiness.Be cooled to 10 DEG C, add a small amount of cefotiam hydrochloride as crystal seed, continue to be cooled to 7 DEG C of insulated and stirred 1 hour.Acetone 130g is again dripped with the time of 1 hours.After dropwising, 2 DEG C of insulated and stirred 2 hours.Suction strainer, must reclaim mother liquor (1) 550g, and filter cake acetone 95g foam washing is filtered dry.Dry solid 35.8g, weight yield 99.4%, purity 99.9%, content 86%.Reclaim mother liquor (1) according to stand-by after step (3) process.
In addition, during recovery mother liquor (1) in Processing Example 1 and 2, propyl carbinol can also be added in recovery mother liquor (1), by stirrings, separatory, discard upper organic phase, acquisition aqueous phase, namely reclaim mother liquor (2).
Although illustrate and describe exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.
Claims (2)
1. a preparation method for cefotiam hydrochloride, said method comprising the steps of:
(1) synthesis of cefotiam hydrochloride crude product
Purified water, acetonitrile is added to reactor, add 7-ACTM again, and add triethylamine and all dissolve to 7-ACTM, then add ATC-HCl under cryostat to react, until it is 0.8 ~ 1.0% end reaction that 7-ACTM remains, then add inconsistent organic solvent, concentrated hydrochloric acid with water, stirring, static layering, obtain aqueous phase; In aqueous phase, add concentrated hydrochloric acid, then add acetone to reaction solution change muddiness, be cooled to 4 ~ 6 DEG C of insulated and stirred 1 hour, and then dropping acetone, 0 ~ 2 DEG C is stirred growing the grain 3 hours, suction strainer, must reclaim mother liquor (1), filter cake uses washing with acetone twice, dry, acquisition cefotiam hydrochloride crude product;
(2) cefotiam hydrochloride crude product is refining
Purified water dissolves cefotiam hydrochloride crude product, add activated carbon decolorizing, suction filtration, in filtrate, add concentrated hydrochloric acid, add acetone to reaction solution again and become muddy, be cooled to 6 ~ 8 DEG C of insulated and stirred 1 hour, and then drip acetone, 0 ~ 5 DEG C of insulated and stirred 2 hours, suction strainer, must reclaim mother liquor (1), filter cake acetone foam washing is filtered dry, and obtains cefotiam hydrochloride;
(3) mother liquor (1) process is reclaimed
Use and reclaim mother liquor (1) with the inconsistent organic solvent extraction of water, obtain aqueous phase, namely reclaim mother liquor (2);
(4) synthesis of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Add to reactor and reclaim mother liquor (2), purified water, acetonitrile, add 7-ACTM again, and add triethylamine and all dissolve to 7-ACTM, then add ATC-HCl under cryostat to react, until it is 0.8 ~ 1.0% end reaction that 7-ACTM remains, then add inconsistent organic solvent, concentrated hydrochloric acid with water, stirring, static layering, obtain aqueous phase; Add successively in aqueous phase and reclaim mother liquor (2), concentrated hydrochloric acid, add acetone to reaction solution again and become muddy, be cooled to 4 ~ 6 DEG C of insulated and stirred 1 hour, and then dropping acetone, 0 ~ 2 DEG C is stirred growing the grain 3 hours, suction strainer, mother liquor (1) must be reclaimed, filter cake makes washing with acetone twice, dry, acquisition cefotiam hydrochloride crude product, reclaims mother liquor (1) according to stand-by after step (3) process;
Wherein, described is methylene dichloride, ethyl acetate or propyl carbinol with the inconsistent organic solvent of water;
(5) primary purification of mother liquor (2) for cefotiam hydrochloride crude product is reclaimed
Reclaim mother liquor (2) and dissolve cefotiam crude product, add activated carbon decolorizing, suction filtration, concentrated hydrochloric acid is added in filtrate, add acetone to reaction solution again and become muddy, be cooled to 6 ~ 8 DEG C of insulated and stirred 1 hour, and then drip acetone, 0 ~ 5 DEG C of insulated and stirred 2 hours, suction strainer, must reclaim mother liquor (1), and filter cake acetone foam washing is filtered dry, obtain cefotiam hydrochloride, reclaim mother liquor (1) according to stand-by after step (3) process;
Wherein, in described step (5), add acetone add crystal seed cefotiam hydrochloride after reaction solution becomes muddiness.
2. the preparation method of cefotiam hydrochloride according to claim 1, is characterized in that, described cryostat temperature is-15 ~-17 DEG C.
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| CN109336906B (en) * | 2018-11-21 | 2020-05-22 | 山东罗欣药业集团股份有限公司 | Drying process of cefotiam hydrochloride |
| CN111039957A (en) * | 2019-12-12 | 2020-04-21 | 江苏汉斯通药业有限公司 | Synthesis method of cefbuperazone |
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| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| CN101633666A (en) * | 2009-08-26 | 2010-01-27 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
| CN102850381A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Preparation method of cefotiam hydrochloride crude product |
| CN103012436A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Preparation method of cefotiam hydrochloride |
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