CN101096373A - Method for preparing cefotiam dihydrate dihydrochloride - Google Patents
Method for preparing cefotiam dihydrate dihydrochloride Download PDFInfo
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- CN101096373A CN101096373A CNA2006100102354A CN200610010235A CN101096373A CN 101096373 A CN101096373 A CN 101096373A CN A2006100102354 A CNA2006100102354 A CN A2006100102354A CN 200610010235 A CN200610010235 A CN 200610010235A CN 101096373 A CN101096373 A CN 101096373A
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Abstract
The invention discloses a synthesizing method of sterile raw material medicine of antibiotic medicine 7-[2-(2-amino thiazole-4-radical)acetylamino]-[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazolium-1-radical] sulphur] methyl]-8 oxo-5-thio-1-azabicyclo [4, 2, 0] octa-2-olefin-2-carboxyl acid] hydrochloride dihydrate, which generates cephamtile with high content and good color and little impurity residual through adding sodium thiosulfate agent in the reflecting system to change the color of product cepham appearance.
Description
Technical field
The present invention relates to a kind of new preparation method of two kinds of antibacterials cefotiams.
Background technology
At present; the chemical name of cefotiam is: 7-[2-(thiazolamine-4-yl) kharophen]-[3-[[[(N; N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4; 2; 0] oct-2-ene-2-carboxylic acid] two hydrochloride dihydrate this product are the plain class antimicrobial drug of s-generation injection antibacterial cephalosporin; this medicine is a starting raw material with the 7-amino-cephalosporanic acid; partly introduce [(N by 3 the acetoxyl group that replaces the 7-amino-cephalosporanic acid; N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole heterocycle, this compound carries out the nitrogen acylation reaction with formamido group-thiazolyl-4-acetate again on 7 side chains then.Reaction need be used methylene dichloride, methyl alcohol, N, and N-dimethyl Acetyl Chloride 98Min. is made solvent, and boron trifluoride is a catalyzer.Above-mentioned technological process level of response is poor, and intermediate content is low, the residual height of impurity, and product look level is high.
Summary of the invention
The object of the invention is to overcome the weak point that exists in the above-mentioned technology, the preparation method of the cefotiam dihydrate dihydrochloride that provide that a kind of cost is low, the solvent in the mother liquor can reclaim, significantly reduce environmental protection pressure, environmental pollution is little.
In order to achieve the above object, the technical solution used in the present invention is: be divided into following step: a.[3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] preparation of hydrochloric acid
Make solvent with a kind of solvent, add a kind of complex compound, after reacting completely, the 7-amino-cephalosporanic acid adds a kind of solvent, and drip a kind of acid, make [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
Reaction equation
The 7-amino-cephalosporanic acid [(N, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] two hydrochloric acid
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
B. make solvent with a kind of solvent, add formamido group-thiazolyl-4-acetate, thionyl chloride turn into under make formamido group-thiazolyl-4-Acetyl Chloride 98Min., chemical formula is:
C. make solvent with a kind of mixed solvent, at a certain temperature with the Compound I dissolving, after the cooling, add compound, make the formyl cefotiam, chemical equation is:
D. add a kind of mineral acid and make solvent in a kind of mixed solvent, drop into compound (III), make the cefotiam crude product, its chemical formula is:
Described solvent is acetone, methylene dichloride, methyl alcohol, acetonitrile, methyl acetate, triethylamine.
A. the first step reaction: in reactor, add a kind of solvent, 5.9 moles of 7-amino-cephalosporanic acids, 5-sulfydryl-(N, N) diformazan ethylamino tetrazole, temperature is in 35 ℃, add 1.8～2.4 moles of boron trifluorides, stirred 5 hours, high performance liquid phase detection level then, when 7-amino-cephalosporanic acid content reacts completely less than 5% the time, add a kind of solvent and 37% hydrochloric acid after reacting completely, stirred 30 minutes, take out material, again with a kind of solvent washing, drain and collect wet product, in reactor, add a kind of solvent, drop into the wet product of collecting, temperature adds deionized water down at 30 ℃, after being stirred to whole dissolvings, add carbon, stir after 30 minutes, suction filtration, with the mixing solutions washing filter of a kind of solvent and water, the solution of collection continues to stir, and adds a kind of solvent, regulate PH, stir, take out material, with a kind of solvent washing, drain, wash once more with a kind of solvent, drying products, up to moisture less than 0.5%, obtain 0.4～0.45 mole of [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid.
B. second step reaction: add a kind of solvent in another reactor, formamido group-thiazolyl-4-acetate adds a kind of solvent, stirs following-20～-30 ℃ of coolings, adds the mixing solutions of a kind of solvent and a kind of solvent, stirs.In reactor B, add a kind of solvent, add [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid, cooling is stirred and is added a kind of solvent down, after the dissolving, above-mentioned reactor B is cooled to-45～-35 ℃, solution in the above-mentioned reactor A is moved in the reactor B, make temperature rise to-10～-20 ℃, after all having moved, temperature-stable at-20～-25 ℃, is stirred down, reacted 60 minutes, sampling, the high performance liquid phase detection level is as [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] content of hydrochloric acid is less than 3% o'clock, reacts completely, after reacting completely, add a kind of solvent,, drip a kind of solvent again in order to precipitate fully.Continue to stir 40 minutes, take out material,, with a kind of solvent washing, obtain wet product and be used for next stage again with a kind of solvent washing.
C.9 go on foot in the production of cefotiam aseptic powder, finished product cefotiam appearance color shows pink colour, has added the thiosulfuric acid sodium reagent in reaction system.
D.9 go on foot in the reaction process, to the residual [3-[[[(N of finished product cefotiam solvent, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid, wash and starch with aqueous methyl acetate, it is suspended in the aqueous acetic acid methyl esters mixing solutions.
Advantage of the present invention is:
(1) the cefotiam content in crude product height produced of the present invention, look fabulous, residual considerably less of impurity;
(2) the present invention has added the thiosulfuric acid sodium reagent to finished product cephalo appearance color in the reflection system in 9 step cefotiam aseptic powder are produced, and has solved this difficult problem;
(3) the present invention does not have the thiosulfuric acid sodium reagent, and output finished product cefotiam look extremely shows pink colour, and checking colors is designated as OR series, do not meet standards of pharmacopoeia, add Sulfothiorine after, finished product look level does not show pink colour, the corresponding colour code of displaing yellow or yellow-green colour position Y series meets standards of pharmacopoeia.
Embodiment
Below embodiments of the invention are described in further detail.
Embodiment 1,
Add acetonitrile, 7-amino-cephalosporanic acid 31.54 g, [(N under the room temperature, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole, add boron trifluoride-acetonitrile complex compound 185ml when temperature is 5 ℃, timing is 5 hours when being warmed up to 20 ℃, adds acetone, when temperature is 18 ℃, drip 37% hydrochloric acid and acetone, add pre-cold acetone again, take out material, use washing with acetone, obtain wet product.Wet product of step add carbon on adding in the first alcohol and water, stir, and suction filtration is with methyl alcohol and water mixed liquid washing.Filtrate drips triethylamine when 15 ± 5 ℃ of temperature, add the first alcohol and water again,, when temperature is 10 ℃, stirred 1 hour to PH=3, take out material, successively, drain, obtain [3-[[[(N with methyl alcohol and washing with acetone, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid solid 39.9g, high performance liquid phase detection level 98.13%.
Embodiment 2,
Add diethyl ether 7-amino-cephalosporanic acid 31.54g, [(N, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole, complete molten after, add boron trifluoride-ether complex 185ml at 5 ℃, timing is 5 hours when temperature is 20 ℃, and sampling records 7-amino-cephalosporanic acid content 4.48%.Add acetone, when temperature is 18 ℃, drip hydrochloric acid and acetone, add pre-cold acetone again.When temperature is 10 ℃, stirred 30 minutes, take out material, use washing with acetone, obtain wet product.Wet product of step add carbon and stirred 30 minutes on adding in the first alcohol and water, and suction filtration is with methyl alcohol and water mixed liquid washing.The filtrate temperature drips triethylamine, first alcohol and water in the time of 15 ± 5 ℃, when being 10 ℃, temperature stirred 1 hour, take out material, successively, drain, obtain [3-[[[(N with methyl alcohol and washing with acetone, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid solid 38.9g, high performance liquid phase detection level 94.58%.
Embodiment 3,
Add acetonitrile, methylcarbonate under the room temperature, 7-amino-cephalosporanic acid 31.54g, [(N, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole, complete molten back adds boron trifluoride-carbonic acid dimethyl ester complex 185ml when temperature is 5 ℃, controlled temperature is 20 ℃ of online recording when 7-amino-cephalosporanic acid content is 4.84%, add acetone, dripping hydrochloric acid and acetone when temperature is 18 ℃ add pre-cold acetone again.Temperature is 10 ℃ and stirred 30 minutes, takes out material, uses washing with acetone, obtains wet product.Wet product of step add carbon on adding in the first alcohol and water, stir 30 minutes, and suction filtration is with methyl alcohol and water mixed liquid washing.When being 15 ± 5 ℃, the filtrate temperature drips triethylamine, methyl alcohol 1, water, in the time of 10 ℃, stirred 1 hour, take out material, successively, drain, obtain [3-[[[(N with methyl alcohol and washing with acetone, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid solid 36.2g, high performance liquid phase detection level 93.86%.
Embodiment 4,
Add acetonitrile, methylcarbonate under the room temperature, 7-amino-cephalosporanic acid 31.54ml, [(N, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole, when temperature is 5 ℃, drip boron trifluoride-acetonitrile complex compound 195ml, timing is 3 hours when 20 ℃ of temperature, surveys 7-amino-cephalosporanic acid content 3.89%, add acetone, drip triethylamine when temperature is 18 ℃, temperature is 10 ℃ and stirred suction filtration 30 minutes, with washing with acetone twice, obtain wet product.The wet product that the step obtains on adding in the first alcohol and water add carbon, stir 30 minutes, with methyl alcohol and water washing.When being 15 ± 5 ℃, the filtrate temperature drips triethylamine.Take out material when temperature is 10 ℃, successively use methyl alcohol and washing with acetone, drain.Obtain [3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid solid 40.10g, high performance liquid phase detection level 96.9%.
Embodiment 5,
Add methylene dichloride, 2-formamido group-thiazolyl-4-acetate 5.5g in the reactor A.Be cooled to-25 ℃ after molten entirely, drip thionyl chloride, stirred 20 minutes.Add methylene dichloride 70ml, [3-[[[(N in the reactor B, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid 10g, complete molten back drips triethylamine when temperature is-5 ± 2 ℃, under-40 ℃ with reactor A in solution move in the reactor B, after reacting 3 hours under 3 ℃, add methylene dichloride, reacted 30 minutes, and added methylene dichloride reaction 30 minutes again, take out material, successively, obtain wet product with methylene dichloride and washing with acetone.Add methyl alcohol, water, hydrochloric acid among the reactor C, add when temperature is 35 ± 2 ℃ and go up wet product of step, stirred 30 minutes, vacuum concentration, concentrated solution add water 23.5ml, add 1.5g carbon, stir suction filtration, successively water and washing with acetone 20 minutes.The filtrate temperature splashes into hydrochloric acid and acetone when being 10 ℃, add acetone again after separating out crystallization.Take out material, use washing with acetone, drain, obtain formyl cefotiam crude product 8.63g, high performance liquid phase detection level 80.02%.
Embodiment 6,
In reactor A, add methylene dichloride, dimethyl acetyl ammonia, 2-formamido group-thiazolyl-4-acetate 16.5g ,-25 ℃ complete molten after, add methylene dichloride, drip thionyl chloride reaction 20 minutes.In reactor B, add methylene dichloride, [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid 30g, when being-5 ℃, temperature drips triethylamine, when being cooled to-40 ℃, solution in the reactor A is moved in the reactor B, controlled temperature reacted 3 hours in the time of-25 ℃, detect [3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] content of hydrochloric acid 1.17%, drip dichloromethane is added methylene dichloride again, reacted 30 minutes, take out material, successively use methylene dichloride and washing with acetone, obtain wet product.Add methyl alcohol, water, hydrochloric acid in reactor C, wet product of step reacted 1 hour down at 35 ℃ in the adding, detected formyl cefotiam content 1.90%.Add carbon in the solution, stirred 30 minutes, suction filtration is with 33ml methanol wash filter cake.Behind the vacuum concentration (40 ℃), add entry and acetone, reacted 20 minutes down, take out material, with acetone and water washing filter cake at 25 ℃.Filtrate drips acetone and hydrochloric acid in the time of 10 ℃, add acetone again after separating out crystallization, takes out material, uses the washing with acetone filter cake, drains high performance liquid phase detection level 96.8%.
Embodiment 7,
Add methylene dichloride, dimethyl acetyl ammonia, 2-formamido group-thiazolyl-4-acetate 17.33g in the reactor A, drip dichloromethane and thionyl chloride when cooling to-25 ℃ remain on 25 ℃, react 25 minutes.In the reactor B, add methylene dichloride, [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid 30g, wet at-5 ℃, drip triethylamine, cool to-40 ℃, solution in the reactor A is moved in the reactor B after molten entirely, reaction is 3 hours in the time of-22 ℃ ℃, detect [3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid residual quantity 2.63%, add methylene dichloride under this temperature, add, material was taken out in 5 ℃ of following reactions in 30 minutes, successively, obtain wet product with methylene dichloride and washing with acetone filter cake.Add methylene dichloride, water and hydrochloric acid among the reactor C, add in the time of 35 ℃ and go up wet product of step, react and detected formyl cefotiam content 2.33% in 1 hour.Add 4.5g carbon, stirred 30 minutes, suction filtration is used the methanol wash filter cake.Filtrate vacuum concentration (40 ℃), concentrated solution add acetone and water ml, add carbon, with acetone and water washing filter cake, filtrate again 10 ℃ drip acetone and hydrochloric acid down, add acetone after separating out crystallization, take out material, use the washing with acetone filter cake, drain.High performance liquid phase detection level 95.96%.
Embodiment 8,
Add methylene dichloride, dimethyl acetyl ammonia, 2-formamido group-thiazolyl-4-acetate 17.3g in the reactor A, drip dichloromethane when cooling to-25 ℃, thionyl chloride 7.8ml keeps 25 ℃ of temperature, reacts 15 minutes.Add methylene dichloride in the reactor B, [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid 30g, when temperature is-5 ± 2 ℃, drip triethylamine, after molten entirely, cool to-40 ℃, solution in the reactor A is moved in the reactor B, when being warmed up to-20 ℃, stirred 3 hours, record [3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid residual quantity 2.45%.Drip dichloromethane is added the wet product of methylene dichloride again, stirs 60 minutes when temperature is 35 ℃, and sampling detects formyl cefotiam content less than 2%, add 4.5g, stirred 30 minutes, suction filtration is used methanol wash, behind the vacuum concentration (40 ℃), in concentrated solution, add entry and acetone, add 4.5g carbon in the time of 25 ℃, stirred 20 minutes, suction filtration, water and washing with acetone, filtrate in the time of 10 ℃, dripping hydrochloric acid and acetone, after separating out crystallization, add acetone, take out material, high performance liquid phase detection level 96.94% is drained in washing.
Embodiment 9
Answer to add cefotiam 20g in the device, add purified water 80ml, all after the dissolving, regulate below the PH=1.0 with hydrochloric acid, add EDTA, add gac, carbon takes off 20 minutes after-filtration, and the washing purified water is collected in the reflecting device, use a kind of solvent crystal, the growing the grain filtration drying is surveyed finished product look level 4#, the outward appearance pink colour, moisture: 6.20%, yield 89.32%.
Embodiment 10
Answer to add cefotiam 20g in the device, add purified water 80ml, all after the dissolving, regulate below the PH=1.0 with hydrochloric acid, add EDTA, add Sulfothiorine again, add gac, carbon takes off 20 minutes after-filtration, the washing purified water, collect in the reflecting device, use a kind of solvent crystal, the growing the grain filtration drying, survey finished product look level Y4#, the appearance white powder, moisture: 5.63%, yield 90.01%.
Embodiment 11,
Answer to add cefotiam 20g in the device, add purified water 80ml, all after the dissolving, regulate below the PH=1.0 with hydrochloric acid, add EDTA, add Sulfothiorine again, add gac, carbon takes off 20 minutes after-filtration, the washing purified water, collect in the reflecting device, use a kind of solvent crystal, growing the grain filters drains the back convection drying, survey finished product look level Y4#, the appearance white powder, moisture: 5.38%, yield 88.76%.Solvent residual 2.60%
Embodiment 12,
Answer to add cefotiam 20g in the device, add purified water 80ml, all after the dissolving, regulate below the PH=1.0 with hydrochloric acid, add EDTA, add Sulfothiorine again, add gac, carbon takes off 20 minutes after-filtration, the washing purified water, collect in the reflecting device, use a kind of solvent crystal, after growing the grain filters and drains, wash and starch finished product materials with the aqueous acetic acid methyl esters, use anhydrous acetic acid methyl esters washing material drying after draining again, survey finished product look level Y4#, the appearance white powder, moisture: 6.45%, yield 87.91%.Solvent is residual: 0.01% and 0.17%
Claims (3)
1. the preparation method of a cefotiam dihydrate dihydrochloride is characterized in that: be divided into following step:
A.[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] preparation of hydrochloric acid,
Make solvent with a kind of solvent, add a kind of complex compound, after reacting completely, the 7-amino-cephalosporanic acid adds a kind of solvent, and drip a kind of acid, make [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
Reaction equation
The 7-amino-cephalosporanic acid [(N, N)-dimethyl-amino-ethyl]-5-sulfydryl-tetrazole
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] two hydrochloric acid
[3-[[[(N, N)-dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid
B. make solvent with a kind of solvent, add formamido group-thiazolyl-4-acetate, thionyl chloride turn into under make formamido group-thiazolyl-4-Acetyl Chloride 98Min., chemical formula is:
C. make solvent with a kind of mixed solvent, at a certain temperature with the Compound I dissolving, after the cooling, add compound, make the formyl cefotiam, chemical equation is:
D. add a kind of mineral acid and make solvent in a kind of mixed solvent, drop into compound (III), make the cefotiam crude product, its chemical formula is:
2. the preparation method of cefotiam dihydrate dihydrochloride according to claim 1 is characterized in that:
Described solvent is acetone, methylene dichloride, methyl alcohol, acetonitrile, methyl acetate, triethylamine.
3. the preparation method of cefotiam dihydrate dihydrochloride according to claim 1 is characterized in that:
A. the first step reaction: in reactor, add a kind of solvent, 5.9 moles of 7-amino-cephalosporanic acids, 5-sulfydryl-(N, N) diformazan ethylamino tetrazole, temperature is in 35 ℃, add 1.8～2.4 moles of boron trifluorides, stirred 5 hours, high performance liquid phase detection level then, when 7-amino-cephalosporanic acid content reacts completely less than 5% the time, add a kind of solvent and 37% hydrochloric acid after reacting completely, stirred 30 minutes, take out material, again with a kind of solvent washing, drain and collect wet product, in reactor, add a kind of solvent, drop into the wet product of collecting, temperature adds deionized water down at 30 ℃, after being stirred to whole dissolvings, add carbon, stir after 30 minutes, suction filtration, with the mixing solutions washing filter of a kind of solvent and water, the solution of collection continues to stir, and adds a kind of solvent, regulate PH, stir, take out material, with a kind of solvent washing, drain, wash once more with a kind of solvent, drying products, up to moisture less than 0.5%, obtain 0.4～0.45 mole of [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid.
B. second step reaction: add a kind of solvent in another reactor, formamido group-thiazolyl-4-acetate adds a kind of solvent, stirs following-20～-30 ℃ of coolings, adds the mixing solutions of a kind of solvent and a kind of solvent, stirs.In reactor B, add a kind of solvent, add [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid, cooling is stirred and is added a kind of solvent down, after the dissolving, above-mentioned reactor B is cooled to-45～-35 ℃, solution in the above-mentioned reactor A is moved in the reactor B, make temperature rise to-10～-20 ℃, after all having moved, temperature-stable at-20～-25 ℃, is stirred down, reacted 60 minutes, sampling, the high performance liquid phase detection level is as [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] content of hydrochloric acid is less than 3% o'clock, reacts completely, after reacting completely, add a kind of solvent,, drip a kind of solvent again in order to precipitate fully.Continue to stir 40 minutes, take out material,, with a kind of solvent washing, obtain wet product and be used for next stage again with a kind of solvent washing.
C.9 go on foot in the production of cefotiam aseptic powder, finished product cefotiam appearance color shows pink colour, has added the thiosulfuric acid sodium reagent in reaction system.
D.9 go on foot in the reaction process, to the residual [3-[[[(N of finished product cefotiam solvent, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid, wash and starch with aqueous methyl acetate, it is suspended in the aqueous acetic acid methyl esters mixing solutions.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633666B (en) * | 2009-08-26 | 2010-08-18 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
| CN102898441A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Method for synthesizing cefotiam |
| CN103012432A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
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| CN101633666B (en) * | 2009-08-26 | 2010-08-18 | 海南永田药物研究院有限公司 | Cefotiam hydrochloride compound in new path |
| CN103159786A (en) * | 2011-12-13 | 2013-06-19 | 辽宁海思科制药有限公司 | Preparation method for high-purity sterilized cefmenoxime hydrochloride and pharmaceutical composition containing cefmenoxime hydrochloride |
| CN103159787A (en) * | 2011-12-13 | 2013-06-19 | 辽宁海思科制药有限公司 | Preparation method for high-purity sterilized cefotiam hydrochloride and pharmaceutical composition containing cefotiam hydrochloride |
| CN103159786B (en) * | 2011-12-13 | 2015-03-25 | 辽宁海思科制药有限公司 | Preparation method for high-purity sterilized cefmenoxime hydrochloride and pharmaceutical composition containing cefmenoxime hydrochloride |
| CN102898441A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Method for synthesizing cefotiam |
| CN103012432A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
| CN103012432B (en) * | 2012-12-04 | 2015-06-03 | 山东鑫泉医药有限公司 | Method for preparing hydrochloride of high purity cefotiam midbody |
| CN104447794A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Method for preparing cefdinir |
| CN104910190A (en) * | 2015-06-17 | 2015-09-16 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotiam dihydrochloride |
| CN104926835A (en) * | 2015-06-24 | 2015-09-23 | 山东罗欣药业集团股份有限公司 | Cefotiam hydrochloride compound, method for preparing same and pharmaceutical composition with cefotiam hydrochloride compound |
| CN105820162A (en) * | 2016-05-12 | 2016-08-03 | 浙江永宁药业股份有限公司 | Synthetic method of cefotiam process impurities |
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