CN107964558A - A kind of cefotiam hydrochloride impurity takes off the preparation method of tetrazole Cefotiam - Google Patents

Abstract

The invention discloses a kind of preparation method of 3 methyl cefotiam chloride of cefotiam hydrochloride impurity, POCl is added in organic solvent₃And DMF, reacted after adding aminothiazole acid hydrochloride, 12~24 it is small when after add mixed solvent after crystallize, filtration washing after growing the grain；Organic base adjusting pH is added after 7 ADCA are added in mixed liquor, aminothiazole chloroacetic chloride is added after 7 DACA dissolve, organic solvent is added when residual is less than 1.0%, water phase is collected after standing split-phase, adds after acetone and concentrated hydrochloric acid dry obtained 3 methyl cefotiam chlorides after growing the grain, filtering, washing.The present invention solves the bottleneck problem in cefotiam hydrochloride R＆D process, change the product form of impurity, improve product stability, high-purity is obtained, the impurity reference substance that property is stablized, the blank of impurity reference substance preparation process has been filled up, has effectively shortened synthesis step, yield reaches 115%, cost reduction reduces impurity synthesis cost to 600 yuan/KG or so.

Description

A kind of cefotiam hydrochloride impurity takes off the preparation method of tetrazole Cefotiam

Technical field

The present invention relates to biology and medical material and intermediate, and in particular in cefotiam hydrochloride quality research it is crucial Know that impurity takes off the synthesis preparation method of tetrazole Cefotiam.

Background technology

Because the adverse reaction of the related material and medicine of medicine has correlation, therefore especially heavy to tracing to the source for impurity of the drug Will, it can effectively be combined with clinical, confirm whether the generation of adverse reaction is related with specific impurities, while the research of related material is The part of most critical in bulk pharmaceutical chemicals and preparation R＆D process, is related to the overall process of drug development, is drug quality research, matter Amount control, the emphasis of security control, at present country the research requirement of the impurity of medicine is gradually stepped up and in line with international standards.At present The impurity research of domestic medicine is more to be studied using area normalization method or Self-control method, and this method cannot meet impurity Ownership classification and qualitative, quantitative control, gradually not by authorized by state, and external standard method carries out quality research and solves the above problems, day Benefit is paid attention to.The primary key to solve the above problems is exactly to obtain impurity reference substance, and current Development Status is impurity control The synthesis of product is not paid attention to, and causes the acquisition of impurity reference substance as the bottleneck problem in drug development process, it is impossible to Solved to effective, cause impurity manufacturing cost high.During cefotiam hydrochloride is researched and developed, de- tetrazole Cefotiam is found For the main degradation products during cefotiam hydrochloride stability, it, which is carried out, to study just becomes the one of kind research and development success or failure A emphasis.

The content of the invention：

The present invention provides the preparation method that a kind of cefotiam hydrochloride impurity takes off tetrazole Cefotiam, high, normal to obtain purity The de- tetrazole Cefotiam product that rule condition property is stablized.

The present invention provides a kind of chemical synthesis means and prepares de- tetrazole Cefotiam method, its synthetic route reactional equation Formula is as follows：

To realize the object of the invention, the preparation method of the de- tetrazole Cefotiam comprises the following steps：

A. the preparation of aminothiazole chloroacetic chloride

Sequentially add POCl3 and DMF in -10~10 DEG C of organic solvent system, whens temperature control to -5~5 DEG C adds aminothiazole Acetic acid hydrochloride is reacted, and is crystallized, is supported after the mixed solvent of organic solvent and acetonitrile composition is added when reacting 12~24 hours Filtered after when crystalline substance 5 is small, then the crystallization after filtering is washed with mixed solvent, then fill obtained aminothiazole chloroacetic chloride wet product Saved backup after nitrogen at -5~5 DEG C；

B. prepared by the conjunction of 7- aminothiazoles acetamidocephalosporanic acid

Sequentially add 7-ACA and protective agent in organic solvent system, temperature control reacted at 10~40 DEG C 3~6 it is small when after by several times Add aminothiazole chloroacetic chloride；

When 7-ACA residuals≤2.0%, pH6.2~7.8 are adjusted after sequentially adding the mixed solution of organic solvent and purified water composition Split-phase is stood, ethyl acetate is then added in the water phase by collection, then adjusts growing the grain behind pH1.5~4.0, filtering, washing, dry It is dry, obtain the 7- aminothiazole acetamidocephalosporanic acids of moisture≤2.0%；

C. preparation of the tetrazole for peace is taken off

Temperature control adjusts pH7.0 to 25~35 DEG C after above-mentioned 7- aminothiazoles acetamidocephalosporanic acid is added in purifying aqueous systems After~8.0 dissolvings, cephalosporin deacetylase is added, tune pH7.3~7.7 when then keeping the temperature 25~35 DEG C, protect when pH value and stablize After be filtered to remove cephalosporin deacetylase, water phase is merged after detersive enzyme filter cake, then 0~15 is cooled to after adjusting pH3.0~4.0 DEG C, then growing the grain, filtering, washing, drying to moisture is less than 1.5%, and obtained product takes off tetrazole Cefotiam；It is described organic molten Agent uses chloroform, dichloromethane or ethyl acetate；The protective agent uses BSA, hexamethyldisilane amine or trim,ethylchlorosilane； The organic solvent is 3 with aminothiazole acid hydrochloride weight ratio:1~8:1；The POCl3 and aminothiazole acid hydrochloric acid Salt molar ratio is 1.5:1~2.2:1；The organic solvent is 5 with 7-ACA weight ratios:1；The protective agent and 7-ACA molar ratios For 1.1:1~1.5:1；The volume ratio of the in the mixed solvent organic solvent and acetonitrile is 2:1~4:1；In the mixed solution The volume ratio of organic solvent and purified water is 2:1~4:1.

Acquisition of technology progress of the present invention：

1st, the present invention solves the bottleneck problem in cefotiam hydrochloride R＆D process, has filled up impurity reference substance preparation process's Blank, has obtained 98% high-purity, the impurity reference substance that property is stablized.

2nd, due to being fed intake using aminothiazole chloroacetic chloride wet product, the energy for not only having saved dry products uses, and keeps away Exempt from destruction of the drying process to aminothiazole chloroacetic chloride, reduce raw material aminothiazole acid hydrochloride usage amount 5~10%, drop Low cost, and the product purity 2% of intermediate 1 is improved, intermediate purity reaches 96%.

3rd, since cephalosporin deacetylase is applied in process of the present invention, not only reaction condition is gentle, causes at the same time Reaction condition is easily controllable, reduces the decomposition of product, obtains the intermediate product of high quality, due to need to only lack in reaction process The weak base of amount maintains pH, the problems such as instead of of high cost, environmental pollution caused by chemical method cracking, so as to reduce production cost And environmental pollution.

Brief description of the drawings

Fig. 1 is the MS figures of de- tetrazole Cefotiam.

Fig. 2 is de- tetrazole Cefotiam¹HNMR schemes.

Fig. 3 is de- tetrazole Cefotiam¹³CNMR schemes.

Embodiment

Embodiment 1：

A. the synthesis of aminothiazole chloroacetic chloride

Chloroform 90mL is added in the four-hole bottle of 1000mL dried and cleans, 36 grams of POCl3 are sequentially added when cooling to 0~10 DEG C With 13 grams of DMF, 23 grams of aminothiazole acid hydrochlorides are slowly added to during 0~5 DEG C of temperature control after stirring 30 minutes and are reacted, reacted 24 it is small when after add and be pre-chilled to 5 DEG C of mixed solvent（50mL chloroform+25mL acetonitriles）, when growing the grain 5 is small after filter, then filter cake is used It is pre-chilled to 0 DEG C of mixed solvent（60mL chloroform+30mL acetonitriles）Washing, obtains the aminothiazole chloroacetic chloride wet product of weight in wet base about 22g, Then the wet product is divided into after 8 equal portions and packed respectively, saved backup after nitrogen charging under 0~5 DEG C of low temperature；

B. the synthesis of 7- aminothiazoles acetamidocephalosporanic acid

320ml chloroforms and 27g7-ACA are sequentially added in 1L dries four-hole boiling flask, stirring controls 25~30 DEG C of temperature after five minutes Lower addition protective agent trim,ethylchlorosilane 38g, maintained the temperature at after adding at 25~30 DEG C reaction 3 it is small when, then 25~30 Added above-mentioned 22g aminothiazoles chloroacetic chloride wet product at DEG C in eight times every 10 minutes, 10min is stirred after adding, sampling measures 7- Reaction terminates during ACA residuals≤2.0%；

It is above-mentioned after reaction, sequentially add 60ml chloroforms and 40ml purified waters composition mixed solution after, with unsaturated carbonate hydrogen Sodium solution adjusts pH to 7.0~7.5, collects water phase after standing 10~15 minutes split-phases, then adds ethyl acetate in water phase 20ml, then with being stirred after the hydrochloric acid tune pH to 3.8 of 4M, growing the grain 30 minutes, then pH value is adjusted in 35~40min with the hydrochloric acid of 4M When growing the grain 2 is small after to 1.8~2.5, then filters, drain, then purify water washing filter cake with 304ml, filter cake is in vacuum drying chamber At 45 DEG C it is dry 3~5 it is small when, 7- aminothiazole acetamidocephalosporanic acids are made in when sampling detection to moisture≤2.0%, it is received Rate 110%, purity >=96.0%；

C. synthesis of the tetrazole for peace is taken off

Addition 440mL purified waters and 30 grams of 7- aminothiazole acetamidocephalosporanic acids in the four-hole bottle of 1L, temperature control to 25~ 35 DEG C, dissolved clarification is dissolved after ammonium hydroxide tune pH7.3~7.7 of 3M are added dropwise, then adds 30 grams of cephalosporin deacetylases, insulation 25 Finely tuned again with the ammonium hydroxide of 3M at~30 DEG C and keep pH7.3~7.7, when pH value 7.6 and keep stablize 3 minutes after reaction knot Beam；Then it is filtered to remove cephalosporin deacetylase, then with merging water phase after 80mL purified water detersive enzyme filter cakes, then with 4M's 5~10 DEG C are cooled to behind hydrochloric acid tune pH3.0~3.5, then growing the grain filters after 30 minutes, then front and rear 100mL purifies water washing knot It is brilliant twice after, de- tetrazole Cefotiam wet product is made, wet product is dried under vacuum to moisture in 35 DEG C less than 1.5%, and yield 65% is left The right side, purity >=98.0%.Structural identification is carried out to product, structural identification is shown in attached drawing 1~3.

Embodiment 2：The present embodiment difference from Example 1 is that organic solvent is used using dichloromethane, protective agent BSA, rate of charge are different.

Dichloro 70mL is added in the four-hole bottle of 1000mL dried and cleans, 39 grams are sequentially added when cooling to -5~5 DEG C POCl3 and 13 gram of DMF, be slowly added to after stirring 30 minutes during 0~5 DEG C of temperature control 23 grams of aminothiazole acid hydrochlorides carry out it is anti- Should, when reaction 24 is small after add and be pre-chilled to 5 DEG C of mixed solvent（40mL dichloro+25mL acetonitriles）, when growing the grain 5 is small after filter, then By the filter cake mixed solvent for being pre-chilled to 0 DEG C（60mL dichloro+40mL acetonitriles）Washing, obtains the aminothiazole second of weight in wet base about 22g The wet product, is then divided into after 8 equal portions and packing respectively, saved backup after nitrogen charging under -5~0 DEG C of low temperature by acyl chlorides wet product；

B. the synthesis of 7- aminothiazoles acetamidocephalosporanic acid

Sequentially add 390ml dichloromethane and 27g7-ACA in 1L dries four-hole boiling flask, stirring control after five minutes temperature 25~ Protective agent BSA 32g are added at 30 DEG C, maintained the temperature at after adding at 25~30 DEG C reaction 4 it is small when, then at 25~30 DEG C Added above-mentioned 22g aminothiazoles chloroacetic chloride wet product in eight times every 10 minutes, 10min is stirred after adding, sampling measures 7-ACA Reaction terminates during residual≤2.0%；

It is above-mentioned after reaction, sequentially add 80ml dichloromethane and 40ml purified waters composition mixed solution after, use saturated carbon Sour hydrogen sodium solution adjusts pH to 7.0~7.5, collects water phase after standing 10~15 minutes split-phases, then adds acetic acid in water phase Ethyl ester 20ml, then with being stirred after the hydrochloric acid tune pH to 3.8 of 4M, growing the grain 30 minutes, then adjusted with the hydrochloric acid of 4M in 35~40min PH value to growing the grain after 1.8~2.5 2 it is small when, then filter, drain, then purify water washing filter cake with 304ml, filter cake is done in vacuum At dry 45 DEG C of case it is dry 3~5 it is small when, 7- aminothiazole acetamidocephalosporanic acids are made in when sampling detection to moisture≤2.0%, Its yield 115%, purity >=96.0%；

C. synthesis of the tetrazole for peace is taken off

Addition 540mL purified waters and 30 grams of 7- aminothiazole acetamidocephalosporanic acids in the four-hole bottle of 1L, temperature control to 25~ 35 DEG C, dissolved clarification is dissolved after ammonium hydroxide tune pH7.3~7.7 of 3M are added dropwise, then adds 30 grams of cephalosporin deacetylases, insulation 25 Finely tuned again with the ammonium hydroxide of 3M at~30 DEG C and keep pH7.3~7.7, when pH value 7.6 and keep stablize 3 minutes after reaction knot Beam；Then it is filtered to remove cephalosporin deacetylase, then with merging water phase after 80mL purified water detersive enzyme filter cakes, then with 4M's 5~10 DEG C are cooled to behind hydrochloric acid tune pH3.0~3.5, then growing the grain filters after 30 minutes, then front and rear 100mL purifies water washing knot It is brilliant twice after, de- tetrazole Cefotiam wet product is made, wet product is dried under vacuum to moisture in 35 DEG C less than 1.5%, its yield 65% Left and right, purity >=98.0%.

Embodiment 3：The present embodiment difference from Example 1 is that organic solvent uses ethyl acetate, and protective agent uses six Methyl disilazane.

Ethyl acetate 120mL is added in the four-hole bottle of 1000mL dried and cleans, is added successively when cooling to -10~0 DEG C Enter 42 grams of POCl3 and 13 gram of DMF, be slowly added to after stirring 30 minutes during 0~5 DEG C of temperature control 23 grams of aminothiazole acid hydrochlorides into Row reaction, when reaction 24 is small after add and be pre-chilled to 5 DEG C of mixed solvent（80mL ethyl acetate+25mL acetonitriles）, when growing the grain 5 is small after Filter, then filter cake use is pre-chilled to 0 DEG C of mixed solvent（100mL ethyl acetate+30mL acetonitriles）Washing, obtains weight in wet base about 22g Aminothiazole chloroacetic chloride wet product, then the wet product is divided into after 8 equal portions and being packed respectively, is protected after nitrogen charging under -2~2 DEG C of low temperature Deposit spare；

B. the synthesis of 7- aminothiazoles acetamidocephalosporanic acid

Sequentially add 480ml ethyl acetate and 27g7-ACA in 1L dries four-hole boiling flask, stirring control after five minutes temperature 25~ Protective agent hexamethyldisilane amine 44g is added at 30 DEG C, maintained the temperature at after adding at 25~30 DEG C reaction 5 it is small when, Ran Hou Added above-mentioned 22g aminothiazoles chloroacetic chloride wet product at 25~30 DEG C in eight times every 10 minutes, 10min is stirred after adding, sample Reaction terminates when measuring 7-ACA residuals≤2.0%；

It is above-mentioned after reaction, sequentially add 80ml ethyl acetate and 40ml purified waters composition mixed solution after, use saturated carbon Sour hydrogen sodium solution adjusts pH to 7.0~7.5, collects water phase after standing 10~15 minutes split-phases, then adds acetic acid in water phase Ethyl ester 20ml, then with being stirred after the hydrochloric acid tune pH to 3.8 of 4M, growing the grain 30 minutes, then adjusted with the hydrochloric acid of 4M in 35~40min PH value to growing the grain after 1.8~2.5 2 it is small when, then filter, drain, then purify water washing filter cake with 304ml, filter cake is done in vacuum At dry 45 DEG C of case it is dry 3~5 it is small when, 7- aminothiazole acetamidocephalosporanic acids are made in when sampling detection to moisture≤2.0%, Its yield 107%, purity >=96.0%；

C. synthesis of the tetrazole for peace is taken off

Addition 540mL purified waters and 30 grams of 7- aminothiazole acetamidocephalosporanic acids in the four-hole bottle of 1L, temperature control to 25~ 35 DEG C, dissolved clarification is dissolved after ammonium hydroxide tune pH7.3~7.7 of 3M are added dropwise, then adds 30 grams of cephalosporin deacetylases, insulation 25 Finely tuned again with the ammonium hydroxide of 3M at~30 DEG C and keep pH7.3~7.7, when pH value 7.6 and keep stablize 3 minutes after reaction knot Beam；Then it is filtered to remove cephalosporin deacetylase, then with merging water phase after 80mL purified water detersive enzyme filter cakes, then with 4M's 5~10 DEG C are cooled to behind hydrochloric acid tune pH3.0~3.5, then growing the grain filters after 30 minutes, then front and rear 100mL purifies water washing knot It is brilliant twice after, de- tetrazole Cefotiam wet product is made, wet product is dried under vacuum to moisture in 35 DEG C less than 1.5%, its yield 65% Left and right, purity >=98.0%.

Claims (1)

1. a kind of cefotiam hydrochloride impurity takes off the preparation method of tetrazole Cefotiam, it is characterised in that includes the following steps：

A. the preparation of aminothiazole chloroacetic chloride

Sequentially add POCl3 and DMF in -10~10 DEG C of organic solvent system, whens temperature control to -5~5 DEG C adds aminothiazole Acetic acid hydrochloride is reacted, and is crystallized, is supported after the mixed solvent of organic solvent and acetonitrile composition is added when reacting 12~24 hours Filtered after when crystalline substance 5 is small, then the crystallization after filtering is washed with mixed solvent, then fill obtained aminothiazole chloroacetic chloride wet product Saved backup after nitrogen at -5~5 DEG C；

B. prepared by the conjunction of 7- aminothiazoles acetamidocephalosporanic acid

Sequentially add 7-ACA and protective agent in organic solvent system, temperature control reacted at 10~40 DEG C 3~6 it is small when after by several times Add aminothiazole chloroacetic chloride；

When 7-ACA residuals≤2.0%, pH6.2~7.8 are adjusted after sequentially adding the mixed solution of organic solvent and purified water composition Split-phase is stood, ethyl acetate is then added in the water phase by collection, then adjusts growing the grain behind pH1.5~4.0, filtering, washing, dry It is dry, obtain the 7- aminothiazole acetamidocephalosporanic acids of moisture≤2.0%；

C. preparation of the tetrazole for peace is taken off

Temperature control adjusts pH7.0 to 25~35 DEG C after above-mentioned 7- aminothiazoles acetamidocephalosporanic acid is added in purifying aqueous systems After~8.0 dissolvings, cephalosporin deacetylase is added, tune pH7.3~7.7 when then keeping the temperature 25~35 DEG C, protect when pH value and stablize After be filtered to remove cephalosporin deacetylase, water phase is merged after detersive enzyme filter cake, then 0~15 is cooled to after adjusting pH3.0~4.0 DEG C, then growing the grain, filtering, washing, drying to moisture is less than 1.5%, and obtained product takes off tetrazole Cefotiam；It is described organic molten Agent uses chloroform, dichloromethane or ethyl acetate；The protective agent uses BSA, hexamethyldisilane amine or trim,ethylchlorosilane； The organic solvent is 3 with aminothiazole acid hydrochloride weight ratio:1~8:1；The POCl3 and aminothiazole acid hydrochloric acid Salt molar ratio is 1.5:1~2.2:1；The organic solvent is 5 with 7-ACA weight ratios:1；The protective agent and 7-ACA molar ratios For 1.1:1~1.5:1；The volume ratio of the in the mixed solvent organic solvent and acetonitrile is 2:1~4:1；In the mixed solution The volume ratio of organic solvent and purified water is 2:1~4:1.