CN101712687A - Method for preparing intermediate of cefetamet pivoxil hydrochloride - Google Patents
Method for preparing intermediate of cefetamet pivoxil hydrochloride Download PDFInfo
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Abstract
The invention belongs to the field of chemistry, which in particular relates to a method for preparing cefetamet which is an intermediate of cefetamet pivoxil hydrochloride. By optimizing the process, especially improving the synthesis ratio of raw materials and a crystal growing process, the invention enhances the yield and the purity of a product. The method for preparing the cefetamet, which is provided by the invention, has the advantages of mild reaction conditions and little discharge of three wastes, also has stable process and is suitable for industrial large-scale production.
Description
Technical field
The invention belongs to chemical field, be specifically related to a kind of Ro 15-8075 intermediates preparation.
Background technology
Ro 15-8075 is the oral precursor medicine of cefetamet, chemical name: (6R, 7R)-the 3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-kharophen }-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid pivalyl oxygen methyl ester hydrochloride, chemical formula is as follows:
This product is by Roche Holding Ag exploitation (Ro15-8075), the development of Japanese military field drugmaker, and in 1987 in the nationwide research of Japan's tissue, since listing in 1992, used in countries in the world.As anti-infective oral pharmaceutical, Ro 15-8075 is the third generation oral cephalosporin precursor medicine of new listing, the product in advance that belongs to cynnematin, the unique advantage of this product is to be that the cefetamet (Cefetamet) with anti-microbial activity plays a role by esterase hydrolyzed in intestines wall and the liver rapidly in vivo after oral, cefetamet all has antibacterial and germicidal action to gram-positive microorganism, negative bacterium, have characteristics such as wide spectrum, efficient, anti-enzyme, low toxicity in view of this product, be widely used in the treatment of various infectation of bacteria clinically.
The cefetamet pivoxil prior synthesizing method is a raw material with the amino 8-oxo of 3-methyl-7-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA); combine with ammonia thiophene Acetyl Chloride 98Min. behind the amido protecting; hydrolysis deprotection base obtains cefetamet again; cefetamet and trimethylacetic acid halogen methyl esters generation esterification are synthesized cefetamet pivoxil; but this synthetic method craft complexity; the importing of protecting group and elimination condition harshness are not suitable for suitability for industrialized production.
The synthetic of cefetamet pivoxil mostly adopts two to go on foot synthesis methods at present, and promptly the first step is the synthetic cefetamet acid of raw material with 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) and 2-methoxy industry amino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester); Second step was raw material and the synthetic cefetamet pivoxil of trimethylacetic acid halogen methyl esters reaction with cefetamet acid.Compare with traditional synthetic method, this method has been optimized the synthesis technique of cefetamet pivoxil, and especially having improved the first step reaction is the synthetic of cefetamet acid.Because second step reaction technique is comparatively ripe, be extremely important so as to improving yield and product purity to the suitability for industrialized production of Ro 15-8075 so the reaction of the research the first step is the synthesis technique of cefetamet acid.
The intermediate of Ro 15-8075 is cefetamet acid in above-mentioned synthetic method, and it has as shown in the formula the chemical structure shown in the II:
Liu Jiajian etc. are in " homemade Preparation of cefetamet pivoxil hydrochloride " (26 2 phases of volume of " Chinese microbiotic magazine " calendar year 2001, the 151-152 page or leaf), with 7-amino-3-deacetoxy cefaeicosanoic acid (7-ADCA) is raw material, on the C7-NH2 position, obtain cefetamet with active ester method and side chain compound 2-(2-amino-4-thiazolyl)-2-methoxy imino guanidine-acetic acid condensation, on the C2-COOH position, carry out esterification then and get cefetamet pivoxil, make hydrochloride again to improve its oral absorption with new the eleventh of the twelve Earthly Branches carboxylic acid halides methyl esters.With 7-ADCA is benchmark, and always synthetic yield is more than 80%.
Jiang Jiafeng is at " Shandong medicine thing " 2008 (8): 489-491, with 7-amino-3-deacetoxy cefaeicosanoic acid (7-ADCA) is initiator and active ester reaction, prepare cefetamet (acid) earlier, reaction generates cefetamet pivoxil with trimethylacetic acid halogen methyl esters then, and last cefetamet pivoxil salify gets Ro 15-8075.
Li Kun etc. are at " synthesizing of Ro 15-8075 intermediate " (Heilungkiang medicine, 2005 the 8th the 2nd phases of volume, the 37-38 page or leaf) a kind of synthetic method of Ro 15-8075 intermediate is disclosed, the drying that experimentation is divided into the crystallization of synthetic, extraction that cefetamet is sour, cefetamet acid of cefetamet acid and cefetamet acid with detect four parts.But the crystallization of cefetamet acid need carry out under 0-5 ℃, wet product need to distinguish water, washing with alcohol, and the acid of product cefetamet only is 79.4% with respect to the molar yield of starting raw material 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA).This shows that this synthetic method crystallization conditional request is comparatively harsh, the washing of wet product increases water and alcoholic acid expends, the difficult operation of industrialization, and also product yield is lower.
An Liya is at " cefetamet acid Study of New Method " (Hebei chemical industry, 2005 28 volume the 35th page of the 3rd phase) synthetic method of a kind of Ro 15-8075 intermediate cefetamet acid is also disclosed, the content of the product cefetamet acid that this method finally obtains is 95%, but impurity is more in the product, causes in the finished product of follow-up synthetic hydrochloric acid cefetamet pivoxil impurity residual more.
The synthetic report in the laboratory of cefetamet acid at present is more, but does not appear in the newspapers with the synthesis technique of starting raw material 7-ADCA charging capacity above the cefetamet acid of 200kg scale.
Summary of the invention
Exist reaction conditions comparatively harsh in the synthetic method at some Ro 15-8075 intermediates, the defective that yield is lower and product purity is lower of product cefetamet acid, the contriver is by optimizing synthesis technique, a kind of synthetic method of Ro 15-8075 intermediate is provided, described Ro 15-8075 intermediate is cefetamet acid, the synthetic method of cefetamet acid provided by the invention, the reaction conditions gentleness, product purity and yield height, and the synthetic method craft of cefetamet acid provided by the invention is stable, is more suitable for large-scale industrial production.
The building-up process that a kind of Ro 15-8075 intermediate provided by the invention is cefetamet acid is as follows: carry out condensation reaction with 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) and 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) under the catalyzer condition, reaction finishes after underpressure distillation, decolouring, crystallization, drying finally obtain the acid of finished product cefetamet.
The synthetic method of Ro 15-8075 intermediate of the present invention is achieved through the following technical solutions:
1) preparation feedback of cefetamet acid
7-ADCA is dissolved in the mixed solvent of acetone-water-triethylamine, forms solution a, the AE active ester is joined among the solution a, carry out insulation reaction in the effect of catalyzer, reaction obtains solution b after finishing;
2) post-reaction treatment of cefetamet acid
Water and methylene dichloride joined among the solution b extract, static separatory discards organic phase, obtains aqueous solution, and methylene dichloride and acetone are removed in underpressure distillation, solution c, in solution c, add medicinal carbon, fully stir, after the filtration solution d;
3) crystallization purifying of cefetamet acid
Stream adds 10%～20% dilute hydrochloric acid and carries out crystallization reaction in solution d, pH value is to begin growing the grain at 4.00～5.00 o'clock, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 2.80～3.30 o'clock crystallization reactions finish suction filtration, washing leaching cake, drain the wet product of cefetamet acid, the wet product oven dry of gained cefetamet acid, cefetamet acid dry product.
The volume ratio of acetone and water is 1: 1～5: 1 in the mixed solvent described in the step 1), and the volume ratio of preferred acetone and water is 4: 1.
The mol ratio of triethylamine described in the step 1) and 7-ADCA is 1: 1～1.2: 1; The mol ratio of preferred triethylamine and 7-ADCA is 1.05: 1～1.1: 1.
The mol ratio of 7-ADCA in AE active ester described in the step 1) and the step 1) is 1.01: 1～1.1: 1, the mol ratio of 7-ADCA in preferred AE active ester and the step 1) is 1.05: 1～1.09: 1, most preferably, the mol ratio of the 7-ADCA in AE active ester and the step 1) is 1.085: 1.
Catalyzer described in the step 1) is N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE or N, the N-dimethyl benzamide, preferred described catalyzer is N, dinethylformamide, and catalyst consumption is 0.5%～1.5% of AE active ester and 7-ADCA gross weight, and the consumption of preferred catalyst is 1% of AE active ester and a 7-ADCA gross weight.
18 ℃～22 ℃ of the temperature of the insulation reaction described in the step 1).
The time of the insulation reaction described in the step 1) is 1～4h, and the time of preferred insulation reaction is 2.5～3.5h.
PH value during beginning growing the grain described in the step 3) is 4.4-4.6, and promptly the pH value of growing the grain point is 4.4～4.6, and further preferably, the pH value of growing the grain point is 4.5.
Rearing crystal time described in the step 3) is 5～60min, and further preferably, rearing crystal time is 25～35min.
Based on the synthetic method of a kind of Ro 15-8075 intermediate provided by the invention, the contriver has carried out enforcement as embodiment 1-8 to this synthetic method, and respectively the pH value of growing the grain point and the mol ratio of raw material A E active ester and 7-ADCA has been carried out preferably.Specifically details are as follows:
In the crystallisation process growing the grain point pH value to the influence of cefetamet acid content and yield.
Wherein embodiment 4-6 is preferred to growing the grain point pH value in the synthetic method process provided by the invention.
The contriver keeps the mol ratio of 7-ADCA and AE active ester constant, acetone and water volume ratio are constant, the time of insulation reaction and temperature-resistant, gac add-on and rearing crystal time are constant, only at the pH value (unique parameter) of growing the grain point from 4.60,4.40,4.50 variations, carried out as above embodiment 4, embodiment 5 and embodiment 6 respectively.Found that under the situation that keeps other parameter constants that the pH value of growing the grain point is controlled at that 4.50 yields are the highest, product purity is also the highest, and is as shown in table 1.
Growing the grain point pH value is to the influence of cefetamet acid content and yield in table 1 crystallisation process
2.AE active ester and 7-ADCA mol ratio are to the influence of cefetamet acid yield and purity
Embodiment 68 be to the mol ratio of raw material A E active ester in the synthetic method provided by the invention and 7-ADCA carry out preferred.
The contriver keeps acetone and water volume ratio constant, the time of insulation reaction and temperature-resistant, pH value, the rearing crystal time of gac add-on and growing the grain point are constant, only at mol ratio (unique parameter) changed from 1.085: 1,1.1: 1,1.07: 1, had carried out as above embodiment 6, embodiment 7 and embodiment 8 respectively.Found that under the situation that keeps other parameter constants that it is the highest that the mol ratio of AE active ester and 7-ADCA is controlled at 1.085: 1 yields, product purity is also the highest.As shown in table 2.
Table 2AE-active ester and 7-ADCA mol ratio are to the influence of cefetamet acid yield and purity
Based on the synthetic method of a kind of Ro 15-8075 intermediate provided by the invention, the contriver has also carried out amplifying as the technology of embodiment 9.Embodiment 9 enlarges 1000 times on the basis of embodiment 6, found that product purity is higher, and product yield is also higher, shows that synthetic method craft provided by the invention is stable, is easy to amplify, and is fit to industrial scale production.
The technology of the present invention effect is:
1) reaction conditions gentleness, energy consumption is low, and entire reaction course just can be finished being lower than slightly under the room temperature environment, has avoided because of cooling or the energy dissipation that heats up and cause.
2) product purity height, yield height are guaranteeing that product purity can guarantee the high yield of product in higher, thereby fine cefetamet acid starting material can be provided for the production of Ro 15-8075, and then reducing the production cost of Ro 15-8075.
3) process stabilizing is easy to amplify, and is suitable for suitability for industrialized production.
4) three wastes are few, significantly reduce environmental pollution.Methylene dichloride and acetone reclaim by condensation, can reuse, and have reduced waste water or exhaust gas discharging when reducing cost again, are beneficial to suitability for industrialized production.
Embodiment
Below further describe the present invention by embodiment.Because preferred following embodiment has described the present invention according to the present invention, some is modified and equivalent variations is conspicuous for those of ordinary skill in the art and comprises within the scope of the invention.
Embodiment 1
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 101.19g (1mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 367.5g (1.05mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 2.9g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 2.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 0.3% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.0 o'clock, and rearing crystal time is 60min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.3 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 391.41g, yield 94.55% (in 7-ADCA), the content of cefetamet acid are 96.0% (HPLC detection).
Embodiment 2
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 100ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 121.43g (1.2mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 353.5g (1.01mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 8.52g N, the N-dimethyl benzamide is as catalyzer, after fully stirring at 18 ℃ of insulation reaction 1h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 0.5% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 5.0 o'clock, and rearing crystal time is 5min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.0 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 410.53g, yield 94.0% (in 7-ADCA), the content of cefetamet acid are 91.0% (HPLC detection).
Embodiment 3
Get 3-methyl-7-amino-8-oxo-5-thia-1 azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 300ml acetone, the 300ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 106.25g (1.05mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 381.5g (1.09mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 6.44g N, the N-N,N-DIMETHYLACETAMIDE is as catalyzer, after fully stirring at 22 ℃ of insulation reaction 4h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.4 o'clock, and rearing crystal time is 25min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 2.8 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 395.41g, yield 94.5% (in 7-ADCA), the content of cefetamet acid are 95.0% (HPLC detection).
Embodiment 4
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 111.31g (1.1mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 379.75g (1.085mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 3.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.6 o'clock, and rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.0 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 393.43g, yield 97.5% (in 7-ADCA), the content of cefetamet acid are 98.5% (HPLC detection).
Embodiment 5
Get 3-methyl-7 amino-8-oxo-5 thias-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 111.31g (1.1mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 379.75g (1.085mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 3.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.4 o'clock, and rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.0 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 389.14g, yield 94.0% (in 7-ADCA), the content of cefetamet acid are 96.0% (HPLC detection).
Embodiment 6
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 111.31g (1.1mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 379.75g (1.085mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 3.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.5 o'clock, and rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.0 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 393.4g, yield 98.0% (in 7-ADCA), the content of cefetamet acid are 99.0% (HPLC detection).
Embodiment 7
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 111.31g (1.1mo]) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 385g (1.1mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 3.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; Slowly the stream dilute hydrochloric acid that adds 10%-20% carries out crystallization reaction in filtrate, treats that pH value is to begin growing the grain at 4.5 o'clock, and rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.00 o'clock crystallization reactions finish, suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 401.75g, yield 93.0% (in 7-ADCA), the content of cefetamet acid are 92.0% (HPLC detection).
Embodiment 8
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA) of 214.25g (1mol), 500ml acetone, the 125ml pure water joins in the there-necked flask of 2000ml, fully stir and be cooled to 20 ℃, slowly drip 111.31g (1.1mol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 374.5g (1.07mol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94g N, dinethylformamide is as catalyzer, after fully stirring at 20 ℃ of insulation reaction 3.5h, after finishing, reaction uses 50ml water, the 50ml dichloromethane extraction, static phase-splitting, discard organic phase, acetone and methylene dichloride are removed in the aqueous portion underpressure distillation, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.Add medicinal carbon then in the aqueous solution of removing acetone and methylene dichloride, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stirs, and filters, and discards gac, gets filtrate; The dilute hydrochloric acid that slow stream adds 10%-20% in filtrate carries out crystallization reaction, treat that pH value is to begin growing the grain at 4.50 o'clock, rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.00 o'clock crystallization reactions finish suction filtration, washing leaching cake, drain the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 388.97g, yield 92.0% (in 7-ADCA), the content of cefetamet acid are 94.0% (HPLC detection).
Embodiment 9
Get 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (7-ADCA), the 3m of 214.25kg (1kmol)
3Acetone, 0.75m
3Pure water joins in the retort, fully stir and be cooled to 20 ℃, slowly drip 111.31kg (1.1kmol) triethylamine, cooling while stirring, be cooled to 20 ℃ after fully stirring, 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylhydrazine thiazole ester (AE active ester) of 379.75kg (1.085kmol) is joined in the above-mentioned mixing solutions that contains 7-ADCA, and adding 5.94kg N, dinethylformamide is as catalyzer, after fully stirring,, after finishing, reaction uses 1m at 20 ℃ of insulation reaction 3.5h
3Water, 0.5m
3Dichloromethane extraction, static phase-splitting discards organic phase, and startup vacuum unit vacuumizes sloughs acetone and methylene dichloride, and acetone reclaims after condenser condenses becomes liquid with methylene dichloride gas.It is above and stop to vacuumize when not having a large amount of bubble that vacuum in the question response jar reaches 0.090MPa, in retort, add medicinal carbon then, the add-on of medicinal carbon (in g) is 1.0% of an aqueous solution cumulative volume (in L), fully stir, filter through the decarburization filter, discard gac, get filtrate; Filtrate is transported in the crystallizer.The dilute hydrochloric acid that slow stream adds 10%-20% in filtrate carries out crystallization reaction, treat that pH value is to begin growing the grain at 4.50 o'clock, rearing crystal time is 35min, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 3.00 o'clock crystallization reactions finish, and starts whizzer, centrifugal get rid of expect the wet product of cefetamet acid; With the wet product oven dry of gained cefetamet acid, dry product that must cefetamet acid, weigh 348.76kg, yield 86.0% (in 7-ADCA), the content of cefetamet acid are 98.0% (HPLC detection).
Claims (18)
1. the preparation method of Ro 15-8075 intermediate cefetamet acid, this method comprises the steps:
1) preparation feedback of cefetamet acid
7-ADCA is dissolved in the mixed solvent of acetone-water-triethylamine, forms solution a, the AE active ester is joined among the solution a, carry out insulation reaction under the effect of catalyzer, reaction obtains solution b after finishing;
2) post-reaction treatment of cefetamet acid
Water and methylene dichloride joined among the solution b extract, static separatory discards organic phase, obtains aqueous solution, and methylene dichloride and acetone are removed in underpressure distillation, solution c, in solution c, add medicinal carbon, fully stir, after the filtration solution d;
3) crystallization purifying of cefetamet acid
Stream adds 10%～20% dilute hydrochloric acid and carries out crystallization reaction in solution d, treat that pH value is to begin growing the grain at 4.00～5.00 o'clock, after growing the grain finishes, continue stream and add dilute hydrochloric acid adjusting PH, pH value is that 2.80～3.30 o'clock crystallization reactions finish suction filtration, washing leaching cake, drain the wet product of cefetamet acid, oven dry, cefetamet acid dry product.
2. the method for claim 1 is characterized in that the volume ratio of acetone and water is 1: 1～5: 1 in the mixed solvent described in the step 1).
3. method as claimed in claim 2, the volume ratio that it is characterized in that described acetone and water is 4: 1.
4. the method for claim 1, the mol ratio that it is characterized in that triethylamine described in the step 1) and 7-ADCA is 1: 1～1.2: 1.
5. method as claimed in claim 4, the mol ratio that it is characterized in that described triethylamine and 7-ADCA is 1.05: 1～1.1: 1.
6. the method for claim 1, the mol ratio that it is characterized in that AE active ester described in the step 1) and 7-ADCA is 1.01: 1～1.10: 1.
7. method as claimed in claim 6, the mol ratio that it is characterized in that described AE active ester and 7-ADCA is 1.05: 1～1.09: 1.
8. method as claimed in claim 7, the mol ratio that it is characterized in that described AE active ester and 7-ADCA is 1.085: 1.
9. the method for claim 1 is characterized in that the catalyzer described in the step 1) is N, dinethylformamide, N,N-dimethylacetamide or N, N-dimethyl benzamide.
10. method as claimed in claim 9 is characterized in that described catalyzer is N, dinethylformamide.
11. the method for claim 1 is characterized in that the catalyst consumption described in the step 1) is 0.5%～1.5% of AE active ester and a 7-ADCA gross weight.
12. method as claimed in claim 11 is characterized in that described catalyst consumption is 1.0% of AE active ester and a 7-ADCA gross weight.
13. the method for claim 1 is characterized in that the insulation reaction time described in the step 1) is 1.0～4.0h.
14. method as claimed in claim 13 is characterized in that the described insulation reaction time is 2.5～3.5h.
15. the method for claim 1 is characterized in that the insulation reaction temperature described in the step 1) is 18 ℃～22 ℃.
16. the method for claim 1, the pH value when it is characterized in that the beginning growing the grain described in the step 3) is 4.40～4.60.
17. method as claimed in claim 16, the pH value when it is characterized in that described beginning growing the grain is 4.50.
18. the method for claim 1 is characterized in that the rearing crystal time described in the step 3) is 25～35min.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193766A (en) * | 2014-08-27 | 2014-12-10 | 庄妍 | Method for preparing cefetamet acid |
| CN104788470A (en) * | 2015-04-30 | 2015-07-22 | 苗怡文 | Cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases |
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2009
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193766A (en) * | 2014-08-27 | 2014-12-10 | 庄妍 | Method for preparing cefetamet acid |
| CN104193766B (en) * | 2014-08-27 | 2016-05-11 | 张金凤 | A kind of preparation method of Cefetamet acid |
| CN104788470A (en) * | 2015-04-30 | 2015-07-22 | 苗怡文 | Cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases |
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