CN101550150B - Cefmenoxime compound and synthetic method thereof - Google Patents
Cefmenoxime compound and synthetic method thereof Download PDFInfo
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- CN101550150B CN101550150B CN2009100149710A CN200910014971A CN101550150B CN 101550150 B CN101550150 B CN 101550150B CN 2009100149710 A CN2009100149710 A CN 2009100149710A CN 200910014971 A CN200910014971 A CN 200910014971A CN 101550150 B CN101550150 B CN 101550150B
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Abstract
The invention relates to a cefmenoxime compound and a synthetic method thereof, in particular to a synthetic method of a cefmenoxime compound, pertaining to the field of drug synthesis technology. Themethod comprises the following steps: (1) aminothiazoly loximate and triphenylchloromethane react in DMF to obtain 2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxy imido acetic acid hydrochloride; (2 ) the 2-(2- triphenylmethylaminothiazol-4-yl)-2-methoxy imido acetic acid hydrochloride and N, N-diisopropylethylamine are added into the DMF and then paratoluensulfonyl chloride is added and the mixture is stirred for reaction, and then 7-ACA and triethylamine are added for reaction. The pH value is adjusted with hydrochloric acid to obtain hydrochloric cefotaxime acid; and (3) the hydrochloric cefotaxime acid and 1-methyl-5- hydrosulphonyl-1H-tetrazolium react in a mixed solvent and the pH value is adjusted respectively with sodium carbonate and hydrochloric acid to obtain cefmenoxime.
Description
Technical field
The present invention relates to a kind of synthetic method of cephalosporin compound, be specifically related to a kind of synthetic method of cefmenoxime compound, belong to technical field of medicine synthesis.
Background technology
Cefmenoxime, its chemical name is: (6R, 7R)-7-[2-(2-amino-4-thiazolyl) (methoxyimino) kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, molecular formula: C
16H
17N
9O
5S
3, molecular weight: 511.55, structural formula is:
Cefmenoxime is the third generation cephalosporin that Japanese Wu Tian company develops, and nineteen eighty-three is a kind of Broad spectrum antibiotics in Japanese Initial Public Offering, reaches germicidal action by the biosynthesizing that suppresses bacteria cell wall.In vitro tests shows, cefmenoxime all has effect to gram-positive microorganism and negative bacterium, it is because the permeability of its pair cell adventitia is good and stable by enzyme to β-Nei acyl that Gram-negative bacteria is had strong anti-microbial effect, and the avidity to penicillin-binding protein (PBPs) 1A, 1B and 3 is strong, thereby pair cell wall mucopeptide is cross-linked to form and has stronger inhibition.
About the synthetic method of cefmenoxime, according to bibliographical information, mainly be raw material with 7-ACA, (1) 3 condensations, 7 condensations more earlier; (2) 7 condensations, 3 condensations more earlier.The condition of 3 condensations has boron trifluoride method, sulfuric acid process etc., and every kind of method has characteristics, and the condition of 7 condensations has active ester method, chloride method, DCC method etc.Wherein, chloride method requires than higher the no water-based of solvent, equipment requirements height, the difficult control of operation; And active ester method and DCC method cost are higher.
At present, domestic each the preparation manufacturer of cefmenoxime relies on the imported raw material medicine to carry out packing to make, and about the production technique of cefmenoxime, not seeing has document and patent report.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of cefmenoxime compound, solved the blank of domestic prior art, made things convenient for the demand of preparation producer bulk drug.
The invention provides a kind of synthetic method of cefmenoxime compound, synthetic route is:
(1) 2-(thiazolamine-4-yl)-2-methoxyimino acetate and triphenylmethyl chloride are reacted in DMF (dimethyl formamide), obtain 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride;
(2) with 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride and N, the N-diisopropylethylamine joins among the DMF (dimethyl formamide), add Tosyl chloride, stirring reaction, add the reaction of 7-ACA (3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2 carboxylic acid) and triethylamine again, add the hydrochloric acid adjust pH, obtain the hydrochloric acid cefotaxime acid;
(3) hydrochloric acid cefotaxime acid and 1-methyl-5-sulfydryl-1H-tetrazole are reacted in mixed solvent, use yellow soda ash and salt acid for adjusting pH value respectively, obtain the final product cefmenoxime, wherein,
Temperature of reaction is a room temperature in the step (1);
Temperature of reaction is 5-10 ℃ before the middle adding of step (2) hydrochloric acid, is warming up to 45 ℃ of reactions behind the adding hydrochloric acid;
Temperature of reaction is 50-60 ℃ in the step (3), and mixed solvent is that volume ratio is water/acetone of 2: 1,
Reaction process is as follows:
Wherein:
(I) is intermediate 2-(thiazolamine-4-yl)-2-methoxyimino acetate;
(II) is intermediate 7-ACA (3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2 carboxylic acid);
(III) is intermediate 1-methyl-5-sulfydryl-1H-tetrazole.
Earlier regulate PH=6.5-7 with yellow soda ash in the above-mentioned described synthetic method, step (3), reaction is filtered, and regulates PH=6 with hydrochloric acid again, ethyl acetate extraction, and water is regulated PH=2.5 with hydrochloric acid.
As the present invention's one concrete preferred version, the synthetic method of cefmenoxime compound provided by the invention comprises the steps:
(1) 2-(thiazolamine-4-yl)-2-methoxyimino acetate and triphenylmethyl chloride are joined among the DMF (dimethyl formamide), room temperature reaction, slowly add diisopropyl ether then, stir, separate out solid, filter, with a small amount of diisopropyl ether washing, drying gets 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride;
(2) with 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride and N, the N-diisopropylethylamine joins among the DMF (dimethyl formamide), be cooled to 10 ℃, add Tosyl chloride, stirring reaction, add 7-ACA (3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2 carboxylic acid) and triethylamine then, 5-10 ℃ of stirring reaction adds hydrochloric acid again, be warmed up to 45 ℃, stirring reaction adds acetone (10-15: 1) stir, separate out solid then, filter, use washing with acetone, vacuum-drying gets the hydrochloric acid cefotaxime acid;
(3) the hydrochloric acid cefotaxime acid is dissolved in the mixed solvent, adds 1-methyl-5-sulfydryl-1H-tetrazole, stir and be warmed up to 50-60 ℃, regulate PH=6.5-7 with yellow soda ash then, insulation reaction adds decolorizing with activated carbon, cool to room temperature filters, and filtrate is regulated PH=6 with hydrochloric acid, ethyl acetate extraction, water is regulated PH=2.5 with hydrochloric acid, stirs and separates out solid, filter, wash with water, drying gets cefmenoxime.
Above-mentioned described synthetic method also can comprise the synthetic method of intermediate (II) and intermediate (III), and this method can be the conventional used or neoteric method steps in this area.
Above-mentioned described synthetic method also can comprise the synthetic method of its corresponding salt, and this method can be the conventional used or neoteric method steps in this area
The synthetic of the cefmenoxime of relevant bibliographical information mainly is the acidylate of 2-methoxyimino-2-(2-amino-4-thiazolyl)-acetate; this reaction pair equipment also requires than higher; because acidylate requires than higher the no water-based of solvent; operate difficult control; bigger to the yield influence; be exactly to prepare the AE-active ester need use a large amount of DCC in addition, increased cost.The present invention studies the butt joint condition, and the employing Tosyl chloride is an activating reagent, and amino under the situation of protection; operant response need not reacted down at-60 ℃ at normal temperatures, and yield; product purity all improves a lot, and lays a good foundation to industrialization.
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment that is provided should not be understood that protection domain of the present invention is construed as limiting.
Synthesizing of embodiment 12-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride
2-(thiazolamine-4-the yl)-2-methoxyimino acetate of 201 grams and the triphenylmethyl chloride of 280 grams are joined among the DMF of 600ml, room temperature reaction 4 hours, slowly add 1 liter of diisopropyl ether then, stir, separate out solid, filter, with a small amount of diisopropyl ether washing, dry that product 460 restrains yield 96%.
Synthesizing of embodiment 2 hydrochloric acid cefotaxime acids
With 2-(2-trityl aminothiazole-4-the yl)-2-methoxyimino acetic acid hydrochloride of 326 grams and the N of 120ml, the N-diisopropylethylamine joins among the DMF of 500ml, reactant is cooled to 10 ℃, add 130 gram (0.68mol) Tosyl chlorides, stirring reaction is 1 hour under this temperature, add 185 gram (0.68mol) 7-ACA and 300ml triethylamines then, 5-10 ℃ of vigorous stirring 0.5 hour, the hydrochloric acid that adds the 6mol/L of 500ml then is warmed up to 45 ℃, stirring reaction 1.5 hours, cool to room temperature, the water that adds 4 liters of acetone and 300ml is then separated out solid in stirring at room, filters, use washing with acetone, 40 ℃ of vacuum-dryings, get product 314 grams, yield: 94%.
Synthesizing of embodiment 3 cefmenoximes
Hydrochloric acid cefotaxime acid 200 grams are dissolved in the mixed solvent of distilled water 5000ml and acetone 2500ml, add 1-methyl-5-sulfydryl-1H-tetrazole 47.2 grams, stirring is warmed up to 55 ℃, use the PH=6.5-7 of 3% aqueous sodium carbonate conditioned reaction system then, reaction is 4 hours under this temperature, add decolorizing with activated carbon, cool to room temperature filters then, filtrate is regulated PH=6 with the hydrochloric acid of 2mol/L, use the ethyl acetate extraction twice of 500ml respectively, water is regulated PH=2.5 with the hydrochloric acid of 2mol/L, stirs and separates out solid, filter, wash filter cake with water, dry that product 202 restrains yield 93.7%.
Product proterties: off-white color crystalline powder.
Purity: 99.4%.
Ultimate analysis C
16H
17N
9O
5S
3, molecular weight: 511.55,
Theoretical value C:37.57%H:3.35%N:24.64%O:15.64%S:18.8%
Measured value C:37.44%H:3.31%N:24.72%O:15.69%S:18.83%
1H-NMR MHz (Bruker AV400mHz) is δ (DMSO-d6): 9.62 (d, 1H, CONH), 6.73 (s, 1H, thiazole ring C
5-H), 5.75 (dd, 1H, C
7-H), 5.11 (d, 1H, C
6-H) 4.23 (q, 2H, C
3-CH
2), 3.93 (s, 3H ,-OCH
3), 3.85 (s, 3H ,-NCH
3), 3.72 (q, 2H, C
2-CH
2).
Claims (2)
1. the synthetic method of a cefmenoxime compound, synthetic route is:
(1) 2-(thiazolamine-4-yl)-2-methoxyimino acetate and triphenylmethyl chloride are reacted in dimethyl formamide, obtain 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride;
(2) with 2-(2-trityl aminothiazole-4-yl)-2-methoxyimino acetic acid hydrochloride and N, the N-diisopropylethylamine joins in the dimethyl formamide, add Tosyl chloride, stirring reaction, add the reaction of 3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2-carboxylic acid and triethylamine again, add the hydrochloric acid adjust pH, obtain the hydrochloric acid cefotaxime acid;
(3) hydrochloric acid cefotaxime acid and 1-methyl-5-sulfydryl-1H-tetrazole are reacted in mixed solvent, use yellow soda ash and salt acid for adjusting pH value respectively, obtain the final product cefmenoxime,
Temperature of reaction is a room temperature in the step (1);
Temperature of reaction is 5-10 ℃ before the middle adding of step (2) hydrochloric acid, is warming up to 45 ℃ of reactions behind the adding hydrochloric acid;
Temperature of reaction is 50-60 ℃ in the step (3), and mixed solvent is that volume ratio is water/acetone of 2: 1;
Reaction process is as follows, wherein,
(I) is intermediate 2-(thiazolamine-4-yl)-2-methoxyimino acetate;
(II) is intermediate 3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2-carboxylic acid;
(III) is intermediate 1-methyl-5-sulfydryl-1H-tetrazole,
2. synthetic method according to claim 1 is characterized in that regulating pH=6.5-7 with yellow soda ash earlier in the step (3), and reaction is filtered, and regulates pH=6 with hydrochloric acid again, ethyl acetate extraction, and water is regulated PH=2.5 with hydrochloric acid.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731530B (en) * | 2011-04-07 | 2016-05-04 | 天津市医药集团技术发展有限公司 | Cephalosporin compound and synthetic method thereof and application |
| CN102329329B (en) * | 2011-07-15 | 2012-09-05 | 海南灵康制药有限公司 | Novel method for preparing cefmenoxime hydrochloride compound |
| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
| CN112661716A (en) * | 2020-12-31 | 2021-04-16 | 山东金城柯瑞化学有限公司 | Preparation method of trityl aminothiazoly loximate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86106602A (en) * | 1985-10-22 | 1987-07-15 | 白奥格尔药物工厂 | New cephalosporins derivatives, its method for making and contain the medical composition of these derivatives |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
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2009
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86106602A (en) * | 1985-10-22 | 1987-07-15 | 白奥格尔药物工厂 | New cephalosporins derivatives, its method for making and contain the medical composition of these derivatives |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
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