CN112457211B - Method for preparing ethyl aminothiazolyloximate intermediate - Google Patents
Method for preparing ethyl aminothiazolyloximate intermediate Download PDFInfo
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- CN112457211B CN112457211B CN202011222244.6A CN202011222244A CN112457211B CN 112457211 B CN112457211 B CN 112457211B CN 202011222244 A CN202011222244 A CN 202011222244A CN 112457211 B CN112457211 B CN 112457211B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for preparing an ethyl aminothiazoly loximate intermediate, which comprises the following steps: dissolving 2-methoxyimino ethyl acetoacetate, 1, 3-dihalogen-5, 5-dimethylhydantoin and protonic acid in a solvent, then carrying out continuous reaction, and carrying out post-treatment after the reaction is finished to obtain an ethyl aminothiazolyloximate intermediate, wherein the ethyl aminothiazolyloximate intermediate is 4-halo-2-methoxyimino ethyl acetoacetate. The invention adopts continuous reaction to complete the reaction steps, can effectively improve the yield of the 4-halogeno-2-methoxyimino acetoacetic acid ethyl ester intermediate of the ethyl aminothiazolyloxime acid, reduces the dosage of a halogenated reagent and protonic acid and shortens the reaction time.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a synthesis process of a medical intermediate, and specifically relates to a method for preparing an ethyl aminothiazoly loximate intermediate.
Background
Ethyl aminothiazolineoxomate, the chemical name of which is (Z) -2- (2-amino-4-thiazole) -2-methoxyiminoacetic acid ethyl ester, is an important medical intermediate and is mainly used for synthesizing cephalosporins such as ceftriaxone, cefotaxime, cefixime, cefdinir, cefetamet, cefazolin and the like. At present, the synthesis method reported by the literature at home and abroad mainly comprises the following 2 methods: acetoacetate (methyl or ethyl) and 4-chloroacetoacetate (methyl or ethyl) processes. The ethyl acetoacetate process is currently the most mature process due to the high price of methyl acetoacetate, the difficulty in preparing 4-chloroacetoacetate and the difficulty in large-scale production.
The preparation of the ethyl aminothiazolyloximate by the ethyl acetoacetate method comprises oximation, methylation, halogenation and cyclization in 4 steps. There are numerous literature reports on optimizing this process to make it more industrially advantageous, where the halogenation reaction is the most difficult and there are problems that have not yet been completely solved. For example, the chlorinated reagents (sulfuryl chloride, liquid chlorine and triphosgene) and the brominated reagents (liquid bromine) used at present still have the defects of high safety operation risk, poor selectivity, high difficulty in three-waste treatment and the like, or have the problems of large dosage of halogenated reagents and protonic acid and long reaction time (12-15 h), and the production efficiency and the production cost control of the ethyl aminothiazoloxime ate are seriously influenced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing an ethyl aminothiazolyloximate intermediate (4-halogeno-2-methoxyimino ethyl acetoacetate) through continuous reaction, so that the using amounts of a halogenating reagent and protonic acid are reduced, the reaction time is shortened, and the yield is improved.
The technical scheme adopted by the invention is as follows:
a process for preparing an ethyl aminothiazolyloximate intermediate comprising the steps of:
dissolving 2-methoxyimino ethyl acetoacetate, 1, 3-dihalogen-5, 5-dimethylhydantoin and protonic acid in a solvent, and then carrying out a continuous reaction process to obtain an ethionamide ethyl intermediate after the reaction is finished and post-treatment is carried out, wherein the ethionamide ethyl intermediate is 4-halo-2-methoxyimino ethyl acetoacetate.
The temperature of the continuous reaction is 50-100 ℃.
The molar ratio of the 2-methoxyimino ethyl acetoacetate to the 1, 3-dihalogen-5, 5-dimethylhydantoin is 1: (1-1.2).
The molar ratio of the 2-methoxyimino ethyl acetoacetate to the protonic acid is 1:0.05 to 0.2, preferably 1:0.05 to 0.1.
The 1, 3-dihalo-5, 5-dimethylhydantoin is selected from at least one of DCDMH (1, 3-dichloro-5, 5-dimethylhydantoin) and DBDMH (1, 3-dichlorobromo-5, 5-dimethylhydantoin).
The protonic acid is at least one of p-toluenesulfonic acid, sulfuric acid and benzenesulfonic acid.
The solvent is selected from organic solvents having a boiling point higher than the reaction temperature, such as toluene, acetone, chloroform, xylene.
The continuous reaction is carried out in a microreactor.
The microreactor is a tubular reactor.
The inner diameter of the tubular reactor is 2-5 mm.
The total volume of the reactor is in the range of 1-5L.
The length of the pipeline can be flexibly adjusted according to the reaction requirement.
The feeding speed of the mixed solution of the 2-methoxyimino ethyl acetoacetate, the 1, 3-dihalogen-5, 5-dimethyl hydantoin and the protonic acid in the microreactor is 10-20 g/min.
The inventor finds through experiments that the reaction time and the yield are influenced by the combined action of the parameters such as the inner diameter and the volume of the microreactor and the feeding speed, but the influence of the parameters such as the inner diameter and the volume of the microreactor and the feeding speed on the reaction time and the yield does not show an obvious rule, and the reaction time can be shortened to the maximum extent under the parameters, and the product yield can be improved.
The tubular reactor is made of silicon carbide material and can resist acid and corrosion.
The invention has the following beneficial effects:
the method adopts continuous reaction to complete the reaction steps, can effectively improve the yield of the 4-halo-2-methoxyimino ethyl acetoacetate serving as the ethyl aminothiazolyloximate intermediate, reduces the dosage of a halogenating reagent and protonic acid, and shortens the reaction time. The reaction condition is mild, the industrial realization is easy, and the product purity is easier to control and the time efficiency is higher; the method has the advantages of low cost and safety of the used raw materials, and effectively reduces the production cost and improves the production efficiency while ensuring that the high-quality ethyl aminothiazolyloximate intermediate is obtained.
Detailed Description
The technical scheme of the invention is further explained by combining the embodiment.
In the following examples, unless otherwise indicated, the experimental method specific conditions are generally in accordance with conventional conditions or manufacturer's recommended practice conditions; the raw materials and the reagents are purchased from commercial products.
Example 1:
a method for preparing an intermediate of ethyl aminothiazoly loximate, namely 4-halogeno-2-methoxyimino ethyl acetoacetate, comprises the following synthetic route:
the specific synthesis steps are as follows:
compound 2-1: synthesis of ethyl 4-chloro-2-methoxyimino-acetoacetate
1500ml of toluene were placed in a 2-liter round-bottomed flask, followed by 86.6g (0.50 mol) of ethyl 2-methoxyiminoacetoacetate (Compound 1), 54.2g (0.28 mol) of 1, 3-dichloro-5, 5-dimethylhydantoin (DCDMH) and 8.6g (0.05 mol) of p-toluenesulfonic acid, and the solution was heated to dissolve.
And (3) feeding the solution into a silicon carbide tubular micro-reactor for reaction at a feeding speed of 15g/min through a peristaltic pump, wherein the inner diameter of the micro-reactor is 2mm, and the total volume is 2L. The temperature of the whole system from the feeding of the micro-reactor to the discharge port is controlled between 50 ℃ and 55 ℃. The material which ran continuously for 30min was worked up (total 450g, 26.8g containing ethyl 2-methoxyiminoacetoacetate in 0.154 mol), 300ml of water was added to the solution for 2 washes and the solution was separated, the toluene phase was dried over anhydrous sodium sulphate and the organic phase was concentrated to dryness to give 28.6g of oily product in 91.8% yield.
Nuclear magnetic data of the product: 1 H NMR(400MHz，CD 3 Cl 3 )(ppm)：1.32(t，3H，CH 3 )，4.04(s，3H，OCH 3 )，4.23(q，2H，CH 2 )，4.52(s，2H，ClCH 2 )。
compound 2-2: synthesis of 4-bromo-2-methoxyimino ethyl acetoacetate
Into a 2L round-bottomed flask was charged 1650ml of toluene, followed by 95.3g (0.55 mol) of ethyl 2-methoxyiminoacetoacetate, 86.6g (0.31 mol) of 1, 3-dibromo-5, 5-dimethylhydantoin and 9.5g (0.55 mol) of p-toluenesulfonic acid, and the mixture was dissolved by heating to prepare a solution.
And (3) feeding the solution into a silicon carbide tubular micro-reactor for reaction at a feeding speed of 15g/min through a peristaltic pump, wherein the inner diameter of the micro-reactor is 2mm, and the total volume is 2L. Controlling the temperature of the whole system from the feeding of the microreactor to the discharge port to be between 60 and 65 ℃. The material, which ran continuously and steadily for 30min, was worked up (total 450g, 26.4g ethyl 2-methoxyiminoacetoacetate, 0.152 mol), 300ml of water was added to the solution, the solution was washed and separated by 2 times, the organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness to give 36.1g of oil, 94.2% yield.
Nuclear magnetic data of the product: 1 H NMR(400MHz，CD 3 Cl 3 )(ppm)：1.30(t，3H，CH 3 )，4.01(s，3H，OCH 3 )，4.20(q，2H，CH 2 )，4.41(s，2H，BrCH 2 )。
comparative example 1:
a method for preparing an intermediate of ethyl aminothiazoly loximate, namely 4-halogeno-2-methoxyimino ethyl acetoacetate, comprises the following synthetic route:
the specific synthesis steps are as follows:
compound 2-1: synthesis of 4-chloro-2-methoxyimino ethyl acetoacetate
In a 500mL round-bottomed flask was added 200mL of methylene chloride, followed by 12.4g (0.06 mol) of ethyl 2-methoxyiminoacetoacetate, 7.9g (0.04 mol) of 1, 3-dichloro-5, 5-dimethylhydantoin and 5.0g (0.03 mol) of p-toluenesulfonic acid, and the reaction mixture was stirred under reflux overnight. After completion of the reaction by TLC (ethyl acetate/n-heptane = 1/10), the reaction solution was cooled to room temperature. The solution was washed and separated by adding 100ml of water 2 times, the dichloromethane phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness to give 9.9g of oil in 85.3% yield.
Compound 2-2: synthesis of ethyl 4-bromo-2-methoxyimino-acetoacetate
300mL of methylene chloride was placed in a 500mL round-bottom flask, followed by 18.6g (0.09 mol) of ethyl 2-methoxyiminoacetoacetate, 17.1g (0.06 mol) of 1, 3-dibromo-5, 5-dimethylhydantoin and 7.5g (0.045 mol) of p-toluenesulfonic acid, and the reaction mixture was stirred under reflux overnight. After completion of the reaction by TLC (ethyl acetate/n-heptane = 1/10), the reaction solution was cooled to room temperature. To the solution was added water 150ml 2 times washing and separating, the dichloromethane phase was dried with anhydrous sodium sulfate, and then the organic phase was concentrated to dryness to give 20.0g of oil, 88.4% yield.
The comparison of the ethyl ester of aminothiazoly loximate intermediate 4-halo-2-methoxyiminoacetoacetate by different methods is as follows:
from the data in the table it can be seen that:
compared with the comparative example 1, the yield of the prepared compounds 2-1 and 2-2 is increased to 91.8% -94.2% in 0.5h by using the microreactor to carry out continuous reaction in the example 1.
Further, compared with the comparative example 1, the unit consumption of the key material dihalogenated hydantoin in the example 1 is reduced from 1.3eq to 1.1eq, the unit consumption of the p-toluenesulfonic acid is reduced from 0.75eq to 0.1eq at most, and the reduction of the unit consumption can greatly reduce the material cost of the product.
Meanwhile, the reaction solvent is replaced by toluene from dichloromethane, the reaction can be carried out at a higher temperature range (more than 50 ℃), the original process which can be finished overnight (12-15 h) can be finished within 0.5h, and the reaction time is obviously shortened. The amplification effect of the continuous reaction is very small, and the reaction can be amplified on the basis, so that the production efficiency can be greatly improved, and the competitiveness of industrial mass production is greatly improved.
Claims (3)
1. A method for preparing an ethyl aminothiazolyloximate intermediate, which is characterized by comprising the following steps: the method comprises the following steps:
dissolving 2-methoxyimino ethyl acetoacetate, 1, 3-dihalogen-5, 5-dimethylhydantoin and protonic acid in a solvent, and then carrying out continuous reaction, and carrying out post-treatment after the reaction is finished to obtain an ethyl aminothiazolyloximate intermediate, wherein the ethyl aminothiazolyloximate intermediate is 4-halo-2-methoxyimino ethyl acetoacetate;
the molar ratio of the 2-methoxyimino ethyl acetoacetate to the 1, 3-dihalogen-5, 5-dimethylhydantoin is 1:1 to 1.2;
the molar ratio of the 2-methoxyimino ethyl acetoacetate to protonic acid is 1:0.05 to 0.2;
the 1, 3-dihalogen-5, 5-dimethylhydantoin is selected from at least one of 1, 3-dichloro-5, 5-dimethylhydantoin and 1, 3-dibromo-5, 5-dimethylhydantoin;
the solvent is selected from toluene;
the temperature of the continuous reaction is 50-100 ℃;
the continuous reaction is carried out in a microreactor;
the microreactor is a tubular reactor, the inner diameter of the tubular reactor is 2-5 mm, and the total volume of the reactor is 2-5L;
the feeding speed of the mixed solution of the 2-methoxyimino ethyl acetoacetate, the 1, 3-dihalogen-5, 5-dimethyl hydantoin and the protonic acid in the microreactor is 10-20 g/min.
2. The process for preparing an ethyl aminothiazoloxime carboxylate intermediate according to claim 1 wherein: the molar ratio of the 2-methoxyimino ethyl acetoacetate to protonic acid is 1:0.05 to 0.1.
3. The process for preparing an ethyl aminothiazoloxime ate intermediate according to any one of claims 1 or 2, wherein: the protonic acid is at least one of p-toluenesulfonic acid, sulfuric acid and benzenesulfonic acid.
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