CN103787883A - Preparation method of 4-chloracetyl ethyl acetate - Google Patents

Abstract

The invention relates to a preparation method of 4-chloracetyl ethyl acetate. The preparation method comprises the following steps: by taking diketene as an initial raw material, synthesizing a 4-chloracetyl ethyl acetate coarse product in two steps: chlorination and esterification; then, rectifying to obtain a finished product, and adding a stabilizer anhydrous cupric sulfate into the chlorination step, wherein the addition is 0.02-1wt% of diketene. Compared with the prior art, the preparation method provided by the invention has the advantages that 1, by adding the stabilizer anhydrous cupric sulfate, the production of a byproduct 2-chloracetyl ethyl acetate is reduced and the production of the byproduct 2-chloracetyl ethyl acetate in the 4-chloracetyl ethyl acetate coarse product can be controlled below 0.5%, so that the distill yield is greatly improved; 2, the yield of 2-chloracetyl ethyl acetate is over 94.5%, and the cost is greatly lowered.

Description

A kind of preparation method of 4-chloroacetyl acetacetic ester

Technical field

The present invention relates to a kind of preparation method of medicine intermediate, relate in particular a kind of preparation method of 4-chloroacetyl acetacetic ester.

Background technology

4-chloroacetyl acetacetic ester is a kind of colourless to light yellow transparent liquid, is mainly used in field of medicaments, and the especially key intermediate of oxiracetam, has wide market outlook.

Through searching related data and comparative analysis, the operational path of synthetic 4-chloroacetyl acetacetic ester mainly contains two both at home and abroad at present, as follows respectively:

1: ethyl chloroacetate method is using benzene as solvent, under mercury chloride exists, two mol-chloric ethyl acetate are carried out condensation one step and are obtained 4-chloroacetyl acetacetic ester, but there is report in patent documentation (Fr1438387) only abroad, although the transformation efficiency of this route higher (70%-85%) simultaneously, but in this route, use deadly poisonous compound mercury chloride and benzene, higher on safety and environmental protection and production cost, be only applicable to laboratory synthetic on a small scale, be not suitable for suitability for industrialized production.

Ethyl chloroacetate method reaction equation

2: diethenone process is take ketene dimer as starting raw material, through superchlorination and the synthetic 4-chloroacetyl acetacetic ester of esterification two steps, its raw material is all cheap and easy to get and become the production method of main flow, realize at present industrialization (as CN201210257429.X and CN201310321570.6), but it also has intrinsic shortcoming own is exactly that product yield is on the low side, only has 75%-88%, cause high expensive, be exactly in reaction process, to generate a certain amount of 2-chloroacetyl acetacetic ester (5% left and right) and cause the reason that yield is low, and the boiling point of 2-chloroacetyl acetacetic ester and reactor product 4-chloroacetyl acetacetic ester differ seldom and (are about 2-3 under reduced pressure ^oc), therefore in the time of rectifying purifying, conventionally want distill repeatedly, cause a large amount of decomposition of product, finally cause yield on the low side.

 

Diethenone process reaction equation.

Summary of the invention

Technical problem to be solved by this invention is to provide a kind of preparation method of 4-chloroacetyl acetacetic ester, overcomes the problems such as the ubiquitous yield causing because of by product 2-chloroacetyl acetacetic ester of prior art is low, production cost is higher

Technical scheme is: take ketene dimer as starting raw material, through superchlorination and the synthetic 4-chloroacetyl acetacetic ester crude product of esterification two steps, then obtain finished product through rectifying, it is characterized in that, in described chlorinating step, add stablizer anhydrous cupric sulfate, its add-on is the 0.02-1% of ketene dimer quality.

Such scheme further comprises:

In described 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester is controlled at 0.3-0.5%.

Described chlorinating step is: in reactor, add ketene dimer 84g, methylene dichloride 220g and anhydrous cupric sulfate 0.08-0.84g, open and stir, be cooled to-10 ℃, pass into chlorine 44 g;

Described esterif iotacation step is: after ventilation, drip ethanol 55g, steam methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product after having reacted.

Just start us and thought that copper sulfate just plays the effect of dewatering agent in system, therefore the dewatering agent that we have attempted other kinds is successively as molecular sieve, silica gel, other neutral salt etc., but all do not obtain satisfied result, therefore we infer, copper sulfate has stronger interaction in chlorination process and between ketene dimer and chlorine, and ketene dimer is tended towards stability, and for generating, intermediate 4-chloracetyl Acetyl Chloride 98Min. is more favourable.

With respect to existing technology, the present invention has the following advantages:

1, adding by stablizer anhydrous cupric sulfate, reduce the growing amount of by product 2-chloroacetyl acetacetic ester, in 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester can be controlled at below 0.5%, and distillation yield is improved greatly;

2, the yield of 4-chloroacetyl acetacetic ester is more than 94.5%, and cost significantly reduces.

Embodiment

The present invention is described by the following examples, but is not limited to this.

Embodiment 1:

In reactor, add ketene dimer 84g, methylene dichloride 220g, anhydrous cupric sulfate 0.4g(0.48%), open and stir, be cooled to-10 ℃, pass into chlorine 44 g, after ventilation, drip ethanol 55g, after having reacted, steam methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.42%).After rectifying, obtain product 156.3g, yield 95.04%.

Embodiment 2:

In reactor, add ketene dimer 84g, methylene dichloride 220g, anhydrous cupric sulfate 0.84g(1%), open and stir, be cooled to-10 ℃, pass into chlorine 44 g, after ventilation, drip ethanol 55g, after having reacted, steam methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.49%).After rectifying, obtain product 155.5g, yield 94.55%.

Embodiment 3:

In reactor, add ketene dimer 84g, methylene dichloride 220g, anhydrous cupric sulfate 0.08g(0.1%), open and stir, be cooled to-10 ℃, pass into chlorine 44 g, after ventilation, drip ethanol 55g, after having reacted, steam methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.31%).After rectifying, obtain product 158g, yield 96.08%.

Below be only the part exemplary embodiments of this programme; those skilled in the art can adopt other embodiment to realize completely within the protection domain of the technical program; and all can make the appropriate adjustments parameters such as proportioning raw materials, temperature of reaction, times, just do not repeat one by one at this.

Claims (3)

1. the preparation method of a 4-chloroacetyl acetacetic ester, take ketene dimer as starting raw material, through superchlorination and the synthetic 4-chloroacetyl acetacetic ester crude product of esterification two steps, then obtain finished product through rectifying, it is characterized in that, in described chlorinating step, add stablizer anhydrous cupric sulfate, its add-on is the 0.02-1% of ketene dimer quality.

2. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1, is characterized in that, in described 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester is controlled at 0.3-0.5%.

3. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 and 2, is characterized in that,

Described chlorinating step is: in reactor, add ketene dimer 84g, methylene dichloride 220g and anhydrous cupric sulfate 0.08-0.84g, open and stir, be cooled to-10 ℃, pass into chlorine 44 g;

Described esterif iotacation step is: after ventilation, drip ethanol 55g, steam methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product after having reacted.