A kind of synthetic method of 2,2-dimethylbutyryl chloride

Abstract

The present invention relates to the technical field of organic synthesis, and proposes a method for synthesizing 2,2-dimethylbutyryl chloride. The method comprises using 2,2-dimethylbutyric acid as a reaction raw material, performing a chloroacylation reaction in the presence of a chlorinating agent, and obtaining 2,2-dimethylbutyryl chloride; the chlorinating agent comprises di(trichloromethyl) carbonate and oxalyl chloride. The above technical solution solves the problems of low yield and low purity of 2,2-dimethylbutyryl chloride in the prior art.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 2,2-dimethylbutyryl chloride. Background Art

[0002] 2,2-Dimethylbutyryl chloride is an important pharmaceutical intermediate that can be used as an intermediate for simvastatin, spirodiclofen, and other pharmaceutical excipients. It is stable at room temperature and pressure and is a light yellow to colorless transparent liquid. Its chemical structure is as follows:

[0003]

[0004] Acyl chloride compounds are carboxylic acid derivatives. The chlorine atoms in their molecules have strong electronegativity, which shows a strong electron-withdrawing inductive effect. Therefore, they are highly active and can react with many types of substances. They are important pharmaceutical intermediates and are widely used in drug synthesis.

[0005] At present, the synthesis process of 2,2-dimethylbutyryl chloride mainly uses 2,2-dimethylbutyric acid as raw material, and undergoes chlorination reaction in the presence of chlorination reagents such as SOCl2, POCl3, PCl3 and PCl5 to obtain 2,2-dimethylbutyryl chloride, but the yield and purity are not ideal. Summary of the Invention

[0006] The present invention provides a method for synthesizing 2,2-dimethylbutyryl chloride, which solves the problems of low yield and low purity of 2,2-dimethylbutyryl chloride in the related art.

[0007] The technical solutions of the present invention are as follows:

[0008] A method for synthesizing 2,2-dimethylbutyryl chloride, comprising using 2,2-dimethylbutyric acid as a reaction raw material and carrying out a chlorination acylation reaction under the action of a chlorinating agent to obtain 2,2-dimethylbutyryl chloride;

[0009] The chlorinating agents include bis(trichloromethyl)carbonate and oxalyl chloride.

[0010] As a further technical solution, the mass ratio of the bis(trichloromethyl)carbonate to oxalyl chloride is 6-8:2-4.

[0011] As a further technical solution, the mass ratio of the bis(trichloromethyl)carbonate to oxalyl chloride is 7:3.

[0012] As a further technical solution, the chloroacylation reaction further comprises a catalyst and a solvent;

[0013] The mass ratio of the 2,2-dimethylbutyric acid to the catalyst is 35-45:1;

[0014] The mass volume ratio of the 2,2-dimethylbutyric acid to the solvent is 1 g:8-10 mL.

[0015] As a further technical solution, the catalyst is DMF and the solvent is toluene.

[0016] As a further technical solution, the mass ratio of the 2,2-dimethylbutyric acid to the chlorination reagent is 1:0.9~1.

[0017] As a further technical solution, the mass ratio of the 2,2-dimethylbutyric acid to the chlorination reagent is 1:0.9.

[0018] As a further technical solution, the synthesis method of 2,2-dimethylbutyryl chloride comprises the following steps:

[0019] S1. dissolving a chlorination reagent in 1 / 2 volume of a solvent to obtain a mixed solution;

[0020] S2. After mixing 2,2-dimethylbutyric acid, a catalyst and 1 / 2 volume of a solvent, the mixture is added dropwise to carry out a chloroacylation reaction. After the reaction is completed, distillation is performed to obtain 2,2-dimethylbutyryl chloride.

[0021] As a further technical solution, the chloroacylation reaction temperature is 45-55° C. and the time is 4-5 hours.

[0022] The working principle and beneficial effects of the present invention are:

[0023] 1. The present invention uses 2,2-dimethylbutyric acid as a reaction raw material, and carries out a chloroacylation reaction under the action of bis(trichloromethyl) carbonate and oxalyl chloride as a chlorination reagent. The prepared 2,2-dimethylbutyryl chloride has a high yield and purity, solves the problems of low yield and low purity of 2,2-dimethylbutyryl chloride in the prior art, and achieves the effect of simultaneously improving the yield and purity of 2,2-dimethylbutyryl chloride.

[0024] 2. The present invention limits the chlorination reagent to bis(trichloromethyl) carbonate and oxalyl chloride in a mass ratio of 6-8:2-4, thereby further improving the yield and purity of 2,2-dimethylbutyryl chloride. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0026] Example 1

[0027] S1. Dissolve 6.3 g of bis(trichloromethyl)carbonate and 2.7 g of oxalyl chloride in 45 mL of toluene to obtain a mixed solution for later use;

[0028] S2. 10 g of 2,2-dimethylbutyric acid, 0.25 g of DMF and 45 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 55° C. for 4.5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0029] Example 2

[0030] S1. Dissolve 6.3 g of bis(trichloromethyl)carbonate and 2.7 g of oxalyl chloride in 40 mL of toluene to obtain a mixed solution for later use;

[0031] S2. 10 g of 2,2-dimethylbutyric acid, 0.3 g of DMF and 40 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 45° C. for 5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0032] Example 3

[0033] S1. Dissolve 6.3 g of bis(trichloromethyl)carbonate and 2.7 g of oxalyl chloride in 50 mL of toluene to obtain a mixed solution for later use;

[0034] S2. After mixing 10 g of 2,2-dimethylbutyric acid, 0.22 g of DMF and 50 mL of toluene, the mixture was added dropwise. After reacting at 50° C. for 4 h, the solvent was distilled off and the mixture was distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0035] Example 4

[0036] S1. Dissolve 5.4 g of bis(trichloromethyl)carbonate and 3.6 g of oxalyl chloride in 45 mL of toluene to obtain a mixed solution for later use;

[0037] S2. 10 g of 2,2-dimethylbutyric acid, 0.25 g of DMF and 45 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 55° C. for 4.5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0038] Example 5

[0039] S1. Dissolve 7.2 g of bis(trichloromethyl)carbonate and 1.8 g of oxalyl chloride in 45 mL of toluene to obtain a mixed solution for later use;

[0040] S2. 10 g of 2,2-dimethylbutyric acid, 0.25 g of DMF and 45 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 55° C. for 4.5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0041] Example 6

[0042] S1. Dissolve 7 g of bis(trichloromethyl)carbonate and 3 g of oxalyl chloride in 45 mL of toluene to obtain a mixed solution for later use;

[0043] S2. 10 g of 2,2-dimethylbutyric acid, 0.25 g of DMF and 45 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 55° C. for 4.5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0044] Comparative Example 1

[0045] S1. Dissolve 12.7 g of bis(trichloromethyl)carbonate in 45 mL of toluene to obtain a mixed solution for later use;

[0046] S2. 10 g of 2,2-dimethylbutyric acid, 0.25 g of DMF and 45 mL of toluene were mixed, and the mixture was added dropwise. The mixture was reacted at 55° C. for 4.5 h, and the solvent was distilled off. The mixture was then distilled under reduced pressure to obtain 2,2-dimethylbutyryl chloride.

[0047] The purity of 2,2-dimethylbutyryl chloride obtained in Examples 1 to 6 and Comparative Example 1 was tested by HPLC, and the yield was calculated according to the following formula:

[0048] Yield (%) = actual mass of 2,2-dimethylbutyryl chloride obtained × purity ÷ theoretical yield × 100

[0049] The results are recorded in Table 1.

[0050] Table 1 Purity and yield of 2,2-dimethylbutyryl chloride

[0051]

[0052] As can be seen from Table 1, the purity of 2,2-dimethylbutyryl chloride obtained by the synthesis method of 2,2-dimethylbutyryl chloride provided by the present invention is above 96.7%, and the yield is as high as above 93.4%.

[0053] Compared with Comparative Example 1, Examples 1 to 6 used chlorination reagents of di(trichloromethyl) carbonate and oxalyl chloride, while the chlorination reagent used in Comparative Example 1 was di(trichloromethyl) carbonate. The purity and yield of 2,2-dimethylbutyryl chloride obtained in Examples 1 to 6 were higher than those in Comparative Example 1.

[0054] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing 2,2-dimethylbutyryl chloride, characterized in that: The following steps are involved: S1. Dissolve the chlorination reagent in 1 / 2 volume of toluene to obtain a mixed solution; S2, after mixing 2,2-dimethylbutyric acid, DMF and 1 / 2 volume of toluene, the mixture in S1 was added dropwise to carry out chloroacylation reaction. After the reaction was completed, distillation was performed to obtain 2,2-dimethylbutyryl chloride; The chloroacylation reaction temperature is 45-55°C and the time is 4-5h; The chlorination reagent is bis(trichloromethyl) carbonate and oxalyl chloride; The mass ratio of the bis(trichloromethyl) carbonate to oxalyl chloride is 6-8:2-4; The mass ratio of the 2,2-dimethylbutyric acid to DMF is 35-45:1; The mass volume ratio of the 2,2-dimethylbutyric acid to toluene is 1 g:8-10 mL; The mass ratio of the 2,2-dimethylbutyric acid to the chlorination reagent is 1:0.9~1.

2. The method for synthesizing 2,2-dimethylbutyryl chloride according to claim 1, wherein The mass ratio of the bis(trichloromethyl)carbonate to oxalyl chloride is 7:

3.

3. The method for synthesizing 2,2-dimethylbutyryl chloride according to claim 1, wherein: The mass ratio of the 2,2-dimethylbutyric acid to the chlorination reagent is 1:0.9.

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