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CN-122010757-A - Process for preparing trans-cyclobutane-1, 2-dicarboxamide

CN122010757ACN 122010757 ACN122010757 ACN 122010757ACN-122010757-A

Abstract

The invention provides a preparation method of trans-cyclobutane-1, 2-dicarboxamide, belonging to the technical field of organic synthesis. Step S1, carrying out substitution reaction on raw materials comprising 1, 2-ethane tricarboxylic acid triethyl ester, 1-bromine-2-chloroethane and a first alkali reagent in a first polar aprotic solvent to obtain 4-chlorobutane-1, 2-tricarboxylic acid triethyl ester; step S2, cyclizing raw materials comprising the triethyl 4-chlorobutane-1, 2-tricarboxylic acid and a second alkali reagent to obtain the triethyl cyclobutane-1, 2-tricarboxylic acid, step S3, hydrolyzing raw materials comprising the triethyl cyclobutane-1, 2-tricarboxylic acid and a third alkali reagent to obtain the cyclobutane-1, 2-tricarboxylic acid, and finally preparing the trans-cyclobutane-1, 2-dicarboxamide from the cyclobutane-1, 2-tricarboxylic acid.

Inventors

  • ZHONG HUI
  • DOU YAQI
  • WANG LIDONG

Assignees

  • 海南长安国际制药有限公司

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. A process for preparing trans-cyclobutane-1, 2-dicarboxamide, said process comprising: Step S1, carrying out substitution reaction on raw materials comprising 1, 2-ethane tricarboxylic acid triethyl ester, 1-bromo-2-chloroethane and a first alkali reagent in a first polar aprotic solvent to obtain 4-chlorobutane-1, 2-tricarboxylic acid triethyl ester; step S2, carrying out cyclization reaction on raw materials comprising the 4-chlorobutane-1, 2-tricarboxylic acid triethyl ester and a second alkali reagent in a second polar aprotic solvent to obtain cyclobutane-1, 2-tricarboxylic acid triethyl ester; Step S3, carrying out hydrolysis reaction on raw materials comprising the cyclobutane-1, 2-tricarboxylic acid triethyl ester and a third alkali reagent in a proton solvent to obtain the cyclobutane-1, 2-tricarboxylic acid; Step S4, sequentially carrying out heating deacidification reaction and chiral resolution on the cyclobutane-1, 2-tricarboxylic acid to obtain trans-cyclobutane-1, 2-dicarboxylic acid; step S5, sequentially carrying out an acyl chlorination reaction and an ammonolysis reaction on the trans-cyclobutane-1, 2-dicarboxylic acid to generate a trans-cyclobutane-1, 2-dicarboxamide crude product; And step S6, recrystallizing the trans-cyclobutane-1, 2-dicarboxamide crude product to obtain the trans-cyclobutane-1, 2-dicarboxamide.
  2. 2. The method for preparing trans-cyclobutane-1, 2-dicarboxylic acid amide according to claim 1, wherein in the step S1, the molar ratio of the triethyl 1, 2-ethanetricarboxylic acid to the 1-bromo-2-chloroethane is 1:2 to 1:4; And/or the mass ratio of the 1, 2-ethane triethyl tricarboxylic acid, the first alkali reagent and the first polar aprotic solvent is 1-1.5:1.5-2:4-6.
  3. 3. The process for preparing trans-cyclobutane-1, 2-dicarboxylic acid amide of claim 1, wherein in step S1, the first base reagent is cesium carbonate; and/or the first polar aprotic solvent is selected from any one or more of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; and/or the temperature of the substitution reaction is 50-70 ℃; and/or, controlling the residual rate of the 1, 2-ethane triethyl tricarboxylic acid to be less than or equal to 5.0% by the end point of the substitution reaction.
  4. 4. The method for producing trans-cyclobutane-1, 2-dicarboxylic acid amide according to any one of claims 1 to 3, wherein in step S2, the mass ratio of the triethyl4-chlorobutane-1, 2-tricarboxylic acid, the second base reagent and the second polar aprotic solvent is 1 to 1.5:0.2 to 0.6:7 to 9.
  5. 5. A process for the preparation of trans-cyclobutane-1, 2-dicarboxylic acid amides according to any one of claims 1 to 3, characterized in that in step S2 the second base reagent is selected from any one or more of potassium tert-butoxide, sodium tert-butoxide; And/or the second polar aprotic solvent is selected from any one or more of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; and/or the temperature of the cyclization reaction is 0-15 ℃; And/or controlling the residual rate of the triethyl 4-chlorobutane-1, 2-tricarboxylic acid to be less than or equal to 5.0% at the end point of the cyclization reaction.
  6. 6. A process for the preparation of trans-cyclobutane-1, 2-dicarboxylic acid amides according to any one of claims 1 to 3, characterized in that in step S3 the third alkaline reagent is selected from any one or more of sodium hydroxide, potassium hydroxide; and/or the proton solvent is selected from any one or more of water, ethanol and isopropanol; and/or the temperature of the hydrolysis reaction is 30-40 ℃; and/or controlling the residual rate of the triethyl cyclobutane-1, 2-tricarboxylic acid to be less than or equal to 3.0% by the end point of the hydrolysis reaction.
  7. 7. The method for producing trans-cyclobutane-1, 2-dicarboxylic acid amide according to any one of claims 1 to 3, wherein in step S4, the temperature of the heating deacidification reaction is 90 to 100 ℃; And/or controlling the residual rate of the cyclobutane-1, 2-tricarboxylic acid to be less than or equal to 1.0% by the end point of the heating deacidification reaction; Adding a chiral resolving agent in the chiral resolving process; and/or the chiral resolving agent is (R) - (+) -phenethylamine.
  8. 8. A process for the preparation of trans-cyclobutane-1, 2-dicarboxylic acid amides according to any one of claims 1 to 3, characterized in that in step S5 the acid chloride reagent used for the acid chloride reaction is thionyl chloride; and/or the reaction solvent used in the acyl chlorination reaction is selected from any one or more of toluene, benzene and xylene; And/or the temperature of the acyl chlorination reaction is 75-85 ℃; And/or the ammonolysis reaction temperature is 0-10 ℃.
  9. 9. The method for preparing trans-cyclobutane-1, 2-dicarboxylic acid amide according to any one of claims 1 to 3, wherein in step S6, the solvent used in the recrystallization process is a mixed solvent of ethanol and water, and the mass ratio of ethanol to water is 3-4:1; the recrystallization process comprises the following steps: heating the crude trans-cyclobutane-1, 2-dicarboxamide to 75-85 ℃ to dissolve the crude trans-cyclobutane-1, 2-dicarboxamide, preserving heat and stirring for 2-3 hours, then slowly cooling to 15-25 ℃ under the protection of nitrogen, continuously stirring for 12-14 hours at 15-25 ℃, and then filtering and drying to obtain the trans-cyclobutane-1, 2-dicarboxamide with the purity of more than or equal to 98.0%.
  10. 10. A process for the preparation of trans-cyclobutane-1, 2-dicarboxamide according to any one of claims 1 to 3, characterized in that the mass content of cis-cyclobutane-1, 2-dicarboxamide impurities in trans-cyclobutane-1, 2-dicarboxamide is less than or equal to 0.5%, the moisture content of trans-cyclobutane-1, 2-dicarboxamide measured by karl fischer method is less than or equal to 0.5% and the mass ratio of (1 r,2 r) -cyclobutane-1, 2-dicarboxamide enantiomer to (1 s,2 s) -cyclobutane-1, 2-dicarboxamide enantiomer is 45:55 to 55:45.

Description

Process for preparing trans-cyclobutane-1, 2-dicarboxamide Technical Field The invention relates to the technical field of organic synthesis, in particular to a preparation method of trans-cyclobutane-1, 2-dicarboxamide. Background Trans-cyclobutane-1, 2-dicarboxamide is a key starting material for synthesizing antitumor drug lobaplatin, and its purity and optical purity directly affect the quality and safety of the final drug. The existing synthetic route has the problems of low yield, use of dangerous reagents (such as bromine and red phosphorus), complex process, poor environmental protection and the like, and is difficult to meet the requirement of industrial production. Provides a preparation method of trans-cyclobutane-1, 2-dicarboxamide with simple steps, high yield, safe operation, environmental protection and controllable product quality. Disclosure of Invention The invention mainly aims to provide a preparation method of trans-cyclobutane-1, 2-dicarboxamide, which aims to solve the problems of low yield, low purity, complex process, poor environmental protection and the like in the preparation method of trans-cyclobutane-1, 2-dicarboxamide in the prior art. In order to achieve the above object, according to one aspect of the present invention, there is provided a process for preparing trans-cyclobutane-1, 2-dicarboxylic acid amide, comprising the steps of S1, carrying out substitution reaction of a raw material comprising 1, 2-ethane tricarboxylic acid triethyl ester, 1-bromo-2-chloroethane, a first base agent in a first polar aprotic solvent to obtain 4-chlorobutane-1, 2-tricarboxylic acid triethyl ester; step S2, cyclizing raw materials comprising the triethyl 4-chlorobutane-1, 2-tricarboxylic acid and a second alkali reagent in a second polar aprotic solvent to obtain the triethyl cyclobutane-1, 2-tricarboxylic acid, step S3, hydrolyzing raw materials comprising the triethyl cyclobutane-1, 2-tricarboxylic acid and a third alkali reagent in a proton solvent to obtain the cyclobutane-1, 2-tricarboxylic acid, step S4, sequentially carrying out heating deacidification and chiral resolution on the cyclobutane-1, 2-tricarboxylic acid to obtain trans-cyclobutane-1, 2-dicarboxylic acid, step S5, sequentially carrying out acyl chlorination and ammonolysis on the trans-cyclobutane-1, 2-dicarboxylic acid to obtain a trans-cyclobutane-1, 2-dicarboxamide crude product, and step S6, recrystallizing the trans-cyclobutane-1, 2-dicarboxamide crude product to obtain the trans-cyclobutane-1, 2-dicarboxamide. Further, in the step S1, the molar ratio of the 1, 2-ethane tricarboxylic acid triethyl ester to the 1-bromo-2-chloroethane is 1:2-1:4, and/or the mass ratio of the 1, 2-ethane tricarboxylic acid triethyl ester, the first alkali reagent and the first polar aprotic solvent is 1-1.5:1.5-2:4-6. Further, in the step S1, the first alkali reagent is cesium carbonate, and/or the first polar aprotic solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, and/or the temperature of the substitution reaction is 50-70 ℃, preferably 55-65 ℃, and/or the end point of the substitution reaction is controlled to control the residual rate of the 1, 2-ethane triethyl tricarboxylate to be less than or equal to 5.0%. Further, in the step S2, the mass ratio of the triethyl 4-chlorobutane-1, 2-tricarboxylic acid, the second alkali reagent and the second polar aprotic solvent is 1-1.5:0.2-0.6:7-9. Further, in the step S2, the second alkaline reagent is selected from any one or more of potassium tert-butoxide and sodium tert-butoxide, and/or the second polar aprotic solvent is selected from any one or more of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, and/or the temperature of the cyclization reaction is 0-15 ℃, and/or the end point of the cyclization reaction is controlled to control the residual rate of the triethyl 4-chlorobutane-1, 2-tricarboxylic acid to be less than or equal to 5.0%. Further, in the step S3, the third alkali reagent is selected from any one or more of sodium hydroxide and potassium hydroxide, and/or the proton solvent is selected from any one or more of water, ethanol and isopropanol, and/or the temperature of the hydrolysis reaction is 30-40 ℃, and/or the residual rate of the triethyl cyclobutane-1, 2-tricarboxylic acid is controlled to be less than or equal to 3.0% by the end point of the hydrolysis reaction. Further, in the step S4, the temperature of the heating deacidification reaction is 90-100 ℃, and/or the residual rate of the cyclobutane-1, 2-tricarboxylic acid is controlled to be less than or equal to 1.0% by the end point of the heating deacidification reaction, and a chiral resolving agent is added in the chiral resolving process, and/or the chiral resolving agent is (R) - (+) -phenethylamine. In step S5, the acyl chloride reagent used in the acyl chloride reaction is thionyl chloride, and/or the reaction solvent used in t