Synthesis method of 3-oxo-1-cyclobutyl carboxylic acid

Abstract

The invention discloses a novel method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, which comprises the following steps: taking dichloroacetyl chloride or trichloroacetyl chloride as a starting raw material, carrying out elimination reaction in a solvent under the catalytic action of alkali or Zn-Cu, and reacting the obtained dichloroketene intermediate with methyl acrylate in situ to generate 3-oxo-2, 2, 3-trimethyl-1-cyclobutanecarboxylic acid, thereby obtaining the 3-oxo-1-cyclobutanecarboxylic acid. The 3-oxo-1-cyclobutanecarboxylic acid is prepared by using 2, 2-dichloro-1-cyclobutanecarboxylic acid as a raw material, then dehalogenation and hydrolysis reactions are carried out to prepare the 3-oxo-1-cyclobutanecarboxylic acid, the 3-oxo-1-cyclobutanecarboxylic acid is a pure product with the content of 99% or above, and the total yield reaches 50% or above. The synthetic route has the advantages of mild conditions, few byproducts, high yield and environmental friendliness, and is suitable for industrial amplification.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 3-oxo-1-cyclobutane carboxylic acid, and belongs to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002] 3-Oxo-1-cyclobutanecarboxylic acid is an important raw material for the synthesis of many antiviral drugs and organic intermediates. It is widely used in the fields of chemistry, chemical engineering, and medicine. For example, it is used in the synthesis of dozens of APIs such as ACK1 antibodies, MDM2 antagonists, JAK inhibitors, CETP inhibitors, kinase inhibitors, and PDE10 inhibitors. Therefore, it is of great significance to study its synthesis method. At present, the synthesis methods of 3-oxo-1-cyclobutanecarboxylic acid are as follows: Stevens et al. reported that it was obtained by [2+2] cycloaddition, hydrolysis, and oxidation using butadiene and acrylonitrile as raw materials; Tishkov et al. reported that it was obtained by silylation, cyclization, and hydrolysis using 5-nitro-2-pentanone as raw materials; Paul et al. reported that it was obtained by cyclization and hydrolysis using malonic acid esters and 1,3-dibromoacetone dimethyl acetal as raw materials. The first two methods are not suitable for industrial production due to harsh reaction conditions and low product yields; the third method is also not suitable for industrial production due to the difficulty in product separation, low yield, and long reaction time. Summary of the invention

[0003] In view of the above problems, the present invention provides an improved synthesis route of 3-oxo-1-cyclobutane carboxylic acid, using dichloroacetyl chloride or trichloroacetyl chloride as a starting material, carrying out an elimination reaction in a solvent under the catalysis of alkali or Zn-Cu, and the obtained dichloroethylene ketone intermediate undergoes in-situ cyclization with methyl acrylate, and then undergoes dehalogenation and hydrolysis to prepare 3-oxo-1-cyclobutane carboxylic acid. The specific mechanism and steps are as follows:

[0004]

[0005] (1) In the first step, dichloroacetyl chloride or trichloroacetyl chloride is used as the starting material and methyl acrylate is reacted under nitrogen protection in a certain amount of solvent, at a certain molar ratio, and at a certain reaction temperature, and a base or Zn-Cu catalyst is slowly added dropwise to carry out a dehydrochlorination elimination reaction to obtain a crude product of 3-oxo-2,2-dichloro-1-cyclobutane carboxylate. Zinc powder and the crude product of 3-oxo-2,2-dichloro-1-cyclobutane carboxylate are dissolved in an organic solvent. The reaction mixture is stirred at room temperature for several hours, and then heated at a certain temperature for several hours. TLC shows that the raw material disappears. The mixture is cooled to room temperature, filtered, the filter cake is washed with water, then washed with brine, and dried to obtain a crude product of 3-oxo-1-cyclobutane carboxylate.

[0006] (2) In the second step, the crude 3-oxo-1-cyclobutane carboxylate is added to a certain amount of acid or alkaline solution and reacted at a certain temperature for a certain time to perform a hydrolysis reaction. After the reaction is completed, the mixture is cooled to room temperature and filtered. The filter cake is washed with water and dried to obtain 3-oxo-1-cyclobutane carboxylic acid.

[0007] Furthermore, in the above scheme, in the first step, the reaction solvent is at least one of hexane, pentane, heptane, benzene, toluene, xylene, DMF, DMSO, NMP, acetonitrile, ether and THF.

[0008] Furthermore, in the above scheme, in the first step, the molar ratio of dichloroacetyl chloride to the base is 1:1-2.0, and the molar ratio of trichloroacetyl chloride to the Zn-Cu system is 1:0.1-2.0.

[0009] Further, the alkaline catalyst is at least one of triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide, MSOK and MEDA.

[0010] Furthermore, in the above scheme, in the first step, the Zn-Cu is at least one of zinc powder, zinc chloride, zinc nitrate, copper sulfate, copper nitrate, diethyl zinc and copper acetylacetonate.

[0011] Furthermore, in the above scheme, in the first step, the reaction temperature is -20 to 180°C, and the reaction time is 10 to 30 hours.

[0012] Furthermore, in the above scheme, in the first step, the organic solvent is at least one of glacial acetic acid, acetic anhydride, DMF, DMSO, NMP, acetonitrile, ethanol, ether, toluene, xylene, chlorobenzene, dichlorobenzene and THF.

[0013] Furthermore, in the above scheme, in the first step, the reaction temperature is 25 to 160° C., and the reaction time is 1 to 30 hours.

[0014] Furthermore, in the above scheme, in the first step, the molar ratio of the 3-oxo-2,2-dichloro-1-cyclobutanecarboxylic acid to the zinc powder catalyst is 1:1 to 3.0.

[0015] Furthermore, in the above scheme, in the second step, the alkaline solution is at least one of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.

[0016] Furthermore, in the above scheme, in the second step, the acid solution is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.

[0017] Furthermore, in the above scheme, in the second step, the reaction temperature is 10 to 140° C., and the reaction time is 2 to 28 hours.

[0018] Furthermore, in the above scheme, in the second step, the molar ratio of the 3-oxo-1-cyclobutanecarboxylate to the acid or base is 1:0.01-0.5 or 1:1.0-1.5.

[0019] Beneficial effects of the invention: (1) This synthetic route has mild reaction conditions, high yield and stable product quality.

[0020] (2) The process is simple, the raw materials are easily available, there is no need for too much supporting equipment, almost no wastewater is generated, it is environmentally friendly, suitable for large-scale industrial production, and has high economic value and social significance.

[0021] Specific implementation examples:

[0022] [Example 1] Synthesis of 3-oxo-1-cyclobutanecarboxylic acid In the first step, in a 1000ml four-necked bottle, under nitrogen protection, 500ml of n-hexane, 29.48g (0.2mol) of dichloroacetyl chloride and 17.2g (0.2mol) of methyl acrylate were added in sequence and stirred. After the temperature was reduced to -20 to -10°C, 25.46g (0.25mol) of triethylamine was slowly added dropwise. After the addition, the temperature was naturally raised to room temperature and stirred for 30 minutes. Then the temperature was raised to reflux and the reaction was carried out for 16h. Then the mixture was cooled and filtered, washed with water and dried to obtain 33.5g of light yellow powder, which was a crude product of 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate, with a yield of 85.5%.

[0023] In the second step, 33.5 g (0.17 mol) of crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate and 13.0 g (0.2 mol) of zinc powder were added to a 1000 ml four-necked flask and dissolved in 400 ml of glacial acetic acid; the reaction mixture was stirred at room temperature for 30 min, and then heated at 120°C for 2 h; TLC showed that the raw material disappeared; the mixture was cooled to room temperature, the mother liquor was filtered, the filter cake was washed with water, and dried to obtain 17.0 g of crude 3-oxo-1-cyclobutanecarboxylate, and the yield was 78.3%.

[0024] In the third step, 17 g (0.133 mol) of crude 3-oxo-1-cyclobutane carboxylate and 300 ml of concentrated hydrochloric acid were added into a 500 ml four-necked bottle, and the mixture was refluxed for 20 h. The mixture was cooled, filtered, slurried with ethanol, and dried to obtain 13.0 g of a white 3-oxo-1-cyclobutane carboxylic acid product with a yield of 86.0%.

[0025] [Example 2] Synthesis of 3-oxo-1-cyclobutanecarboxylic acid In the first step, in a 1000ml four-necked bottle, under nitrogen protection, 500ml DMF, 29.48g (0.2mol) dichloroacetyl chloride and 17.2g (0.2mol) methyl acrylate were added in sequence and stirred. After cooling to -20 to -10°C, 53g (0.5mol) sodium carbonate was added in batches and stirred for 2 hours. Then the temperature was raised to reflux and the reaction was carried out for 12h. After cooling and filtration, the mixture was washed with water and dried to obtain 32.3g of light yellow solid, which was crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate, with a yield of 82.2%.

[0026] In the second step, 32.3 g (0.164 mol) of crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate and 14.3 g (0.22 mol) of zinc powder were added to a 1000 ml four-necked bottle and dissolved in 400 ml of glacial acetic acid; the reaction mixture was stirred at room temperature for 1 h, and then heated at 120°C for 4 h; TLC showed that the raw material disappeared; the mixture was cooled to room temperature, the mother liquor was filtered, the filter cake was washed with water, and dried to obtain 16.5 g of crude 3-oxo-1-cyclobutanecarboxylate, and the yield was 78.6%.

[0027] In the third step, 16.5 g (0.13 mol) of crude 3-oxo-1-cyclobutane carboxylate and 300 ml of concentrated sulfuric acid were added into a 500 ml four-necked bottle, and the mixture was refluxed for 20 h. The mixture was cooled, filtered, slurried with ethanol, and dried to obtain 13.5 g of a white 3-oxo-1-cyclobutane carboxylic acid product with a yield of 91.1%.

[0028] [Example 3] Synthesis of 3-oxo-1-cyclobutanecarboxylic acid In the first step, in a 1000ml four-necked bottle, under nitrogen protection, 500ml of tetrahydrofuran, 36.26g (0.2mol) of trichloroacetyl chloride and 17.2g (0.2mol) of methyl acrylate were added in sequence, and after cooling to -20 to -10°C, 14.3g (0.22mol) of zinc powder and 1.17g (0.0073mol) of copper sulfate were added in batches, stirred for 2 hours, and refluxed for 8h; then cooled and filtered, washed with water and dried to obtain 30.9g of light yellow solid as crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate, with a yield of 78.5%.

[0029] In the second step, 30.9 g (0.157 mol) of crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate and 13.0 g (0.2 mol) of zinc powder were added to a 1000 ml four-necked flask and dissolved in 400 ml of glacial acetic acid; the reaction mixture was stirred at room temperature for 30 min, and then heated at 130°C for 4 h; TLC showed that the raw material disappeared; the mixture was cooled to room temperature, the mother liquor was filtered, the filter cake was washed with water, and dried to obtain 15.3 g of crude 3-oxo-1-cyclobutanecarboxylate, and the yield was 76.4%.

[0030] In the third step, 15.3 g (0.12 mol) of crude 3-oxo-1-cyclobutane carboxylate and 300 ml of sodium hydroxide solution (40%) were added into a 500 ml four-necked bottle, and the mixture was refluxed for 20 h. The mixture was cooled, filtered, washed with water, slurried with ethanol, and dried to obtain 12.0 g of a white 3-oxo-1-cyclobutane carboxylic acid product with a yield of 88.3%.

[0031] [Example 4] Synthesis of 3-oxo-1-cyclobutanecarboxylic acid In the first step, in a 1000ml four-necked bottle, under nitrogen protection, 500ml toluene, 36.26g (0.2mol) trichloroacetyl chloride and 18.9g (0.22mol) methyl acrylate 14.3g were added in sequence, and the temperature was lowered to -20 to -10°C, and then (0.22mol) zinc powder and 1.5g (0.008mol) copper nitrate were added in batches, stirred for 2h, and then refluxed for 12h; then cooled and filtered, washed with water and dried to obtain 32.9g of light yellow solid as crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate, with a yield of 83.5%.

[0032] In the second step, 32.9 g (0.167 mol) of crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate and 19.5 g (0.3 mol) of zinc powder were added to a 1000 ml four-necked flask and dissolved in 400 ml of glacial acetic acid; the reaction mixture was stirred at room temperature for 30 min, and then heated at 120°C for 4 h; TLC showed that the raw material disappeared; the mixture was cooled to room temperature, the mother liquor was filtered, the filter cake was washed with water, and dried to obtain 16.3 g of crude 3-oxo-1-cyclobutanecarboxylate, and the yield was 76.2%.

[0033] In the third step, 16.3 g (0.127 mol) of crude 3-oxo-1-cyclobutane carboxylate and 300 ml of potassium hydroxide solution (40%) were added into a 500 ml four-necked bottle, and the mixture was refluxed for 30 h. The mixture was cooled, filtered, washed with water, slurried with ethanol, and dried to obtain 13.5 g of a white 3-oxo-1-cyclobutane carboxylic acid product with a yield of 93.2%.

Claims

1. A method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized by the following two Synthesis steps: (1) Using dichloroacetyl chloride or trichloroacetyl chloride as the starting material, under the protection of nitrogen, in a certain amount of solvent, at a certain molar ratio and at a certain reaction temperature, slowly dropwise adding alkali or Zn-Cu catalyst to carry out dehydrochlorination elimination reaction to obtain crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate; dissolving zinc powder and crude 3-oxo-2,2-dichloro-1-cyclobutanecarboxylate in an organic solvent, stirring the reaction mixture at room temperature for several hours, and then heating at a certain temperature for several hours; TLC shows that the raw material disappears; cooling the mixture to room temperature, filtering, washing the filter cake with water, then washing with brine, and drying to obtain crude 3-oxo-1-cyclobutanecarboxylate; (2) The crude 3-oxo-1-cyclobutanecarboxylate is added to a certain amount of acid or alkaline solution and reacted at a certain temperature for a certain time to perform a hydrolysis reaction. After the reaction is completed, the mixture is cooled to room temperature and filtered. The filter cake is washed with water and dried to obtain 3-oxo-1-cyclobutanecarboxylic acid.

2. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The reaction solvent in step (1) is at least one of hexane, pentane, heptane, benzene, toluene, xylene, DMF, DMSO, NMP, acetonitrile, ether and THF.

3. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that In step (1), the molar ratio of dichloroacetyl chloride to the base is 1:1-2.0, and the molar ratio of trichloroacetyl chloride to the Zn-Cu system is 1:0.1-2.

0.

4. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The alkaline catalyst in step (1) is at least one of triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide, MSOK and MEDA.

5. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The reaction temperature in step (1) is -20 to 180° C., and the reaction time is 2 to 30 hours; the Zn-Cu is at least one of zinc powder, zinc chloride, zinc nitrate, copper sulfate, copper nitrate, diethyl zinc and copper acetylacetonate.

6. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The organic solvent in step (1) is at least one of glacial acetic acid, acetic anhydride, DMF, DMSO, NMP, acetonitrile, ethanol, ether, toluene, xylene, chlorobenzene, dichlorobenzene and THF; the reaction temperature is 25 to 160° C., and the reaction time is 1 to 30 hours; the molar ratio of the 3-oxo-2,2-dichloro-1-cyclobutanecarboxylic acid to the zinc powder catalyst is 1:1 to 3.

0.

7. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The alkaline solution in step (2) is at least one of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.

8. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The acid solution in step (2) is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.

9. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that The reaction temperature in step (2) is 10 to 140° C., and the reaction time is 2 to 28 hours.

10. According to claim 1, a method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, characterized in that In step (2), the molar ratio of the 3-oxo-1-cyclobutanecarboxylate to the acid or base is 1:0.01-0.5 or 1:1.0-1.5.

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