Synthesis method of 3-oxocyclobutanecarboxylic acid

Abstract

The invention relates to a synthesis method of 3-oxocyclobutanecarboxylic acid. The synthesis method comprises the following concrete steps: (1) adding N,N-dimethyl formamide and potassium tert-butoxide into a flask, stirring, carrying out an ice bath, dropping diisopropyl malonate to be dissolved in DMF, stopping dropping after 3.0 hours, heating and stirring, adding 2,2-dimethoxy-1,3-dibromopropane, stirring and heating to 140 DEG C, keeping the temperature for 4 days, distilling off half of DMF, cooling, adding water, stirring uniformly, adding 1kg of normal heptane, extracting for four times, drying an organic phase, and then carrying out reduced pressure distillation to obtain a product A; and (2) adding the product A obtained in the step (1) into the flask, adding water and concentrated hydrochloric acid while stirring, heating for boiling off 2 / 3 of solvent, extracting with dichloromethane, drying an organic phase with anhydrous sodium sulfate, then concentrating to obtain a crude product, and re-crystallizing dichloromethane and normal heptane to obtain a final product. The synthesis method provided by the invention has the advantages of few steps, easiness in operation and simple after-treatment, and prepared 3-oxocyclobutanecarboxylic acid has relatively high purity.

Description

technical field

[0001] The invention belongs to the field of chemical synthesis, and relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of 3-oxocyclobutane carboxylic acid. Background technique

[0002] 3-oxocyclobutane carboxylic acid is an important pharmaceutical intermediate, which can be applied to the synthesis of various raw materials. Such as thrombin inhibitors, kinase inhibitors and many anti-tumor drugs are used. 3-Oxocyclobutanecarboxylic acid is also in high demand. The raw material cost of the conventional 3-oxocyclobutane carboxylic acid synthetic method mentioned in the current literature is relatively high, resulting in its high cost, and the process is relatively complicated in the conventional 3-oxo cyclobutane carboxylic acid synthetic method , quality control is comparatively difficult in the synthetic technique, the product yield of the 3-oxocyclobutane carboxylic acid that prepares is also lower in a...

Examples

Embodiment 1

[0011] (1) Take 2.2 kg of DMF and 424 g of potassium tert-butoxide into a 5L flask, stir, put in an ice bath, and add 678 g of diisopropyl malonate to dissolve in 1.0 LDMF dropwise at -5°C. After 3.0 hours, the dropwise addition is completed. Raise the temperature to 20°C and stir for 1.0h, add 472g of 2,2-dimethoxy-1,3-dibromopropane, stir for 1 hour, then raise the temperature to 140°C, keep it for 4 days, evaporate it after the reaction half of DMF, lower the temperature to 15°C, add 1.5L of water, stir evenly, add 1 kg of n-heptane for extraction four times, dry the organic phase and distill under reduced pressure to obtain 400 g of the product.

[0012] (2) Put 250g of the product obtained in step (1) into a 2L flask, add 350g of water and 460g of concentrated hydrochloric acid during stirring, raise the temperature to 75-80°C, keep for 30h, raise the temperature to 102-106°C, keep for 120h, after the reaction Two-thirds of the solvent was evaporated, extracted with dich...

Embodiment 2

[0014] 1. Add 550kg of DMF and 225Kg of potassium tert-butoxide into a 1500L reactor, stir, put in an ice bath, and add 350Kg of diisopropyl malonate to dissolve in 250Kg of DMF dropwise at -5°C. h, add 234Kg of 2,2-dimethoxy-1,3-dibromopropane, stir for 1 hour, raise the temperature to 130°C, keep it for 85 hours, evaporate most of the DMF after the reaction, cool down to 15°C, add 300Kg water, stirred evenly, added 300L of n-heptane to extract 3 times, dried the organic phase and distilled under reduced pressure to obtain 295Kg of the product.

[0015] 2. Add 295Kg of the product obtained in the previous step into a 2000L reactor, add 450Kg of water and 450Kg of concentrated hydrochloric acid while stirring, raise the temperature to 75-80°C, keep it for 32h, raise the temperature to 102-106°C, keep it for 120h, evaporate one-third of it after the reaction The solvent of dichloromethane was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium ...

technical field

[0001] The invention belongs to the field of chemical synthesis, and relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of 3-oxocyclobutane carboxylic acid. Background technique

[0002] 3-oxocyclobutane carboxylic acid is an important pharmaceutical intermediate, which can be applied to the synthesis of various raw materials. Such as thrombin inhibitors, kinase inhibitors and many anti-tumor drugs are used. 3-Oxocyclobutanecarboxylic acid is also in high demand. The raw material cost of the conventional 3-oxocyclobutane carboxylic acid synthetic method mentioned in the current literature is relatively high, resulting in its high cost, and the process is relatively complicated in the conventional 3-oxo cyclobutane carboxylic acid synthetic method , quality control is comparatively difficult in the synthetic technique, the product yield of the 3-oxocyclobutane carboxylic acid that prepares is also lower in a...

Examples

Embodiment 1

[0011] (1) Take 2.2 kg of DMF and 424 g of potassium tert-butoxide into a 5L flask, stir, put in an ice bath, and add 678 g of diisopropyl malonate to dissolve in 1.0 LDMF dropwise at -5°C. After 3.0 hours, the dropwise addition is completed. Raise the temperature to 20°C and stir for 1.0h, add 472g of 2,2-dimethoxy-1,3-dibromopropane, stir for 1 hour, then raise the temperature to 140°C, keep it for 4 days, evaporate it after the reaction half of DMF, lower the temperature to 15°C, add 1.5L of water, stir evenly, add 1 kg of n-heptane for extraction four times, dry the organic phase and distill under reduced pressure to obtain 400 g of the product.

[0012] (2) Put 250g of the product obtained in step (1) into a 2L flask, add 350g of water and 460g of concentrated hydrochloric acid during stirring, raise the temperature to 75-80°C, keep for 30h, raise the temperature to 102-106°C, keep for 120h, after the reaction Two-thirds of the solvent was evaporated, extracted with dich...

Embodiment 2

[0014] 1. Add 550kg of DMF and 225Kg of potassium tert-butoxide into a 1500L reactor, stir, put in an ice bath, and add 350Kg of diisopropyl malonate to dissolve in 250Kg of DMF dropwise at -5°C. h, add 234Kg of 2,2-dimethoxy-1,3-dibromopropane, stir for 1 hour, raise the temperature to 130°C, keep it for 85 hours, evaporate most of the DMF after the reaction, cool down to 15°C, add 300Kg water, stirred evenly, added 300L of n-heptane to extract 3 times, dried the organic phase and distilled under reduced pressure to obtain 295Kg of the product.

[0015] 2. Add 295Kg of the product obtained in the previous step into a 2000L reactor, add 450Kg of water and 450Kg of concentrated hydrochloric acid while stirring, raise the temperature to 75-80°C, keep it for 32h, raise the temperature to 102-106°C, keep it for 120h, evaporate one-third of it after the reaction The solvent of dichloromethane was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium ...