A kind of synthetic method of dimethyl 2,2-difluoromalonate

Abstract

The invention discloses a synthetic method of 2,2-difluoromalonate, comprising the following steps: step 1, in a three-necked flask equipped with a tetrafluoro stirring magnet, methyl tetrafluoromethoxy propionate is added, then a catalyst is added, concentrated sulfuric acid is added dropwise, sulfuric acid is added dropwise and stirred at room temperature; step 2, sampling and filtering GC detects the surplus of methyl tetrafluoromethoxy propionate, then the temperature is raised to continue the reaction, and the surplus of the raw material is sampled and detected; step 3, cooling the reaction materials are all put into a vacuum distillation device, fraction, and the content of the product is determined. The present invention reduces the amount of concentrated sulfuric acid to 0.4-0.5 times under the action of catalysts such as silicon-based, silicates, and aluminosilicates, does not produce hydrogen fluoride, can be produced in enamel equipment, is conducive to industrialized production, and the yield is significantly improved at the same time, the yield is 85-95%, and the production process of 2,2-difluoromalonate does not require special equipment, providing a convenient and efficient production process for production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for synthesizing dimethyl 2,2-difluoromalonate. Background Art

[0002] Entering the 21st century, fluorinated groups play an important role in the development of new drugs because they can improve the metabolic stability of drugs, regulate the physicochemical properties of drugs, increase the bioavailability of drugs, and enhance the targeting selectivity of drugs. The design inspiration of many new drugs comes from natural metabolites. By introducing fluorinated groups, the biological activity and stability of drugs can be significantly improved, thereby accelerating the development of new drugs. The role of fluorinated groups in new drugs is multifaceted. They not only improve the metabolic stability and bioavailability of drugs, but also enhance the targeting selectivity and therapeutic effects of drugs. They are an indispensable element in modern drug development. The incidence and mortality of breast cancer are affected by many factors, including the external environment, lifestyle, reproductive behavior, dietary structure, hormone levels and genetic factors. Globally, estrogen receptor-positive estrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2-) breast cancer account for 80% of all cases. Selective estrogen receptor degraders (SERDs) are a class of ligands that selectively act on estrogen receptor (ER) proteins. Their antagonism can also degrade ER proteins in target tissues. Therefore, SERD ligands have attracted widespread attention as a treatment for breast cancer. GDC-9545 (Girette) is a SERO clinical candidate drug under development for the treatment of ER+ / HER2- metastatic breast cancer. Dimethyl 2,2-difluoromalonate is the main raw material for synthesizing the important fragment tryptamine of the selective estrogen receptor degrader GDC-9545 (Girette).

[0003] The main method for synthesizing dimethyl 2,2-difluoromalonate is to oxidize methyl tetrafluoromethoxypropionate under the action of sulfuric acid. U.S. Patent US20220002304A1 describes that the yield of this method is 60%. It requires the consumption of a large amount of concentrated sulfuric acid and produces a large amount of hydrogen fluoride, which seriously corrodes the equipment and has a low yield. The synthesis of GDC-9545 (Girette) requires more than a dozen reactions. The yield and industrialization of dimethyl 2,2-difluoromalonate have a great impact on the application of Girite. There is an urgent need to improve the yield and a reliable industrialization route. Summary of the invention

[0004] Purpose of the invention: The prior art is to oxidize methyl tetrafluoromethoxypropionate under the action of sulfuric acid, and the amount of sulfuric acid used is 1-1.05 times that of methyl tetrafluoromethoxypropionate. A large amount of hydrogen fluoride will be generated during the oxidation process, which will corrode the equipment and the yield is only 60%. In order to solve the shortcomings of the prior art, the present invention provides a method for synthesizing dimethyl 2,2-difluoromalonate.

[0005] Technical solution: A method for synthesizing dimethyl 2,2-difluoromalonate, comprising the following steps:

[0006] Step 1: In a 1000ml three-necked flask equipped with a tetrafluoroethylene stirring magnet, add 500g of methyl tetrafluoromethoxypropionate, then add 50g of a silicon-based catalyst, a silicate catalyst or an aluminosilicate catalyst, and dropwise add 200g of concentrated sulfuric acid. During the dropwise addition, the temperature in the kettle is controlled at 0-50°C. After the sulfuric acid is added, stir at room temperature for 2-8 hours.

[0007] Step 2: Sampling, filtering and GC detection of the residual amount of methyl tetrafluoromethoxypropionate, then heating to 30-60°C and continuing the reaction for 1-4 hours, sampling and detecting the residual amount of the raw material;

[0008] Step 3: Cooling: Put all the reaction materials into a 1000 ml vacuum distillation device, collect the fraction with a top temperature of 54-55° C., and determine the content of the product.

[0009] As an optimization: in the step 1, the catalyst is 400-800 mesh silica gel or 4A, 5A molecular sieve.

[0010] As an optimization: in the step 1, the temperature of adding sulfuric acid is 20-30°C and the reaction time is 2-4h.

[0011] As an optimization: in the step 1, the weight of sulfuric acid is 0.4-0.5 times that of methyl tetrafluoromethoxypropionate

[0012] Beneficial effects: Under the action of catalysts such as silicon-based, silicate, and aluminosilicate, the present invention reduces the amount of concentrated sulfuric acid to 0.4-0.5 times, does not produce hydrogen fluoride, can be produced in enamel equipment, is conducive to industrial production, and significantly improves the yield, the yield is 85-95%, and provides a more economical raw material for the production of GDC-9545 (Girite). The production process of dimethyl 2,2-difluoromalonate does not require special equipment, providing a convenient and efficient production process for production. DETAILED DESCRIPTION

[0013] The technical solutions in the embodiments of the present invention will be described clearly and completely below so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the protection scope of the present invention. The embodiments described in the present invention are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. Specific embodiment 1

[0015] A method for synthesizing dimethyl 2,2-difluoromalonate comprises the following steps:

[0016] In a 1000ml three-necked flask equipped with a tetrafluoroethylene stirring magnet, 500g (2.63mol) of methyl tetrafluoromethoxypropionate was added, and then 50g of 600-mesh silica gel was added dropwise, and 200g of concentrated sulfuric acid was added dropwise. The temperature in the kettle was controlled to be less than 30°C during the addition process. After the addition of sulfuric acid was completed, the mixture was stirred at room temperature for 2 hours. Samples were taken for filtration and GC detection showed that methyl tetrafluoromethoxypropionate remained at 1%. The temperature was raised to 40°C and the reaction was continued for 1 hour. Samples were taken for detection of the remaining 0.1% of the raw materials. The temperature was lowered and all the reaction materials were put into a 1000ml vacuum distillation equipment. 380g (2.262mol) of the fraction with a top temperature of 54-55°C was collected, with a content of 99.8512%. The yield of the product was 86%. Specific embodiment 2

[0018] A method for synthesizing dimethyl 2,2-difluoromalonate comprises the following steps:

[0019] In a 1000ml three-necked flask equipped with a tetrafluoroethylene stirring magnet, 500g (2.63mol) of methyl tetrafluoromethoxypropionate was added, and then 80g of 5A molecular sieve (aluminosilicate catalyst) was added dropwise, and 200g of concentrated sulfuric acid was added dropwise. The temperature in the kettle was controlled to be less than 30°C during the addition process. After the addition of sulfuric acid was completed, the mixture was stirred at room temperature for 2 hours. Samples were taken for filtration and GC detection showed that 0.2% of methyl tetrafluoromethoxypropionate remained. The temperature was raised to 40°C and the reaction was continued for 1 hour. No residual raw materials were detected by sampling. The reaction materials were cooled and all put into a 1000ml vacuum distillation equipment. 405g (2.409mol) of a fraction with a top temperature of 54-55°C was collected, with a content of 99.6297%. The yield of the product was 91.6%. Specific embodiment 3

[0021] A method for synthesizing dimethyl 2,2-difluoromalonate comprises the following steps:

[0022] In a 100-liter reactor equipped with a mechanical tetrafluoroethylene stirrer, 57.02 kg (300 mol) of methyl tetrafluoromethoxypropionate was added, and then 9 kg of 5A molecular sieve was added, and 28.51 kg of concentrated sulfuric acid was added dropwise. The temperature in the reactor was controlled to be less than 30°C during the addition process. After the addition of sulfuric acid was completed, the mixture was stirred at room temperature for 2 hours. Samples were taken for filtration and GC detection showed that 0.5% of methyl tetrafluoromethoxypropionate remained. The temperature was raised to 40°C and the reaction was continued for 2 hours. Samples were taken for detection of the remaining 0.1% of the raw materials. The temperature was raised for vacuum distillation, and 47.91 kg (285 mol) of the fraction with a top temperature of 53-55°C was collected, with a content of 99.523%. The yield of the product was 94.55%.

[0023] The present invention reduces the amount of concentrated sulfuric acid to 0.4-0.5 times under the action of catalysts such as silicon-based, silicate, and aluminosilicate, does not produce hydrogen fluoride, can be produced in enamel equipment, is conducive to industrial production, and significantly improves the yield, providing a more economical raw material for the production of GDC-9545 (Girute).

Claims

1. A method for synthesizing dimethyl 2,2-difluoromalonate, characterized in that: The steps include: Step 1: In a 1000ml three-necked flask equipped with a tetrafluoroethylene stirring magnet, add 500g of methyl tetrafluoromethoxypropionate, then add 50g of a silicon-based catalyst, a silicate catalyst or an aluminosilicate catalyst, and dropwise add 200g of concentrated sulfuric acid. During the dropwise addition, the temperature in the kettle is controlled at 0-50°C. After the sulfuric acid is added, stir at room temperature for 2-8 hours. Step 2: Sampling, filtering and GC detection of the residual amount of methyl tetrafluoromethoxypropionate, then heating to 30-60°C and continuing the reaction for 1-4 hours, sampling and detecting the residual amount of the raw material; Step 3: Cooling: Put all the reaction materials into a 1000 ml vacuum distillation device, collect the fraction with a top temperature of 54-55° C., and determine the content of the product.

2. The synthetic method of dimethyl 2,2-difluoromalonate according to claim 1, characterized in that: In the step 1, the catalyst is 400-800 mesh silica gel or 4A, 5A molecular sieve.

3. The synthetic method of dimethyl 2,2-difluoromalonate according to claim 1, characterized in that: In the step 1, the temperature of adding sulfuric acid is 20-30°C and the reaction time is 2-4h.