Closed-loop production process of 2, 5, 6-trichloronicotinic acid

Abstract

The invention discloses a ring closing production process for producing 2, 5, 6-trichloronicotinic acid. The synthesis method comprises the following four steps: carrying out cyclization reaction, electrophilic chlorination reaction, hydroxyl chlorination reaction and hydrolysis reaction to obtain the product 2, 5, 6-trichloronicotinic acid. The total yield of the four steps is about 60%. The process has the advantages of cheap and easily available raw materials and simple process operation, and is a ring-closing production process suitable for industrial preparation of 2, 5, 6-trichloronicotinic acid. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and specifically relates to a cyclization production process of 2,5,6-trichloronicotinic acid. Background Art

[0002] 2,5,6-Trichloronicotinic acid is an important intermediate for pharmaceutical synthesis and is widely used in the synthesis of therapeutic drugs for oncological diseases. Its molecular formula is C6H2Cl3NO2, with a molecular weight of 226.44 and a CAS number of 54718-39-7.

[0003] The RAS gene is the first human tumor gene discovered and is one of the most common mutated genes in tumors. The three human RAS genes, HRAS, KRAS, and NRAS, are located on chromosomes 11, 12, and 1 respectively. Mutations that permanently activate RAS exist in 20-25% of human tumors, and KRAS mutations account for approximately 85% of all RAS mutations in human tumors. The US FDA approved the KRAS G12C inhibitor Lumakras (Sotorasib) of Amgen in May 2021 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying the KRAS G12C mutation who have received at least one prior systemic therapy. Sotorasib became the world's first approved tumor treatment drug targeting KRAS mutations.

[0004] 2,5,6-Trichloronicotinic acid is a key intermediate in the synthesis of Sotorasib drug molecules and a series of KRAS-targeted drug molecules, with a huge market demand. Therefore, the synthesis process and industrialization research of 2,5,6-trichloronicotinic acid have broad market prospects, social benefits, and economic value. Currently, there are mainly four reported process routes in the existing literature.

[0005] Process Route 1: The synthesis route disclosed in Patent WO200682392A1 is as follows:

[0006] The yield of the three-step reaction in Route 1 is only 6%. The last step of oxidizing the methyl group of the pyridine ring with KMnO4 has obvious safety risks and is not suitable for industrial production.

[0007] Route 2 is from the literature Bioorg. Med. Chem. Lett. 10(2002)1973-1804, which optimized the oxidation step of Route 1. The methyl group of 2,5,6-trichloro-3-methylpyridine in Route 1 was brominated. Route 2 is as follows:

[0008] Although Route 2 optimized the yield of the oxidation step through the bromination of the methyl group on the pyridine ring, the bromination used photoinitiation and did not give a clear yield. In addition, this route still did not avoid the production safety risks caused by oxidation.

[0009] Route 3 is from the literature Bioorg. Med. Chem. Lett. 10 (2002) 1973 - 1804. The listed Route 3 is as follows:

[0010] The overall literature did not report the yield of Route 3, and the raw materials are rare. Chlorine gas and metallic mercury are used in the route, which is not environmentally friendly and limits its industrial production capacity.

[0011] Route 4: Patent US5968875 reported a method using the hydrolysis of 2,3,6 - trichloro - 5 - trichloromethylpyridine. The raw materials of this method are not available in the market and are not easy to prepare. Therefore, this method cannot be industrially produced. Route 4 is as follows:

[0012] In summary, there is a huge market demand for 2,5,6 - trichloronicotinic acid, but the reported process routes currently all have certain defects: such as high temperature, strong acid, strong base conditions and oxidation reactions, the reactions are violent, there are more three wastes, and there are safety hazards, and none of them have the conditions for industrial production.

[0013] Therefore, how to optimize the preparation and purification methods of 2,5,6 - trichloronicotinic acid compounds to achieve a process suitable for industrial scale - up has important social and economic value for the production of such compounds, and at the same time provides guarantee for the production of downstream products and the industrial production and cost control of related drugs. Summary of the Invention

[0014] The present invention overcomes the deficiencies in the existing production process of 2,5,6-trichloronicotinic acid that are not suitable for industrial production, and provides a new synthetic process suitable for industrial production. Using 1,3-dimethyluracil as the raw material, the product is obtained through four process steps: cyclization, electrophilic chlorination, hydroxy chlorination, and hydrolysis. This method uses conventional and easily controllable chemical reactions and raw materials that are abundant, readily available, and inexpensive from suppliers in the market, and is a suitable method for preparing 2,5,6-trichloronicotinic acid. The technical solution adopted by the present invention to achieve the above object is: a method for synthesizing 2,5,6-trichloronicotinic acid, with four synthesis steps: The first step is the cyclization reaction: The raw material 1,3-dimethyluracil is cyclized with cyanoacetamide under alkaline conditions to obtain intermediate 01; The second step is the electrophilic chlorination reaction: Intermediate 01 reacts with an electrophilic chlorination reagent, and after filtration, the acid is adjusted to obtain intermediate 02; The third step is the hydroxy chlorination reaction: Intermediate 02 is chlorinated with a conventional hydroxy chlorination reagent, and after post-treatment and purification, intermediate 03 is obtained; The fourth step is the cyano hydrolysis reaction: Intermediate 03 is hydrolyzed to a carboxyl group under acidic conditions to obtain the product 2,5,6-trichloronicotinic acid.

[0015] The described synthetic method of 2,5,6-trichloronicotinic acid, specific process: The first step of cyclization reaction: The raw materials 1,3-dimethyluracil, cyanoacetamide, alkali, and solvent are mixed and heated to 60 °C, and the reaction is kept warm until the reaction is completed as monitored by liquid phase. The system is cooled to 0 °C, filtered, the filter cake is neutralized with acid, filtered, and the material is dried to obtain intermediate 01, and the HPLC purity is measured to be 97%; The second step of electrophilic chlorination reaction: Intermediate 01, alkali, and solvent are mixed, the temperature is controlled at 30 °C, the chlorination reagent is added to the reaction system, and the reaction is kept warm until the reaction is completed as monitored by HPLC. The pH of the system is adjusted to 1 with acid, filtered, and the filter cake is dried to obtain intermediate 02, and the HPLC purity is measured to be 90%; The third step is the hydroxy chlorination reaction: Intermediate 02 is mixed with a solvent, the chlorination reagent is added, the reaction is heated to reflux, and the reflux is kept until the reaction ends as monitored by HPLC; After concentrating out the solvent, the remaining concentrate is added to water, extracted with a solvent, washed, concentrated to dryness, and finally a poor solvent is added for pulping and purification, filtered and dried to obtain intermediate 03, and the HPLC purity is measured to be 90%; The fourth step is the cyano hydrolysis reaction: Water and acid are mixed, the temperature is controlled at 0 °C, intermediate 03 is added, the reaction is heated to 60 °C, and the reaction is stirred until the reaction is completed as monitored by HPLC; The reaction is cooled to room temperature; The temperature is controlled at 20 °C, the reaction is added to water, filtered to obtain intermediate amide; The filter cake is added to acid, heated to 80 °C, and the reaction is stirred until the intermediate amide is completely converted as monitored by HPLC; The system is cooled to 0 °C, filtered and dried to obtain the product 2,5,6-trichloronicotinic acid, and the HPLC purity is measured to be 99%.

[0016] Further, for the third-step hydroxy-chlorination reaction, the chlorinating reagent used is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, or a compound reagent of several chlorinating reagents.

[0017] Further, for the third-step hydroxy-chlorination reaction, the solvents used are toluene, thionyl chloride, phosphorus oxychloride, tetrahydrofuran, and methyltetrahydrofuran; the extraction agents used are ethyl acetate, methyl acetate, isopropyl acetate, and methyl tert-butyl ether; the poor solvents used are n-heptane, n-hexane, and cyclohexane.

[0018] Further, for the fourth-step hydrolysis reaction, the acids used are concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0019] Further, for the fourth-step hydrolysis reaction, the extraction solvents used are toluene, dichloromethane, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether.

[0020] The present invention adopts conventional chemical reactions, which are easy to operate and control, with a safe and controllable production process, stable process, and good reproducibility. High-quality products can be obtained, and it is a process route suitable for production scale-up. The raw materials used, such as 1,3-dimethyluracil, cyanoacetamide, sodium hydroxide, NCS, etc., are all bulk chemical raw materials with low prices and sufficient market supply. The overall yield of the four steps is about 60%. This method has a safe and controllable process, good reproducibility, and inexpensive and easily available raw materials, and is a suitable method for producing 2,5,6-trichloronicotinic acid. Description of the Drawings

[0021] Figure 1 It is the production process diagram of 2,5,6-trichloronicotinic acid of the present invention. Detailed Embodiments

[0022] As Figure 1 shown, the present invention discloses a preparation process of 2,5,6-trichloronicotinic acid. The route adopted by this method uses 1,3-dimethyluracil as the raw material, cyclizes with cyanoacetamide under alkaline conditions, and then obtains the product 2,5,6-trichloronicotinic acid through electrophilic chlorination, hydroxy-chlorination, and cyano hydrolysis.

[0023] The preparation process of 2,5,6-trichloronicotinic acid of the present invention specifically includes the following steps:

[0024] The first step of cyclization: Add 1,3-dimethyluracil (100 g, 1.0 eq.), cyanoacetamide (72 g, 1.2 eq.), sodium methoxide (69.4 g, 1.8 eq.) and methanol (600 mL, 6 V) into the reaction flask. Heat the reaction to 60 °C and keep the reaction temperature until the reaction is completed by liquid-phase monitoring. Cool the reaction temperature to 0 °C and filter. Add the filter cake and water (100 mL) into the reaction flask, adjust the pH of the system to 1 with hydrochloric acid, filter, and dry the material to obtain 87 g of intermediate 01 with a purity of 97% and a yield of 93%. The second step of electrophilic chlorination: Dissolve sodium hydroxide (29.4 g, 1.0 eq.) in water (800 mL, 8V), add intermediate 01 (100 g, 1.0 eq.), control the temperature at 30 °C, and add N-chlorosuccinimide (128 g, 1.3 eq.) to the reaction in batches and keep stirring until the reaction is completed by liquid-phase monitoring. Adjust the pH value of the system to 1 with hydrochloric acid, cool the reaction solution to 0 °C, stir for 2 hours, filter, and dry the filter cake in a blast dryer at 50 °C to obtain 111.5 g of intermediate 02 with a purity of 90% and a yield of 89%. The third step of hydroxy chlorination reaction: Add intermediate 02 (100 g, 1.0 eq.), phosphorus oxychloride (658 g, 4V) and phosphorus pentachloride (610 g, 5.0 eq.) into the reaction flask, heat the reaction solution to 100 °C, and keep the reaction until the reaction is completed by liquid-phase monitoring. Concentrate the reaction under reduced pressure until no distillate flows out, and add the concentrated residue to water (800 mL, 8V). Extract the system twice with toluene (400 mL, 4V), wash the combined organic phases with water, and concentrate until no distillate flows out basically. Dropwise add n-heptane (300 mL, 3V) to the concentrated residue, stir for 2 hours, filter, and dry the material to obtain 103.4 g of yellow intermediate 03 with a purity of 95% and a yield of 85%. The fourth step of hydrolysis reaction: Add water (20 mL, 0.2V) and concentrated sulfuric acid (300 mL, 3V) into reaction flask 1 in sequence, control the temperature of reaction flask 1 at 0 °C, and add intermediate 03 into reaction flask 1. Heat the reaction to 60 °C and keep the reaction until the reaction is completely detected by liquid phase. Add water (1000 mL, 10V) into reaction flask 2 and lower the temperature to 0 °C. Cool the reaction solution in reaction flask 1 to 0 °C and transfer the materials in the flask into reaction flask 2. Filter to obtain the intermediate amide. Add the intermediate amide into concentrated hydrochloric acid (800 mL, 8V), heat to 80 °C, and keep the reaction until the conversion of the intermediate amide is complete by liquid-phase monitoring. Cool the temperature to 0 °C, centrifuge, and dry the material to obtain 93.8 g of light yellow to off-white solid with a purity of 99% and a yield of 85%.

[0025] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A ring-closing production process of 2,5,6-trichloronicotinic acid, characterized in the following Four-step synthesis process; the first step is the cyclization reaction: cyclize the raw material 1,3-dimethyluracil with cyanoacetamide under alkaline conditions to obtain intermediate 01; the second step is the electrophilic chlorination reaction: react intermediate 01 with an electrophilic chlorination reagent, adjust the acidity after filtration to obtain intermediate 02; the third step is the hydroxy chlorination reaction: chlorinate intermediate 02 with a conventional hydroxy chlorination reagent, and obtain intermediate 03 after post-treatment and purification; the fourth step is the cyanide hydrolysis reaction: hydrolyze the cyanide group of intermediate 03 to a carboxyl group under acidic conditions to obtain the product 2,5,6-trichloronicotinic acid.

2. The ring-closing production process of 2,5,6-trichloronicotinic acid according to claim 1, characterized in that, The specific process is as follows: The first step, the cyclization reaction: Mix the raw materials 1,3-dimethyluracil, cyanoacetamide, base and solvent, heat up to 60 °C, keep the temperature for reaction until the reaction is completed monitored by liquid phase. Cool the system to 0 °C, filter, neutralize the filter cake with acid, filter and then dry the material to obtain intermediate 01, and the HPLC purity is measured to be 97%; The second step, the electrophilic chlorination reaction: Mix intermediate 01, base and solvent, control the temperature at 30 °C, add the chlorination reagent to the reaction system, and keep the temperature for reaction until the reaction is completed monitored by HPLC. Adjust the pH of the system to 2 with acid, filter, and dry the filter cake to obtain intermediate 02, and the HPLC purity is measured to be 90%; The third step is the hydroxy chlorination reaction: Mix intermediate 02 and solvent, add the chlorination reagent, heat the reaction to reflux, and keep the reflux until the reaction ends monitored by HPLC; Concentrate the solvent, add the remaining concentrate to water, extract with a solvent, wash, concentrate to dryness, and finally add a poor solvent for slurry purification, filter and dry to obtain intermediate 03, and the HPLC purity is measured to be 90%; The fourth step is the cyanide hydrolysis reaction: Mix water and acid, control the temperature at 0 °C, add intermediate 03, heat the reaction to 60 °C, stir the reaction until the reaction is completed monitored by HPLC; Cool the reaction to control the temperature at 20 °C, add the reaction to water, filter to obtain intermediate amide; Add the filter cake to acid, heat up to 80 °C, stir the reaction until the intermediate amide is completely converted monitored by HPLC; Cool the system to 0 °C, filter to obtain the crude product. Mix the crude product with water, adjust the pH of the system to 9 with base, and then extract impurities; Adjust the pH of the aqueous phase to 1 with hydrochloric acid, filter and dry the material to obtain the product 2,5,6-trichloronicotinic acid, and the HPLC purity is measured to be 99%.

3. The ring - closing production process of 2,5,6 - trichloronicotinic acid according to claim 2, characterized in that, For the first-step cyclization reaction described above: The bases used are sodium methoxide, sodium ethoxide, lithium bis(trimethylsilyl)amide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, cesium hydroxide; The solvents used are methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile.

4. The ring-closing production process of 2,5,6-trichloronicotinic acid according to claim 2, characterized in that, For the second-step electrophilic chlorination reaction described above: The chlorination reagents used are chlorine, N-chlorosuccinimide, dichlorohydantoin, sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride.

5. The ring-closing production process of 2,5,6-trichloronicotinic acid according to claim 2, characterized in that, The second step of the electrophilic chlorination reaction: The bases used are sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylamine, ammonia water, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-ene; the solvents used are water, methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, N,N-dimethylformamide, and N-methylpyrrolidone; the acids used are hydrochloric acid, sulfuric acid, acetic acid, and oxalic acid.

6. The ring-closing production process of 2,5,6-trichloronicotinic acid according to claim 2, characterized in that The third step of the hydroxy chlorination reaction: The chlorinating reagents used are thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, and a compound reagent of several chlorinating reagents.

7. The ring - closing production process of 2,5,6 - trichloronicotinic acid according to claim 2, characterized in that, The third step of the hydroxy chlorination reaction: The solvents used are toluene, thionyl chloride, phosphorus oxychloride, tetrahydrofuran, and methyltetrahydrofuran; the extractants used are ethyl acetate, methyl acetate, isopropyl acetate, and methyl tert-butyl ether; the poor solvents used are n-heptane, n-hexane, and cyclohexane.

8. A cyclization production process of 2,5,6-trichloronicotinic acid according to claim 2, characterized in that The fourth step of the hydrolysis reaction: The acids used are concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

9. The ring - closing production process of 2,5,6 - trichloronicotinic acid according to claim 2, characterized in that, The fourth step of the hydrolysis reaction: The extraction solvents used are toluene, dichloromethane, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether.

Images