Synthesis method of polyhalogenated nicotinic acid compound

Abstract

The invention discloses a synthesis method of a polyhalogenated nicotinic acid compound. The polyhalogenated nicotinic acid compound is a compound shown as a formula I, the synthetic route of the synthetic method is as follows: R1, R2, R3 and R4 are respectively and independently H, Cl, Br or F, and more than two (including the number) of R1, R2, R3 and R4 are halogens; x is Br or I; m is Mg or Li; the synthesis method comprises the following steps: 1, in a fluorine-containing solvent, carrying out an electrophilic halogenation reaction on a compound shown in a formula II to obtain a compound shown in a formula III; 2, performing halogen-metal exchange reaction on the compound shown in the formula III under the action of a metal organic reagent to obtain a compound shown in a formula IV; and introducing carbon dioxide into the compound as shown in the formula IV for carboxylation reaction to obtain the polyhalogenated nicotinic acid compound. According to the method, efficient electrophilic halogenation of polyhalogenated pyridine is realized on the basis of activation of an electron-deficient pyridine ring by a fluorine-containing solvent.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis process, and particularly relates to a synthesis method of a polyhalogenated nicotinic acid compound. BACKGROUND

[0002] Nicotinic acid is a pyridine derivative, and its chemical name is pyridine-3-carboxylic acid. Nicotinic acid is mainly present in animal viscera, muscle and other tissues, and is one of the 13 essential vitamins for the human body. Nicotinic acid compounds are not only widely used in the field of medicine (such as anti-rough skin disease, as a vasodilator and an intermediate for producing isoniazid, nicotinamide and other drugs), but also as an important additive, and are widely used in the fields of food, feed, dye, photosensitive material and air deodorant. Polyhalogenated nicotinic acid (nicotinic acid with ≥2 halogen atom substituents on the pyridine ring) has multiple active functional groups, so it has multiple reaction sites. Different reaction sites and different halogens can be used for selective reaction and are widely used in the synthesis of bulk drugs and key intermediates.

[0003] The first KRAS G12C new drug Sotorasib (AMG510) (WO2020102730A1) approved by the US Food and Drug Administration (FDA) for listing in the world is applied by Amgen, USA, and the KRAS G12C new drug Garsorasib (D-1553) (WO2021121330A1) in clinical phase III in China is applied by Yifang Bio. Both of them are synthesized by using 2,6-dichloro-5-fluoronicotinic acid as a key raw material. Glecirasib (WO2021121367A1) developed by Gossamer Bio for treating at least one systemic treatment of KRAS G12C mutant advanced non-small cell lung cancer (NSCLC) adult patients was approved by the National Medical Products Administration (NMPA) of China on May 22, 2025, and officially listed. It is prepared by using 2,5,6-trichloronicotinic acid as a starting material. The synthesis methods of 2,6-dichloro-5-fluoronicotinic acid reported in the literature mainly include the following two methods, and other methods basically include these two methods: Method one: EP0333020A3 reported a three-step method of cyclization, chlorination, and hydrolysis to synthesize 2,6-dichloro-5-fluoronicotinic acid. Ethyl fluoroacetate, ethyl formate, and cyanoacetamide were cyclized under basic conditions to give 2,6-dihydroxy-3-cyano-5-fluoropyridine, which was then chlorinated and hydrolyzed to give 2,6-dichloro-5-fluoronicotinic acid. This method is economical and has high economic efficiency, although it uses chlorination and strong acid hydrolysis. When we used this method to develop a route for 2,5,6-trichloronicotinic acid, we found that replacing ethyl fluoroacetate with ethyl chloroacetate resulted in the main product being a substitution byproduct due to the leaving ability of chlorine, and the target intermediate 2,6-dihydroxy-3-cyano-5-chloropyridine could not be obtained, and thus the target product 2,5,6-trichloronicotinic acid could not be obtained. Therefore, this method is not a universal method for the preparation of polyhalogenated nicotinic acid. The route of method one for the synthesis of 2,6-dichloro-5-fluoronicotinic acid is as follows: .

[0004] Method two: US4840954A reported a four-step method for synthesizing 2,6-dichloro-5-fluoronicotinic acid, which used 2,6-dichloro-3-amino-5-methylpyridine as the starting material, and then performed diazotization, fluorination, and free radical chlorination to chlorinate the methyl group to a trichloromethyl group, and finally hydrolysis to give 2,6-dichloro-5-fluoronicotinic acid. Although this method can obtain chlorinated or brominated pyridine by changing the halogen source after diazotization, and then synthesize 2,5,6-trichloronicotinic acid or 2,6-dichloro-5-bromonicotinic acid. Through market research, the raw material 2,6-dichloro-3-amino-5-methylpyridine is not commercially available, and the four-step process involves reactions such as diazotization, fluorination, and free radical chlorination, which are not friendly to the process. Therefore, whether from the feasibility of commercialization or economic efficiency, it is not as good as method one. The route of method two for the synthesis of 2,6-dichloro-5-fluoronicotinic acid is as follows: .

[0005] In the route development of polyhalogenated nicotinic acid compounds, we have successfully developed a one-generation process for 2,5,6-trichloronicotinic acid CN116199624A. By using 2,6-dichloronicotinic acid as the starting material, hydrolyzing the 6-position chlorine to a hydroxyl group to improve the electron cloud density of the pyridine ring, and then performing electrophilic chlorination at the 5-position of the pyridine ring, and then chlorinating the 6-position hydroxyl group with chlorosulfuric acid to prepare 2,5,6-trichloronicotinic acid with a total yield of ~ 46%. This three-step process uses classical chemical reactions and is easy to implement. Using this three-step process, we have successfully produced several tons of product, ensuring the use of KRAS12C target new drug research by several domestic new drug research and development enterprises. The three-step route of CN116199624A is as follows: .

[0006] CN117263854A reports a two-step route to synthesize 2,5,6-trichloronicotinic acid. 2,5-dichloro-6-hydroxy nicotinic acid is obtained by alkaline hydrolysis of 2,5,6-trichloro-3-trifluoromethylpyridine, and then the 6-hydroxyl group is chlorinated to obtain 2,5,6-trichloronicotinic acid. This method has short steps, simple chemistry and is easy to control, and is evaluated as a suitable synthetic method for commercial production. The patent states that 2,3,6-trichloro-5-trifluoromethylpyridine is a byproduct in the production of bulk industrial product 2,3-dichloro-5-trifluoromethylpyridine, so the raw material is cheap and easy to obtain. Further market research found that 2,3-dichloro-5-trifluoromethylpyridine has no mature market supply at present, which limits the process production advantage of this route. The two-step route of CN117263854A is as follows: .

[0007] In view of the growing demand for polyhalogenated nicotinic acid and cost pressure, it is necessary to further develop a more cost-effective and stable supply of universal synthesis route to ensure the demand for drug research and commercialization after listing.

[0008] From the perspective of retrosynthetic analysis, there are mainly two methods for the synthesis of nicotinic acid compounds: the first is based on the functional group transformation of nicotinic acid compounds, CN116199624A uses 2,6-dichloronicotinic acid as the raw material, through functional group transformation, chlorination, and further functional group transformation to obtain the target product. The second is to construct a carboxyl group at the β-position of the pyridine ring to obtain the target nicotinic acid.

[0009] Based on the strong market demand prospect of multi-substituted nicotinic acid, the synthesis methods of the following 15 kinds of multi-halogenated nicotinic acid currently on the market are researched and summarized, and the current synthesis methods of multi-halogenated nicotinic acid are summarized in Table 1. Analyzing the above methods, due to factors such as raw material supply, none of them can be used as a universal method for the preparation of multi-halogenated nicotinic acid. In addition, the method of alkali metal reagent dehydrogenation to form alkali metal salt and then passing through carbon dioxide generally requires special deep cooling equipment; the cyanide hydrolysis method generally requires the use of highly toxic or toxic cyanide during the construction of the cyano group; the methyl oxidation method generally requires the use of strong oxidants such as KMnO4 and SeO2. From the perspective of conventional chemistry, such reactions generally have the risk of exothermic reaction or delayed exothermic reaction in scale-up production; the trichloromethyl or trifluoromethyl hydrolysis method has difficulties in the supply or direct construction of trichloromethyl intermediates or trifluoromethyl intermediates; the hydroxyl halogenation method generally requires multi-step construction of hydroxyl pyridine intermediates; the halogen reduction method is limited to specific structure of raw materials and target products, and generally requires the use of noble metal reducing agents.

[0010] The existing literature reported implementation methods all have obvious defects. In theory, aromatic electrophilic halogenation is the most direct and economic method for introducing halogen. WO2023205226A1 reports nicotinic acid 9 (4-fluoro-6-chloronicotinic acid), using iodo intermediate 9-3 (2-chloro-4-fluoro-5-iodopyridine) to carry out Grignard exchange with Grignard reagent (isopropyl magnesium chloride), and then introducing carbon dioxide to synthesize the target product. Although this method introduces more stable magnesium salt through Grignard exchange, through the synthesis of intermediate 9-3, it is found that 2-chloro-4-fluoropyridine is introduced by 2-step diisopropyl lithium (LDA) hydrogen abstraction and iodination, so the step is long and the economy is poor. EP0634413A1 reports nicotinic acid 5 (2,5-dichloronicotinic acid), using bromo intermediate 5-2 (2,5-dichloro-3-bromopyridine) as raw material, using n-butyl lithium to carry out Li-Br exchange to obtain lithium salt, and then introducing carbon dioxide to prepare nicotinic acid 5, and the intermediate 5-2 has no market supply, and generally needs to be prepared by diazotization bromination or pyridine hydroxyl bromination using the corresponding amino compound, which is long in steps and poor in safety and economy compared with direct electrophilic halogenation.

[0011] Aromatic compound electrophilic halogenation is one of the most direct and economic methods for introducing halogen on the aromatic ring, so if direct aromatic electrophilic halogenation can be achieved, then Grignard exchange is formed to form magnesium salt, and then reacted with carbon dioxide to construct carboxyl, which will be a universal and economic method for preparing polyhalogenated nicotinic acid. In the research on the synthesis methods of 15 kinds of commercial polyhalogenated nicotinic acid corresponding halopyridine compounds (bromides and iodides), bromides 4-2, 11-2, 15-2 and iodides 6-3, 8-3, 11-3, 13-3, 14-3, 15-3 have no reported synthesis method. Other bromides and iodides have no method for directly using electrophilic bromination or iodination to synthesize the corresponding bromide and iodide.

[0012] Literature research shows that for most target polyhalogenated nicotinic acids, the synthesis method of the key bromination or iodination intermediate is not reported, and it cannot be obtained by conventional direct electrophilic halogenation. Therefore, how to realize the direct electrophilic halogenation of polyhalogenated pyridine has become the core technical bottleneck to break through this general synthesis path. SUMMARY

[0013] In order to solve the above problems in the prior art, the technical scheme provided by the present application is as follows: A synthesis method of a polyhalogenated nicotinic acid compound, the polyhalogenated nicotinic acid compound is a compound of formula I; the synthesis route of the synthesis method is: wherein R1, R2, R3and R4are independently H, Cl, Br or F, and two or more of R1, R2, R3and R4are halogen; X is Br or I; and M is Mg or Li; The synthesis method comprises the following steps: Step one: electrophilic halogenation reaction: in a fluorine-containing solvent, the compound of formula II is subjected to electrophilic halogenation reaction to obtain a compound of formula III; Step two: halogen-metal exchange and carboxylation reaction: the compound of formula III is subjected to halogen-metal exchange reaction under the action of a metal organic reagent to obtain a compound of formula IV; carbon dioxide is introduced into the compound of formula IV to perform carboxylation reaction to obtain the polyhalogenated nicotinic acid compound.

[0014] In some embodiments, in step one, the fluorine-containing solvent is selected from one or more of hexafluoroisopropanol, trifluoroethanol and trifluoroacetic acid.

[0015] In some embodiments, in step one, the fluorine-containing solvent is a combination of hexafluoroisopropanol and trifluoroacetic acid, or is trifluoroacetic acid.

[0016] In some embodiments, the compound of formula I is selected from the following 14 compounds: ; wherein X is Br.

[0017] In some embodiments, the compound of formula I is selected from the following 10 compounds: .

[0018] In some embodiments, in step one, the reaction reagent for electrophilic halogenation reaction with the compound of formula II is selected from one or more of bromine, dibromohydantoin, N-bromosuccinimide, N-iodosuccinimide, elemental iodine and iodine chloride, preferably dibromohydantoin or N-iodosuccinimide.

[0019] In some embodiments, in step one, the electrophilic halogenation reaction is performed at a temperature of 40-100°C, preferably at a temperature of 50-75°C, and more preferably at a temperature of 50-55°C.

[0020] In some embodiments, in step two, the metal organic reagent is selected from one or more of methyllithium, butyllithium, n-hexyllithium, sec-butyllithium, phenyllithium, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium bromide, n-butylmagnesium chloride and isopropylmagnesium chloride-lithium chloride, and is preferably isopropylmagnesium chloride; the reaction temperature for halogen-metal exchange and carboxylation reaction is -60-5°C.

[0021] In some embodiments, the metal organic reagent is Grignard reagent, the reaction temperature of halogen-metal exchange and carboxylation reaction is -10°C to 5°C, preferably -5°C to 5°C.

[0022] In some embodiments, in step two, the organic solvent used in halogen-metal exchange and carboxylation reaction is tetrahydrofuran, methyl tetrahydrofuran and cyclohexane mixture, n-hexane, toluene or methyl tert-butyl ether; preferably methyl tert-butyl ether.

[0023] In some embodiments, in step two, after the carbon dioxide is passed, the pH of the reaction system is adjusted to 1-3, the solid is precipitated, and the said polyhalogenated nicotinic acid compound is separated.

[0024] In some embodiments, in step two, the pH is adjusted to 1-3 using an aqueous acid solution; the aqueous acid solution is aqueous hydrochloric acid and / or aqueous sulfuric acid.

[0025] In view of the economic ring-closing route of nicotinic acid 15 (see EP0333020A3), the present application focuses on the study of 14 commercial polyhalogenated nicotinic acids in Table 2.

[0026] Table 2, 14 commercially available polyhalogenated nicotinic acids, precursor halides and raw materials From the structure, the raw material polyhalogenated pyridine listed in Table 2, because of the strong electron-withdrawing ability of pyridine N, combined with the high electronegativity of halogen atom, the electron cloud density on the pyridine ring is greatly reduced, so the conventional electrophilic halogenation reaction cannot be carried out, and the target bromide or iodide cannot be obtained. The present application screens the conditions for electrophilic bromination and iodination of polyhalogenated pyridine through systematic screening of electrophilic halogenation conditions, breaks through the direct bromination and iodination of polyhalogenated pyridine and introduces bromide or iodide into the synthesis of nicotinic acid, and successfully realizes the synthesis of the above-mentioned 14 kinds of polyhalogenated nicotinic acids. It is proved that by direct bromination or iodination of polyhalogenated pyridine, the corresponding bromide or iodide is obtained, and then the corresponding magnesium salt intermediate is produced by Grignard exchange with Grignard reagent, and then the corresponding nicotinic acid is prepared by reaction with carbon dioxide. The development of high-efficiency general synthesis method is of great importance to industrialization and social economic value.

[0027] In view of the market demand for polyhalogenated nicotinic acid, developing a general synthetic method of polyhalogenated nicotinic acid with high efficiency to achieve a suitable process for industrial amplification has important social value and economic value for the production of such compounds, and provides a guarantee for the production of downstream products and the industrial production and cost control of related drugs. The present application screens a series of electrophilic bromination and iodination reaction conditions, and finally selects the conditions capable of directly brominating and iodinating a series of polyhalogenated pyridine derivatives. From the literature research, there is no report on direct electrophilic halogenation of polyhalogenated pyridine, and there is no literature report on the synthesis of polyhalogenated nicotinic acid by combining the synthesis of polyhalogenated pyridine and M-X exchange. The present application breaks through the direct electrophilic halogenation of polyhalogenated pyridine, and combines the classical carboxyl construction method. From the traditional chemical knowledge, the present application adopts conventional and easy-to-control chemical reactions, which is suitable for further industrial production, and is a suitable method for preparing polyhalogenated nicotinic acid, and has certain universality. The method realizes the efficient electrophilic halogenation of polyhalogenated pyridine based on the activation of the electron-deficient pyridine ring by fluorine-containing solvent, and has the characteristics of general route, mild condition, and scalable production, and the product yield and purity are excellent.

[0028] The above description is only a summary of the technical scheme of the embodiments of the present application, in order to more clearly understand the technical method of the embodiments of the present application, and to be implemented according to the content of the specification, and in order to make the above and other purposes, characteristics and advantages of the embodiments of the present application more obvious and easy to understand, the specific embodiments of the present application are described below. BRIEF DESCRIPTION OF DRAWINGS

[0029] In order to more clearly illustrate the technical scheme of the embodiments of the present application, the drawings required by the embodiments of the present application will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creating any creative labor.

[0030] Figure 1 for intermediate 1-2 1 HNMR; Figure 2 for intermediate 1-3 1 HNMR; Figure 3 for intermediate 6-2 1 HNMR; Figure 4 for intermediate 12-2 1 HNMR; Figure 5 for intermediate 12-3 1 HNMR; Figure 6 for nicotinic acid 1 1 HNMR; Figure 7 for nicotinic acid 6 1 HNMR; Figure 8 for nicotinic acid 12 1 HNMR. DETAILED DESCRIPTION

[0031] In order to make the technical means, creative features, purposes and effects of the application easy to understand, the technical solutions in the embodiments of the application are described clearly and completely below in combination with specific drawings. Obviously, the described embodiments are part of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the application.

[0032] It should be understood that the structures, proportions, sizes, etc. shown in the drawings attached to the specification are only used to cooperate with the content disclosed in the specification for the understanding and reading of those skilled in the art, and do not have technical substantial significance to limit the implementation conditions of the application, so any modification of the structure, change of the proportion relationship or adjustment of the size, without affecting the effects and purposes that can be achieved by the application, should still fall within the scope of the technical content disclosed by the application.

[0033] The present inventors found that the synthesis of polyhalogenated nicotinic acid can generally use cyanolysis, methyl oxidation or alkali metal reagent method, etc. However, these methods use toxic reagents, strong oxidants, or require cryogenic conditions, and have problems such as high safety risk, difficulty in industrialization or poor universality. In known technologies, constructing a carboxyl group through metal exchange-carboxylation of an aromatic halide compound is an economical and ideal path, but due to the extremely strong electron deficiency of the polyhalogenated pyridine ring, the key bromine / iodine intermediate cannot be obtained by conventional electrophilic halogenation method, which has long hindered this ideal path. Therefore, the present application provides a synthesis method of polyhalogenated nicotinic acid compounds, which successfully realizes the direct electrophilic halogenation of polyhalogenated pyridine through a fluorine-containing solvent system, and further opens up this general and efficient synthesis route.

[0034] Example 1: Condition screening and optimization of electrophilic bromination reaction The present application first screens the conditions of direct electrophilic bromination and iodination of polyhalogenated pyridine, and selects compound 6-1 (2,3,6-trichloropyridine) and compound 12-1 (2,6-difluoropyridine) as template raw materials for reaction condition screening research.

[0035] The first round of using selected template raw materials, the conventional solvent screening, bromine reagent screening, found that under conventional conditions, no target product is generated. Speculation possible reason is the multi-halogenated pyridine (pyridine ring halogen atom ≥2) ring for electron-deficient structure, low electron cloud density, therefore the substrate activity is low, the conventional conditions can not be carried out to obtain the target product. The experimental results are shown in Table 3. Note: NBS is N-bromosuccinimide, Br2 is bromine, DBDMH is dibromo hydantoin, DMF is N,N-dimethylformamide, AcN is acetonitrile, NMP is N-methyl pyrrolidone, THF is tetrahydrofuran, DCM is dichloromethane, CS2 is carbon disulfide, CCl4 is carbon tetrachloride. 1.0 eq. represents 1.0 equivalent; 10 V indicates the amount is 10 times the volume of the raw material.

[0036] The second round of using selected template raw materials, the combination of solvent, bromination reagent and commonly used catalysts is screened, the results show that by using commonly used catalysts and solvent, the bromination reagent combination system is screened, no target product is obtained. Even under the condition of using sulfuric acid as solvent, no target product is obtained. The experimental results are shown in Table 4.

[0037] Table 4, the second round of electrophilic bromination condition screening results In the case of no ideal result in the combination screening of conventional solvent, bromination reagent and catalyst, considering the strong acidity of fluorine-containing solvent, such as hexafluoroisopropanol (HFIP) is significantly stronger than common alcohol (pKa<≈9.3, while ethanol pKa≈16), and it has the characteristics of strong hydrogen bond formation ability and stable charged transition state. The fluorine-containing solvent (HFIP, TFE-trifluoroethanol, TFA-trifluoroacetic acid) is specially selected for the third round of condition screening. The results show that the HFIP / TFA solvent combination or TFA as solvent can obtain a relatively good conversion rate of 86-93%, and successfully realize the direct bromination of template compounds 6-1 and 12-1. The experimental results are shown in Table 5.

[0038] Table 5, the third round of electrophilic bromination condition screening results *The product ratio is the HPLC peak area ratio.

[0039] Under the optimal reaction conditions (HFIP / TFA and TFA as solvent), the remaining corresponding raw materials are brominated, and the remaining 12 bromide intermediates 1-2, 2-2, 3-2, 4-2, 5-2, 7-2, 8-2, 9-2, 10-2, 11-2, 13-2, 14-2 are successfully obtained.

[0040] Example 2: Screening of electrophilic iodination conditions Based on the data of the third round, using starting compounds 6-1 and 12-1 as templates, the optimized bromination conditions were introduced into the evaluation of iodination conditions, and the iodination condition screening was carried out. The results showed that using compound 6-1 as the starting material, the target product was not obtained, while using compound 12-1 as the starting material, the conversion rate reached 65-73%. The reason why starting compound 6-1 did not obtain the target product is not clear, which may be related to the electron cloud density of the pyridine ring and steric hindrance. The experimental results are shown in Table 6.

[0041] Table 6: Screening results of electrophilic iodination conditions using compounds 6-1 and 12-1 as template starting materials Using the optimal reaction conditions (HFIP / TFA and TFA as solvent), iodination of the remaining corresponding starting materials was carried out, and 10 iodide intermediates, intermediates 1-3, 2-3, 3-3, 4-3, 5-3, 7-3, 9-3, 11-3, 12-3, 14-3 were successfully obtained. Intermediates 6-3, 8-3, 10-3 and 13-3 were not obtained by this method, which may be due to the combined reasons of substrate electron cloud density and steric hindrance.

[0042] Example 3: Screening of halogen-metal exchange reagents After successfully breaking through the bromination (obtaining 14 bromides) and iodination (obtaining 10 iodides) of the above 14 polyhalogenated pyridines, the intermediates bromide and iodide were respectively evaluated for nicotinic acid preparation, and the results showed that using Grignard exchange method, the target nicotinic acid could be obtained at conventional reaction temperature, avoiding the need for deep cold special equipment of alkali metal reagents (n-BuLi, LDA, etc.), improving the industrialization ability of the synthesis method. Using compounds 6-2 and 12-2 as template starting materials, the method evaluation and metal reagent screening results are shown in Table 7.

[0043] Table 7: Screening of halogen-metal exchange reagents The results showed that using isopropyl magnesium chloride (i-PrMgCl), isopropyl magnesium bromide (i-PrMgBr), n-butyl magnesium bromide (n-BuMgBr), n-butyl magnesium chloride (n-BuMgCl) and other Grignard reagents, the reaction could be efficiently completed at mild temperature of-10℃ to 0℃, with yield better than or equivalent to that of n-butyllithium at-65℃ deep cold condition, greatly improving the industrialization feasibility of the method.

[0044] Example 4: Preparation of intermediate 1-2 (laboratory synthesis) Compound 1-1 (10 g) was dissolved in hexafluoroisopropanol (80 g), and trifluoroacetic acid (3.9 g, 0.5 eq.) was added, to which dibromohydantoin (15.5 g, 0.8 eq.) was added, and the reaction was controlled at 60-65 °C until the reaction was complete by HPLC detection. The reaction solution was concentrated and dropped into 20% potassium hydroxide solution until the pH was 9-10, extracted twice with dichloromethane, and the organic phase was combined and concentrated to obtain a crude product, which was recrystallized with ethyl acetate / n-hexane (20 mL, 1:10, V / V), and after drying, 13.83 g of a white solid was obtained, with a purity of ~97%, and a yield of 90.2%. 1 H-NMR (400 MHz, DMSO-d6): δ ppm 8.3 (d,1H), 7.5 (d, 1H), see Figure 1 .

[0045] Example 5: Preparation of intermediate 1-2 (laboratory synthesis) Compound 1-1 (10 g) was dissolved in trifluoroacetic acid (74.5 g), and dibromohydantoin (15.5 g, 0.8 eq.) was added, and the reaction was controlled at 50-55 °C until the reaction was complete by HPLC detection. The reaction solution was concentrated and dropped into 20% potassium hydroxide solution until the pH was 9-10, extracted twice with dichloromethane, and the organic phase was combined and concentrated to obtain a crude product, which was recrystallized with ethyl acetate / n-hexane (22 mL, 1:10, V / V), and after drying, 13.95 g of a white solid was obtained, with a purity of ~97%, and a yield of about 91%.

[0046] After market research, the price of hexafluoroisopropanol is higher than that of trifluoroacetic acid, so trifluoroacetic acid is used as the solvent for production.

[0047] Example 6: Preparation of intermediate 1-2 (factory production) Compound 1-1 (200 kg) and trifluoroacetic acid (1490 kg) and dibromohydantoin (309 kg, 0.8 eq.) were added to a 2000 L porcelain-lined reaction kettle. The temperature of the reaction kettle was controlled at 50-55 °C, and the reaction was kept until the reaction was complete by HPLC detection, about 28 h.

[0048] Reduce the temperature of the reaction solution to 20-30℃ and concentrate it under reduced pressure to approximately 400-600 L. Maintain the temperature at 20-30℃, and add the remaining concentrate dropwise to a 20% potassium hydroxide aqueous solution (1000 kg). Add dichloromethane (1300 kg) to the reactor for extraction, and collect the organic phase. Extract the aqueous phase once with dichloromethane (1300 kg). Combine the organic phases, wash once with water (500 kg), and collect the organic phase. Concentrate the organic phase under reduced pressure until almost no liquid flows out. Add n-heptane (272 kg) and ethyl acetate (36 kg) to the reactor. While stirring, raise the temperature of the reactor to 50-60℃ until the system dissolves and becomes clear. Cool the system to a programmed temperature of 10-15℃ with a cooling gradient of 5℃ / h. Continue to maintain the system at 10-15℃ with stirring for 4-5 h. Centrifuge to obtain the wet product. Dry the wet product under vacuum at 45-50℃ for 12 h. The product was discharged, yielding 277.6 kg of off-white product with a purity of 97.3% and a yield of 90.5%.

[0049] Example 7: Preparation of intermediates 1-3 10 g of 2,6-dichloropyridine was dissolved in 74.5 g of trifluoroacetic acid, and 16.7 g of N-iodosuccinimide (1.1 eq.) was added. The reaction was carried out at 60-65 °C until complete as detected by HPLC. The reaction solution was concentrated and added dropwise to 50 g of 20% potassium hydroxide aqueous solution. The solution was extracted twice with dichloromethane, 50 mL each time. The organic phases were combined and washed once with 50 mL of water. The organic phase was concentrated under reduced pressure until almost no liquid flowed out. Cyclohexane (40 mL) was added for recrystallization. After drying, 15.7 g of the target product was obtained as a pale yellow solid with a purity of 97.6% and a yield of 85%. 1 H-NMR (400 MHz, DMSO-d6): δ ppm 8.40 (d, 1H), 7.35 (d, 1H), see Figure 2 .

[0050] Example 8: Preparation of intermediate 6-2 (laboratory synthesis) Dissolve compound 6-1 (10 g) in trifluoroacetic acid (74.5 g). Add dibromohydantoin (12.5 g, 0.8 eq.) to the reaction flask and control the temperature at 70-75 °C until the reaction is complete by HPLC. Cool the reaction to 20-25 °C and concentrate under reduced pressure until substantially no liquid distillate is coming over. Control the temperature at 20-30 °C and add the concentrated residue dropwise to 20% aqueous potassium hydroxide (50 mL). Extract the system twice with dichloromethane (50 mL). Combine the organic phases and wash once with water (50 mL). Concentrate the organic phase until substantially no liquid distillate is coming over and crystallize the concentrated residue with methyl tert-butyl ether (5 mL) and n-heptane (20 mL) to give the product 12.7 g in 89% yield and 98.3% purity. 1 H-NMR (400 MHz, DMSO-d6): δ ppm 8.72 (s, 1H), see Figure 3 .

[0051] Example 9: Preparation of intermediate 6-2 (manufacturing scale) Add compound 6-1 (250 kg, 1.0 eq.), trifluoroacetic acid (1865 kg), and dibromohydantoin (313 kg, 0.8 eq.) to a 2000 L glass-lined reaction kettle. Control the temperature of the reaction kettle at 75-80 °C and maintain the reaction until complete by HPLC, which takes about 32 h for the production reaction.

[0052] Cool the reaction to 20-30 °C and concentrate the reaction until substantially 500-700 L. Control the temperature at 20-30 °C and add the concentrated residue dropwise to 20% aqueous potassium hydroxide (1200 kg). Extract the reaction with dichloromethane (1500 kg) and collect the organic phase. Extract the aqueous phase once with dichloromethane (1500 kg). Combine the organic phases and wash once with water (800 kg). Collect the organic phase and concentrate under reduced pressure until substantially no liquid distillate is coming over. Add n-heptane (340 kg) and methyl tert-butyl ether (92 kg) to the reaction kettle. While stirring, warm the reaction kettle to 50-60 °C and dissolve the system. Program the system to cool to 10-15 °C at a rate of 5 °C / h. Continue to control the system at 10-15 °C and maintain stirring for 4-5 h. Centrifuge to give the wet product. Dry the wet product under vacuum at 45-50 °C for 12 h. Discharge to give 315 kg of the product as a white solid in 98.5% purity and 88% yield.

[0053] Example 10: General method for the preparation of a series of bromide intermediates Intermediates 2-2, 3-2, 4-2, 5-2, 6-2, 7-2, 8-2, 9-2, 10-2, 11-2, 12-2, 13-2, 14-2 were synthesized according to the procedure described for Intermediate 1-2 (Example 5). The data for the bromide intermediates are summarized in Table 8.

[0054] Table 8, data for bromide intermediates and 1 HNMR data Note: *HNMR data for Intermediate 12-2 1 HNMR data Figure 4 .

[0055] Example 11: General procedure for the preparation of a series of iodide intermediates Intermediates 2-3, 3-3, 4-3, 5-3, 6-3, 7-3, 8-3, 9-3, 10-3, 11-3, 12-3, 13-3, 14-3 were synthesized according to the procedure described for Intermediate 1-3 (Example 7). The data are summarized in Table 9.

[0056] Table 9, data for iodide intermediates and 1 HNMR data Note: *HNMR data for Intermediate 12-3 1 HNMR data Figure 5 .

[0057] Example 12: Preparation of nicotinic acid 1 (using Intermediate 1-2 as starting material) Intermediate 1-2 (100 g) was dissolved in tetrahydrofuran (650 mL). The system was replaced with nitrogen for three times, and then cooled to -5-5 °C. Isopropyl magnesium chloride (245 mL, 2M in tetrahydrofuran, 1.1 eq.) was added dropwise at -5-10 °C. The reaction was kept at -5-5 °C until it was completed by HPLC. Carbon dioxide was bubbled into the reaction at -5-5 °C until it was completed by HPLC. 4N hydrochloric acid (400 mL) was added dropwise into the reaction. The system was concentrated under reduced pressure until no distillate was observed. 30% potassium hydroxide aqueous solution was added to adjust the pH to 9-10 at 20-30 °C (about 500 mL was used). The system was extracted with ethyl acetate (500 mL) once. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid. White solid was precipitated. The mixture was stirred for 1-2 h, and then filtered to give 2,6-dichloronicotinic acid as a crude product. The crude product was dissolved in a mixture of ethanol (50 mL) and water (500 mL) at 50-60 °C. The system was cooled to 10-15 °C. The mixture was stirred for 1-2 h, and then filtered to give 72 g of the product as a white solid with purity >99% and yield 84%. 1 HNMR (400 MHz, CD3OD) δ ppm, 7.52 (d, 1H), 8.27 (d, 1H), see Figure 6 .

[0058] Example 13: Preparation of nicotinic acid 1 (using intermediate 1-3 as the starting material) Compound 1-3 (10 g) was dissolved in tetrahydrofuran (65 mL). The system was replaced with nitrogen for three times, and then cooled to -15-5 °C. Isopropyl magnesium chloride (20 mL, 2M in tetrahydrofuran, 1.1 eq.) was added dropwise at -10-5 °C. The reaction was kept at -5-5 °C until it was completed by HPLC. Carbon dioxide was bubbled into the reaction at -5-5 °C until it was completed by HPLC. The reaction was quenched by adding 4N hydrochloric acid until the pH was 4-5. The system was concentrated under reduced pressure until no distillate was observed. 30% potassium hydroxide aqueous solution was added to adjust the pH to 9-10. The system was extracted with ethyl acetate (1000 mL*2) twice. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid. White solid was precipitated. The mixture was stirred for 1-2 h, and then filtered to give 2,6-dichloronicotinic acid as a crude product. The crude product was purified by the same method to give 5.6 g of the product with purity >99% and yield 80%.

[0059] Example 14: Preparation of nicotinic acid 1 (on a factory scale) Into a 2000 L reaction kettle, add compound 1-2 (150 kg), tetrahydrofuran (860 kg, KF < 200 ppm). Replace the reaction kettle with nitrogen for 3 times. Cool down to -5-5 °C under nitrogen protection. Control the temperature at -5-10 °C, and drop isopropyl magnesium chloride (360 kg, 2M tetrahydrofuran solution, 1.1 eq.) into the reaction. Keep the temperature at -5-10 °C, and react until the reaction is complete by HPLC detection. Control the temperature at -5-5 °C, and bubble carbon dioxide gas (290 kg, 10 eq.) into the reaction for 5-6 h. Control the temperature at -5-5 °C, and keep the reaction until the reaction is complete by HPLC detection. Drop 4N hydrochloric acid (600 kg) into the reaction. Concentrate the system under reduced pressure until there is basically no distillate. Control the temperature at 20-30 °C, and add 30% potassium hydroxide aqueous solution (750 kg) into the system, and the pH of the system is > 9. Add ethyl acetate (750 kg) into the reaction kettle to extract the impurities once. Control the temperature at 5-15 °C, and adjust the pH of the water phase to 1-2 with concentrated hydrochloric acid (120 kg), and a large amount of white solid is precipitated. Control the temperature at 5-15 °C, and keep stirring for 1-2 h, and centrifuge to obtain the crude product. Add the crude product into the reaction kettle, and add ethanol (60 kg) and water (750 kg) into the system, and heat the system to 50-60 °C, and stir for 1 h, and the system is dissolved and clear. Program the system to cool down to 10-15 °C, and the cooling rate is ~ 5 °C / h. Keep the temperature at 10-15 °C, and continue to stir for 5-6 h, and centrifuge. Dry the centrifugation filter cake at 50-60 °C under vacuum for 24 h to obtain white product 112.5 kg, the yield is 99.8%, and the yield is 88%.

[0060] Example 15: Preparation of nicotinic acid 6 (using intermediate 6-2 as raw material) Compound 6-2 (100 g) was dissolved in tetrahydrofuran (650 mL). Nitrogen was replaced for three times, temperature was controlled at -5-5 ℃, isopropyl magnesium chloride (210 mL, 2M tetrahydrofuran solution, 1.1 eq.) was added dropwise, reaction was kept at -5-5 ℃ until the reaction was completed by HPLC detection. Carbon dioxide gas was bubbled into the reaction (100 g scale, about 1 h for bubbling). Reaction was kept at -5-5 ℃ until the reaction was completed by HPLC detection. 4N hydrochloric acid (400 mL) was added dropwise into the reaction. The system was concentrated under reduced pressure until there was no distillate. Temperature was controlled at 20-30 ℃, 30% potassium hydroxide aqueous solution was added to adjust pH to 9-10 (about ~ 500 mL). The system was extracted with ethyl acetate (500 mL) once. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid, white solid was precipitated, stirred for 1-2 h, filtered to obtain 2,6-dichloronicotinic acid crude product. The crude product was added to a solution of ethanol (50 mL) and water (500 mL), heated to 50-60 ℃, the system was dissolved and clear. The system was cooled to 10-15 ℃, stirred for 1-2 h, filtered and dried to obtain 75.4 g of white solid product, purity greater than 99%, yield 87%; 1 HNMR (400 MHz, DMSO-d6) δ ppm 14.26 (br s, 1H),8.53(s, 1H), see Figure 7 .

[0061] Example 16: Preparation of nicotinic acid 6 (plant scale) Into a 3000 L reaction kettle, compound 1-2 (250 kg), tetrahydrofuran (1125 kg, KF < 200 ppm) were added. The reaction kettle was replaced with nitrogen for 3 times. The temperature was lowered to -5-5°C under nitrogen protection. The temperature was controlled at -5-10°C, and isopropyl magnesium chloride (525 kg, 2M tetrahydrofuran solution, 1.1 eq.) was added dropwise. The reaction was kept at -5-10°C until the reaction was completed by HPLC detection. Carbon dioxide gas (420 kg, 10 eq.) was introduced into the reaction at a temperature of -5-5°C. The time for introducing carbon dioxide in a single batch was about 7-8 h. The reaction was kept at a temperature of -5-5°C until the reaction was completed by HPLC detection. 4N hydrochloric acid (1000 kg) was added dropwise to the reaction solution. The system was concentrated under reduced pressure until there was basically no distillate. The temperature was controlled at 20-30°C, and 30% potassium hydroxide aqueous solution (1250 kg) was added, and the pH of the system was > 9. Ethyl acetate (1250 kg) was added to the reaction kettle to extract the impurities once. The temperature was controlled at 5-15°C, and the pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid (240 Kg), and a large amount of white solid was precipitated. The temperature was controlled at 5-15°C, and the stirring was kept for 1-2 h, and the centrifugation was performed to obtain the crude product. The crude product was added to the reaction kettle, and acetone (125 kg) and water (1250 kg) were added. The system was heated to 60-70°C, stirred for 1 h, and the system was dissolved and clarified. The system was programmed to cool to 10-15°C at a rate of ~ 5°C / h. The temperature was kept at 10-15°C, and the stirring was continued for 5-6 h, and the centrifugation was performed. The centrifugation filter cake was dried at 50-60°C under vacuum for 24 h to obtain white product 182 kg, purity 99.85%, yield 84%.

[0062] Example 17: Synthesis summary of the remaining nicotinic acid The synthesis summary data of the remaining nicotinic acid are shown in Table 10.

[0063] Table 10, synthesis data of polyhalogenated nicotinic acid Note: *nicotinic acid 12 1 HNMR, see Figure 8 .

[0064] In summary, the synthesis method of the polyhalogenated nicotinic acid compound provided by the present application can realize universal and efficient preparation in the synthesis of various drug intermediates. The raw materials and reagents of the method are sufficient in the market, low in cost, simple in route steps, and mild and controllable in reaction conditions. In drug research and production, the method can stably guarantee the supply of series of high-value polyhalogenated nicotinic acid, which has important practical significance for reducing the cost of raw drugs and accelerating the development of innovative drugs.

[0065] Those skilled in the art will clearly understand that, for the sake of convenience and brevity, the detailed process of the specific operation steps in the above embodiments has been specifically described in the method description, and will not be repeated here.

[0066] In the embodiments provided by this invention, it should be understood that the disclosed synthesis method can be implemented in other ways. For example, the process parameters such as reaction temperature, reaction time, and material equivalence ratio described in the embodiments are only exemplary ranges, and can be adaptively adjusted according to the specific substrate reactivity and the purity requirements of the target product in actual applications; for example, the fluorinated solvents hexafluoroisopropanol and trifluoroacetic acid can be replaced with other fluorinated media with similar acidity and solvation ability, and the Grignard reagent isopropyl magnesium chloride can be replaced with other alkyl Grignard reagents or aryl Grignard reagents. These equivalent substitutions or modifications based on the core principles of this invention should not be considered as departing from the essence and protection scope of this invention.

[0067] The operational steps involved in the above embodiments can be implemented individually, or they can be combined or separated according to experimental needs. Some or all of the steps can be selected to achieve the technical effects of the present invention based on actual sample processing requirements.

[0068] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions such as parameter adjustments and equivalent equipment replacements that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for synthesizing polyhalogenated nicotinic acid compounds, characterized in that, The polyhalogenated nicotinic acid compound is a compound of formula I; the synthetic route of the synthetic method is as follows: Among them, R1, R2, R3, and R4 are independently H, Cl, Br, or F, and more than two of R1, R2, R3, and R4 are halogens; X is Br or I; M is Mg or Li; The synthesis method includes the following steps: Step 1: Electrophilic halogenation reaction: In a fluorine-containing solvent, the compound of formula II is subjected to an electrophilic halogenation reaction to obtain the compound of formula III; Step 2: Halogen-metal exchange and carboxylation reaction: Compound III undergoes halogen-metal exchange reaction under the action of organometallic reagent to obtain compound IV; carbon dioxide is introduced into compound IV to carry out carboxylation reaction to obtain the polyhalogenated nicotinic acid compound.

2. The method according to claim 1, characterized in that, In step one, the fluorinated solvent is selected from one or more combinations of hexafluoroisopropanol, trifluoroethanol, and trifluoroacetic acid; the fluorinated solvent is preferably a combination of hexafluoroisopropanol and trifluoroacetic acid, or trifluoroacetic acid.

3. The method according to claim 1, characterized in that, The compound of formula I is selected from the following 14: Where X is Br.

4. The method according to claim 1, characterized in that, The compound of formula I is selected from the following 10: 。 5. The method according to claim 1, characterized in that, In step one, the reagent that undergoes the electrophilic halogenation reaction with the compound of formula II is selected from one or more of bromine, dibromohydantoin, N-bromosuccinimide, N-iodosuccinimide, elemental iodine, and iodine chloride.

6. The method according to claim 1, characterized in that, In step one, the electrophilic halogenation reaction is carried out at a temperature of 40°C to 100°C, preferably at a temperature of 50°C to 75°C.

7. The method according to claim 1, characterized in that, In step two, the organometallic reagent is selected from one or more of methyl lithium, butyl lithium, n-hexyl lithium, sec-butyl lithium, phenyl lithium, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium bromide, n-butyl magnesium chloride, and isopropyl magnesium chloride-lithium chloride; the reaction temperature of the halogen-metal exchange and carboxylation reaction is -60℃ to 5℃.

8. The method according to claim 1, characterized in that, The organometallic reagent is selected from Grignard reagents, and the reaction temperature for halogen-metal exchange and carboxylation is -10℃ to 5℃, preferably -5℃ to 0℃.

9. The method according to claim 1, characterized in that, In step two, the organic solvents used for the halogen-metal exchange and carboxylation reactions are tetrahydrofuran, a mixture of methyltetrahydrofuran and cyclohexane, n-hexane, toluene, or methyl tert-butyl ether.

10. The method according to any one of claims 1 to 8, characterized in that, In step two, carbon dioxide is introduced to adjust the pH of the reaction system to 1-3, and a solid is precipitated, from which the polyhalogenated nicotinic acid compounds are obtained.

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