A preparation method of pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester

Abstract

The invention discloses a preparation method of a pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, belongs to the field of organic synthesis technology, using 2-halogenated-4,6-dimethoxypyrimidine as raw material, preparing intermediate 4,6-dimethoxy-2-pyrimidinecarboxylic acid methyl ester through carbonylation reaction, then achieving ether bond cleavage and chlorination under the conditions of phenyl dichlorophosphate to obtain 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester. In this synthetic method, starting raw materials are cheap and easy to obtain, and intermediates are prepared by conventional carbonylation reaction, without the need for low-temperature operation, simple reaction, and easy operation; pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester is finally obtained with short steps, simple operation, low cost, and relatively mild reaction conditions, and the product yield is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester. Background Art

[0002] Pyrimidines are an important class of nitrogen-containing heterocyclic compounds, widely present in the human body and other organisms. For example, three of the five most common nitrogen-containing basic components in nucleic acids contain pyrimidine structures: uracil, cytosine, and thymine. Numerous studies have demonstrated that pyrimidine compounds possess insecticidal, fungicidal, herbicidal, antiviral, and anticancer biological activities. For example, 5-fluorouracil, a widely used antimetabolite and antitumor drug, inhibits various tumors. Pyrrolo[2,3-d]pyrimidine compounds, as immunosuppressants, can be used to treat organ transplantation, type 1 diabetes and diabetic complications, cancer, asthma, and other autoimmune diseases. Ethylpyrimidine and dimethomorph, as fungicides, can control powdery mildew in crops. The insecticides fenazaquin, pyrimidine, and pyrimidinecarb exhibit insecticidal activity.

[0003] The pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester is an important pharmaceutical and pesticide intermediate with potential applications in these fields. Developing a synthesis method for this compound is of considerable significance. While no methods for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester have been reported in the prior art, the preparation of its precursor, 4,6-dichloro-2-pyrimidinecarboxylic acid, has been reported. Literature reports that a vinyl lithium reagent, formed by tetravinyltin and n-butyllithium, attacks 4,6-dichloropyrimidine to form 4,6-dichloro-2-vinylpyrimidine. The double bond is then ozonolytically decomposed to produce 4,6-dichloropyrimidine-2-carboxaldehyde, which is then oxidized to produce 4,6-dichloro-2-pyrimidinecarboxylic acid. This method uses expensive tetravinyltin reagents and has low atom utilization. Furthermore, the ozonolytic decomposition process is not suitable for industrial production. In addition, there is also patent CN113767925 that uses 4,6-dichloro-2-methylpyrimidine as a raw material to directly oxidize the methyl group to prepare carboxylic acid, but the methyl group oxidation in this method is difficult and the yield is low.

[0004] In summary, the existing preparation method of methyl oxidation is difficult and the yield is low. In view of the above problems, the existing method needs to be improved. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing a pyrimidine derivative, 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, so as to solve the problems of difficulty in methyl oxidation and low yield proposed in the above background technology.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, a pyrimidine derivative, using 2-halogenated-4,6-dimethoxypyrimidine as a raw material, and preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester through a two-step conversion. The specific route is as follows:

[0007]

[0008] Furthermore, the following experimental steps are included:

[0009] (1) Compound 1 (2-halogenated-4,6-dimethoxypyrimidine) is dissolved in methanol, and then a base and a catalyst are added. Carbon monoxide is introduced, and the mixture is heated to 90-150°C and stirred for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2.

[0010] (2) Compound 2 is dissolved in an organic solvent 1, and then phenyl dichlorophosphate and concentrated hydrochloric acid are added. The mixture is heated to 100-180°C and stirred for 1-7 days. After the reaction is completed, the reaction solution is post-treated to obtain compound 3 (methyl 4,6-dichloro-2-pyrimidinecarboxylate).

[0011] Furthermore, in step (1), compound 1 is one of 2-bromo-4,6-dimethoxypyrimidine, 2-iodo-4,6-dimethoxypyrimidine, and 2-chloro-4,6-dimethoxypyrimidine.

[0012] Furthermore, in step (1), the base is one or more of triethylamine, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, and potassium phosphate.

[0013] Furthermore, in step (1), the catalyst is one or more of palladium acetate (Pd(OAc)2), bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), and palladium dichloride (PdCl2).

[0014] Furthermore, in step (1), the mass volume ratio of compound 1 to solvent methanol is 1:(5-40) g / mL;

[0015] The molar ratio of compound 1 to base is 1:(1-5);

[0016] The molar ratio of compound 1 to the catalyst is 1:(0.01-0.05).

[0017] Furthermore, in step (1), the post-treatment is to cool the reaction solution, flush it into water, extract it twice with an organic solvent, combine the organic phases, wash the organic phases, dry them, and concentrate them to obtain a crude product, which is purified to obtain compound 2.

[0018] Furthermore, in step (1), the second organic solvent is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0019] Furthermore, in step (1), the purification method includes one or more of column chromatography, recrystallization, and distillation.

[0020] Furthermore, in step (2), the organic solvent is one or more of toluene, dioxane, phenyl dichlorophosphate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0021] Furthermore, in step (2),

[0022] The mass volume ratio of compound 2 to solvent methanol is 1:(5-40) g / mL;

[0023] The mass volume ratio of compound 2 to concentrated hydrochloric acid (mass fraction 37%) is 1:(0.4-1.0) g / mL;

[0024] The molar ratio of compound 2 to phenyl dichlorophosphate is 1:1-10.

[0025] Furthermore, in step (2), the post-treatment is to cool the reaction solution, pour it into ice water, stir it for 1-5 hours, extract it three times with an organic solvent, combine the organic phases, wash the organic phases with an alkaline aqueous solution, dry it, and concentrate it to obtain a crude product, which is purified to obtain the target compound 3.

[0026] Furthermore, in step (2), the third organic solvent is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0027] Furthermore, in step (2), the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, and potassium hydroxide solution;

[0028] Furthermore, in step (2), the purification method includes one or more of column chromatography, recrystallization, and distillation.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention provides a method for preparing the pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester. Using 2-halogenated-4,6-dimethoxypyrimidine as the starting material, 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester is prepared through a two-step conversion. In this synthesis method, the starting material is inexpensive and readily available. The intermediate is prepared through a conventional carbonyl insertion reaction, which does not require low-temperature operation, resulting in a simple reaction and easy operation. Ultimately, the pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester is prepared in a short process, simple operation, low cost, and relatively mild reaction conditions, with a high product yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The hydrogen nuclear magnetic spectrum of 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester of the present invention is shown in FIG. DETAILED DESCRIPTION

[0032] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0033] A method for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, a pyrimidine derivative, uses 2-halogenated-4,6-dimethoxypyrimidine as a raw material and obtains 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester through a two-step conversion. The specific route is as follows:

[0034]

[0035] Furthermore, it includes the following experimental steps:

[0036] (1) Compound 1 (2-halogenated-4,6-dimethoxypyrimidine) is dissolved in methanol, and then a base and a catalyst are added. Carbon monoxide is introduced, and the mixture is heated to 90-150°C and stirred for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2.

[0037] (2) Compound 2 is dissolved in an organic solvent 1, and then phenyl dichlorophosphate and concentrated hydrochloric acid are added. The mixture is heated to 100-180°C and stirred for 1-7 days. After the reaction is completed, the reaction solution is post-treated to obtain compound 3.

[0038] The synthesis method provided by the present invention has the advantages of relatively mild reaction conditions, high yield, low cost, etc., and can be used to prepare compounds with specific structures.

[0039] In the following examples, unless otherwise specified, all reagents used are commercially available reagents, and all detection methods and means used are conventional detection methods and means in the art.

[0040] Example 1

[0041] A method for preparing methyl 4,6-dichloro-2-pyrimidinecarboxylate, the synthetic route is as follows:

[0042]

[0043] The specific steps are:

[0044] (1) Compound 1a (200.00 g, 1.15 molmol, 1.00 eq) was dissolved in methanol (2000 mL), and potassium acetate (337.29 g, 3.44 mol, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (25.15 g, 34.37 mmol, 0.03 eq) were added. Carbon monoxide was introduced, and the mixture was purged three times. The mixture was heated to 130°C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled, poured into water (4000 mL), and extracted three times with ethyl acetate (2000 mL*3). The organic phases were combined, washed once with water (4000 mL) and saturated brine (4000 mL), dried, and concentrated to obtain a crude product. The crude product was slurried with petroleum ether for 30 minutes to obtain compound 2 (weight 195 g, purity 98%, yield 84%).

[0045] (2) Phenyl dichlorophosphate (1.04 kg, 4.92 mol, 5.00 eq) was added to compound 2 (195.00 g, 983.96 mmol, 1.0 eq), and 37% concentrated hydrochloric acid (97.5 mL) was added. The mixture was heated under reflux at 150°C for 2 days. After the reaction was completed, the reaction solution was cooled, poured into ice water (2000 mL), stirred for 2 h, and extracted three times with ethyl acetate (1500 mL*3). The organic phases were combined, washed once with saturated sodium bicarbonate aqueous solution, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound 3 (weight 171.00 g, purity 98%, yield 82%).

[0046] The H NMR spectrum of the obtained compound 3 is as follows Figure 1 The obtained characterization data are as follows:

[0047] 1 H NMR (400MHz, cdcl3) δ7.59 (s, 1H), 4.06 (s, 3H).

[0048] Example 2

[0049] A method for preparing methyl 4,6-dichloro-2-pyrimidinecarboxylate, the synthetic route is as follows:

[0050]

[0051] The specific steps are:

[0052] (1) Compound 1b (200.00 g, 913.08 mmol, 1.00 eq) was dissolved in methanol (2000 mL), and potassium acetate (268.84 g, 2.74 mol, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (20.04 g, 27.39 mmol, 0.03 eq) were added. Carbon monoxide was introduced, and the mixture was purged three times. The mixture was heated to 130°C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled, poured into water (4000 mL), and extracted three times with ethyl acetate (2000 mL*3). The organic phases were combined, washed once with water (4000 mL) and saturated brine (4000 mL), dried, concentrated, and beaten with petroleum ether for 30 minutes to obtain compound 2 (weight 157.30 g, purity 98%, yield 85%).

[0053] (2) Phenyl dichlorophosphate (798.44 g, 3.78 mol, 5.00 eq) was added to compound 2 (150.00 g, 756.90 mmol, 1.0 eq), and 37% concentrated hydrochloric acid (75.0 mL) was added. The mixture was heated under reflux at 150°C for 2 days. After the reaction was completed, the reaction solution was cooled, poured into ice water (2000 mL), stirred for 2 h, and extracted three times with ethyl acetate (1500 mL*3). The organic phases were combined, washed once with saturated sodium bicarbonate aqueous solution, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound 3 (weight 131.20 g, purity 98%, yield 82%).

[0054] The H NMR spectrum of the obtained compound 3 is as follows Figure 1 The obtained characterization data are as follows:

[0055] 1 H NMR (400MHz, cdcl3) δ7.59 (s, 1H), 4.06 (s, 3H).

[0056] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, a pyrimidine derivative, characterized by: Using 2-halogenated-4,6-dimethoxypyrimidine as raw material, 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester is prepared through two-step conversion. The specific route is as follows: ； The following steps are involved: (1) Compound 1 is dissolved in methanol, and then a base and a catalyst are added, and carbon monoxide is introduced, and the mixture is heated to 90-150° C. and stirred for reaction for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2; (2) Compound 2 is dissolved in an organic solvent 1, and then phenyl dichlorophosphate and concentrated hydrochloric acid are added, heated to 100-180°C, and stirred for reaction for 1-7 days. After the reaction is completed, the reaction solution is post-treated to obtain compound 3; In step (1), the base is one or more of triethylamine, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, and potassium phosphate; In step (1), the catalyst is one or more of palladium acetate (Pd(OAc)2), bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), and palladium dichloride (PdCl2); The X is a halogen.

2. The method for preparing a pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester according to claim 1, characterized in that: In step (1), compound 1 is one of 2-bromo-4,6-dimethoxypyrimidine, 2-iodo-4,6-dimethoxypyrimidine, and 2-chloro-4,6-dimethoxypyrimidine.

3. The method for preparing a pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester according to claim 1, characterized in that: In step (1), the mass volume ratio of compound 1 to solvent methanol is 1:(5-40) g / mL; The molar ratio of compound 1 to base is 1:(1-5); The molar ratio of the compound to the catalyst is 1:(0.01-0.05).

4. The method for preparing a pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester according to claim 1, characterized in that: In step (1), the post-treatment is to cool the reaction solution, flush it into water, extract it twice with an organic solvent, combine the organic phases, wash the organic phases, dry them, and concentrate them to obtain a crude product, which is purified to obtain compound 2.

5. The method for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, a pyrimidine derivative, according to claim 4, characterized in that: In step (1), the second organic solvent is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane; Purification methods include one or more of column chromatography, recrystallization, and distillation.

6. The method for preparing a pyrimidine derivative 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester according to claim 1, characterized in that: In step (2), the organic solvent is one or more of toluene, dioxane, phenyl dichlorophosphate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide; The mass volume ratio of compound 2 to solvent methanol is 1:(5-40) g / mL; The mass volume ratio of compound 2 to concentrated hydrochloric acid is 1:(0.4-1.0) g / mL, and the mass fraction of the concentrated hydrochloric acid is 37%; The molar ratio of compound 2 to phenyl dichlorophosphate is 1:1-10; The post-treatment is to cool the reaction solution, pour it into ice water, stir it for 1-5 hours, extract it three times with an organic solvent, combine the organic phases, wash the organic phases with an alkaline aqueous solution, dry it, and concentrate it to obtain a crude product, which is purified to obtain the target compound 3.

7. The method for preparing 4,6-dichloro-2-pyrimidinecarboxylic acid methyl ester, a pyrimidine derivative, according to claim 6, characterized in that: In step (2), the organic solvent three is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane; Purification methods include one or more of column chromatography, recrystallization, and distillation.

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