Rapid synthesis method of polysubstituted pyrimidine carboxylic acid compound
Through the 4-step rapid synthesis method, Grignard reaction, Suzuki reaction, sodium hydroxide saponification reaction and hydroiodic acid reaction were used to solve the problems of long routes and complex separation and purification in the synthesis of multi-substituted pyrimidine carboxylic acid compounds, and an efficient, safe and environmentally friendly synthesis process was achieved, which facilitates industrial production and subsequent derivatization.
Patent Information
- Application Number
- CN202411698169.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-26
- Publication Date
- 2025-03-11
AI Technical Summary
The existing synthesis process of multi-substituted pyrimidine carboxylic acid compounds has problems such as long routes, complex separation and purification, and high safety and environmental pressure, which is difficult to meet the needs of expanding production capacity and industrial production.
A 4-step rapid synthesis method was adopted, including Grignard reaction, Suzuki reaction, sodium hydroxide saponification reaction and hydroiodic acid reaction. Using mild conditions and high atomic utilization, tetrahydrofuran and N,N-dimethylformamide were used as solvents and media to achieve efficient conversion of intermediates.
The efficient synthesis of multi-substituted pyrimidine carboxylic acid compounds has been achieved, the process route has been simplified, the safety and environmental protection have been improved, industrial production has been facilitated, and important pharmaceutical and chemical blocks have been provided for subsequent derivatization.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, in particular to a rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound. Background Art
[0002] Polysubstituted pyrimidinecarboxylic acid derivatives are important pharmaceutical and chemical intermediates used to synthesize anti-tumor drugs, and their downstream products are various kinase inhibitors, etc. The demand for polysubstituted pyrimidinecarboxylic acid compounds and their derivatives is increasing year by year, but due to the constraints of safety and environmental protection, the production capacity cannot be expanded, and there are problems such as long routes and complex separation and purification.
[0003] Based on this, the present invention provides a method for rapidly synthesizing a polysubstituted pyrimidinecarboxylic acid compound to solve the above-mentioned technical problems. Summary of the invention
[0004] The purpose of the present invention is to provide a rapid synthesis method for polysubstituted pyrimidine carboxylic acid compounds. The provided method should only require 4 steps, with mild conditions and high atomic utilization, making the route safer, more environmentally friendly, and convenient for industrial production. It can also be used as an important pharmaceutical and chemical building block for subsequent derivatization.
[0005] To achieve the above object, the present invention provides the following technical solutions:
[0006] The present invention provides a method for rapidly synthesizing a polysubstituted pyrimidinecarboxylic acid compound, comprising the following steps:
[0007] S1. Add the first solution dropwise to the second solution at 0°C, and keep the temperature to react for 1.5h to obtain intermediate 1;
[0008] S2, dispersing the reaction product, palladium catalyst and cyanide source in N,N-dimethylformamide, heating to 100°C under nitrogen protection for 10 to 12 hours to obtain intermediate 2;
[0009] S3, dissolving the intermediate 2 with ethanol aqueous solution, adding sodium hydroxide to the reaction, and heating the reaction. After the reaction is completed, cool the reaction to room temperature, adjust the pH to acidic with saturated sodium bisulfate solution, extract with dichloromethane, and dry under reduced pressure to obtain the intermediate 3;
[0010] S4. At 25°C, add hydroiodic acid dropwise into the round-bottom flask containing the intermediate three and heat to react. After the reaction is completed, cool to room temperature, add water to quench the reaction, filter, and purify the residue with acetonitrile to obtain the product 5-hydroxy-6-methylpyrimidine-4-carboxylic acid.
[0011] The present invention is further configured as follows: in the step S1, the first solution is formed by mixing methylmagnesium bromide and tetrahydrofuran.
[0012] The present invention is further configured as follows: in the step S1, the second solution is formed by mixing 4,6-dichloro-5-methoxypyrimidine and tetrahydrofuran.
[0013] The present invention is further configured as follows: in step S1, the molar ratio of the first solution to the second solution is 1:9.
[0014] The present invention is further configured as follows: in step S2, the palladium catalyst is tetrakis(triphenylphosphine)palladium, and the cyanide source is zinc cyanide.
[0015] The present invention is further configured as follows: in step S3, the ethanol aqueous solution is prepared by mixing ethanol and water in a volume ratio of 1:1.
[0016] The present invention is further configured as follows: in step S3, the heating temperature is 78° C. and the reaction time is 12 h.
[0017] The present invention is further configured as follows: in step S4, the heating temperature is 40° C. and the reaction time is 12 hours.
[0018] Compared with the prior art, the present invention has the following beneficial effects:
[0019] The invention discloses a highly efficient synthesis method of polysubstituted pyrimidinecarboxylic acid, which uses 4,6-dichloro-5-methoxypyrimidine as a raw material, tetrahydrofuran as a solvent, performs a Grignard reaction to obtain an intermediate 1, performs a Suzuki reaction to obtain an intermediate 2, performs a sodium hydroxide saponification reaction, and reacts with hydroiodic acid to obtain a polysubstituted pyrimidinecarboxylic acid derivative. The reaction requires only four steps, has mild conditions, and has a high atomic utilization rate, making the route safer, more environmentally friendly, and convenient for industrial production. The polysubstituted pyrimidinecarboxylic acid derivative can be used as an important pharmaceutical and chemical building block for subsequent derivatization. DETAILED DESCRIPTION
[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. 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 creative work are within the scope of protection of the present invention.
[0021] Example
[0022] This embodiment provides a rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound, and the process route is as follows:
[0023]
[0024] The specific process is as follows:
[0025] Step 1: Synthesis of A-1
[0026] Under nitrogen protection, methylmagnesium bromide tetrahydrofuran solution (3.0M, 234.0mL) was added dropwise to a tetrahydrofuran (200.0mL) solution of 4,6-dichloro-5-methoxypyrimidine (125.0g, 700.0mmol) at 0°C, and the temperature was maintained for 1.5 hours. After the reaction was completed, water (80.0mL) was added to quench the reaction, and then extracted with ethyl acetate (200mL×3), the organic phase was dried with sodium sulfate, and column chromatography (petroleum ether / ethyl acetate = 95:5 gradient elution) was performed to obtain intermediate A-1 (76g, yield 53%).
[0027] Step 2: Synthesis of A-2
[0028] INT-1-1 (75.0 g, 472.5 mmol), tetrakis(triphenylphosphine)palladium (54.8 g, 47.3 mmol), zinc cyanide (83.0 g, 710.0 mmol) were dispersed in N,N-dimethylformamide (240.0 mL), and the reaction was heated to 100 ° C for 12 hours under nitrogen protection. After the reaction was completed, the reaction temperature was cooled to room temperature, and water (80 mL) was added to quench the reaction, and then extracted with ethyl acetate (200 mL×3), and the organic phase was dried with sodium sulfate and purified by column chromatography (petroleum ether / ethyl acetate = 95:5 gradient elution) to obtain intermediate A-2 (47 g, yield 67%).
[0029] Step 3: Synthesis of A-3
[0030] A-2 (30.0 g, 201.3 mmol) was dissolved in ethanol (90.0 mL) / water (90.0 mL), and sodium hydroxide (25.0 g, 367.0 mmol) was added to the reaction, and then heated to 80 ° C for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, and the pH was adjusted to acidic with saturated sodium bisulfate solution, extracted with dichloromethane (150 mL × 3), and dried under reduced pressure to obtain intermediate A-3 (23.0 g, yield 67%).
[0031] Step 4: Synthesis of A
[0032] Hydroiodic acid (51.0 g, 182.3 mmol, 45% purity) was added dropwise to a round-bottom flask containing A-3 (22.5 g, 133.8 mmol) at 25°C and heated to 40°C for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, and water (80.0 mL) was added to quench the reaction, and a large amount of brown precipitate was precipitated. The residue was filtered and purified by slurrying with acetonitrile (80.0 mL) to obtain the product 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (10.0 g, yield 48%).
[0033] The provided method for rapid synthesis of polysubstituted pyrimidine carboxylic acid compounds uses 4,6-dichloro-5-methoxypyrimidine as a raw material, tetrahydrofuran as a solvent, a Grignard reaction to obtain an intermediate 1, and then a Suzuki reaction to obtain an intermediate 2, and then a sodium hydroxide saponification reaction and a reaction with hydroiodic acid to obtain a polysubstituted pyrimidine carboxylic acid derivative; the reaction requires only 4 steps, mild conditions, and a high atomic utilization rate, making the route safer, more environmentally friendly, and convenient for industrial production, and can be used as an important pharmaceutical and chemical building block for subsequent derivatization. Using the same method, replacing methyl magnesium bromide with ethyl magnesium bromide and cyclopropyl magnesium bromide can also synthesize analog polysubstituted pyrimidine carboxylic acid compounds B and C.
[0034]
[0035] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.
[0036] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.
Claims
1. A rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound, characterized in that: The following steps are involved: S1. Add the first solution dropwise to the second solution at 0°C, and keep the temperature to react for 1.5h to obtain intermediate 1; S2, dispersing the reaction product, palladium catalyst and cyanide source in N,N-dimethylformamide, heating to 100°C under nitrogen protection for 10 to 12 hours to obtain intermediate 2; S3, dissolving the intermediate 2 with ethanol aqueous solution, adding sodium hydroxide to the reaction, and heating the reaction. After the reaction is completed, cool the reaction to room temperature, adjust the pH to acidic with saturated sodium bisulfate solution, extract with dichloromethane, and dry under reduced pressure to obtain the intermediate 3; S4. At 25°C, add hydroiodic acid dropwise into the round-bottom flask containing the intermediate three and heat to react. After the reaction is completed, cool to room temperature, add water to quench the reaction, filter, and purify the residue with acetonitrile to obtain the product 5-hydroxy-6-methylpyrimidine-4-carboxylic acid.
2. The rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In the step S1, the first solution is prepared by mixing methylmagnesium bromide and tetrahydrofuran.
3. The rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In the step S1, the second solution is prepared by mixing 4,6-dichloro-5-methoxypyrimidine and tetrahydrofuran.
4. The rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In the step S1, the molar ratio of the first solution to the second solution is 1:
9.
5. The rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In the step S2, the palladium catalyst is tetrakis(triphenylphosphine)palladium, and the cyanide source is zinc cyanide.
6. The rapid synthesis method of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In step S3, the ethanol aqueous solution is prepared by mixing ethanol and water in a volume ratio of 1:
1.
7. The method for rapid synthesis of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In step S3, the heating temperature is 78° C. and the reaction time is 12 h.
8. The method for rapid synthesis of a polysubstituted pyrimidinecarboxylic acid compound according to claim 1, characterized in that: In the step S4, the heating temperature is 40° C. and the reaction time is 12 h.