High-yield synthesis method of trimethoprim

Abstract

The invention provides a high-yield synthesis method of trimethoprim, which comprises the following steps: (a) adding 3-methoxypropionitrile and 3, 4, 5-trimethoxybenzaldehyde into an organic alcohol alkali-organic alcohol solution, heating to 30-45 DEG C, and carrying out condensation reaction; (b) directly decompressing the condensation product obtained in the step (a) to remove most organic alcohol, then adding an alcohol ether solvent and guanidine nitrate, heating to 70-80 DEG C, and reacting until the reaction is finished; and cooling to 0-5 DEG C to obtain a trimethoprim crude product. The trimethoprim with high yield can be obtained only by using a one-pot method without treating an intermediate, so that the process is simple, and the working procedure and the working hour are saved; alcohol ether is used as a solvent in the ring closing step, so that the yield is further improved.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical product technology, specifically relating to a high-yield synthesis method for methoxybenzidine. Background Technology

[0002] Trimethoprim (TMP) is an organic compound with the chemical formula C64-320. 14 H 18 N4O3 is a white or pale yellow crystalline powder, odorless, bitter in taste, slightly soluble in chloroform, sparingly soluble in ethanol or acetone, practically insoluble in water, and readily soluble in glacial acetic acid. Trimethoprim is a synthetic broad-spectrum antibacterial agent used alone for respiratory tract infections, urinary tract infections, intestinal infections, etc., and can be used to treat sepsis, meningitis, otitis media, typhoid fever, and Shigella disease (bacterial dysentery) caused by susceptible bacteria.

[0003] Chinese invention patent application number 202410065716.3 discloses a method for synthesizing trimethoprim, relating to the field of pharmaceutical technology. The method includes the following steps: acrylonitrile and methanol react under the catalysis of sodium methoxide to prepare 3-methoxypropionitrile, which then undergoes a condensation reaction with 3,4,5-trimethoxybenzaldehyde to generate intermediate A; intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate intermediate B; intermediate B undergoes a cyclization reaction with guanidine hydrochloride to obtain trimethoprim. This application requires the separate preparation of intermediates A and B in two parts, followed by a cyclization reaction to obtain the final product, which is complex and costly. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide a high-yield synthesis method for trimethoprim.

[0005] To address the aforementioned technical problems, this invention provides a high-yield synthesis method for methoxybenzidine, comprising the following steps: (a) Add 3-methoxypropionitrile and 3,4,5-trimethoxybenzaldehyde to an organic alcohol base-organic alcohol solution and heat to 30~45℃ to carry out a condensation reaction; (b) The condensation product obtained in step (a) is directly removed under reduced pressure to remove most of the organic alcohol, and then an alcohol ether solvent and guanidine nitrate are added. The temperature is raised to 70-80°C and the reaction is continued until the reaction is complete. The temperature is then lowered to 0-5°C to obtain crude trimethoprim.

[0006] Ideally, it also includes the following steps: (c) Add the crude trimethoprim to purified water and add sulfuric acid solution dropwise to dissolve it; decolorize with activated carbon, filter, and then adjust the pH to ≥8.5 with ammonia water to precipitate a large amount of white solid; filter and dry to obtain the finished trimethoprim.

[0007] Optimally, in step (a), the molar ratio of 3-methoxypropionitrile to 3,4,5-trimethoxybenzaldehyde is 1.1 to 1.5:1, and the molar ratio of the organic alcohol base to 3,4,5-trimethoxybenzaldehyde is 2 to 3:1.

[0008] Further, in step (a), the organic alcohol is a mixture selected from one or more of methanol, ethanol and isopropanol, and the organic alcohol base is a mixture selected from one or more of sodium methoxide, sodium ethoxide and potassium tert-butoxide.

[0009] Further, in step (b), the alcohol ether solvent is a mixture of one or more selected from diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monobutyl ether.

[0010] Furthermore, in step (b), the molar ratio of guanidine nitrate to 3,4,5-trimethoxybenzaldehyde is 1.2 to 1.8:1.

[0011] Ideally, in step (c), the sulfuric acid solution is an aqueous solution of sulfuric acid with a mass content of 60%.

[0012] Further, in step (c), the temperature of the purified water is 90~98°C or the purified water is heated to 90~98°C.

[0013] Furthermore, in step (c), the filtrate is filtered while hot, then heated back to 80-85°C, and the pH is adjusted with 25% ammonia.

[0014] Furthermore, in step (c), after a large amount of white solid precipitates, the pH is retested 20-30 minutes later and does not decrease. The mixture is then cooled to room temperature and filtered.

[0015] The present invention provides a high-yield synthesis method for trimethoprim, which can obtain high-yield trimethoprim in a single-pot process without the need for intermediate processing. The process is simple and saves time and steps. Furthermore, the use of alcohol ether as a solvent in the cyclization step further improves the yield. Detailed Implementation

[0016] The present invention provides a high-yield synthesis method for trimethoprim, comprising the following steps: (a) adding 3-methoxypropionitrile and 3,4,5-trimethoxybenzaldehyde to an organic alcohol-base-organic alcohol solution and heating to 30-45°C for a condensation reaction; (b) directly removing most of the organic alcohol from the condensation product obtained in step (a) under reduced pressure, then adding an alcohol ether solvent and guanidine nitrate, heating to 70-80°C and reacting until the reaction is complete; cooling to 0-5°C to obtain crude trimethoprim. This method achieves high yields of trimethoprim using only a one-pot process without intermediate treatment, resulting in a simple process that saves time and steps; furthermore, the use of an alcohol ether as a solvent in the ring-closing step further improves the yield.

[0017] The above-mentioned high-yield synthesis method of trimethoprim further includes the following steps: (c) adding the crude trimethoprim to purified water and adding sulfuric acid solution dropwise to dissolve it; decolorizing with activated carbon, filtering, and then adjusting the pH to ≥8.5 with ammonia water to precipitate a large amount of white solid; filtering and drying to obtain the finished trimethoprim.

[0018] In step (a), the molar ratio of 3-methoxypropionitrile to 3,4,5-trimethoxybenzaldehyde is 1.1 to 1.5:1, and the molar ratio of the organic alcohol base to 3,4,5-trimethoxybenzaldehyde is 2 to 3:1. In step (a), the organic alcohol is a mixture selected from one or more of methanol, ethanol, and isopropanol (preferably methanol), and the organic alcohol base is a mixture selected from one or more of sodium methoxide, sodium ethoxide, and potassium tert-butoxide (preferably sodium methoxide). In step (b), the alcohol ether solvent is a mixture selected from one or more of diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monobutyl ether (preferably diethylene glycol monomethyl ether, used in an amount 2 to 5 times the volume of 3,4,5-trimethoxybenzaldehyde). In step (b), the molar ratio of guanidine nitrate to 3,4,5-trimethoxybenzaldehyde is 1.2 to 1.8:1. In step (c), the sulfuric acid solution is a 60% (w / w) aqueous solution of sulfuric acid. In step (c), the temperature of the purified water is 90-98°C, or the purified water is heated to 90-98°C. In step (c), the solution is filtered while hot, and the filtrate is reheated to 80-85°C, then the pH is adjusted with 25% ammonia. In step (c), after a large amount of white solid precipitates, the pH is retested after 20-30 minutes; if it does not decrease, the solution is cooled to room temperature and filtered.

[0019] The present invention will be further described below with reference to the embodiments shown. Example 1

[0020] This embodiment provides a high-yield synthesis method for trimethoprim, including the following steps: (a) Add 3-methoxypropionitrile and 3,4,5-trimethoxybenzaldehyde to an organic alcohol base-organic alcohol solution and heat to 30~45℃ to carry out a condensation reaction; The specific steps are as follows: At room temperature, 60 ml of methanol, 20 g of 3,4,5-trimethoxybenzaldehyde, 45.89 g of 30% sodium methoxide-methanol solution, and 11.29 g of methoxypropionitrile were added sequentially to the reaction vessel. The temperature was then raised to 40°C and the mixture was stirred to maintain the temperature. TLC analysis was performed on the sample. The reaction was stopped after the reactant 3,4,5-trimethoxybenzaldehyde had completely reacted.

[0021] (b) The condensation product obtained in step (a) was directly subjected to reduced pressure to remove most of the organic alcohol, and then an alcohol ether solvent and guanidine nitrate were added. The mixture was heated to 70-80°C and reacted until the reaction was completed. The mixture was then cooled to 0-5°C to obtain crude trimethoprim. Specifically, the product obtained in step (a) was concentrated under reduced pressure to remove 80% methanol. Then, 60 ml of diethylene glycol monomethyl ether and 18.67 g of guanidine nitrate were added, and the mixture was heated to 75 °C and reacted for 10 hours (the reaction was complete by TLC sampling). The reaction was stopped, and the mixture was cooled to 0-5 °C to crystallize for 2 hours. The mixture was then filtered, and the filter cake was washed successively with an appropriate amount of ice-cold methanol and tap water. The solid was then mixed with 60 g of water and stirred for 20 min before being filtered. The filter cake was dried at 60 °C to obtain 23.97 g of light yellow crude trimethoprim, with a yield of 81%. Example 2

[0022] This embodiment provides a high-yield synthesis method for trimethoprim, which is basically the same as that in Example 1, except that in step (b), the alcohol ether solvent is ethylene glycol monoethyl ether, and finally 22.78 g of light yellow crude trimethoprim is obtained, with a yield of 77%. Example 3

[0023] This embodiment provides a high-yield synthesis method for trimethoprim, which is basically the same as that in Example 1, except that in step (b), the alcohol ether solvent is ethylene glycol monobutyl ether, and finally 23g of light yellow crude trimethoprim is obtained, with a yield of 78%. Example 4

[0024] This embodiment provides a high-yield synthesis method for trimethoprim, which is basically the same as that in Example 1, except that it further includes step (c): Refining: Take a portion of the light yellow crude trimethoprim (10g), add 40ml of water, heat to 95℃, then add 60% sulfuric acid solution dropwise until the solid is completely dissolved; add 1g of activated carbon and keep warm for 30min for decolorization, then filter off the activated carbon while hot, reheat the filtrate to 80℃, then slowly add 25% ammonia water to adjust the pH to above 8.5, a large amount of white solid precipitates, and if the pH does not drop after 30 minutes, cool to room temperature (30℃), filter, and dry the solid at 60℃ for 12 hours to obtain 9.5g of finished trimethoprim (TMP) with a purity of 99.8%.

[0025] Comparative Example 1 This embodiment provides a high-yield synthesis method for trimethoprim, which is basically the same as that in Example 1, except that 60 ml of diethylene glycol monomethyl ether was not added. The final yield was 18.64 g of pale yellow crude trimethoprim, with a yield of 63%.

[0026] Comparative Example 2 This embodiment provides a high-yield synthesis method for trimethoprim, which is basically the same as that in Comparative Example 1, except that 86.7 g of 20% sodium ethoxide-ethanol solution is used instead of sodium methoxide-methanol solution. The final yield is 17.46 g of pale yellow crude trimethoprim, with a yield of 59%.

[0027] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A high-yield synthesis method for methoxybenzidine, characterized in that, Includes the following steps: (a) Add 3-methoxypropionitrile and 3,4,5-trimethoxybenzaldehyde to an organic alcohol base-organic alcohol solution and heat to 30~45℃ to carry out a condensation reaction; (b) The condensation product obtained in step (a) is directly removed under reduced pressure to remove most of the organic alcohol, and then an alcohol ether solvent and guanidine nitrate are added. The temperature is raised to 70-80°C and the reaction is continued until the reaction is complete. The temperature is then lowered to 0-5°C to obtain crude trimethoprim.

2. The high-yield synthesis method of methoxybenzidine according to claim 1, characterized in that, It also includes the following steps: (c) Add the crude trimethoprim to purified water and add sulfuric acid solution dropwise to dissolve it; decolorize with activated carbon, filter, and then adjust the pH to ≥8.5 with ammonia water to precipitate a large amount of white solid; filter and dry to obtain the finished trimethoprim.

3. The high-yield synthesis method of methoxybenzidine according to claim 1, characterized in that: In step (a), the molar ratio of 3-methoxypropionitrile to 3,4,5-trimethoxybenzaldehyde is 1.1 to 1.5:1, and the molar ratio of the organic alcohol base to 3,4,5-trimethoxybenzaldehyde is 2 to 3:

1.

4. The high-yield synthesis method of methoxybenzidine according to claim 1 or 3, characterized in that: In step (a), the organic alcohol is a mixture of one or more of methanol, ethanol and isopropanol, and the organic alcohol base is a mixture of one or more of sodium methoxide, sodium ethoxide and potassium tert-butoxide.

5. The high-yield synthesis method of methoxybenzidine according to claim 1 or 3, characterized in that: In step (b), the alcohol ether solvent is a mixture of one or more selected from diethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monobutyl ether.

6. The high-yield synthesis method of methoxybenzidine according to claim 5, characterized in that: In step (b), the molar ratio of guanidine nitrate to 3,4,5-trimethoxybenzaldehyde is 1.2 to 1.8:

1.

7. The high-yield synthesis method of methoxybenzidine according to claim 2, characterized in that: In step (c), the sulfuric acid solution is an aqueous solution of sulfuric acid with a mass content of 60%.

8. The high-yield synthesis method of methoxybenzidine according to claim 2 or 7, characterized in that: In step (c), the temperature of the purified water is 90~98℃ or the purified water is heated to 90~98℃.

9. The high-yield synthesis method of methoxybenzidine according to claim 8, characterized in that: In step (c), filter while hot, reheat the filtrate to 80-85°C, and then adjust the pH with 25% ammonia.

10. The high-yield synthesis method of methoxybenzidine according to claim 8, characterized in that: In step (c), after a large amount of white solid precipitates, the pH is retested 20-30 minutes later and does not decrease. The sample is then cooled to room temperature and filtered.