AU2016102204A4

AU2016102204A4 - Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method

Info

Publication number: AU2016102204A4
Application number: AU2016102204A
Authority: AU
Inventors: xiangliang peng
Original assignee: Xiamen Lai En Si Te Information Technology Co Ltd
Current assignee: Xiamen Lai En Si Te Information Technology Co Ltd
Priority date: 2015-12-23
Filing date: 2016-12-23
Publication date: 2017-02-16
Anticipated expiration: 2024-12-23

Abstract

Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method, comprising the following steps: 800-1000ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2), 150-200ml water was slowly added 50mL concentrated phosphoric acid solution, controlling the solution temperature raised to 80--95C, generating phosphates, the resulting suspension was cooled to 15--20 C, 0.25mol sodium hydrogen sulfite was slowly added dropwise in 100ml aqueous solution, controlling the stirring rate at 100--300rpm process during the process, KI paper measuring the end of the reaction; controlling the temperature of the solution at 30C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 90--95C, holding 10min, decolorized with molecular sieves, filtered while hot, the filter cake was washed with solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution to recrystallize, filtered and dried to obtain p-hydroxybenzaldehyde.

Description

Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method

TECHNICAL FIELD

The present invention relates totrimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method.

BACKGROUND ART

Trimethoprim as broad-spectrum antibiotics, antibacterial spectrum is similar to sulfa drugs, it has an effect on inhibit dihydrofolate reductase, but easier to produce bacterial resistance, rarely used alone, while sulfa drugs inhibit dihydrofolate synthase. The two combined, can double blocking the folate metabolism of bacteria, thus greatly improve the antibacterial activity (synergistic be several times to several times), it is known as sulfa synergist, can reduce the appearance of resistant strains. P-hydroxy benzaldehyde as trimethoprim drug intermediates, its synthesis method is of great economic significance for improving drug synthesis product quality, reducing the by-product content.

SUMMARY OF THE INVENTION

Object of the present invention is to provide trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method, comprising the following steps: (i) 800-1000ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2), 150-200ml water was slowly added 50mL concentrated phosphoric acid solution, controlling the solution temperature raised to 80—95°C, generating phosphates, the resulting suspension was cooled to 15—20 °C, 0.25mol sodium hydrogen sulfite was slowly added dropwise in 100ml aqueous solution, controlling the stirring rate at 100—300rpm process during the process, KI paper measuring the end of the reaction; (ii) controlling the temperature of the solution at 30°C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 90—95 °C, holding lOmin, decolorized with molecular sieves, filtered while hot, the filter cake was washed with solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution to recrystallize, filtered and dried to obtain p-hydroxybenzaldehy de; wherein, concentrated phosphoric acid in step (i) has a mass fraction of 50% —70%, the speed of concentrated phosphoric acid’s addition in step (i) was 10-12ml per hour; the solvent used for filter cake washing in step (ii) is any one of diethyl ether, acetone, ethyl acetate; sodium chloride solution in step (ii) has a mass fraction of 10% —15 %.

Throughout the reaction can be summarized as the following reaction formula:

(3) m tjj (j)

Advantage of the present invention is that: reducing the reaction intermediate links, decreasing the reaction temperature and reaction time, improving the reaction yield.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THEINVENTION

Embodiment 1 800ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2), 150ml water was slowly added 50mL concentrated phosphoric acid solution with a mass fraction of 50%, controlling the solution temperature raised to 80°C, generating phosphates, the resulting suspension was cooled to 15°C, 0.25mol sodium hydrogen sulfite was slowly added drop wise in 100ml aqueous solution, controlling the stirring rate at lOOrpm process during the process, KI paper measuring the end of the reaction; controlling the temperature of the solution at 30°C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 90 °C, holding lOmin, decolorized with molecular sieves, filtered while hot, the filter cake was washed with ethyl ether solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution with a mass fraction of 10% to recrystallize, filtered and dried to obtain p-hydroxybenzaldehydel6.18g, yield 78%.

Embodiment 2 900ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2), 180ml water was slowly added 50mL concentrated phosphoric acid solution with a mass fraction of 60%, controlling the solution temperature raised to 90°C, generating phosphates, the resulting suspension was cooled to 17°C, 0.25mol sodium hydrogen sulfite was slowly added dropwise in 100ml aqueous solution, controlling the stirring rate at 200rpm process during the process, KI paper measuring the end of the reaction; controlling the temperature of the solution at 30°C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 92°C, holding lOmin, decolorized with molecular sieves, filtered while hot, the filter cake was washed with acetone solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution with a mass fraction of 12% to recrystallize, filtered and dried to obtain p-hydroxybenzaldehydel7.21g, yield 83%.

Embodiment 3 1000ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2), 200ml water was slowly added 50mL concentrated phosphoric acid solution with a mass fraction of 60%, controlling the solution temperature raised to 95°C, generating phosphates, the resulting suspension was cooled to 20°C, 0.25mol sodium hydrogen sulfite was slowly added drop wise in 100ml aqueous solution, controlling the stirring rate at 300rpm process during the process, KI paper measuring the end of the reaction; controlling the temperature of the solution at 30°C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 95°C, holding lOmin, decolorized with molecular sieves, filtered while hot, the filter cake was washed with ethyl acetate solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution with a mass fraction of 15% to recrystallize, filtered and dried to obtain p-hydroxybenzaldehydel7.84g, yield 86%.

While a number of preferred embodiments have been described, it will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method, comprising the following steps: (1) 800-1000ml reaction vessel was added 0.17mol p-aminobenzaldehyde (2) , 150-200ml water was slowly added 50mL concentrated phosphoric acid solution, the solution temperature is raised to 80—95°C, generating phosphates, the resulting suspension was cooled to 15—20°C, 0.25mol sodium hydrogen sulfite was slowly added dropwise in 100ml aqueous solution, controlling the stirring rate at 100—300rpm process during the process, KI paper measuring the end of the reaction;(ii) controlling the temperature of the solution at 30°C, standing for 20min, 5g urea was added, the temperature gradually increased, until a large number of gas evolution, the solution was heated to 90—95°C, holding lOmin, decolorized with molecular sieves, filtered while hot, the filter cake was washed with solvent, combined filtrate and washings, until the temperature dropped to precipitate a solid, the solid was added to sodium chloride solution to recrystallize, filtered and dried to obtain p-hydroxybenzaldehyde;wherein, concentrated phosphoric acid in step (i) has a mass fraction of 50% —70%.

2. Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method according to claim 1 wherein the speed of concentrated phosphoric acid’s addition in step (i) was 10-12ml per hour.

3. Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method according to claim 1 wherein the solvent used for filter cake washing in step (ii) is any one of diethyl ether, acetone, ethyl acetate.

4. Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method according to claim 1 wherein sodium chloride solution in step (ii) has a mass fraction of 10% —15 %.