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Preparation of trimethoprim and intermediate

A technology of trimethoprim and trimethoxybenzaldehyde, which is applied in the field of medicine and can solve the problems of no obvious increase in yield

Inactive Publication Date: 2008-12-24
SHOUGUANG FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another research report uses acrylonitrile to replace methoxyacrylonitrile and 3,4,5-trimethoxybenzaldehyde (TMB) condensation, and the yield of its condensation step and subsequent cyclization step does not significantly improve (Chinese Science Journal of Technical University, 31(2) April 2001, pp. 229-234)

Method used

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  • Preparation of trimethoprim and intermediate
  • Preparation of trimethoprim and intermediate
  • Preparation of trimethoprim and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] In a 1000mL four-necked flask (equipped with a reflux separator), add 49g (0.25mol) of TMB, 42.5g (0.29mol) of anilinopropionitrile, 150mL of dimethylsulfoxide, 15g of sodium methoxide, and 100mL of toluene, and heat up to 110°C , when the reflux reaction brings water until no water drops are generated in the water separator, stop the reaction, distill toluene under reduced pressure, then add 400mL of water, stir and cool to 5-10°C, filter with suction, and obtain 78.5g of product after drying (yield 97%). mp: 132.5-132.5°C.

[0017] Take 32g of the above-mentioned compound, 19g of guanidine hydrochloride, and 50g of sodium methoxide into a 500mL three-necked flask, add 100mL of ethanol, heat and reflux for 1 hour, evaporate part of the solvent, add 100mL of water, stir and cool down to 5-10°C, filter with suction, and bake TMP27.5g (yield 96%) was obtained after drying. mp: 201.5-201.7°C; HPLC content: 98.7%.

Embodiment 2

[0019] In a 2000mL four-neck flask (equipped with a reflux separator), add TMB98g (0.5mol), anilinopropionitrile 85 (0.58mol)g, dimethylsulfoxide 250mL, sodium methoxide 50g, benzene 300mL, heat up to reflux at 85°C Separate the water until no water drops are formed in the water separator, stop the reaction, recover benzene under reduced pressure, then add 750mL of water, stir and cool down to 5-10°C, filter with suction, and dry to obtain 155g of the product (95.5% yield) . mp: 132.0-132.2°C.

[0020] Take 64g of the above compound, 38g of guanidine hydrochloride, and 100g of sodium methoxide into a 1000mL three-necked flask, add 200mL of ethanol, heat and reflux for 1 hour, evaporate part of the solvent, add 200mL of water, stir and cool down to 5-10°C, and suction filter to obtain the product 56g (96.1% yield). mp: 201.6-201.8°C; HPLC content: 98.8%.

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Abstract

The invention provides a method for preparing trimethoprim, comprising the following steps: (1) performing a condensation reaction by using 3,4,5-trimethoxybenzaldehyde and aniline propionitrile as raw materials; (2) performing a cyclization reaction among condensation reaction products and guanidine compounds; wherein an inertia solution is added in a reaction system in the step (1), in a reflux reaction water is brought to a water knockout vessel; and in the step (2) the condensation compound and the guanidine compounds are dissolved in ethanol, and are heated and reflowed. The preparation method of the invention is convenient in operation, high in yield low in cost and is easy to controlled in industry.

Description

technical field [0001] The invention relates to a preparation method in the technical field of medicine, in particular to a preparation method of trimethoprim (TMP). Background technique [0002] Trimethoprim (TMP), whose chemical name is 5-[(3,4,5-trimethoxyphenyl)-methyl]-2,4-pyrimidinediamine, is a broad-spectrum high-efficiency and low-toxicity Antimicrobials and fungicides. It has been widely used in the pharmaceutical industry as a fungicide and a fungicide synergist for decades. It not only has excellent synergistic effect in combination with sulfonamide drugs, but also has good synergistic effect on various biological antibiotics and synthetic antibiotics, so it has been widely used in clinical medicine and veterinary animal husbandry, and has become my country's pharmaceutical industry. One of the pillar products. [0003] At present, most industrial manufacturers of TMP use methoxypropionitrile and 3,4,5-trimethoxybenzaldehyde (TMB) to condense to form methyl eth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/43C07D239/49
Inventor 杨磊宋伟国高东圣袁晋亭杨春程甲宗青
Owner SHOUGUANG FUKANG PHARMA
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