CN101792387A - Preparation method of 2,3,4-trimethoxybenzoic acid - Google Patents

Abstract

The present invention relates to the preparation method of 2,3,4-trimethoxybenzoic acid, as shown in the following reaction equation: The method adopts green chemical reagents dimethyl carbonate and pyrogallic acid to carry out methylation reaction under ionic liquid catalysis, and then synthesizes TBA through bromination, cyanation and hydrolysis, and the total yield of TBA reaches 38.2%. The method of the invention has cheap raw materials and mild reaction conditions, and opens up a new route for synthesizing TBA.

Description

The preparation method of 2,3,4-trimethoxybenzoic acid

technical field

The invention relates to a method for synthesizing a pharmaceutical intermediate 2,3,4-trimethoxybenzoic acid (TBA).

Background technique

TBA is widely used as an important pharmaceutical intermediate, and its demand is increasing. Therefore, it is necessary to develop an effective synthetic route.

Making a general survey of domestic and foreign reports, there are mainly two synthetic routes about TBA: (1) is to be raw material with 2,3,4-trihydroxybenzoic acid, obtain through methylation with dimethyl sulfate, used in this method Dimethyl sulfate is a highly toxic chemical with high pollution. (2) is obtained through oxidation with 2,3,4-trimethoxybenzaldehyde, but there are also high raw material costs, a stoichiometric solid oxidant used in the oxidation process, and a large amount of slurry-like residue and waste produced in the production process. Acid, corrosion of equipment is also quite serious and other problems.

Contents of the invention

The purpose of the present invention is to provide a more complete route for the synthesis of TBA to meet the needs of industrial production. The advantages of the present invention are as follows: the raw material pyrogallic acid PA used in the etherification process is relatively cheap and has a wide range of sources, and DMC is a kind of non-toxic and pollution-free green chemical, which rarely pollutes the environment; the used imidazole catalyst [Bmim]Br is also a kind of green chemical, and it is easy to be separated from the product, and can be recycled after a little treatment; the raw materials NBS and CuCN used in the bromination and cyanidation process are relatively low in toxicity and relatively low in environmental pollution. Small; hydrolysis reaction occurs easily in alkaline solution.

The method of the present invention uses DMC and PA as raw materials to obtain the pharmaceutical intermediate TBA through four-step finishing synthesis.

This method comprises following reaction equation:

Specific steps are as follows:

(1) Place dimethyl carbonate DMC, pyrogallic acid (PA) and ionic liquid in a pressure-resistant reactor and stir them magnetically, and react at 150°C for 7 hours. Dimethyl carbonate DMC and methanol at the boiling point were then extracted three times with diethyl ether twice the volume of the original solution, the extracts were combined, and the extracts were crystallized at low temperature to obtain the crude trityl ether, which was dissolved in two Add activated carbon to petroleum ether twice the mass of the original crude product, wherein the mass of activated carbon is 3-10% of the crude product, heat at 40°C for 30 minutes, then heat filter, then wash the filter paper with an appropriate amount of petroleum ether, and evaporate part of the petroleum ether After putting into the refrigerator and crystallizing to obtain the pure product of white trityl ether; the described ionic liquid catalyst is [Bmim]Br, and the amount of the substance amount of the described ionic liquid catalyst [Bmim]Br and pyrogallic acid PA The ratio is 0.5-2:1; the ratio of the amount of dimethyl carbonate DMC and pyrogallic acid PA is 3-9:1;

(2) Dissolve trityl ether in DMF, add NBS in batches at a temperature lower than 20°C, keep warm for 0.5-1h, then pour the mixed solution into an appropriate amount of water to separate the organic phase, and the water layer is twice as much as the original The volume of the solution was extracted with diethyl ether 2-3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, the solid was washed 1-2 times with an appropriate amount of diethyl ether, and the diethyl ether was removed by rotary evaporation to obtain 4-bromotrityl ether The amount of wherein said solvent DMF is about the sum of two kinds of raw material quality; The amount ratio of the substance of described NBS and trityl ether is 1-2: 1; The quality of described anhydrous sodium sulfate is 10-20% of the raw material mass;

(3) Dissolve CuCN in DMF, stir and add 4-bromotrityl ether, heat to 120°C for 4-5h, then heat up to 160°C and reflux for about 4h, then cool to room temperature, add appropriate amount of ammonia and stir After 1h, it was poured into water, a solid was precipitated, and filtered with suction. Wash the filter cake with a large amount of ammonia water for 2-3 times, then recrystallize with an appropriate amount of absolute ethanol and add activated carbon, wherein the mass of activated carbon is 3-10% of the mass of the original solution to decolorize, filter while it is hot, and the filtrate will precipitate off-white when cooled Needle crystal 2,3,4-trimethoxybenzonitrile; wherein the quality of the solvent DMF is about twice the sum of the mass of the two raw materials, the material of the raw material CuCN and 4-bromotrityl ether The amount ratio is 1-2:1;

(4) Add 2,3,4-trimethoxybenzonitrile to NaOH aqueous solution, react at 90-100°C for 24h, cool to room temperature, and filter with suction. The filtrate was extracted 2-3 times with an appropriate amount of 1,2-dichloroethane, and the pH of the aqueous phase was adjusted to 2-3 with 10% hydrochloric acid, and a solid was precipitated, filtered with suction, and dried to obtain the white product 2,3,4-trimethyl Oxybenzoic acid; the ratio of the amount of sodium hydroxide to 2,3,4-trimethoxybenzocyanide is 2.5-3:1.

The invention adopts green chemical reagents dimethyl carbonate and pyrogallic acid to carry out methylation reaction under ionic liquid catalysis, and then synthesizes TBA through bromination, cyanation and hydrolysis, and the total yield of TBA reaches 38.2%. The method of the invention has cheap raw materials and mild reaction conditions, and opens up a new route for synthesizing TBA.

Detailed ways:

Embodiment one:

①Weigh 31.5g of pyrogallic acid, 135g of dimethyl carbonate DMC and 54.76g of 1-n-butyl-3-methylimidazolium bromide, place them in a 500mL pressure-resistant reactor, stir them magnetically, and react at 150°C After 7 hours, cool to room temperature, then distill off low-boiling dimethyl carbonate DMC and methanol under reduced pressure, then extract with ether (150mL×3), combine the extracts, distill off part of the ether, and crystallize at low temperature Crude triphenylmethyl ether, dissolve the crude product in 150mL of petroleum ether, add 5g of activated carbon and heat it slightly (about 40°C, 30min), then heat filter, then wash the filter paper with 30mL of petroleum ether, evaporate part of the petroleum ether and put it in the refrigerator After crystallization, 38.9 g of pure white trityl ether was obtained, with a yield of 92.6%.

②Add 35mL DMF and 16.8g (0.1mol) trityl ether into a 100mL four-neck flask, stir to dissolve completely, add 18.6g (0.105mol) NBS in batches at no more than 20°C, and then keep warm for 0.5 -1h. After the reaction was complete, the product was poured into an appropriate amount of water to separate the organic phase, the aqueous layer was extracted with ether (35mL×3), and the organic phases were combined. Wash the organic phase with a certain amount of water for 2-3 times, then add 5g of anhydrous sodium sulfate to dry, filter with suction, wash the solid with ether (30mL×2), and remove the ether by rotary evaporation to obtain 22.7g of a light yellow transparent liquid. The yield is 92%.

③Add 60mL DMF and 8.8g (0.096mol) CuCN to a 150mL four-neck flask, add 20g (0.08mol) 4-bromotrityl ether under stirring, heat to 120°C for 4-5h, then heat to 160°C Reflux reaction for about 4h. After that, cool to room temperature, add 100 mL of ammonia water, and stir for 1 h. Poured into water, precipitated solid, suction filtration. The resulting solid was washed 3 times with copious amounts of ammonia. Recrystallize with absolute ethanol, add 2.5 g of activated carbon for decolorization, filter while hot, and cool the filtrate to precipitate crystals, filter with suction to obtain 8.72 g of off-white needle-like crystals, with a yield of 56%.

④Add 20mL water and 3.4g (0.085mol) NaOH to a 100mL four-neck flask, stir to dissolve it fully, then add 5.4g (0.03mol) 2,3,4-trimethoxybenzonitrile, heat to 90-100 ℃ reaction 24h. Stop heating, cool to room temperature, and filter with suction. The filtrate was extracted with 1,2-dichloroethane (25mL×3), and the pH of the aqueous phase was adjusted to 2-3 with 10% HCl, and a solid precipitated, filtered with suction, and dried to obtain 4.75g of a white product. The total yield obtained by the above four steps is 38.2%.

Embodiment two:

① Weigh 31.5g of pyrogallic acid, 135g of DMC and 37.38g of 1-n-butyl-3-methylimidazolium bromide, place them in a 500mL pressure-resistant reactor and stir them magnetically, react at 150°C for 7h, finish, and cool to room temperature, then distill off low-boiling DMC and methanol under reduced pressure, then extract with diethyl ether (150mL×3), combine the extracts, distill off part of the diethyl ether, and crystallize at low temperature to obtain the crude trityl ether. Dissolve in 150mL of petroleum ether, add 5g of activated carbon, heat for a while (about 40°C, 30min), then heat filter, then wash the filter paper with petroleum ether, evaporate part of the petroleum ether and put it in the refrigerator to crystallize to obtain white trityl ether The pure product is 38.9g, and the yield is 92.6%.

② Add 35ml DMF and 16.8g (0.1mol) trityl ether into a 100mL four-neck flask, stir to dissolve completely, add 18.6g (0.105mol) NBS in batches at no more than 20°C, and keep warm for 0.5- 1h. After the reaction was complete, the product was poured into water to separate the organic phase, the aqueous layer was extracted with ether (35mL×3), and the organic phases were combined. Wash the organic phase with a certain amount of water for 2-3 times, then add 5g of anhydrous sodium sulfate to dry, filter with suction, wash the solid with ether (30mL×2), and remove the ether by rotary evaporation to obtain 22.7g of a light yellow transparent liquid. The yield is 92%.

③Add 60mL DMF and 8.8g (0.096mol) CuCN to a 150mL four-neck flask, add 20g (0.08mol) 4-bromotrityl ether under stirring, heat to 120°C for 4-5h, then heat to 160°C Reflux reaction for about 4h. After that, cool to room temperature, add 100 mL of ammonia water, and stir for 1 h. Poured into water, precipitated solid, suction filtration. The resulting solid was washed 3 times with copious amounts of ammonia. Recrystallize with absolute ethanol, add 2.5 g of activated carbon for decolorization, filter while hot, and cool the filtrate to precipitate crystals, filter with suction to obtain 8.72 g of off-white needle-like crystals, with a yield of 56%.

④Add 20mL water and 3.4g (0.085mol) NaOH to a 100mL four-neck flask, stir to dissolve it fully, then add 5.4g (0.03mol) 2,3,4-trimethoxybenzonitrile, heat to 90-100 ℃ reaction 24h. Stop heating, cool to room temperature, and filter with suction. The filtrate was extracted with 1,2-dichloroethane (25mL×3), and the pH of the aqueous phase was adjusted to 2-3 with 10% HCl, and a solid precipitated, filtered with suction, and dried to obtain 4.75g of a white product. The total yield obtained by the above four steps is 33%.

Embodiment three:

① Weigh 31.5g of pyrogallic acid, 67.5g of DMC and 54.76g of 1-n-butyl-3-methylimidazolium bromide, place them in a 500mL pressure-resistant reactor and stir them magnetically, and react at 150°C for 7 hours. Cool to room temperature, distill off low-boiling DMC and methanol under reduced pressure, then extract with diethyl ether (150mL×3), combine the extracts, evaporate part of the diethyl ether, and then crystallize at low temperature to obtain the crude trityl ether. Dissolve in 150mL of petroleum ether, add 5g of activated carbon, heat for a while (about 40°C, 30min) and heat filter, then wash the filter paper with petroleum ether, evaporate part of the petroleum ether, put it in the refrigerator to crystallize to obtain pure white trityl ether The product was 38.9g, and the yield was 92.6%.

②Add 35mL DMF and 16.8g (0.1mol) trityl ether into a 100mL four-neck flask, stir to dissolve completely, add 18.6g (0.105mol) NBS in batches at no more than 20°C, and then keep warm for 0.5 -1h. After the reaction was complete, the product was poured into water to separate the organic phase, the aqueous layer was extracted with ether (35mL×3), and the organic phases were combined. Wash the organic phase with a certain amount of water for 2-3 times, then add 5g of anhydrous sodium sulfate to dry, filter with suction, wash the solid with ether (30mL×2), and remove the ether by rotary evaporation to obtain 22.7g of a light yellow transparent liquid. The yield is 92%.

③Add 60mL DMF and 8.8g (0.096mol) CuCN to a 150mL four-neck flask, add 20g (0.08mol) 4-bromotrityl ether under stirring, heat to 120°C for 4-5h, then heat to 160°C Reflux reaction for about 4h. After that, cool to room temperature, add 100 mL of ammonia water, and stir for 1 h. Poured into water, precipitated solid, suction filtration. The resulting solid was washed 3 times with copious amounts of ammonia. Recrystallize with absolute ethanol, add 2.5 g of activated carbon for decolorization, filter while hot, and cool the filtrate to precipitate crystals, filter with suction to obtain 8.72 g of off-white needle-like crystals, with a yield of 56%.

④Add 20mL water and 3.4g (0.085mol) NaOH to a 100mL four-neck flask, stir to dissolve it fully, then add 5.4g (0.03mol) 2,3,4-trimethoxybenzonitrile, heat to 90-100 ℃ reaction 24h. Stop heating, cool to room temperature, and filter with suction. The filtrate was extracted with 1,2-dichloroethane (25mL×3), and the pH of the aqueous phase was adjusted to 2-3 with 10% HCl, and a solid precipitated, filtered with suction, and dried to obtain 4.75g of a white product. The total yield obtained by the above four steps is 21.4%.

Claims (1)

1.2,3, the preparation method of 4-trimethoxybenzoic acid, as shown in following reaction equation:

It is characterized in that the specific steps are as follows: (1) Place dimethyl carbonate, pyrogallic acid and ionic liquid in a pressure-resistant reaction kettle and stir them magnetically, react at 150°C for 7 hours, after completion, cool to room temperature, and then evaporate dicarbonate with a low boiling point under reduced pressure Methyl ester and methanol, then extracted three times with diethyl ether twice the volume of the original solution, combined the extracts, and then crystallized the extracts at low temperature to obtain the crude trityl ether, which was dissolved in twice the volume of the original crude product Add activated carbon to the petroleum ether, wherein the quality of activated carbon is 3-10% of the crude product, heat at about 40°C for 30 minutes and then heat filter, then wash the filter paper with an appropriate amount of petroleum ether, evaporate part of the petroleum ether and put it in the refrigerator Crystallization obtains white trityl ether pure product; Described ionic liquid catalyst is [Bmim]Br, and the ratio of the amount of substance of described ionic liquid catalyst [Bmim]Br and pyrogallic acid is 0.5-2: 1; The ratio of the amount of dimethyl carbonate and pyrogallic acid is 3-9: 1; (2) Dissolve trityl ether in DMF, add NBS in batches at a temperature lower than 20°C, keep warm for 0.5-1h, then pour the mixed solution into an appropriate amount of water to separate the organic phase, and the water layer is twice as much as the original The volume of the solution was extracted with diethyl ether 2-3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, the solid was washed 1-2 times with an appropriate amount of diethyl ether, and the diethyl ether was removed by rotary evaporation to obtain 4-bromotrityl ether The amount of wherein said solvent DMF is about the sum of two kinds of raw material quality; The amount ratio of the substance of described NBS and trityl ether is 1-2: 1; The quality of described anhydrous sodium sulfate is 10-20% of the raw material mass; (3) Dissolve CuCN in DMF, stir and add 4-bromotrityl ether, heat to 120°C for 4-5h, then heat up to 160°C and reflux for about 4h, then cool to room temperature, add appropriate amount of ammonia and stir After 1h, it was poured into water, a solid was precipitated, and filtered with suction. Wash the filter cake with a large amount of ammonia water for 2-3 times, then recrystallize with an appropriate amount of absolute ethanol and add activated carbon, wherein the mass of activated carbon is 3-10% of the mass of the original solution to decolorize, filter while it is hot, and the filtrate will precipitate off-white when cooled Needle crystal 2,3,4-trimethoxybenzonitrile; wherein the quality of the solvent DMF is about twice the sum of the mass of the two raw materials, the material of the raw material CuCN and 4-bromotrityl ether The amount ratio is 1-2:1; (4) Add 2,3,4-trimethoxybenzonitrile to NaOH aqueous solution, react at 90-100°C for 24h, cool to room temperature, and filter with suction. The filtrate was extracted 2-3 times with an appropriate amount of 1,2-dichloroethane, and the pH of the aqueous phase was adjusted to 2-3 with 10% hydrochloric acid, and a solid was precipitated, filtered with suction, and dried to obtain the white product 2,3,4-trimethyl Oxybenzoic acid; the ratio of the amount of sodium hydroxide to 2,3,4-trimethoxybenzocyanide is 2.5-3:1.