HU190120B - Improved process for production of 3,4,5-trimetoxibenzaldehid - Google Patents

Abstract

The present invention relates to a process for the preparation of 3,5-trimethoxybenzaldehyde by hydrolysis of 3-methoxy-4-hydroxy-5-bromobenzaldehyde in the presence of a catalyst, under pressure, with alkali metal hydroxide, under heating, followed by 3-methoxy-4, \ t 5-Dihydroxybenzaldehyde without methylation in the presence of a base and an organic solvent with dimethyl sulfate. According to the invention, the copper complex of formula (I) is used as the catalyst and the hydrolysis is carried out for 4 to 8 hours at 120-125 ° C, the resulting 3-methoxy-4,5-dihydroxybenzaldehyde in its reaction mixture with water and aromatic hydrocarbon or chlorinated. in a heterogeneous system with aliphatic hydrocarbons, methylating the dimethyl sulfate in at least two portions, the copper complex of formula (I) is separated by filtration after hydrolysis or methylation and used as a catalyst for subsequent hydrolysis and, if desired, dimethoxyhydroxybenzaldehyde in the aqueous phase of the methylation reaction mixture. after mineral acid treatment and extraction with aromatic hydrocarbon or chlorinated aliphatic hydrocarbon, it is used for subsequent methylation. 190120 -1-

Description

The present invention relates to an improved process 3, 4,

For the preparation of 5-trimeloxybenzaldehyde by hydrolysis of 3-methoxy-4-hydroxy-5-bromobenzaldehyde in the presence of a catalyst with alkali metal hydroxide under pressure, followed by isolation of the resulting 3-methoxy-4,5-dihydroxybenzaldehyde, by methylation with dimethyl sulfate in the presence of a base and an organic solvent.

The 3,4,5-trimethoxy-benzaldehyde compound is a valuable pharmaceutical agent having antibacterial activity, of 2,4-diamino-5- ^(3, 4 ', 5'-trimethoxybenzyl) -pyrimidine (trimethoprim) economical industrial synthesis.

A number of processes for the preparation of 3,4,5-trimethoxybenzaldehyde are known. Of these, one of the most favorable on a laboratory scale is the 165,663. 3-methoxy-4-hydroxybenzaldehyde is brominated, the resulting 3-methoxy-4-hydroxy-5-bromobenzaldehyde is hydrolyzed with alkali metal hydroxide at 50-120 ° C in the presence of copper powder, and finally 3-methoxy-4, 5-Dihydroxybenzaldehyde is methylated with dimethyl sulfate in the presence of an alkali metal carbonate. On a laboratory scale, a total yield of 75-78% can be obtained, but there are several problems with increasing the scale.

Hydrolysis of 3-methoxy-4-hydroxy-5-bromo-benzaldehyde and processing of the reaction mixture takes about 80 hours and is carried out in about 40-fold volumes. On an operational scale, this is extremely disadvantageous as a batch providing 200 kg of 3,4,5-trimethoxybenzaldehyde would require a 10 m ³ heated unit and would take days to react. In the known process, hydrolysis is unacceptably slow at 50-120 ° C.

Although the above anleriority indicates that the process can be carried out without isolation of 3-methoxy-4,5-dihydroxybenzaldehyde, this does not mean that methylation is carried out in the hydrolysis reaction containing a large amount of water, since in the latter reaction water is practically absent and methylation is carried out in acetone in the presence of powdered sodium carbonate monohydrate and methanolic potassium hydroxide for 24 hours.

Industrial-scale methylation under these conditions does not result in complete dimethylation of 3-methoxy-4,5-dihydroxybenzaldehyde, and with the 3,4,5-trimethoxybenzaldehyde formed, significant amounts of 3,4-dimethoxy-5-hydroxybenzaldehyde and 3, 5-Dimethoxy-4-hydroxybenzaldehyde is also present. They are not separated in the known process. The purification of the 3,4,5-trimethoxybenzaldehyde contaminated with these requires additional operations and reduces production. The reaction time of 24 hours is not favorable for methylation.

Based on the above, it is 165,363. The process of the Hungarian patent does not meet the requirements of the economical industrial method.

It has been found that the above drawbacks associated with the known process can be overcome and that 3,4,5-trimethoxybenzaldehyde can be prepared economically on an industrial scale in the presence of 3-methoxy-4-hydroxy-5-bromobenzaldehyde in the presence of a catalyst under pressure with alkali metal hydroxide. hydrolysis, followed by methylation of the resulting 3-methoxy-4,5-dihydroxybenzaldehyde with dimethyl sulfate without isolation in the presence of a base and an organic solvent, using the copper complex of formula (I) as catalyst and hydrolysis for 120-8 hours. At 125 DEG C., the resulting 3-methoxy-4,5-dihydroxybenzaldehyde is methylated in a heterogeneous system with water and an aromatic hydrocarbon or a chlorinated aliphatic hydrocarbon in the reaction mixture by addition of at least two portions of the dimethyl sulfate, the copper complex of formula (I). it is filtered after hydrolysis or methylation Hassel collected and used as a catalyst in a subsequent hydrolysis and, if desired Dimethoxy-hydroxybenzaldehyde mineral acid treatment in the methylation reaction the aqueous phase of use in subsequent metilezéahez as sending After extraction with an aromatic hydrocarbon or a chlorinated aliphatic hydrocarbon.

In view of the above known process, it is surprising that under the conditions of the present invention, hydrolysis of 3-meloxy-4-hydroxy-5-bromobenzaldehyde occurs in approximately 6-fold volumes over 4-8 hours instead of 80 hours without damaging the resulting product.

The copper complex of formula (I) used as a catalyst is reacted with 3-methoxy-4,5-dihydroxybenzaldehyde by reaction of copper powder or an inorganic or organic copper salt such as copper sulfate or copper acetate with hydrolysis to give 3-methoxy-4-hydroxy-5-bromo. by hydrolysis of benzaldehyde. Once the hydrolysis is complete, the copper complex can be reused for the next hydrolysis, at any time, only to make up for any losses. The copper complexes of formula (I) can be isolated either immediately after hydrolysis or by puncturing the methylation.

The 3-methoxy-4,5-dihydroxybenzaldehyde obtained by hydrolysis is methylated in the reaction mixture, optionally after removal of the copper complex of formula (I).

It has been found that the methylation reaction is carried out on a large scale with a short reaction time and good yield when the dimethylsulphate used in the heterogeneous system used is added in at least a small amount, preferably in three or four portions.

Suitable aromatic hydrocarbons are, for example, benzene, toluene or xylene, and chlorinated aliphatic hydrocarbons, for example, dichloromethane, 1,2-dichloroethane, chloroform or benzene tetrachloride.

Industrial methylation of 3-methoxy-4,5-dihydroxybenzaldehyde also contains, in addition to the desired 3,4,5-trimethoxybenzaldehyde, a smaller amount of a product having one of the hydroxyl groups at position 4 or 5. not methylated. This material which

3.4-Dinethoxy-5-hydroxybenzaldehyde and / or

It can be 3,5-dimethoxy-4-hydroxybenzaldehyde, for simplicity it is referred to herein as dimethoxybenzaldehyde. Under the conditions of the process of the invention, a

3.4.5-Trimethoxybenzaldehyde is found in the organic phase of the heterogeneous system, while dimethoxybenzaldehyde is present in the alkaline aqueous phase of the heterogeneous system. After separation of the two phases, a pure product is obtained from the organic phase, and after acidification of the aqueous phase, dimethylhydroxybenzaldehyde can be extracted with an aromatic hydrocarbon or a chlorinated aliphatic hydrocarbon, and the resulting organic solution can be subjected to subsequent methylation.

The starting 3-methoxy-4-hydroxy-5-bromobenzaldehyde is prepared by bromination of vanillin in a known manner.

The process of the present invention also provides an economical production of 3,4,5-trimethoxybenzaldehyde on an industrial scale.

Hydrolysis of 3-methoxy-4-hydroxy-5-bromobenzaldehyde takes place in a relatively small volume with a short reaction time and the catalyst can be reused. 3-Methoxy-4,5-dihydroxybenzaldehyde is methylated in the reaction mixture. This reaction also takes place in a short reaction time and the product can be easily isolated without any by-products. The economicality of the process is enhanced by the fact that the dimethoxy hydroxybenzaldehyde by-product is extremely easy to separate and can be converted to the desired product in a subsequent batch.

The invention is illustrated in detail by the following examples.

Preparation of the starting compound

(a) 152 kg of vanillin, 300 liters of 1,2-dichloroethane and

To 100 L of water was added 126 kg of bromine at 28-38 ° C over 3 hours, and the reaction mixture was stirred at this temperature for an additional 3 hours. The crystalline material is centrifuged, washed with 80 liters of 1,2-dichloroethane and 100 liters of water, and dried. 226 kg (98%) of 3-methoxy-4-hydroxy-5-bromobenzaldehyde are obtained, m.p. 160-162 'C.

b) To a mixture of 152 kg of vanillin, 200 L of 48% aqueous hydrogen bromide solution and 200 L of 1,2-dichloroethane is added dropwise a solution of 55 kg of sodium bromate in 180 L of water at 20-22 ° C. After completion of the reaction, the product is filtered, washed with 80 L of 1,2-dichloroethane and 100 L of water. 221 kg (96%) of 3-methoxy-4-hydroxy-5-bromobenzaldehyde, m.p. 159-162 »C.

Example 1

Weigh 1600 liters of water into a 4000 liter enamel autoclave, dissolve in 500 kg potassium hydroxide, add 400 kg of 3-methoxy-4-hydroxy-5-bromobenzaldehyde and 5.5 kg of copper powder. The apparatus was purged with nitrogen, sealed and warmed to 123-125 ° C. Stir at this temperature for 5 hours. After cooling to 35 'C, toluene (800 L) was added and then 500 kg of dimethyl sulfate was added at 33-35' C with cooling over 2 hours. After the addition was complete, the reaction mixture was heated at the same temperature for 2 hours, then 100 kg of dimethyl sulfate was added over 1 hour, 100 kg of dimethyl sulfate and 25% sodium hydroxide (about 150 kg) were added again after 2 hours. the pH of the reaction mixture should be above 9. After the addition, the mixture was heated to 40-42 ° C, reacted for 2 hours and then cooled to 25-30 ° C. The reaction mixture was filtered and the filtrate filtered

Wash with 100 liters of water. The organic phase of the filtrate was separated by stirring with 400 L of water and washing after separation. To the organic phase is added 1500 liters of water and toluene is distilled off from the system. When the distillate is free of toluene, the mixture is cooled to 40 DEG C., 150 kg of sodium bisulfite and 10 kg of clarifying charcoal are added and, after stirring for 1 hour, filtered. The filtrate was cooled to 20 ° C and basified to pH 10 with 25% 40% sodium hydroxide solution. The resulting crystal slurry was filtered through a centrifuge, washed with water to neutral, and the product was dried to give 255 kg (75%) of 3,4,5-trimeloxybenzaldehyde, m.p. 74-75 ° C.

After the methylation reaction, the aqueous phase of the reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and extracted with 2 x 200 L of toluene. The toluene phase contains gaseous dimethoxybenzaldehyde compounds. The toluene solution is added to the next batch instead of toluene.

The solid which was filtered off from the reaction mixture was suspended in 1000 L of water, acidified to pH 2 with concentrated hydrochloric acid and filtered. The filtrate was basified to pH 9 with 40% sodium hydroxide solution, and after stirring for several hours, the precipitated rose-3-methoxy-4,5-dihydroxybenzaldehyde complex was filtered, washed with water. The resulting complex compound, according to its copper content, is used in the next batch instead of copper powder.

Example 2

Example 1 except that the diraethoxydroxybenzaldehyde solution from the previous batch was used in toluene and the copper 3-methoxy-4,5-dihydroxybenzaldehyde complex. In this case, 550 and 2x200 kg of dimethyl sulfate are required, and 180 kg of sodium bisulfite are used to purify the crude product. This gives 292 kg (86%) of 3,4,5-trimethoxybenzaldehyde, m.p. 73-74.5 'C.

Example 3

Weigh 1600 liters of water into a 4000 liter enamel autoclave, dissolve in 500 kg potassium hydroxide, add 400 kg of 3-methoxy-4-hydroxy-5-bromobenzaldehyde and 6 kg of copper powder. The apparatus was purged with Ni gas, sealed and heated to 123-125 ° C. Stir at this temperature for 5 hours. It is then cooled to 30 'C and filtered. The filtered material is 50-55 kg of the above copper complex, which is used as a catalyst instead of metal copper in the next batch. 800 liters of 1,2-dichloroelane are added to the filtrate, and 500 kg of dimethyl sulfate are added under cooling at 33-35 ° C over 2 hours. After the addition, 100 kg of dimethyl sulfate are added over 1 hour, 100 kg of dimethyl sulfate and 25% sodium hydroxide solution (about 150 kg) are added again after 2 hours, so that the pH of the reaction mixture is y above 9. After the addition, it is heated to 40-42 'C, reacted for 2 hours, and cooled to 25-30' C. The reaction mixture was filtered from the solid impurities. The organic phase of the filtrate was separated by stirring with 400 liters of water and washing after separation. To the organic phase is added 1500 liters of water and the organic solvent is distilled off from the system. When the distillate is free of organic solvent, the mixture is cooled to 40 ° C, added with 150 kg of sodium bisulfite and 10 kg of clarifying charcoal and filtered after stirring for 1 hour. The filtrate was cooled to 20 ° C and basified to pH 10 with 25% sodium hydroxide solution. The resulting crystalline suspension was filtered through a centrifuge, washed with water to neutral and then the product was sprayed. 241 µl (71%) of 3,4,5-trimethoxybenzaldehyde are obtained, m.p. 73-75 'C.

The aqueous phase of the methylation reaction mixture was acidified to pH 2 with hydrochloric acid (2 x 200 L)

Extract with stirring with 1,2-dichloroethane. The organic phase contains dimethoxy hydroxybenzaldehyde compounds. The organic solution is mixed with the following batches of 1,2-dichloroethane.

Example 4

Example 3 was carried out with the difference that the organic solution from the previous batch containing dimethoxybenzaldehyde and the copper complex were used according to their copper content. In this case, the amount of dimethyl sulfate is 550 and 2x200 kg, and 180 kg of sodium bisulfite are used to purify the crude product.

289 kg (85%) of 3,4,5-trimethoxybenzaldehyde are obtained, m.p. 74-75 'C.

Claims (2)

A patent claim Improved process for the preparation of 3,4,5-trimethoxybenzaldehyde by hydrolysis of 3-methoxy-4-hydroxy-5-bromo-30-benzaldehyde in the presence of a catalyst under pressure with alkali metal hydroxide, followed by Methylation of 3-methoxy-4,5-dihydroxybenzaldehyde with dimethyl sulfate in the presence of a base and an organic solvent without isolation, characterized in that the copper complex of formula I is used as the catalyst and the hydrolysis is carried out at 120-125 ° C for 4-8 hours. the resulting 3-methoxy-4,5-dihydroxybenzal 40 dehyde is methylated in the reaction mixture in a heterogeneous system with water and an aromatic hydrocarbon or a chlorinated aliphatic hydrocarbon, by addition of at least two portions of dimethyl sulfate, The copper complex of formula (I) is isolated by filtration after hydrolysis or methylation and used as a catalyst for subsequent hydrolysis, and optionally dimeroxy-50-hydroxybenzaldehyde in an aqueous phase of the methylation reaction after treatment with mineral for the next methylation.