HU188299B - Process for preparing veratrol and derivatives thereof - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of a veratrol derivative of the formula (I) wherein R is hydrogen or (C1-C4) -alkyl, the pyroctecholine and / or guaiacol derivatives of formula (II) wherein R 'is hydrogen. or methyl and R is methylated in methylene chloride and / or methyl bromide in the presence of a base. According to the invention, the methylation is carried out in the presence of a base having a stoichiometric amount or an excess of not more than 25 equivalents of s% by weight at a temperature of from 60 to 100 ° C. If desired, a quaternary ammonium compound and / or an organic diluent known per se is added as the phase transfer catalyst. By this method, final products of 99% or greater purity are obtained with a yield of at least 94%. (I) (II) -1-

Description

The present invention relates to a novel process for the preparation of veratrol derivatives of formula I wherein R is hydrogen or C 1-4 alkyl, preferably methyl, pyrocatechin and / or guaiacol derivatives of formula If wherein wherein R 'is hydrogen or methyl and R is methylated above with an aqueous halide in the presence of a base in an aqueous medium.

The compounds of formula (I) may be used as starting materials in the preparation of chemicals with valuable biological activity; For example, veratrol (R = H) is an essential starting material for the synthesis of, inter alia, α-methyl-u-amino-3- (3,4-dihydroxyphenyl) propionic acid (Dopegyt).

Veratrol is usually prepared using dimethyl sulfate alkylation of pyrocatechin (J. Chem. Soc. 89, 1649). A disadvantage of the known process is that very large amounts of dimethyl sulfate have to be used because in the aqueous-alkaline medium used for methylation, dimethyl sulfate is rapidly hydrolyzed in parallel with the methylation. The dimethylation of pyrocatechin is not complete, despite the large excess of alkylating agent, and the veratrol formed contains in each case at least 5-10% guaiacol. A further disadvantage is that dimethyl sulfate is a highly toxic substance, so special safety precautions are required when using it on an industrial scale.

Attempts have already been made to replace dimethyl sulfate with methyl chloride in the methylation of pyrocatechin. Thus, U.S. Pat. No. 1,277,186. According to the British patent, pyrocatechin is reacted with methyl chloride in the presence of an alkali metal carbonate or bicarbonate at a temperature of 110-130 ° C. However, under these conditions, only guaiacol is obtained with a yield of about 60%.

No. 76,122,030. Japanese Patent Laid-Open Publication discloses the preparation of alkoxyphenols, including guaiacol, in a gas phase. In the process, pyrocatechin is reacted with methanol at 285 ° C in the presence of a contact catalyst to obtain guaiacol with a 45-46% conversion and 88-91% selectivity.

No. 211,123. Spanish Patent Specification [Chem. Abstr. 50, 7858d (1956)], pyrocatechin is reacted with methyl chloride at 120 ° C in aqueous or methanolic medium in the presence of an alkali. With a yield of about 80%, the product can be isolated as a mixture of veratrol, guaiacol and pyrocatechin containing 50-75% veratrol. Veratrol can only be separated from guaiacol and pyrocatechin by a lengthy, step-by-step purification process, which, in addition to heavy chemicals and labor, also results in significant material loss.

A common feature of known processes for the production of verartrole by reaction with pyrocatechin and methyl chloride is the use of very violent reaction conditions (temperatures above 110 ° C, pressures above 10 bar), but even under these conditions they do not achieve full dimethylation. Therefore, the known methods are uneconomical and unsuitable for large-scale implementation.

According to the present invention, by eliminating the drawbacks of the known processes, the compounds of formula I, i.e. veratrole and C 1-4 alkyl homologues of veratrol, can be obtained in a high yield by a simple and economical process.

The present invention is based on the discovery that the methylation of the compounds of the formula II can be completed and the veratrol derivatives of the formula I can be prepared in an over 90% yield if the reaction is carried out with methyl halide (methyl chloride and / or methyl). bromide) and the compound of formula (II) are kept as high as possible and the concentration of hydroxyl ions is kept as low as possible. Such conditions can be achieved by using the base in a stoichiometric amount of 25 equivalents or less (i.e., 2-2.5 molar equivalents of base with respect to 1 mol of the pyrocatechin derivative of formula II (R '= H). The base used is T-1.25 molar equivalent based on 1 molar guaiacol derivative (R '= methyl). In this case, surprisingly, both the hydroxyl groups of the pyrocatechin compounds of the formula II and the hydroxyl groups of the guaiacol compounds of the formula II are already completely mild (60-100 ° C and 1-6 bar). methylation to give pure veratrol derivatives of formula (I) in 90-95% yield.

The present invention relates to a process for the preparation of veratrol derivatives of the formula I by methylation of the pyrocatechin and / or guaiacol derivatives II with methyl chloride and / or methyl bromide in the presence of a base. According to the invention, the methylation is carried out at a temperature of 60-100 ° C and a pressure of 1-6 bar, and the base is used in a stoichiometric amount or in an excess of up to 25 equivalent%.

In the process according to the invention, the temperature and pressure used are closely related. When working at higher temperatures (e.g., 90-100 ° C), higher pressures (e.g., 4 to 6 bar) are expedient. The reaction time may vary within wide limits depending on the temperature and pressure used; the reaction usually takes a few hours.

The methylating agent used in the process of the invention is methyl chloride and / or methyl bromide. The methylating agent may also be used in the form of methyl chloride and / or methyl bromide-containing waste gas, which is formed, for example, by demethylation of compounds containing methoxy with hydrochloric acid and / or hydrobromic acid. The use of such waste gases does not require the complete removal of contaminating components; hydrochloric or hydrobromic acid gas and various organic solvent vapors no longer interfere in a few volume percentages.

Inorganic and organic bases may be used as bases in the process of the invention, optionally in the form of mixtures thereof. Examples of inorganic bases are alkali metal hydroxides and organic bases include pyridine.

As a biphasic reaction takes place, care should be taken to obtain an appropriate reaction rate

188 299 on a thorough mixing of the gaseous methylating agent and the starting material in solution. It has also been found that the use of phase transfer catalysts and auxiliary solvents to promote the dissolution of the methylating agent can significantly speed up the reaction. The use of phase transfer catalysts and co-solvents in the preparation of veratrol and veratrol derivatives has not yet been described; however, other biphasic reactions, such as the production of 1,3-benzodioxole from pyrocatechin and methylene bromide, have already been used to increase the reaction rate (Tetrahedron 30, 1379 (1974); Tetrahedron Letters 3489 (1975) and 3361 (1976)].

Quaternary ammonium compounds may be used as phase transfer catalysts in the reaction. The methylating agent used as the reagent is significantly more soluble in the organic phase of the biphasic reaction mixture (consisting of the final product of formula I) than in the aqueous phase containing the starting material of formula II, but the starting material is only slightly soluble in the organic phase. The role of the phase transfer catalysts is to make the starting material (II) soluble in the organic phase, thus greatly facilitating the contact of the reagents and thereby accelerating the reaction.

Suitable quaternary ammonium compounds are, for example, tetramethylammonium halides, benzyltrimethylammonium halides, cetyltrimethylammonium halides, the corresponding ammonium hydroxides and the like. When used as quaternary ammonium compounds, ammonium hydroxides may also serve as bases. The quaternary ammonium compounds can also be prepared in the reaction mixture in a manner known per se by reaction of ammonia or an amine with the methylating agent (methyl chloride and / or methyl bromide) used.

The amount of quaternary ammonium compounds is not critical. If only quaternary ammonium hydroxides are used as the base, these compounds will, of course, need to be added in the proportions given above (stoichiometric or at most 25 equivalents). In other cases, the quaternary ammonium compounds will generally be employed in an amount of from 0.1 to 5 mol% relative to the starting material of formula II; the upper limit of the amount of phase transfer catalyst is essentially determined solely by economic factors.

If desired, auxiliary solvents for promoting the dissolution of the methylating agent may be added to the reaction mixture. Organic liquids such as aliphatic or aromatic hydrocarbons which are inert to the reaction and which are highly soluble in the methylating agent employed may be used as auxiliary solvents. The amount of cosolvent is generally from 10 to 1000% by volume of the aqueous reaction mixture; the upper limit of the amount of auxiliary solvent is determined primarily by economic factors and processing factors.

The process according to the invention can be carried out batchwise by weighing the starting material (II), water and base in a gas-liquid contact device and at a temperature of 60-100 ° C and a pressure of 1-6 bar. chloride and / or methyl bromide or a gas containing said compound (s) is introduced into the reactor at a rate corresponding to the reaction. Alternatively, the base is continuously added to the reaction mixture at the same time as the methylating agent is introduced. The reaction may also be carried out by coupling several reactors (preferably 3-6) to a so-called cascade and preferably introducing at one end of the reactor series a methylating agent and at the other end a mixture of starting material (II), water and base. ; i.e., reactants are contacted in countercurrent flow. The reaction is further provided in packed or plate column (s). as well as any other apparatus for gas and liquid coin injection.

The reaction mixture obtained in the process of the invention is worked up in a manner known per se and the final product can be isolated by known methods (for example, extraction, steam distillation, phase separation, pH adjustment, crystallization, distillation or a combination of these).

The process of the present invention provides pure compounds of formula (I) in 90-95% yield. The process is easy to carry out with a short reaction time. Due to the relatively low reaction temperature employed and the exothermic nature of the reaction, the heat demand is minimal.

The process of the invention is described in detail in the following examples without limiting the scope of the invention.

EXAMPLE 1 2 L of water, 400 g of sodium hydroxide and 550 g of pyrocatechin were weighed into a 1 liter acid-proof steel autoclave. At a temperature between 70 ° C and 80 ° C, about 10 moles of methyl chloride gas are introduced into the reactor at the rate at which it reacts. 100 g of sodium hydroxide are then dissolved in the biphasic reaction mixture and the mixture is steam distilled. Pure veratrole is obtained as the lower phase. After acidifying the reaction mixture and steam distillation, a small amount of guaiacol is obtained which can be recycled to the reaction. This gives pure veratrol in 92% yield. The product was found to be more than 99% pure by gas chromatography.

Example 2

Example 1 is followed. but the reaction is carried out at 4 bar and 100 ° C. After working up the reaction mixture, veratrol is obtained in 95% yield.

After recirculation of 188 299 ri, 95% yield is obtained; the product was found to contain only 0.5% guaiacol by gas chromatography.

Example 3

The apparatus described in Example 1 was charged with 2 liters of water, 400 g of sodium hydroxide and 440 g of pyrocatechin. The reaction was carried out at 4 bar and 90-100 ° C. After absorption of 10 moles of methyl chloride, the reaction mixture is cooled, the phases are separated and a few percent of guaiacol separated from the lower alkaline phase for acidification is recycled. The upper phase was distilled under vacuum at 26 mbar to give veratrol in 95% yield.

Example 4

In the apparatus described in Example 1, 2 liters of water, 500 g of sodium hydroxide and 550 g of pyrocatechin were weighed, and methyl chloride was introduced at 3 bar and 100 ° C until absorption was observed. The layers were separated and the upper layer was washed twice with 200 mL of 20% aqueous sodium hydroxide solution and then distilled. The basic washings were viszszavezetjük the machine, and after 400 g of sodium hydroxide, 1.5 liters of water and 495 g of catechol Replies ² ^ administered the same conditions as above methyl chloride was passed into the reaction again.

Similarly, the reaction was repeated twice more to give veratrol of greater than 99% purity in 90% yield. ³⁰

Example 5

A 1-1 per liter of gas and liquid on three absorber ³⁵ and a suitable outlet bonded in series to form a cascade that. To the first absorber, methyl chloride gas was added at a constant rate over a gas hour, and to the last, an aqueous solution of 13.5% w / w sodium hydroxide and 18.6% pyrocatechin was added at a constant rate of about 25 ml / min. temperature and atmospheric pressure. After steady-state, the product leaving the first reactor contains 90% of veratrole in 45 units of pyrocatechin added per unit time.

Example 6 50

The apparatus described in Example 1 is charged with 2 liters of water, 220 g of sodium hydroxide and 480 g of guaiacol. About 5.1 moles of methyl chloride were introduced into the reactor at 4 bar. The cooled reaction mixture is then separated. Distillation of the organic phase gives 94% purity of veratrol by gas chromatography (> 99%).

Example 7

In the same manner as in Example 4, 2 g of benzyltrimethylammonium chloride were added to the reaction mixture. Unreacted guaiacol is three to three pages

Example 8-liter steel autoclave 2 liters of water, 0.5 L of toluene, 440 g of sodium hydroxide, ¹⁰⁵⁵⁰ g of catechol and 1 g of cetyl amine is used. The mixture was saturated with methyl chloride at room temperature and 4 bar, and the temperature was slowly raised to 100 ° C. After the methyl chloride had reacted, the reaction according to Example 3, was worked up by fractional distillation to ^15. 95% yield yields veratrol greater than 99%.

EXAMPLE 9 610 g of 4-methylpyrocatechin, 2 liters of water, 1 liter of toluene and 440 g of sodium hydroxide were charged into a stainless steel autoclave. The reaction mixture was reacted with methyl chloride at 4 bar and 100 ° C. After cessation of methyl chloride consumption, the organic phase was extracted with 10% aqueous sodium hydroxide solution and then distilled. 4-methylveratrole was obtained in 95% yield. MP: 120 ° C / 1.3 kPa; purity:> 99%.

Claims (4)

Patent claims A process for the preparation of a vetatrol derivative of formula I wherein R is hydrogen or C1-C4 alkyl: Pyrocatechin and / or guaiacol derivative of formula II: wherein R 'is hydrogen or methyl and R is methylated by methyl chloride and / or methyl bromide in aqueous medium in the presence of a base, characterized in that the methylation is carried out at a temperature of 60-100 ° C, a pressure of 1-6 bar, in a stoichiometric amount or at most 25 excess of base equivalent, optionally in the presence of a quaternary ammonium compound known per se as a phase transfer catalyst and / or an organic cosolvent. The process of claim 1 wherein the base is a quaternary ammonium hydroxide. 3. A process according to claim 1 wherein the methylation is 0.1-5 mol% of the quaternary ammonium salt, preferably benzyltrimethylammonium halide or cetyltrimethylammonium, based on the starting material (II). halide. A method according to any one of the preceding claims. characterized in that the organic cosolvent used is an aromatic hydrocarbon, preferably toluene.