FI107530B - Process for preparing 3-acetoxy-2-methylbenzoyl chloride - Google Patents

Description

107530

Process for the preparation of 3-acetoxy-2-methylbenzoyl chloride

The present invention relates to a process for the preparation of 3-acetoxy-2-methylbenzoyl chloride by reaction between 3-acetoxy-2-methylbenzoic acid and thionyl chloride.

A variety of reagents have been used to make acid chlorides from acids, one of the basic reactions in organic chemistry, described in, e.g. in Comprehensive Organic Synthesis, Vol. 6 pages 302-306 (ISBN 0-08-040597-5), as well as various catalysts and solvents. Polar solvents normally increase the reaction rate. The solvent must be inert, so halogenated hydrocarbons, aromatic and aliphatic hydrocarbons 10 are suitable solvents. Ethers and esters have also been used. A common practical way to prepare acid chlorides is to dissolve the starting acid in an inert solvent such as toluene, add the catalyst and then gradually add a reagent such as thionyl chloride to the heated mixture. Another basic method used in a laboratory laboratory is to mix the acid directly with excess thionyl chloride and heat the mixture until the reaction is complete and then distill under normal pressure, first with excess thionyl chloride and then with product under reduced pressure. This is suitable for stable acid chlorides and on a small scale where the rate and amount of gas formation is not a problem.

Problems with the preparation of acid chlorides are encountered when purification of the product by distillation or crystallization is difficult, especially if a particular purity of the product is required.

Preparation of 3-acetoxy-2-methylbenzoyl chloride from 3-acetoxy-2-methylbenzoic acid is known from WO 98/09951, pages 34-35 of which describes the process of dissolving the starting acid in methyl tert-butyl ether in the reaction step ( 2% of acid) dimethylformamide and then thionyl chloride is added at once. Further treatment is evaporation of the solvent, removal of excess thionyl chloride by addition and evaporation of a second solvent (toluene), recrystallization from a third solvent (heptane) below 5 ° C and drying under vacuum at below 20 ° C. The yield is 82.3% of a brown product with a purity of 97.5% by HPLC-30.

The disadvantage of the above process is the use of many solvents and the required evaporation steps, the low temperature required for crystallization, partly due to the low melting point of the product itself (about 32-36 ° C depending on purity) and the same low temperature required for drying. Nevertheless, the product is colored, which is a problem when used in drug applications where the color tends to remain in the final product. The production capacity important for industrial production in the above process remains relatively low due to the large amounts of solvent required which reduce the amount of product obtained from one reactor.

It is an object of the invention to provide an improved process for the preparation of 3-acetoxy-2-methylbenzoyl chloride based on the use of basic reagents, which avoids the above-mentioned prior art problems. The invention is characterized in that 3-acetoxy-2-methylbenzoic acid is gradually added to a mixture of thionyl chloride and dimethylformamide acting as a catalyst, while maintaining the temperature of the mixture below 45 ° C and removing thionyl chloride after the reaction step. excess.

It has been found that practically quantitative yields of colorless or nearly colorless acid chloride can be obtained when operating according to the invention. The amount of impurities, such as anhydride, is small. In addition, the process is simple and gives good production capacity and no separate purification step is required at all. The process is characterized in that no separate solvent is used in the reaction, that the reaction is carried out in a limited temperature range, and that a certain addition order is followed.

The preparation process uses good quality colorless 3-acetoxy-2-methyl-20-benzoic acid (AMBA), thionyl chloride (SOCl2) and dimethylformamide (DMF). The process does not remove the color or impurities of the starting materials, but the quality of the starting material is maintained by the process of the invention. When the limits of the invention are exceeded, the product acid chloride is colored and / or the amount of impurities is increased, even if the starting material is of good quality. In the process, thionyl chloride and a catalytic amount of DMF are first added to the reactor. Solid AMBA is gradually added to this mixture. The reaction is allowed to proceed only at a slightly elevated temperature and upon completion of the reaction, the excess thionyl chloride is removed, e.g. by evaporation initially under reduced pressure and only at a slightly elevated temperature, followed by the completion of thionyl chloride. from the reaction mixture by supplying, under reduced pressure, a slightly inert gas, e.g. dry nitrogen, helium or argon, to the reaction mixture. Excess thionyl chloride may be removed by other known methods. Thin-film evaporation and chemical destruction of thionyl chloride with, for example, formic acid are suitable; these methods also achieve low levels of thionyl chloride.

The method of the invention is described in more detail in the Examples and in the following. The amount of thionyl chloride should be at least slightly more than 1 equivalent relative to AMBA 107530 3, since some thionyl chloride is evaporated with the HCL and SO2 gases formed in the reaction. A suitable amount is from about 1.1 to about 1.3 equivalents, most preferably from 1.1 to 1.2 equivalents. A larger amount can be used but is unnecessary although the reaction may be slightly accelerated. With minor excesses, the reaction is slightly refluxed towards the end. A very small excess runs the risk of the reaction remaining due to evaporation of thionyl chloride. The amount of DMF catalyst can be kept below 0.6% of the amount of AMBA. A preferred amount is 0.04-0.1% which may be left in the product as a minor impurity. A higher amount will speed up the reaction but is not necessary. The absence or very small amount of catalyst requires a long re-10 reaction time or a harmful high temperature. The reaction temperature is maintained below 45 ° C and preferably at about 22-35 ° C. The reaction is endothermic and can advantageously be carried out near room temperature by introducing only a little heat into the mixture. At higher temperatures, e.g., above 50 ° C, the reaction mixture begins to turn yellow and a significant amount of thionyl chloride evaporates with the gases. At temperatures below 20 ° C, the reaction-15 mixture may partially crystallize. The gradual addition of AMBA to thionyl chloride keeps the formation of by-products, such as anhydride, low. In addition, the feed rate can be used to control the amount of gas evolved, thus avoiding any risk of pressure build-up. The reaction is complete about one hour after completion of the feed (time depends on amount of catalyst and temperature). The reactor is aspirated under reduced pressure and allowed to evaporate most of the excess thionyl chloride while heating the mixture slightly, but keeping it below 45 ° C. When evaporation is clearly retarded, dry nitrogen or other inert gas is introduced into the reaction mixture while still maintaining the reaction temperature below 45 ° C, most preferably between 30 and 40 ° C.

Example 1

36.8 g (0.31 mol, 1.2 eq.) Of distilled thionyl chloride and 0.029 g (0.058% of the amount of AMBA) were weighed into the flask. To this mixture was added a minimum of 50 g (0.26 mol, 1 equiv.) Of AMBA over a period of 3 hours while maintaining the temperature at 25-30 ° C. After all was added, the mixture was allowed to stir for a further two and a half hours and then suctioned under reduced pressure and evaporated with thionyl chloride for an hour, gradually raising the temperature to 30-35 ° C. Subsequently, a small stream of dry nitrogen was passed under the liquid surface for an hour while still maintaining the vacuum in the flask and allowing the temperature to rise to about 40 ° C. The product then contained only a small amount of thionyl chloride, was almost colorless and crystallized as a white crystalline mass. In addition to the catalyst and thio-35-yl chloride residues, the product contained significantly less than 0.5% AMBA, AMBA anhydride, other dimeric products, and other impurities less than 0.1%.

107530 4

Example 2: amount of catalyst added

36.8 g (0.31 mol, 1.2 eq.) Of distilled thionyl chloride and 0.29 g (0.58% of AMBA) were weighed into the flask. To this mixture was added a minimum of 50 g (0.26 mol, 1 equiv.) Of AMBA over 2 hours while maintaining the temperature at 22-5 ° C. After all was added, the mixture was allowed to stir for an additional hour and then suctioned under reduced pressure and thionyl chloride evaporated for 1 hour, gradually raising the temperature to 30-35 ° C. Subsequently, a small stream of dry nitrogen was passed under the liquid surface for an hour while still maintaining the vacuum in the flask and allowing the temperature to rise to about 40 ° C. The product then contained only a small amount of thionyl chloride, was almost colorless and crystallized as a white crystalline mass. In addition to the catalyst and thionyl chloride residues, the product contained significantly less than 0.5% AMBA, AMBA anhydride, other dimeric products, and other impurities less than 0.1%.

From the example it can be concluded that the added amount of catalyst gives a slightly faster reaction but does not affect the color of the product or the amount of by-products if the other conditions are considered correct. However, the added amount of catalyst remains as an impurity in the product.

Comparative Example 1

18.4 g (0.15 mol, 1.2 eq.) Of distilled thionyl chloride and 0.0152 g (0.058% of the amount of AMBA) were weighed into the flask. To this mixture was added a minimum of 25 g (0.13 mol, 1 equiv.) Of AMBA over an hour while maintaining the temperature between 50-20 ° C. After all was added, the mixture was allowed to stir for another hour. The mixture was still cloudy and sampled with 9.2% of unreacted AMBA and 1.56% of AMBA anhydride. The thionyl chloride content was then determined and was 3.7%. After stirring the reaction mixture for another hour at about 50 ° C, the mixture was still cloudy. When 5.7 g (about 0.37 eq.) Of thionyl chloride were added, the reaction continued. Evaporation of SOCl2 first in vacuo and then bubbled with helium under reduced pressure gave a product which was clearly yellowish.

From the example it is observed that at higher temperatures the amount of thionyl chloride was not sufficient due to evaporation, a by-product and discoloration were formed.

Comparative Example 2 18.4 g (0.15 mol, 1.2 eq.) Of distilled thionyl chloride and 0.50 g (2% of AMBA) were weighed into a flask. To this mixture was added 25 g (0.13 mol, 1 eq.) AMBAa during half an hour in five 5 gram portions maintaining the temperature between 33-37 ° C. After all was added, the mixture was allowed to stir for 1 hour and then the temperature of the mixture was gradually raised to 80-90 ° C to distil excess thionyl chloride under normal pressure for 1 hour. Thereafter, distillation was continued at about 82 ° C at 0.45 bar for one hour. The product mixture contained approximately 0.23% AMBA, dimeric acid chloride by-product 0.2% and thionyl chloride approximately 1%. 5 However, the product was yellow in color.

Claims (8)

107530 A process for the preparation of 3-acetoxy-2-methylbenzoyl chloride by reaction between 3-acetoxy-2-methylbenzoic acid and thionyl chloride, characterized in that 3-acetoxy is gradually added to a mixture of thionyl chloride and dimethylformamide acting as a catalyst -2-methylbenzoic acid while maintaining the temperature of the mixture below 45 ° C and removing excess thionyl chloride after the reaction step. Process according to Claim 1, characterized in that the reaction is carried out at a temperature in the range of 20-45 ° C, preferably in the range of 22-35 ° C. Process according to Claim 1 or 2, characterized in that the amount of thionyl chloride used is from 1.1 to 1.3 equivalents per equivalent of 3-acetoxy-2-methylbenzoic acid. Process according to one of the preceding claims, characterized in that the amount of dimethylformamide is 0.04-0.6% by weight, preferably 0.04-0.1% by weight, of the amount of 3-acetoxy-2-methylbenzoic acid used in the reaction. . Process according to one of the preceding claims, characterized in that the thionyl chloride is removed from the reaction mixture by evaporation. Process according to any one of the preceding claims, characterized in that the thionyl chloride is removed by passing an inert gas such as nitrogen into the reaction mixture. . Process according to claim 5 or 6, characterized in that during the removal of thionyl chloride the temperature of the mixture is kept below 45 ° C, preferably between 30 and 40 ° C. Process according to one of Claims 5 to 7, characterized in that the thionyl chloride is removed by evaporation and / or by a stream of hydrogen gas under reduced pressure. 107550