HU187145B - Process for preparing 2-/3,4-dimethoxy-phenyl/-2-isopropyl-acetonitrile - Google Patents

Abstract

The present invention relates to an improved process for the preparation of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile of formula I by reacting a nitrile and a halide of formula II with the reaction in a protic solvent medium with excess alkali hydroxide and general IV. a quaternary ammonium compound of the formula EMI3.1 wherein R1, R2, R3, and R4 are C1-6 straight or branched alkyl groups or phenylalkyl containing from 1 to 2 carbon atoms; Q is hydroxyl, halide or 1/2 SOJ in the presence of a catalytic amount by heating. H3CO-γ-CH2-CN II.1-UC0%> - Br III r 'r5 qh arc yv, -1-

Description

The present invention relates to a new economical preparation of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile of formula (1).

2- (3,4-Dimethoxyphenyl) -2-isopropylacetonitrile of formula I is a very important intermediate during the synthesis of Verapamil cardiac therapies.

Various methods for the synthesis of Verapamil are known, one of the most common of which is that one of the starting components is the acetonitrile derivative of formula 1 (No. 1 154 810,

No. 158,083 U.S. Patent Nos. 2,263,527; 2,631,222; German Patent Publication Nos. 78 92,732, 73 42,870; and U.S. Pat. Japanese release documents).

According to one of the literature methods for the synthesis of compound 1, the compound 11 is reacted with freshly prepared sodium ethylate in ethyl alcohol to form a sodium salt and then condensed with acetone and the resulting u-isopropylidene-3,4-dimethoxyphenylacetonitrile is palladium catalyst under pressure. reduced to give the compound of formula I. (J. Med. Chem. 1967, 262 cs. U.S. Patent 3,415,866). This method can hardly be used for industrial synthesis because the yield is poor: 45.4 '/, based on the compound of formula II.

There are two variants of other literature methods for the synthesis of the compound of formula (1). In these processes, the yields are appropriate (over 90%) but require very specific conditions.

The essence of these methods is to form a salt of compound II in an aprotic medium and then alkylate the salt with isopropyl bromide 111.

No. 2,263,527. According to German Patent Publication, compound II is formed with sodium amide under ice-cooling in various ethereal solvents, preferably 1,2-dimethoxyethane, and is then reacted overnight at room temperature with a solution of 111 in 1,2-dimethoxyethane. . The whole process is characterized by the high degree of caution usual for sensitive reactions. It is not substantially different from the method described above in U.S. Pat. and the process described in Japanese Patent Application Laid-Open, wherein the reaction of compound II with compound III is carried out at a higher temperature (70 ° C). This process is quicker, but requires this expensive and similarly aprotic dimethyl sulfoxide solvent and 1,2-dimethoxyethane, and a highly sensitive sodium hydride salt-forming reagent even more active than sodium amide.

Both methods require a highly aprotic special organic solvent and a highly active, explosive salt-forming reagent.

From an industrial point of view, they have the common disadvantage of being expensive solvents (1,2-dimethoxyethane or dimethylsulfoxide) and also expensive and explosive salt-forming reagents (sodium amide or sodium hydride) and super-anhydrous. The need for aprotic media to develop side-by-side protocols has also been implicated in avoiding side reactions, in particular the possible hydrolysis of the nitrile group, since it is known that the protic tube is highly hydrolyzable, especially when heated, in a highly basic medium.

Surprisingly, it has now been found that the compound of formula I can be obtained in a very simple manner, under high purity, under industrial conditions, by reacting a compound of formula II with a compound of formula IV in a protic medium and

Ft represents the same or different C 1-6 straight or branched alkyl groups, or C 1 -C 1-2 alkylene chains.

Q is hydroxide, halide, or 1 2 SO 2 ions can be performed by heating a quaternary ammonium compound by heating.

Ismer In light of the literature on the preparation of a compound of Formula I, it is surprising that even under these conditions, the carbon-carbon bond is formed without any side reaction.

Surprisingly, water is the most preferred solvent for the process according to the invention, and sodium hydroxide and potassium hydroxide are preferred as the alkali hydroxide. Catalysts of Formula IV are preferred as easy-to-handle telraalkylammonium halides, with tetrahutylammonium bromide being particularly preferred.

In our process, it is preferred that the compound of formula III

A 50% excess of I is used, but it is preferred that a large excess of alkaline hydroxide is present, particularly preferred is a 10-fold excess of alkaline hydroxide based on compound II.

The catalyst of formula IV is preferably a

0.01 to 0.1 mol, especially 0.02 to 0.03 mol, are used per compound II.

The process of the present invention is preferably carried out by heating at 70-150 ° C, particularly preferably 100-125 ° C.

In the process according to the invention, it is very advantageous to use stirring while boiling the alkali hydroxide solvent, but it is preferable to carry out the reaction in a closed system under pressure, also under stirring. If the process is carried out by boiling, it is highly advantageous to add the isopropyl bromide of formula III in divided portions. In the case of a closed system, it is also possible to carry out a single weighing of all reagents, but in this case it is also advantageous to add 5-15% of the compound of formula III used after a certain time in the middle of the reaction.

The compound of formula I formed during our process is very pure; it is sufficient to isolate the reaction with a water immiscible organic solvent, preferably aromatic hydrocarbons, after the reaction. particularly preferably, extraction with toluene followed by distillation of the solvent so that it can be directly used for further processing.

187 145 congregations are obtained. The crude product can also be distilled, the distillation being practically without loss, since there is no distillation residue due to the purity of the product.

The following examples illustrate the details of our procedure.

Example I

A mixture of 141.7 g of 3,4-dimethoxyphenylacetonitrile, 37.5 cm ^{3 of} isopropyl bromide, 256.0 g of sodium hydroxide, 224 cm ^{3 of} water and 6.4 g of tetrabutylammonium bromide is heated to reflux with stirring. Under stirring and refluxing the mixture was added 30.0 cm ³ of isopropyl bromide, a reaction time of 8 minutes for a further 15 cm ³ of isopropyl bromide, and a reaction time for 30 to 15 cm ³ of isopropyl bromide, a reaction time of 90 minutes, a further 7.5 cm ³ of isopropyl bromide. The mixture was refluxed for another 2.5 hours, cooled to 35 ° C, 100 cm ^{3 of} toluene was added, the two phases were separated and the aqueous phase was extracted with 100 cm ^{3 of} toluene. The combined organic phases were concentrated under reduced pressure to give 175.0 g (100%) of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile, 97% pure by gas chromatography and directly work-up. Distillation of the crude product gave 167.0 g (95.2%) of 176-177'Con, 133 psi, m.p. 62-64'C, which was completely homogeneous by gas chromatography.

Example 2

17.7 g of 3,4-dimethoxyphenylacetonitrile, 48.0 g of 50% w / w sodium hydroxide solution, 0.8 g of tetrabutylammonium bromide and 13.53 g of isopropyl bromide in a sealed apparatus at 120 ° C mixed. After a reaction time of 4 hours, additional isopropyl bromide (1.3 g) was added and the mixture was heated with stirring for a further 6 hours. The cooled mixture was worked up as in Example 1 to give 21.85 g (100%) of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile, which was directly processed. The gas content of this crude product was found to be 96.5% by gas chromatography.

Example 3

88.6 g of 3,4-dimethoxyphenylacetonitrile, 393 g of 50% potassium hydroxide solution, 4.0 g of tetrabutylammonium bromide, 47.0 cm ^{3 of} isopropyl bromide are heated under reflux. One hour, a reaction time of 2.5 hours and then 9.4 cm ³ -9,4cm ³ of isopropyl bromide was added, and after 3.5 hours reaction time (85%) 33 g of potassium hydroxide, 4.5 hours reaction time After cooling the mixture and working up as in Example 1. 101.6 g (92.7%) of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile are obtained which is directly suitable for further processing (97% active ingredient).

Example 4

8.85 g of 3,4-dimethoxyphenylacetonitrile, 33.6 g of 50% potassium hydroxide solution, 0.4 g of tetrabutylammonium bromide and 5.16 g of isopropyl bromide in a sealed apparatus at 120 ° C. mixed. After one hour of reaction, 0.47 cm ^{3 of} isopropyl bromide was added to the reaction and stirred for one hour at 120 ° C. After cooling, working up as in Example 1 gives 10.3 g (94%) of I, which is directly suitable for further processing.

Example 5

8.86 g of 3,4-dimethoxyphenylacetonitrile, 33.6 g of 50% potassium hydroxide solution, 0.35 g of benzyltriethylammonium bromide and 5.16 g of isopropyl bromide in a sealed apparatus at 120 ° C mixed. After a reaction time of two hours, an additional 0.62 g of isopropyl bromide was added to the reaction mixture and stirred for an additional hour at 120 ° C. After cooling, work up as in Example 1 to obtain 9.75 g (89%) of I, which is directly suitable for further work-up.

Example 6

8.86 g of 3,4-dimethoxyphenylacetonitrile, 24.0 g of 50% w / w sodium hydroxide solution, 0/45 g of tetrabutylammonium hydrogen sulphate and 6.7 g of isopropyl bromide in a sealed apparatus at 120 ° C mixed. After 4 hours, an additional 0.65 g of isopropyl bromide was added and the mixture was heated with stirring for an additional 3 hours. The cooled mixture was worked up as in Example 1 to give 9.96 g (90.8%) of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile, which was directly suitable for further processing.

Example 7

8.86 g of 3,4-dimethoxyphenylacetonitrile, 24.0 g of 50% sodium hydroxide solution, 1.0 g of 40% aqueous solution of tetrabutylammonium hydroxide and 4.7 cm ³ isopropyl bromide is heated under reflux with stirring. After 1 hour and then 2.5 hours, 1.0 cm ³ -1.0 cm ^{3 of} isopropyl bromide are added to the reaction mixture. After a reaction time of 4.5 hours, the mixture was cooled and worked up as in Example 1. 9.53 g (87%) of I are obtained, which is directly suitable for further processing.

Claims (7)

Patent claims An improved process for the preparation of 2- (3,4-dimethoxyphenyl) -2-isopropylacetonitrile of formula I by reacting a nitrile of formula II with a halide of formula III, characterized in that the reaction is carried out in a protic solvent medium with excess alkali hydroxide ammonium compound - where R 1, R ² , R ³ and R * are C 1-6, 3 187,145 straight or branched alkyl groups or phenylalkyl groups having 1 to 2 carbon atoms, Q is performed by heating in the presence of a catalytic amount of hydroxy, halide, or 1/2 SO2. Second embodiment of the method according to claim 1, characterized in that alkálihidorxidként sodium hydroxide or potassium hydroxide in 3-10-fold excess of the calculated θ II terms but _one needle nitrile, the protic solvent employed is water. 3. A method according to Claim embodiment wherein the catalyst is calculated as the nitrile of formula II, 0,01 -0, 1 mole ratio of _1g is preferably used in a molar ratio from 0.02 to 0.03. 4. A process according to any one of claims 1 to 3, wherein the catalyst is tetrabutylammonium bromide. 5. A process according to any one of claims 1 to 4, wherein the halide of formula III is present in an amount of 1-50%. 6. The process of claim 1, wherein the reaction is carried out at 70-150 ° C. 7. The process of claim 6, wherein the reaction is carried out under reflux or under pressure in a closed system at 100-120 ° C with stirring. 1 figure