HU206080B - Process for producing cinnamic acid nitrile derivatives - Google Patents

Abstract

Cinnamic-acid-nitrile derivs of formula (1) - where R = H, NO2-, CH3O gp or Cl- ion; R' = hydrogen, CH3-, C6H5-, or nucleus substd. phenyl gp; and R'' = H or 1-4C alkyl gp - are prepd from cpds (ii) and (iii), by boiling at 100-150deg.C for 4-8 hours, in the presence of an alkali, alkoxide-, or a mixed alkali-hydroxide and alkali-alkoxide condensing agent. - The condensing agent is prepd prior to the reaction by boiling alkali-hydroxide with methanol or ethanol. Benzene followed by water is added to the reaction mix after cooling. Phases are sepd. Cinnamic nitrile is obtd. from the oil phase by distillation

Description

Scope of the description: 6 pages (including Figure I)

4,

EN 206 080 Β

FIELD OF THE INVENTION The present invention relates to cinnamic acid nitrile derivatives of formula I wherein R is hydrogen, chloro or nitro, amino or methoxy;

R 'is hydrogen or methyl, phenyl or halophenyl, and

R 'is hydrogen or a C1-C4 alkyl group by reaction of the aromatic aldehydes of formula (II) or ketones (III) and the nitriles of formula (III), wherein R, R', R 'are as defined above.

Cinnamic acid nitrile derivatives are important substances in the manufacture of N- (3-phenylpropyl- [2] [1,1-diphenylpropyl-3] -amine) lactate (prenylamine lactate) used in medicine. Several processes are known for their preparation, such as those described in No. 7020094. According to Japanese patent specification, acetonitrile is reacted with metal sodium, and the acetonitrile solution of the product formed is boiled with benzaldehyde, acetophenone or benzophenone for 9 hours, when cinnamon nitrile, 3-methyl cinnamitrile or 3-phenylfahynitrile are produced in good yield. The aromatic aldehyde or ketone, acetonitrile, metal sodium molar ratio is 1: 29: 2.

Another solution is described in J. Med. Chem., 12, 271 (1969), according to which equimolar amounts of aromatic aldehydes or ketones, aliphatic nitriles and sodium amide are reacted in ether solution at room temperature or boiled when saturated 3-hydroxy compound. In the second step, it is converted to cinnamic acid nitrile by boiling with phosphorus pentoxide or acid (e.g. formic acid). In this process, compounds of formula (I) are prepared in which R is hydrogen or halogen, R 'is phenyl or halophenyl, and R' is hydrogen or methyl.

3-Hydroxy-3-phenylpropionitrile is also the product when benzophenone and acetonitrile are reacted in the presence of butyl lithium (J. Org, Chem. 33, 3402 (1968). The 3-hydroxy compound can be converted to cinnamic acid nitrile by dehydration.

No. 7,449,940. According to Japanese patent specification, compounds of formula I wherein R 1 is hydrogen, alkyl or alkoxy, R 'is phenyl and R' are prepared by reacting 1 mole of keto compound with 811 moles of acetone iteration with 3-5 moles of potassium. in the presence of hydroxide.

The disadvantage of these technologies is that their condensing devices are dangerous and the reactions with them are quite complicated and that a relatively large excess of the starting nitrile or the condensing agent has to be used.

Our aim was to find an easy-to-use, simple technology condensing agent for the preparation of the cinnamic acid nitrile derivatives in order to overcome these disadvantages.

In our experimental work, it has been found that alkali metal alkoxide or specially prepared alkali metal hydroxide alkali metal alkoxide blend is excellent?

reacting the reaction with a good yield and the compound having a purity of at least 96%.

According to the invention, the compounds of formula (I) are prepared by reacting an aldehyde or ketone of formula (II) with a mole of 0.5 to 1 mole of alkali metal / C 1 to 1 mole of alkali metal prior to the reaction. in the presence of an alkali metal hydroxide and alkali metal / 1-2 carbon atoms produced by boiling with hydroxide and C 1-2 alkanol at 80-180 ° C for 38 hours, preferably with stirring of 2-5 molar equivalent of Formula III. the reaction mixture is cooled, benzene and water are added and the resulting compound of formula (I) is isolated in a manner known per se from the benzene phase.

The reaction is preferably carried out using 3 moles of nitrile III and 0.6 moles of condensing agent per mole of aromatic aldehyde of formula (II) or ketone. The reaction temperature is preferably 100-150 ° C, and the reaction time is preferably 4-8 hours.

When the reaction mixture is worked up, the compound of formula (I) is isolated by evaporation from the benzene phase after neutralization and drying, followed by fractional distillation of the residue. The residue is distilled at a pressure of up to 133 Pa.

It is therefore an object of the present invention to use an alkali metal alkoxide or a less expensive mixture of special alkali metal hydroxide and alkali metal alkoxide prepared prior to the reaction as the condensing agent, thus eliminating dangerous and expensive metal sodium, sodium amide and butyl lithium. In addition, the relative proportions of the materials used can be significantly reduced (2-5 moles of acetonitrile and 0.51 moles of condensing agent are required per mole of keto compound).

Our recognition is surprising because the beneficial effect was attributed to the basicity of the compound used, and although alkali alkoxides are known to be weaker bases than alkali hydroxides, the result was more favorable in all respects.

Another important advantage of using our method is that by reducing the high excess of expensive nitrile reactant, the material-specifics are improved, the processing of the product becomes simpler and more favorable, and thus the economy of the process is naturally improved.

As an advantage, unlike metal sodium and sodium amide solutions, in which a large amount of solvent is used, our technology does not need to be a solvent during the reaction.

For the condensation of aromatic aldehydes or ketones with 2 to 6 carbon atoms, an alkali alkoxide or a mixture of alkali hydroxide and alkali alkoxide is used, the latter being produced in a first step of technology by boiling with potassium hydroxide and at least twice the amount of methyl or ethyl alcohol. during 1/2 hour. The residual solvent is then distilled off under reduced pressure and the reactants are added to the residue and heated to 120-130 ° C for at least 4 hours.

After addition of benzene, water was added and, after drying from the benzene moiety, the final product was recovered by vacuum distillation. The yield is 70-82% based on the oxo compound and 97-98% purity.

The process according to the invention can be ascertained below in comparison with the process starting from cinnamon aldehyde

- a cinnamon nitrile derivative formed in one step, which is hydrogenated to be an important intermediate in the pharmaceutical industry and can be converted to the corresponding primary saturated amine;

- in the prior art process, three steps are required to prepare the saturated nitrile compound (oxime, dehydration, arylation) (the nitrile compound can also be converted to a saturated amine by hydrogenation).

The following examples illustrate the process of the invention.

Example 1

With stirrers, a thermometer and a reflux condenser, 45.56 g (0.25 mol) of benzophenone, 30.79 g (0.75 mol) of acetonitrile and 9 ml were added to a 0.5 dm ^{2 3} flask equipped with a calcium chloride tube. , 5 g (0.15 mole) of potassium hydroxide and potassium hydroxide, prepared as follows: Dissolve 8.42 g of potassium hydroxide in 25 ml of ethyl alcohol with stirring for 0.5 h. boiled under reflux. The solution was then evaporated to dryness and the residue containing 20% potassium ethylate was used as a catalyst. The reaction mixture was boiled under stirring for four hours while gradually increasing to 120-130 ° C. The reaction mixture was cooled with stirring, 100 cm ^{3 of} benzene and 100 cm ^{3 of} water was added at a rate such that the temperature was max. 4-5 ° C. The benzene and aqueous phases were separated in a separatory funnel. The aqueous phase was extracted with 50 cm ^{3 of} benzene and the combined benzene phase was washed with water (three to four washes with 100-100 cm ^{3 of} water). The benzene solution was dried over magnesium sulfate, the solution was filtered and concentrated in vacuo (water jet pump). Finally, the residue is equipped with a rectifying column filled with Raschig rings (diameter: 3 cm, height: 20 cm) in a vacuum distillation apparatus with max. It was fractionated at 133 Pa. The main product distils at 160-172 ° C. Mass, 43.0 g, 97-98% purity. The yield for benzophenone is 81.7%. The pre-distillate is 7580% by volume of benzophenone, which can be reused during further production. The mixture of the product mixture and the distillates was determined by gas chromatography, on a 3 m column filled with 10% SE-30 silicone on Chromosorb W stationary phase at 200 ° C.

Example 2

In the device described in Example 1, benzophenone (45.56 g, 0.25 mol), acetonitrile (30.79 g, 0.75 mol) and potassium hydroxide (8.42 g, 0.15 mol) in 25 cm ^{3 were added.} A catalyst consisting of potassium hydroxide and potassium methylate was prepared as described in Example III. The reaction and processing of the reaction mixture were carried out as described in Example 1.

Production of phenyl cinnamic acid nitrile is 80-82%.

$ 3 Example

In the apparatus described in Example 1, benzophenor (45.56 g, 0.25 mol), acetonitrile (30.79 g, 0.75 mol) and potassium methylate (10.52 g, 0.15 mol) were weighed. Reaction mixture közben was stirred with stirring for four hours, then a reflux condenser, coupling cooler and collector were placed in the reflux condenser, and 4-5 cm ^{3 of} liquid was distilled off under strong heating. The duration of the distillation is 10-15 minutes, while the temperature of the reaction mixture has increased to 120-130 ° C during the distillation. The reaction mixture was then processed and the product recovered as in Example 1.

The weight of the main product, 97-98% pure, was 41.90 g, and the yield calculated for benzophenone was 79.6%.

Example 4

In the apparatus described in Example 1, benzophenone (45.56 g, 0.25 mole), acetonitrile (20.53 g, 0.50 mole) and potassium hydroxide (7.01 g, 0.125 mole) were weighed with 21 cm @ ^{3 of} ethanol. The catalyst consisting of potassium hydroxide and potassium ethylate was prepared as described in Example III. The reaction and processing of the reaction mixture were carried out as described in Example 1.

Production is 78%.

Example 5

All were carried out as described in Example 4, using only 7.01 g (0.125 mole) of potassium hydroxide in 21 cm ^{3 of} methanol.

The yield of benzophenone is 75%.

Example 6

In the apparatus described in Example 1, benzophenone (45.56 g, 0.25 mole), acetonitrile (51.32 g, 1.25 mole) and potassium hydroxide (14.03 g, 0.25 mole) were weighed with methanol (43 cm ^3). A catalyst consisting of potassium hydroxide and potassium methylate was prepared as described in Example 1A. The reaction and processing of the reaction mixture were carried out as described in Example 1.

Production is 80%.

Example 7

In each case, as described in Example 6, only 14.03 g (0.25 mol) of potassium hydride oxide in 43 cm ^{3 of} ethanol were used as catalyst. Yield: 80%.

Example 8

The apparatus described in Example 1 was weighed

26.53 g (0.25 mole) of benzaldehyde, 30.79 g of acetonitrile (0.75 mol) and potassium in 21 cm ³ of ethanol and as described in Example 1. 8.42 g of potassium hydroxide (0.15 mol) a catalyst consisting of hydroxide and potassium alkoxide. The reaction and processing of the reaction mixture are described in FIG.

as described in Example III.

EN 206 080 Β

The production of cinnamic acid is 75% on benzaldehyde.

Example 9

The technology described in Example 8 was repeated, except that the catalyst used was 8.42 g (0.15 mole) of potassium hydroxide in 21 cm ^{3 of} methanol.

Production was the same as in Example 8.

Example 10

Benzaldehyde (26.53 g, 0.25 mol), acetonitrile (30.79 g, 0.75 mol) and potassium methylate (10.52 g, 0.15 mol) were added to the apparatus described in Example 1. The reaction and processing of the reaction mixture were carried out as described in Example 1.

The production of cinnamic acid is 70.4% on benzaldehyde,

Example 11

It was weighed into the apparatus described in Example 1. 30.04 g (0.25 mol) of acetophenone, 30.79 g of acetonitrile (0.75 mol) in 21 cm ³ of ethanol and powdered potassium hydroxide (8.42 g, 0.15 mol) catalyst prepared as described in Example 1. The reaction and processing of the reaction mixture were carried out as described in Example 1.

The production of 3-phenyl-3-methyl cinnamic acid nitrile was 77.3%.

Example 12

The procedure of Example 11 was repeated with a catalyst of 14.03 g of potassium hydroxide and 21 cm ^{3 of} methanol.

Yield 77.5%.

Example 13

The apparatus described in Example 1 was charged with 30.04 g (0.25 mol) of acetophenone, 30.79 g (0.75 mol) of acetonitrile and 10.52 g (0.15 mol) of potassium methylate. The reaction and processing of the reaction mixture were carried out as described in Example 1.

The production of 3-phenyl-3-methyl cinnamic acid nitrile was 75.2%.

Claims (3)

CLAIMS 1. A process according to claim 1 for the preparation of cinnamic acid nitrile derivatives of formula (I) R represents a hydrogen atom, a chlorine atom or a 'nitro, amino or methoxy group, R 'is hydrogen or methyl, phenyl or halophenyl, and R 'is hydrogen or C 1-4 alkyl by reaction of aromatic aldehydes or ketones of formula II with nitriles of formula III in which R, R' and R 'are as defined above, in the presence of a condensing agent. The condensing agent used is an alkali metal (C 1 -C 2) alkoxide or a mixture of alkali metal hydroxide and alkali metal (C 1 -C 2) alkoxide prepared by boiling the alkali metal hydroxide and C 1 -C 2 alkanol, the reaction being 1: 2 -5) :( 0.5-1) starting from a molar ratio of aromatic aldehyde or ketone: nitrile: condenser at 80180 ° C for 3 to 8 hours, preferably with stirring, the reaction mixture is cooled, benzene and water are added and isolating the compound of formula (I) formed from the benzene phase in a known manner. 2. A process according to claim 1 wherein the molar ratio of aromatic aldehyde or ketone: nitrile to conditioner is 1: 3: 0.6. Process according to claim 1 or 2, characterized in that the reaction is carried out at 100-150 ° C for 4-8 hours.