ITMI992493A1 - PROCESS FOR THE PREPARATION OF (4-METHYLTHIO-FENYL) -ACETONITRILE - Google Patents

Description

"Process for the preparation of (4-methylthio-phenyl) -acetonitrile"

Description

The present invention relates to a process for the preparation of (4-methylthiophenyl) -acetonitrile and, more particularly, it relates to a process for the preparation of (4-methylthio-phenyl) -acetonitrile starting from 4-methylthio-benzaldehyde by means of homologation, formation of the corresponding oxime and subsequent dehydration to nitrile.

(4-Methylthio-phenyl) -acetonitrile is a known compound, widely described in literature, which can be used as a synthetic intermediate for the preparation of compounds with biological or photochemical activity.

For example, in patents US 41 15578 and US 4118461 (Rohm and Haas Co.) it is used for the preparation of fungicides with an imidazole structure.

A further example of the use of (4-methylthio-phenyl) -acetonitrile as a synthetic intermediate is reported in patent application DE 19644797 (Ciba Geigy A.-G.) concerning the preparation of substituted phenylacetonitriles, claimed as photoinitiators.

Finally in the patent DE 3117510 (Mitsui Toatsu Chemicals, Ine.) It is used for the preparation of 2-aryl-propyl ethers endowed with insecticidal and acaricidal activity.

Various processes for the preparation of (4-methylthiophenyl) -acetonitrile are described in the literature.

These processes involve the nucleophilic substitution of 4-methylthio-benziIchloride or of the corresponding mesylate with alkaline cyanides.

For example, the European patent application EP5 10526 (Hoffmann-La Roche) reports the preparation of (4-methylthio-phenyl) -acetonitrile starting from 4methylthio-benzaldehyde by reduction of the carbonyl group to benzyl alcohol, subsequent transformation into chloride, with thionyl chloride, and reaction with potassium cyanide and sodium iodide in dimethylformamide.

Also M.B.Sommer et al. in J.Org.Chem. (1990), 55, 481, prepare (4-methylthiophenyl) -acetonitrile starting from the corresponding benzyl alcohol, by treatment with thionyl chloride and, subsequently, with sodium cyanide, in dimethyl sulfoxide. The process described by J.M.van der Zanden et al. in Rec.trav.chim. (1957), 76, 669, differs from the previous ones for the method of preparation of 4-methylthiobenzyl chloride, through chloromethylation of thioanisole with chloromethyl methyl ether and for the use of sodium cyanide in ethanol in the last step.

A similar synthesis route in which the intermediate benzyl alcohol is activated as mesylate instead of as chloride is described in US patent 4105762 (Rohm and Haas Company).

However, the above methods require the use of corrosive and carcinogenic chemical reagents, such as thionyl chloride and chloromethyl methyl ether, for the preparation of 4-methylthio-benzyl chloride and extremely toxic alkaline cyanides, for the final step to give (4 -metitio-phenyl) -acetonitrile.

In particular, due to the high toxicity of alkaline cyanides, it is necessary to take appropriate safety measures in their use and storage; moreover, rigorous additional procedures must be used for the remediation, control and disposal of processing waste.

Therefore, the difficulties in handling corrosive and carcinogenic reagents such as thionyl chloride and chloromethyl methyl ether and the extreme toxicity of alkaline cyanides make the processes for the preparation of (4-methylthio-phenyl) -acetonitrile, described in the literature, difficult to apply. industrial.

To the best of our knowledge, a process for the preparation of (4-methylthiophenyl) -acetonitrile by homologation of 4-methylthio-benzaldehyde, formation of the corresponding oxime and dehydration to nitrile has never been described in the literature.

We have now found a process for the preparation of (4-methylthio-phenyl) -acetonitrile starting from 4-methylthio-benzaldehyde particularly suitable for industrial application, which uses readily available, non-aggressive and above all non-toxic reagents.

Therefore, the object of the present invention is a process for the preparation of (4-methylthio-phenyl) -acetonitrile of formula

(I) which includes

a) the reaction between 4-methylthio-benzaldehyde II and a compound of formula III

(III) wherein X represents a chlorine or bromine atom and R represents a linear or branched C1-C4 alkyl;

to prepare a compound of formula IV

where R has the above meaning;

b) the hydrolysis reaction of the ester group of the compound of formula IV to obtain the corresponding compound V

(V)

wherein Y represents a hydrogen atom or an alkali or alkaline earth metal;

c) the transformation of compound V into compound VI

(YOU)

d) dehydration of compound VI to obtain the compound of formula I.

Compound VI constitutes a further object of the present invention.

The process object of the present invention is easy to carry out and allows to obtain (4-methylthio-phenyl) -acetonitrile (I) with good yields with respect to starting 4-methylthio-benzaldehyde, without using toxic reagents.

Step a) of the process object of the present invention provides for the condensation reaction between 4-methylthio-benzaldehyde (II) and a haloacetate of formula (ΙΠ). Compounds II and III are known compounds, available commercially or easily prepared with known methods, for example 4-methylthio-benzaldehyde can be prepared by formylation of thioanisole [Bull.Soc.Chim.Fr., (1955), 1594] while the methyl chloroacetate from chloroacetic acid by reaction with methanol and sulfuric acid [J.Am.Chem.Soc., (1937), 1972],

In the process object of the present invention the compound of formula III is preferably used in which X is a chlorine atom and R is a methyl group.

The compounds of formula II and ΙII are preferably used in a molar ratio between 1: 0.5 and 1: 2.

Even more preferably, the molar ratio of compounds II and ΙΠ is comprised between 1: 0.9 and 1: 1.5.

The aforesaid condensation reaction between compound II and compound III is carried out in the presence of strong bases such as, for example, alkaline or alkaline-earth metal alcoholates.

Preferred examples of bases are sodium and potassium alcoholates of the formula RONa and ROK in which R has the meanings reported above.

The alcoholates of the RONa formula can optionally be prepared in situ by reaction between metallic sodium and the corresponding ROH alcohol.

The compound molar ratio Π: base is generally between 1: 0.9 and 1: 2. A molar ratio comprised between 1: 1 and 1: 1.5 is preferably used. The condensation reaction is carried out in the presence of a suitable organic solvent.

Organic solvents that can be used are, for example, aromatic hydrocarbons, such as toluene or xylene, ethers, such as tetrahydrophyran, alcohols such as methanol, ethanol, isopropanol, n.butanol, sec-butanol, tert-butanol and their mixtures.

From a practical point of view, lower alcohols are preferred.

In particular, alcohol is preferably used whose residue R corresponds to that of the aloacetate ΙII used for the condensation reaction. For example, in the case of condensation with methyl haloacetate, the reaction is preferably carried out in methanol.

The reaction temperature is generally between -20 and 50 ° C, preferably between -10 and 20 ° C.

The condensation reaction in question leads to obtaining the crude compound of formula IV with a degree of purity sufficient for its direct use in the subsequent step.

Step b) of the process object of the present invention provides for the hydrolysis reaction of the ester group of the compound of formula IV to obtain the corresponding compound V.

The hydrolysis reaction can be carried out under acidic or, preferably, basic conditions.

If acidic conditions are used, the intermediate V will be obtained, in which Y represents hydrogen, which by spontaneous decarboxylation will directly provide (4-methylthio-phenyl) -acetaldehyde VII.

When the hydrolysis reaction is carried out in a basic environment, compound V is obtained as a salt corresponding to the base used.

The aforesaid basic hydrolysis reaction is carried out in the presence of inorganic bases such as, for example, hydroxides of alkali or alkaline-earth metals.

Preferably sodium or potassium hydroxide is used.

The compound IV: base molar ratio is between 1: 1 and 1: 5.

Preferably a molar ratio between 1: 1 and 1: 1.5 is used.

In the process object of the present invention the above hydrolysis reaction is preferably carried out in a basic environment.

The basic hydrolysis reaction can be carried out in the presence of a suitable solvent.

Examples of usable solvents are those used in step a) and their mixtures with water.

For practical reasons the lower alcohols are particularly preferred.

The hydrolysis reaction is carried out at a temperature between 0 ° C and the reflux temperature of the solvent.

Preferably one operates at a temperature comprised between room temperature and 60 ° C.

The step c) of the process object of the present invention provides, in the case in which the previous step b) has been carried out in basic conditions, the "one-pot" transformation of the compound V, in which Y represents an alkaline or alkaline-earth metal , in compound VI.

This transformation takes place by decarboxylation and rearrangement of compound V, to give (4-methylthio-phenyl) -acetaldehyde VII which, by subsequent reaction with a hydroxylamine salt, gives compound VI.

The decarboxylation reaction is generally carried out in an acid environment. Examples of usable acids are organic acids such as acetic acid and chloroacetic acid or inorganic acids such as hydrochloric acid and sulfuric acid.

Preferably acetic acid is used.

The pH of the decarboxylation reaction is generally maintained between 2 and 7, preferably between 3 and 6, by adding a suitable quantity of the aforesaid acids. The present decarboxylation reaction is carried out in a suitable solvent or mixture of solvents.

Examples of usable solvents are those used in step a) and their mixtures with water.

For practical reasons a biphasic mixture of toluene and water is preferably used.

The temperature adopted in the aforementioned decarboxylation step is generally comprised between the ambient value and the reflux temperature of the solvent.

It is preferably operated at a temperature between 30 and 50 ° C.

At the end of the decarboxylation reaction, a hydroxylamine salt is directly added to the reaction mixture to then obtain compound VI. Examples of usable hydroxylamine salts are hydrochloride and sulfate.

Particularly preferred is the hydrochloride.

The compound molar ratio V: hydroxylamine salt is generally between 1: 1 and 1: 2.

Preferably a molar ratio between 1: 1 and 1.3 is used.

The pH of the reaction environment is generally maintained between 4 and 7.

Particularly preferred is a pH range between 5 and 6.

The pH of the oximation reaction can generally be controlled by adding a base.

The temperature adopted in the oximation reaction is generally comprised between the ambient value and the reflux temperature of the solvent.

It is preferably operated at a temperature between 40 and 60 ° C.

In a variant of the process, the hydroxylamine salt itself is used as an acidifying agent.

In practice, step c) is carried out by adding directly to the mixture the compound V, in which Y represents an alkali metal or alkali no-earth, in a biphasic system consisting of water and a solvent immiscible with it, such as for example toluene, suitably buffered at pH 5-6 by adding a weak organic acid, the hydroxylamine salt as acidifying agent.

Step c) of the process object of the present invention leads to obtaining the raw compound of formula VI with a degree of purity sufficient for its direct use in the next step.

Step d) of the present process provides for the dehydration of compound VI to obtain compound I.

The dehydration reaction of compound VI is carried out by reaction with suitable dehydrating agents, optionally in the presence of a suitable solvent. Usable dehydrating agents are, for example, those reported by J. March in “Advanced Organic Chemistry”, IV ed., Pp. 1038-1039.

In particular, among the known dehydrating agents the anhydrides are preferred, such as for example acetic and trifluoroacetic anhydride.

For practical reasons acetic anhydride is preferably used.

The compound molar ratio VI: dehydrating agent is generally between 1: 1 and 1: 5.

Preferably a molar ratio between 1: 1 and 1: 3 is used.

Examples of solvents optionally usable in the dehydration reaction are aromatic hydrocarbons, such as for example toluene or xylene, and organic acids, such as for example acetic acid.

Preferably the aforesaid reaction is carried out in the absence of solvent.

The temperature adopted in the dehydration reaction is generally comprised between the ambient value and the reflux temperature of the reaction mixture.

It is preferably operated at a temperature of between 50 and 100 ° C.

The process object of the present invention is used for the preparation of (4-methylthio-phenyl) -acetonitrile.

In a preferred embodiment of the process object of the present invention, compound II and compound ΙΠ are added to the cooled solution of sodium alcoholate in alcohol. At the end of the addition it is left cold until the reaction is complete.

The raw compound IV is dissolved under hot stirring in alcohol and added with the appropriate base solution. Compound V precipitates from the reaction mixture and can be recovered by filtration or used as it is. Compound V, in a mixture of water and an organic solvent immiscible with it, is added under hot stirring with the appropriate acid. At the end of the development of carbon dioxide, after a slight cooling, the hydroxylamine salt and the base are added in alternating portions, maintaining an optimal pH.

As an alternative to the hydrolysis mixture of compound IV, an appropriate amount of weak acid is added to correct the pH to 5-6 and, subsequently, the hydroxylamine salt.

The crude compound VI is recovered by separation of the organic phase. The crude compound VI is added in portions under stirring to the preheated dehydrating agent. The mixture is heated until the reaction is complete, then divided between the aqueous phase and the organic phase; the latter evaporated to dryness provides the raw compound I, which can be purified by filtration on a silica panel or by distillation.

The process object of the present invention is easy to carry out and allows obtaining (4-methylthio-phenyl) -acetonitrile of formula I in mild conditions and with good yields.

A significant advantage of the aforementioned process consists in the use of harmless and easily manageable and above all non-toxic reagents instead of the commonly used alkaline cyanides which require, for industrial use, particular precautions of use and expensive safety procedures, due to of their extreme toxicity.

Furthermore, the aforesaid process, even though it is multistage, is of simple and economical industrial implementation since it allows to operate directly on the reaction blanks, thus avoiding complex additional purification procedures of the intermediates.

In conclusion, the use of stable, economical, easy to handle and above all non-toxic reagents and the direct use of raw intermediates without further purification, make the process object of the present invention particularly suitable for industrial application.

In order to illustrate the present invention, the following examples are now given.

Example 1

Preparation of methyl 3- (4-methylthio-phenin-glycidate

Methanol (200 g) and 30% sodium methylate (385 g; 2.14 moles) were introduced into a 2 liter reactor, equipped with a mechanical stirrer, thermometer and loading funnel. The solution was cooled to -10 ° C and then 4-methylthio-benzaldehyde (250 g; 1.64 mol) was dropped in 30 minutes. At the end of the dripping, methyl chloroacetate (215 g; 1.98 moles) was added to the solution in 2 hours, keeping the reaction mixture at a temperature of -7 / -8 ° C. The reaction mixture is then kept at a temperature of -10 ° C for 30 minutes, then the temperature is allowed to rise to 0 ° C and is maintained for another hour in these conditions. The mixture is then left at room temperature overnight. Acetic acid (30 g; 0.5 moles) and toluene (218 g) were then added to thin the mass. The mixture was transferred to a beaker containing toluene (305 g) and water (450 g) preheated to 50 ° C. The resulting emulsion was left under stirring for 30 minutes at 50 ° C, then stirring was stopped for 10 minutes and the phases were separated. The aqueous phase was again extracted with toluene (87 g). The combined organic phases were washed again at 50 ° C with water (150 g). The resulting toluene phase, concentrated to dryness under reduced pressure, yielded crude methyl 3- (4-methylthio-phenyl) -gicidate (380 g), which was used in the next step without further purification.

Example 2

Preparation of potassium 3- (4-methylthio-phenir) -glycidate.

In a 2 liter reactor equipped with mechanical stirrer, thermometer and loading funnel, crude methyl 3- (4-methylthio-phenyl) -glycidate (380 g; 1.64 moles) was dissolved at 40 ° C, as prepared in Example 1, in methanol (803 g). A 90% potassium hydroxide solution (112 g; 1.8 moles) in methanol (658 g) was added to the solution heated to 50 ° C by dropping and under stirring. After having introduced 40% of the potassium hydroxide solution, the mixture became cloudy due to the precipitation of salts. At the end of the dripping it was cooled to 15 ° C, keeping it under stirring for 30 minutes, then the solid was separated by filtration. The solid thus obtained was washed with methanol (2 x 119 g) and then dried under reduced pressure providing potassium 3- (4-methylthiophenyl) -glycidate (338 g).

Example 3

Preparation of (4-methylthio-phenyl-D-acetaldehyde oxime

3- (4-methylthio-phenyl) -glycidate of potassium (338 g; 1.36 moles), prepared as described in example 2, were introduced into a 3-liter reactor, equipped with a mechanical stirrer, thermometer and dropping funnel. water (1014 g) and toluene (1352 g). The mixture was heated to 35 ° C and added drop by drop in 1 hour with glacial acetic acid (98 g; 1.63 moles), under stirring. During the dripping of the acid, the development of carbon dioxide from the solution was noted. On completion of the dripping, the solution was kept at 35 ° C for 2 hours, then cooled to 30 ° C and added, under stirring and in 40 minutes, with hydroxylamine hydrochloride (114 g; 1.64 moles) and sodium carbonate (96 g; 0.91 moles) in alternating portions, adjusting the addition according to the pH which must be between 5 and 6. At the end the mixture was kept at 30 ° C for 1 hour, then a control of reaction by 1H-NMR to verify the disappearance of the starting product. The suspension was then heated to 50 ° C and left under vigorous stirring until complete dissolution of the bottom body. Maintaining the temperature at 50 ° C the phases were separated and the aqueous phase was extracted with toluene (59 g). The combined toluene phases were washed at 50 ° C with water (338 g). The organic extracts, concentrated under reduced pressure, provided (4-methylthio-phenyl) -acetaldehyde oxime (265 g; title 79.5%).

Example 4

Preparation of (4-methylthio-phenO-acetonitrile

Acetic anhydride (311 g; 3.05 moles) was introduced into a 1 liter reactor, equipped with mechanical stirrer, thermometer and dropping funnel, heated to 60 ° C and added with (4-methylthio-phenyl) -acetaldehyde oxime al 79.5% (265 g; 1.16 moles), prepared as described in Example 3, in several portions in 30 minutes. The resulting solution was kept under stirring for 18 hours at 60 ° C, added with toluene (164 g) and further stirred for 20 minutes. The mixture was finally added to a suspension of sodium carbonate (358 g; 3.38 moles) in water (865 g) and stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene (147 g). The combined organic phases were washed with water (169 g) and concentrated under reduced pressure to constant weight, yielding a brown oil which was dissolved in methylene chloride (500 g). The resulting solution was filtered on a silica cake and the filtrate was concentrated under reduced pressure to constant weight, obtaining pure (4-methylthio-phenyl) -acetonitrile (151 g).

Claims (3)

Claims 1) Process for the preparation of (4-methylthio-phenyl) -acetonitrile of formula (I) which comprises a) the reaction between 4-methylthio-benzaldehyde II and a compound of formula III (III) in which X represents a chlorine or bromine atom and R represents a linear or branched C1-C4 alkyl; to prepare a compound of formula IV where R has the above meaning; b) the hydrolysis reaction of the ester group of the compound of formula IV to obtain the corresponding compound V wherein Y represents a hydrogen atom or an alkali metal or alkali no-earth; c) the transformation of compound V into compound VI (VI) d) dehydration of compound VI to obtain the compound of formula 1. 2) Process for the preparation of a formula compound comprising steps a), b) and c) of claim 1. 3) Process for the preparation of (4-methylthio-phenyl) -acetonitrile of formula by dehydration of a compound of formula 4) Process according to claim 1 wherein X is a chlorine atom and R is a methyl group. 5) Process according to claim 1 which comprises a) the reaction between a compound li and an ITI compound in a molar ratio between 1.0.5 and 1: 2, catalyzed by an alcoholate of an alkaline or alkaline-earth metal, in a compound II: alcohol molar ratio between 1 : 0.9 and 1: 2, in an organic solvent selected from aromatic hydrocarbons, ethers, alcohols and their mixtures; b) the basic hydrolysis reaction of the ester group of the compound of formula IV catalyzed by hydroxides of alkaline or alkaline-earth metals, in a compound IV: base molar ratio between 1: 1 and 1: 5, in an organic solvent selected from aromatic hydrocarbons, ethers, alcohols and their mixtures with water; c) the transformation of compound V into compound VI by decarboxylation of compound V, catalyzed by an organic acid or an inorganic acid in which the reaction pH is maintained between 2 and 7, in an organic solvent selected from aromatic hydrocarbons, ethers, alcohols and their mixtures with water, and subsequent oximation by reaction with a hydroxylamine salt, in which the compound molar ratio V: hydroxylamine salt is between 1: 1 and 1: 2 and the reaction pH is maintained between 4 and 7 ; d) the dehydration of compound VI by reaction with an anhydride of an organic acid, in which the molar ratio of compound VI: anhydride is between 1: 1 and 1: 5, in a solvent selected from aromatic hydrocarbons and organic acids or in absence of solvent. 6) Process according to claim 5 which comprises a) the reaction between a compound Π and a compound III in a molar ratio between 1: 0.9 and 1: 1.5, catalyzed by a sodium or potassium alcoholate of the formula RONa and ROK in which R represents an alkyl Linear or branched C1-C4, in a compound II: alcohol molar ratio between 1: 1 and 1: 1.5, in an organic solvent selected from the lower alcohols and their mixtures; b) the basic hydrolysis reaction of the ester group of the compound of formula IV catalysed by sodium or potassium hydroxide, in a compound IV: base molar ratio between 1: 1 and 1: 1.5, in an organic solvent selected from alcohols and their mixtures with water; c) the transformation of compound V into compound VI by decarboxylation of compound V, catalyzed by an acid selected from acetic, chloroacetic, hydrochloric and sulfuric acid in which the reaction pH is maintained between 3 and 6, and subsequent oximation by reaction with a hydroxylamine salt selected from hydrochloride and sulphate, in which the compound molar ratio V: hydroxylamine salt is between 1: 1 and 1: 1.3 and the reaction pH is maintained between 5 and 6, d) the dehydration of compound VI by reaction with an anhydride chosen from acetic and trifluoroacetic anhydride, in which the compound VI: anhydride molar ratio is between 1: 1 and 1: 3, in the absence of solvent. 7) Process according to claim 6 which comprises a) the reaction between a compound n and a compound III catalyzed by sodium methylate in methanol; b) the basic hydrolysis reaction of the ester group of the compound of formula IV catalyzed by potassium hydroxide in a methanol / water mixture; c) the transformation of compound V into compound VI by decarboxylation of compound V, catalyzed by acetic acid, into a two-phase toluene / water mixture, and subsequent oximation by reaction with hydroxylamine hydrochloride; d) dehydration of compound VI by reaction with acetic anhydride. 8) Compound of formula