JP2875036B2 - Cyanoalkenylation method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to 1-cyano-1- (4-alkylphenyl) alkenes, and more particularly to a process for their preparation.

[0002] α-aryl-acrylonitrile is useful as a chemical intermediate, as disclosed in US Pat. Nos. 4,536,343 (Ramathiandran) and 4,581,176 (Davidudson); It is known that they can be prepared by reacting a suitable aryl ketone with an alkali metal cyanide, preferably in the presence of an activating amount of water and / or HCl. One of the ketones described as being useful in the Ramachiandran and Davidsson processes is 4-isobutylacetophenone, which is disclosed in U.S. Pat. No. 3,228,831 (Nicholson et al.)
It teaches that it can be synthesized by the reaction of isobutylbenzene and acetyl chloride.

When subjecting the reaction of ramatiandran or davidudson to 4-isobutylacetophenone or a similar ketone, the product is a 1-cyano-1- (4-alkylphenyl) alkene. Such products can be synthesized directly from the appropriate alkyl benzene and have two separate reactions, the synthesis of ketones followed by 1-
It would be desirable if the need for its conversion to a cyano-1- (4-alkylphenyl) alkene could be avoided.

It has been found that 1-cyano-1- (4-alkylphenyl) -alkenes can be prepared by reacting alkylbenzenes with alkali metal cyanides and acid halides in the presence of aluminum chloride. Was issued.

Although alkylbenzenes are generally useful as reactants for the practice of the present invention, the most interesting are those in which the alkyl group contains from 1 to 6 carbons. Such compounds include, for example, methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, pentyl-, and hexylbenzene. The preferred alkylbenzene is usually isobutylbenzene, due to its utility in synthesizing the ibuprofen intermediate according to the method of the present invention.

The alkali metal cyanide used is lithium, sodium, potassium, rubidium or cesium, preferably sodium or potassium cyanide, and more preferably sodium cyanide. In order to achieve good yields of the desired product, generally 1
1 to 5, preferably 1 for moles of alkylbenzene
It is desirable to use ~ 2 moles of cyanide.

[0007] The acid halide reactant is usually from 2 to 6
Alkanoyl halides containing carbon, ie compounds corresponding to the formula RCOX, wherein R is from 1 to 5
X is a carbon alkyl group and is fluoro, chloro, bromo or iodo. Examples of such compounds are acetyl chloride, acetyl fluoride, propanoyl chloride, butanoyl chloride, butanoyl bromide, pentanoyl chloride, and hexanoyl chloride. Chloride, especially acetyl chloride, is preferred. The acid halide and alkylbenzene are usually used in substantially equimolar amounts, but either can be used in excess. The amount of aluminum chloride used is generally between 1.0 and 1.5, preferably between 1.0 and 1.1 mole per mole of alkylbenzene.

[0008] In some cases, the reaction is carried out in the presence of water and / or concentrated HCl as an activator which would activate one or more of the reactants to increase the yield. Is desirable.

The specific amount of water and / or HCl used is an activating amount, that is to say an insufficient amount to completely hydrolyze the aluminum chloride, and is merely one or more of the other components of the reaction mixture. It can be supplied by water naturally present in it. If it is desired to use more water and / or HCl, the amount added will generally be in the range of 0.1 to 1.0 mole per mole of alkylbenzene.

The reaction is suitably carried out in a solvent,
It can be any solvent that dissolves the reactants, such as, for example, an aliphatic or aromatic hydrocarbon (eg, toluene, xylene or pentene), chlorobenzene, nitrobenzene, and the like.

In the practice of the present invention, the components of the reaction mixture can be mixed in any suitable manner and heated to a suitable temperature, for example, from 60 to 120 ° C, preferably from 90 to 100 ° C. The product of 1-cyano-1- (4
-Alkylphenyl) alkenes can be produced. The time required to achieve good yields varies with temperature, but often ranges from 4 to 10 hours.
A preferred method of mixing the reactants is to first stir the alkali metal cyanide, aluminum chloride and solvent until the reaction between the cyanide and aluminum chloride is complete,
Add the remaining reaction components.

After completion of the reaction, the product can be recovered in a conventional manner or, if the subsequent reaction is not hindered by impurities in the crude product, without isolation. Can be used for subsequent reactions. Often, it is desirable to perform a subsequent reaction on the 1-cyano-1- (4-alkylphenyl) alkene, for example, hydrogenation and / or hydrolysis. For example, 1-cyano-1- (4-isobutylphenyl) ethane is hydrogenated in a conventional manner, for example in the presence of a palladium on carbon catalyst, and then in a conventional manner, for example in the presence of acetic acid and sulfuric acid. In the above, hydrolysis can produce useful pharmaceutical drug ibuflophene; and other 1-cyano-1- (4-alkylphenyl) alkenes can be similarly treated to produce similar pharmaceutical drugs. Can be done.

An advantage of the present invention is that the desired reaction is achieved by first reacting the alkylbenzene with an acid halide to form a ketone and then converting the ketone to a 1-cyano-1- (4-alkylphenyl) alkene. It is a streamlining of the known method of producing a product.

The following examples are intended to illustrate the present invention and should not be construed as limiting the invention.

[0015]

EXAMPLE 1.1 in nitrobenzene (1.1 mmol)
ml of 1.0 M aluminum chloride solution and 100 mg
(2.0 mmol) of a mixture of finely ground sodium cyanide was stirred at room temperature and 73 microliters (1.
(0 mmol) of acetyl chloride, 450 mg of activated 3A molecular sieve and 160 microliters (1.0 mmol) of 98% isobutylbenzene. After heating the reaction mixture at 100 ° C. for 2 hours, GC analysis showed 25
Area% of 1-cyano-1- (4-isobutylphenyl)
Showed ethane.

The main features and embodiments of the present invention are as follows.

1. Alkylbenzene is reacted with alkali metal cyanides and acid chlorides in the presence of aluminum chloride to give 1-cyano-1- (4-alkylphenyl)
A method comprising producing an alkene.

2. The alkyl group of the alkylbenzene is 1 to
2. The method of claim 1 containing 6 carbons.

3. 3. The method according to claim 2, wherein the alkylbenzene is isobutylbenzene.

4. 4. The method according to any one of the above items 1 to 3, wherein the alkali metal cyanide is sodium cyanide.

5. A method according to any of the preceding claims wherein the acid halide is an alkanoyl halide containing 2 to 6 carbons.

6. 6. The method according to claim 5, wherein the alkanoyl halide is acetyl chloride.

7. 7. The method according to any one of the above items 1 to 6, wherein the reaction is carried out in a solvent.

8. The seventh solvent in which the solvent is nitrobenzene.
The method described in the section.

9. Activate the reaction with an activating amount of water and / or HCl
9. The method according to any of the above items 1 to 8 carried out in the presence of

10. 10. The method according to any one of the above items 1 to 9, wherein the reaction is performed at a temperature of 60 to 120 ° C.

Claims (1)

(57) [Claims] 1. A process comprising reacting an alkylbenzene with an alkali metal cyanide and an acid halide in the presence of aluminum chloride to form a 1-cyano-1- (4-alkylphenyl) alkene.