The present invention relates to a commercial and economical method for manufacturing cyclopropyl keto a, a-dimethylphenyl acetic acid of structural Formula I, as shown in the accompanied drawings. The said compound is an useful intermediate for synthesis of fexofenadine of structural formula II as shown in the accompanied drawings.
Fexofenadine, a widely used antihistamine is chemically 4[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyl]-α,α-dimethylbenzene acetic acid.
The strategy adopted in prior art for the preparation of cyclopropyl keto a, a- dimethylphenyl acetic acid comprises of treating the corresponding alcohol of structural formula III, as shown in the accompanied drawings by various conventional oxidizing agent. The oxidation can be done in either two steps or a single step.
Oxidizing agents known in the literature for such reactions are ruthenium chloride / sodium periodate in solvents like acetonitrile or carbon tetrachloride, fuming nitric acid in acetic acid, dimethyl sulphoxide/ oxalyl chloride/ triethylamine, Dess Martin reagent, chromium 4-oxide, nickel peroxide, sodium dichromate, manganese dioxide.
The prior art methods are not found suitable from commercial point of view as they are not environmental friendly, expensive and require troublesome work up. Most of the reagents are disadvantageous due to run away conditions which lowers the yields and makes the process inefficient on an industrial scale.
Thus the present invention provides a process for the preparation of cyclopropyl keto a, a dimethylphenyl acetic acid without use of any solvent during oxidation i.e., in the presence of water.
Accordingly, the present invention provides an efficient process to overcome the problems associated with prior art and improves the economy by resulting in higher yields (>90%) of desired product which is used to prepare substantially pure fexofenadine, with an ease of operation and ambient reaction conditions.
The process of the present invention reduces the impurities, eliminates the costly and time consuming purification step as it forms fexofenadine without any further purification.
In accordance with the present invention the process for preparing the cyclopropy keto a, a dimethylphenyl acetic acid comprises, treating 4-(cyclopropyloxomethyl)-2,2-dimethylphenethyl alcohol with hydroxides of alkali metal, and adding oxidizing agent to the obtained suspension.
Hydroxide of alkali metal is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide. Most preferred is sodium hydroxide.
A preferred embodiment of the present invention comprises treating treating 4-(cyclopropyloxomethyl)-2,2-dimethylphenethyl alcohol with hydroxides of alkali metals, at room temperature, and adding potassium permanganate in small lots.
A further aspect of the present invention comprises adding organic solvent to the solution, after the oxidation is completed, and filtering off the inorganic solid. The non-acidic impurities from the filtrate are removed by washing with chlorinated hydrocarbons, and the product is isolated from the aqueous layer after acidification.
Organic solvent comprises ketones, chlorinated hydrocarbons, or mixtures thereof.
Ketones are selected from acetone, ethyl methyl ketone, methyl iso-butyl ketone, or mixtures thereof. Most preferred is acetone.
Chlorinated hydrocarbons are selected from chloroform, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
In the following section preferred embodiments are described by a way of example to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the claims.
EXAMPLE
To a solution of sodium hydroxide (11.5 g) in water, 4-(cyclopropyloxomethyl)-2,2-dimethylphenethyl alcohol (125 g) was added at room temperature. To the above suspension, solid potassium permanganate was added in small lots over a period of 4-5 hours at room temperature. After the completion of reaction, acetone (1ml) was added, manganese dioxide formed was filtered. The filtrate was washed with dichloromethane (25 ml + 12.5 ml) to remove non acidic impurities. The product was isolated from the aqueous layer by acidification with hydrochloric acid to yield 23.7 g material of good purity.

WE CLAIM:
1. A process for the preparation of cyclopropyl keto α,α-dimethylphenyl acetic acid of structural Formula I, as shown in the accompanied drawings comprises, treating 4-(cyclopropyloxomethyl)-2,2-dimethylphenethyl alcohol of structural Formula III, as shown in the accompanied drawings with hydroxides of alkali metals.
2. The process of claim 1 wherein the hydroxide of alkali metal is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide.
3. The process of claim 2 wherein the alkali metal hydroxide is sodium hydroxide.
4. The process of claim 1 further comprises, subjecting the reaction mixture to oxidation with potassium permanganate.
5. The process of claim 1 further comprises, adding organic solvent to the solution, after the oxidation is completed.
6. The process of claim 5 wherein organic solvent is selected from chlorinated hydrocarbons, ketones, or mixtures thereof.
7. The process of claim 6 wherein ketone is selected from acetone, methyl ethyl ketone, methyl iso-butyl ketone, or mixtures thereof.
8. The process of claim 7 wherein ketone selected is acetone.
9. The process of claim 5 further comprises, filtering the solid and washing the filtrate with chlorinated hydrocarbon selected from dichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof.
10. The process of claim 9 further comprises, isolating cyclopropyl keto a,a-dimethylphenyl acetic acid from the aqueous layer by acidification.
11.The process for the conversion of cyclopropyl keto a, a-dimethylphenyl acetic acid of structural formula I, as shown in the accompanied drawings prepared by the process of claim 1 to give fexofenadine of structural formula II, as shown in the accompanied drawings.
12. The process for the preparation of cyclopropyl keto a, a-dimethylphenyl acetic acid of structural formula I, as shown in the accompanied drawings, substantially described herein and exemplified by the examples.