SUBSTANTIALLY PURE FLUINDIONE AND PROCESS FOR ITS PREPARATION

FIELD OF THE INVENTION

The present patent application relates substantially pure Flumdione and process for its preparation.

BACKGROUND OF THE INVENTION

Fluindione is chemically known as 2-(4-fluorophenyl) indane-1,3- dione and has structural Formula 1.

Formula I

Fluindione is a vitamin K antagonist, which belongs to the class of anticoagulants act by inhibiting the action of vitamin K. It is marketed under trade name Previscan.

J. Org. Chem. 26, 3580-3582 fj 96 J j discloses a process for txic preparation of 2-arylindandiones by reacting phthalide with 4- halobenzladehydes in presence of sodium methoxide. Hovv^ever, this process resulted in Fluindione having impurities, which is not suitable for pharmaceutical preparations.

Similarly other processes for the preparation of Fluindione are reported in French patent Nos.FR 1369396, FR 6913 and Chemicke Zuesti 16, 200-205 (1962).

The aforementioned processes does not mention any details regarding purification of the crude Fluindione or details regarding purity of the product obtained

Impurities in any active pharmaceutical ingredient (API) are undesirable as they might be harmful to the patient treated with the dosage form of the API in which sufficient amount of impurity is present. It is well known to those skilled in art that impurities may arise from the degradation of the API in chemical synthesis or in storage, or due to un-reacted starting materials or synthetic by products.

Hence it is important to identify the source of impurity, optimize the reaction conditions to minimize the formation and device a purification method to eliminate the impurity that is inevitable.

Consequently, it would be a contribution to the art to provide a scalable and safe process for the preparation of highly pure Fluindione using commercially available raw materials

SUMMARY OF THE INVENTION

In one aspect the present patent application provides substantially pure Fluindione characterized by having total purity more than 99% w/w and less than 0.5% of desfluoro fluindione as determined by HPLC.

In another aspect the present patent application is related to a process for the preparation of substantially pure Fluindione comprising:

a) reacting phthalide of Formula III with p-fluoro benzaldehyde of Formula IV in the presence of a base and an organic solvent to obtain Fluindione;

Formula III

CHO

Formula iV

b) purification of Fluindione obtained in step a) using acetic acid followed by an alcohol.

DETAILED DESCRIPTION OF THE INVENTION

As used herein refers to the word "desfluoro fluindione" refers to 2- phenyl-lH-indene-l,3-dione represented by structural Formula II.

In one aspect the present patent application provides substantially pure Fluindione.

As used herein the word "substantially pure Fluindione" refers Fluindione having purity more than 99% w/w and less than 0.5% of desfluoro fluindione as determined by HPLC

In another aspect the present patent application is related to a process for the preparation of substantially pure Fluindione comprising: a) reacting phthalide of Formula III with p-fluoro benzaldehyde of Formula IV in the presence of a base and an organic solvent to obtain Fluindione;

Formula III

OHO

b) purification of Fluindione obtained in step a) using acetic acid followed by methanol.

The p-fluoro benzaldehyde used in the process of step a) may have less than about 3% of benzaldehyde as impurity. Even though it is preferable to have the benzaldehyde impurity in p-fluoro benzaldehyde to minimum possible extent, but it may be noted that the desfmoio F.aindione is formed during the reaction as a side product.

The mole ratio of p-fluoro benzaldehyde to phthalide is about 1:3, preferably about 1:1.1.

Suitably the reaction is carried out in presence of base such as sodium methoxide , sodium ethoxide, preferably sodium methoxide.

Sodium methoxide may be added to the reaction mixture directly or in the form of a mixture of sodium methoxide in methanol at abou^ 0-5 °C optionally under nitrogen.

Suitable organic solvent that may be used in the reaction include and alcohols such as methanol, ethanol, isopropanol, preferably methanol.

Suitably the reaction is carried out in the presence of an ester such C3-C7 esters such as ethyl acetate, isopropyl acetate, ethyl propionate and the like.

Suitable temperatures for conducting the reaction can range from about 20°C to 60°C, preferably at about 40-50°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about one hour to four hours preferably at two hours.

It is advantageous to maintain the reaction at 40-50°C as the content of desfluoro Fluindione would increase if the reaction is maintained at high temperature for longer times.

After completion of the reaction, solvent may be removed by distillation followed by addition of water.

The reaction mixture may be washed with non polar solvento such as toluene, xylene, n-hexane and the like, preferably toluene.

It was observed that several impurities are eliminated in the non-polar solvent washings

After solvent washings the aqueous layer pH may be adjusted to about 2 to 3 using hydrochloric acid for precipitation of the product.

For complete isolation to occur, the reaction mass may be maintained farther at temperatures lower than the operating temperatures such as for example below about 10 °C to about 30 °C, for a period of time as required for a more complete isolation of the product The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art.

The solid material isolated is recovered from the final mixture using techniques such as filtration by gravity, or by suction, centrifugation, and the like. The solid so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the solid may be washed with a water to wash out the mother liquoi. Optionally, the solid isolated may be further dried or the wet solid may be used directly in the next reaction. Drying can be carried out at reduced pressures at temperatures such as about 25 °C to about 40 °C.

Step b) involves purification of Fluindione obtained in step a) using acetic acid followed by an alcohol solvent.

The purification process involves combining the Fluindione with the solvent selected from polar protic solvents, most preferably acetic acid.

Suitable temperature for purification of the reaction mass with acetic acid can range from about 50 °C to reflux temperature, preferably at about 70°C for about 30 minutes to 2 hours.

The mixture may be cooled to 20-30°C and stirred for about 30 minutes to 2 hours followed by filtration of the solid material.

Suitably the Fluindione obtained above is further purified with an alcoholic solvent.

Suitable alcoholic solvent that may be used for further purification include methanol, ethanol, isopropanol, n-butanol and the like; preferably methanol.

The purification process involves combining the Fluindione with the alcoholic solvent, heating the mixture from about 50 °C to reflux temperature, preferably at about 60X for about 30 minutes to 2 hours.

The mixture may be cooled to 20-30°C and stirred for about 30 minutes to 2 hours followed by filtration of the solid material.

Purification process may be repeated in the similar manner for 2-3 times in order to increase purity of Fluindione as required.

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way.

EXAMPLES

Example 1: Preparation of 2-(4-fluorophenyl)

In a dry reaction flask, 200 ml of methanol was cooled to 0~5°C under nitrogen. 48.5 gm of sodium methoxide was slowly added to the methanol at O-S^C and stirred for about 30 min.

In another dry reaction flask 400 ml of ethyl acetate, 44 gm of phthalide was charged and stirred to dissolve under nitrogen. 37.2 gm of p- fluoro benzaldehyde was added at 25-30°C and stirred for 10 m^n. Sodium methoxide solution prepared above was added to the reaction mass at 25- 30°C and heated to 40-50°C and maintained for about 2 hours. The completion of reaction was checked with thin layer chromatography (TLC). The solvent was distilled off completely from the reaction mass under vacuum and 400 ml of water was added under stirring. The reaction mixture was washed with n-hexane (100 ml X 1, 50 ml X 2). The aqueous layer was separated and pH was adjusted to about 2 using 80 ml aqueous hydrochloric acid. The reaction mixture was maintained for 1 hour at 25- 30°C, filtered the solid and washed with 100 ml water to obtain 110 gm of the title compound as wet solid. Sxampie 2: Purification of 2-(4-fluorophenyl) inda.itTs-}i„3-dioms

In a dry reaction flask, 110 gm of the wet compound obtained from example 1, 100 ml of acetic acid was charged and heated to about 70°C for 30 minutes. The reaction suspension was cooled to about 20°C and maintained for 30 minutes. The solid was filtered to get 54 gm c/ wet solid.

The wet solid was charged in 210 ml of methanol and heated to reflux for 30 minutes. The reaction mass was cooled to 5°C and stirred for 30 minutes. The solid was filtered to obtain 48 gm of wet compound.

The wet compound was again charged in 95 mi of acetic acid, heated to 70°C and stirred for 30 min. The reaction mass was cooled 20°C, maintained for 30 minutes and filtered to get 40 gm of the wet compound.

The wet compound was charged in 250 ml of methanol and heated to reflux to form clear solution. The reaction solution was filtpred through high-flow and washed with methanol. The mother liquor was charged in a flask and cooled to 0-5°C. The reaction mixture was maintained for 30 minutes, filtered the solid and washed with 30 ml methanol. The wet solid was dried to get 36 gm of the pure title compound.

Purity by HPLC: 99.7%. Desfluoro impurity content: 0.11%

We Claim:

1. A compound which is substantially pure Fluindione.

2. A process for the preparation of substantially pure Fluindione comprising Formula IV

a) reacting phthalide of Formula III with p-fluoro benzaldehyde of Formula IV in the presence of a base and an organic solvent to obtain Fluindione; ,CHO

Formula III

b) purification of Fluindione obtained in step a) using acetic acid and methanol.

3. The process of claim 2, wherein the molar ratio of p-fluoro benzaldehyde to phthalide is about 1:3

4. The process of claim 2, wherein p-fluoro benzaldehyde contains less than about 3% of benzaldehyde impurity.

5. The process of claim 2, wherein the reaction of step a) is carried out from about 20°C to 60°C.

6. The process of claim 2, wherein water is added to the reaction mixture after reaction completion and washed with non polar solvents selected from toluene, xylene, n-hexane.

7. The process of claim 2, wherein Fluindione is purified using acetic acid followed by an alcohol solvent.

8. The process of claim 2, wherein alcoholic solvent include methanol, ethanol, isopropanol, n-butanol and the like; preferably methanol.

9. A process for purification of Fluindione comprising recrystallization of Fluindione using acetic acid followed by methanol.

10. A process for the preparation of is substantially pure Fluindione by a process as described in the examples.