CLIAMS:We Claim:

1. A process for the preparation of Oxo Ropinirole of formula II

Formula II

or pharmaceutically acceptable salt thereof, which comprising: oxidation of ropinirole or pharmaceutically acceptable salt thereof with Jones reagent in presence of a solvent.

2. The process of claim 1, wherein the said solvent is water.

3. The process of claim 1, wherein the Jones reagent used for reaction is about 0.1 to 1 molar equivalents per molar equivalent of Ropinirole or its salt.

4. The process of claim 1, wherein the reaction is performed at about 95 °C.

5. The process of claim 1, wherein the Oxo-ropinirole or its salt is having purity greater than 95% by HPLC.

6. The process of claim 1, wherein the oxo-ropinirole of compound of formula II can be used as reference standard or pure intermediate to provide pure ropinirole.

7. The process of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride salt obtained from treatment of compound with hydrochloric acid.
,TagSPECI:4. DESCRIPTION

The present invention provides a chemical process for preparing intermediate as well as isolated impurity of Ropinirole or its pharmaceutically acceptable salt, for example, oxo Ropinirole of Formula II, which is useful as reference marker.

Formula II

Ropinirole hydrochloride, chemically known as 4-[2-(di-n-propylamino)-ethyl]-2(3H)-indolone hydrochloride of Formula I:

Formula I

The hydrochloride salt of ropinirole is commercially available under the trade name REQUIP. Ropinirole hydrochloride is a non-ergoline dopamine agonist with high relative in vivo specificity and full intrinsic activity at the D2 and D3 dopamine receptors subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole hydrochloride is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). Ropinirole is a member of indolone class of potent non-ergot dopamine receptor antagonist marketed as a symptomatic treatment for Parkinson's disease. EP-0113964-B describes the use of such compounds as being useful in cardiovascular therapy.

PCT application publication No. 94/15918 discloses a process for preparing ropinirole, which involves i) providing 4-(2-di-n-propylamino)ethylisatin (oxo ropinirole) from condensation of isatinethyl derivative with di-n-propylamine; and ii) reducing oxo-ropinirole using reducing agent to provide ropinirole. However, the process of ‘918 has a drawback with respect to production of greater purity for oxo ropinirole.

The skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).

The use of a compound as a reference marker requires recourse to a sample of substantially pure compound.

The Oxo-ropinirole is a key intermediate as well as a key impurity for Ropinirole. Therefore, there is a need to develop a simple and inexpensive process to provide pure compound of Oxo-ropinirole, which will be useful as reference marker as well as a key intermediate to provide pure ropinirole hydrochloride.

The present inventors developed a simple, conventional and industrial feasible process to provide compound of Oxo ropinirole of Formula II or pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for the preparation of Oxo Ropinirole of formula II or pharmaceutically acceptable salt thereof, which comprising: oxidation of ropinirole or pharmaceutically acceptable salt thereof with Jones reagent in presence of a solvent to provide Oxo ropinirole having purity greater than or equal to 95 %.

The suitable solvent used for the preparation of Oxo ropinirole includes but are not limited to water, alcohol such as methanol, ethanol, isopropyl alcohol and the like; chlorinated solvent such as dichloromethane, chloroform, chlorobenzene and the like, hydrocarbon such as n-hexane, cyclohexane, n-heptane, toluene, and the like or combination thereof.

In another aspect, the present invention provides a process for the preparation of Oxo Ropinirole of formula II or pharmaceutically acceptable salt thereof, which comprising: oxidation of ropinirole or pharmaceutically acceptable salt thereof with Jones reagent in presence of water to provide Oxo ropinirole having purity greater than or equal to 95 %.

Ropinirole or its pharmaceutically acceptable salt used for providing Oxo-ropinirole may be any solid or the solution comprising Ropinirole or its salt obtained from the previous reaction.

The quantity of Jones reagent may be in the range of 0.1 to 1 molar equivalents or more per the molar equivalent of starting material. The Jones reagent is added to the reaction mixture at a low temperature and later elevated to a high temperature.

The Jones Reagent is a solution of chromium trioxide in diluted sulfuric acid, which may be used for oxidations of ropinirole in a solvent. This reagent is safe for handing and available commercially.

The reaction for providing oxo-ropinirole may be conducted at elevated temperature, for example, about 35 °C to 100 ° depends on the solvent used. The reaction may be maintained at elevated temperature for a period of 30 minutes or more. In an embodiment, the reaction is performed at a temperature of about 95 °C when the solvent is water.

After completion of the reaction, the reaction mixture may be subjected to pH adjustment and then isolation of solid. The isolation of solid can be performed using any suitable precipitation technique, for example, concentration, anti-solvent technique, recrystallization and the like.

The compound Oxo-ropinirole or its pharmaceutically acceptable salt of the present invention may have the purity greater than or equal to 95% by HPLC. The present process provides greater purity for Oxo-ropinirole directly with out utilizing purification technique.

The pharmaceutically acceptable salt of the present invention includes inorganic and organic salt such as hydrochloride, sulfate, phosphate, acetate, fumarate, tartrate and the like. In the case of resultant compound is oxo-ropinirole, it is converted to its pharmaceutically acceptable salt by the treatment of Oxo-Ropinirole with an acid, for example, hydrochloric acid, sulfuric acid, acetic acid, and the like.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLE:

Example-1: Process for Oxo-Ropinirole Hydrochloride

Ropinirole hydrochloride (10 g) was dissolved in distilled water (70 ml), cooled to 0 °C and Jones reagent (80 ml) was added. The reaction mass was heated to 90-95 °C for 2 hours. The reaction was monitored by TLC. After completion, the reaction mass was cooled to 10 °C and neutralized with ammonia. The aqueous layer was extracted with ethyl acetate (300ml) and the oxo-ropinirole was isolated as a hydrochloride salt.

Yield: 5.5 g
HPLC purity (Area %): 95.7%

1H NMR (400 MHz, DMSO–d6): δ 0.92(6H, t), 1.62-1.78(4H,m), 3.0-3.1(4H,m), 3.1-3.26(4H, m), 6.80(1H, d, J=8Hz), 6.97(1H, d, J=7.6Hz), 7.5(1H,t, J=8Hz), 10.2(1H,bs), 11.1(1H,s).
Mass: 275.2 (M+1).