CLIAMS:We Claim:

1. A process for preparation of methoxy ropinirole having purity greater than 94%, which comprises:

a) reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or pharmaceutically acceptable salt thereof with zinc in presence of acid to provide N-hydroxy ropinirole or its pharmaceutically acceptable salt; and

b) reaction of N-hydroxy ropinirole of step a) with dimethyl sulfate in presence of base to provide methoxy ropinirole or its pharmaceutically acceptable salt.

2. The process of claim 1, wherein the acid of step a) is acetic acid.

3. The process of claim 1, wherein the reaction of step a) and b) is performed in presence of solvent, for example, water.

4. The process of claim 1, wherein the reaction of step a) conducted at a temperature of about 45 to about 50 °C.

5. A process for the preparation of N-hydroxy ropinirole having purity greater than 94%, which comprises reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or pharmaceutically acceptable salt thereof with zinc in presence of acid.

6. The process of claim 5, wherein the reaction is performed in presence of water.

7. The process of claim 5, wherein the acid is selected from the group of acetic acid, formic acid and trifluoroacetic acid.

8. The purity of compound of N-hydroxy ropinirole according to claim 5, is greater than 94% by HPLC.

Dated this 7th day of May 2013 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention provides a chemical process for preparing intermediates and impurities of Ropinirole or its pharmaceutically acceptable salt, for example, hydroxy and alkoxy-ropinirole of Formula II, which is useful as reference marker or a key intermediate to provide pure ropinirole.

Formula II
wherein R is hydrogen or C1-4 alkyl.

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 No. 2011/072704 A1 and IN 2715/MUM/2010 disclose N-hydroxy ropinirole as a key impurity for ropinirole. However, these applications are not provided any process to prepare the key impurity.

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).

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

Therefore, there is a need to develop a simple and inexpensive process to provide pure compound of formula II, 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 Formula II or pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for the preparation of compound of formula II or pharmaceutically acceptable salt thereof, which comprises reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid of formula III or its ester derivative or pharmaceutically acceptable salt thereof with zinc in presence of acid, for example, acetic acid.

The reaction may be conducted at a temperature of about 30 to about 60 °C for period of about 5 to 10 hours or more. Generally, the reaction of the present invention is conducted in presence of solvent, for example, water, alcohol, hydrocarbon and the like.

The resultant compound of Formula II of the present invention may have the purity greater than 94% determined by HPLC.

Optionally, the present invention provides conversion of hydroxy ropinirole of Formula II (where R=H) to alkoxy ropinirole of formula II (where R=alkyl group selected from C1-4) by alkylation process.

In anther aspect, the present invention provides a process for the preparation of N-hydroxy ropinirole having purity greater than 94%, which comprises reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or pharmaceutically acceptable salt thereof with zinc powder in presence of acid.

In anther aspect, the present invention provides a process for preparation of methoxy ropinirole having purity greater than 94%, which comprises:
a) reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or pharmaceutically acceptable salt thereof with zinc in presence of acid to provide N-hydroxy ropinirole or its pharmaceutically acceptable salt; and

b) reaction of N-hydroxy ropinirole of step a) with dimethyl sulfate in presence of base to provide methoxy ropinirole or its pharmaceutically acceptable salt.

The process for preparing N-hydroxy ropinirole of the present invention involve reaction of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or pharmaceutically acceptable salt thereof with zinc in presence of acid to provide N-hydroxy ropinirole.

The zinc powder used in the present invention is for the purpose of reduction of nitro group and to initiate cyclization in presence of acid, for example, acetic acid, formic acid, trifuloroacetic acid and the like. In an embodiment, the present invention utilizes zinc powder in presence of acetic acid for reduction and cyclization to provide N-hydroxy Ropinirole of Formula II (wherein R=H) or its pharmaceutically acceptable salt.

The reaction of step a) may be conducted in presence or absence of solvent at a temperature of about 30 to about 60 °C or 45 to about 50 °C. The solvent which may be used include but are not limited to water, alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; hydrocarbon such as n-hexane, cyclohexane, n-heptane, benzene and the like.

The reaction may be stirred for sufficient period of time, for example more than 5 hours or more than 10 hours, to complete the consumption of starting material completely at a temperature from 30 °C to 60 °C.

After completion of the reaction, the reaction mixture may be treated with base, for example, sodium hydroxide, and then subjected for extraction with organic solvent to provide pure compound of formula II (wherein R=H) or its pharmaceutically acceptable salt.

The resultant compound of N-hydroxy ropinirole of formula II or its pharmaceutically acceptable salt may have the purity greater than 94% determined by HPLC.

The step b) of the present invention involves reaction of N-hydroxy ropinirole or its pharmaceutically acceptable salt with dimethyl sulfate in presence of base to provide methoxy ropinirole.

The reaction may be performed in presence of solvent such as water, methanol, ethanol, isopropyl alcohol, hexane, heptane, benzene and the like.

The present invention may also provide use of single solvent for the reactions of step a) and b) and in-situ formation of N-hydroxy ropinirole to provide inexpensive process to obtain the compound of formula II or its pharmaceutically acceptable salt.

In an embodiment, the resent invention provides conversion of 2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid or its ester derivative or pharmaceutically acceptable salt thereof to the compound of Formula II (wherein R=alkyl C1-4) or its pharmaceutically acceptable salt by using single solvent such as water.

The reaction of step b) may be conducted at a temperature of 20 to about 35 °C and maintained for about 5 hours or more.

The suitable base for performing the reaction may be inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; organic base such as triethyl amine and the like.

The quantity of dimethyl sulfate can be in the range of about 0.5 to about 1.2 or 1 molar equivalent per molar equivalent of N-hydroxy-ropinirole of formula II.

After completion of the reaction, the reaction mixture may be subjected for isolation of solid in suitable organic solvent by using suitable techniques.

The suitable techniques for precipitation or isolation of solid are recrystallization, decantation, anti-solvent technique, crash cooling and the like. The solvent used for isolation of solid is selected from chlorinated solvent such as dichloromethane, dichloroethane, chloroform, and the like; ester such as ethyl acetate, isopropyl acetate and the like; ketone such as acetone, methyl ethyl ketone and the like.

The resultant solid of compound of formula II or its pharmaceutically acceptable salt (wherein R=C1-4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl) may have purity of about 94% determined by HPLC.

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 free-base, it is converted to its pharmaceutically acceptable salt by the treatment of free-base 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 preparing hydroxy-Ropinirole [4-(2-(dipropylamino)ethyl)-1-hydroxyindolin-2-one]

2-(2-(2-(dipropylamino)ethyl)-6-nitrophenyl)acetic acid hydrochloride (5 g, 0.014 mol) was dissolved in water (30ml). After cooling to 5 °C, acetic acid (10 ml) was added followed by Zn-powder (2.12 g, 0.0324 mol). The reaction was continued for 20 hours at 45-50 °C. The reaction was diluted with water (50ml) and neutralized with sodium hydroxide solution. The Product was extracted with dichloromethane (200 ml), washed with water and concentrated to get 1.7g N-Hydroxy Ropinirole.

1H NMR (400 MHz, CDCl3–d6): d 0.91(6H, t), 1.45-1.65 (4H, m), 2.55-2.65(6H, m), 2.70-2.80(2H, m), 3.05(2H, s), 6.79(1H, d, J=7.6Hz), 6.85(1H, d, J=7.6Hz), 7.18(1H, t, J=8Hz).

Mass: 277.2 (M+1).

HPLC purity (Area %):-95 %

Example-2: Process for preparing Methoxy-Ropinirole [4-(2-(dipropylamino)ethyl)-1-methoxyindolin-2-one]

N-Hydroxy Ropinirole (1.7g 0.006 mol) was suspended in water (17 ml), potassium carbonate (0.85g, 0.006 mol) was added followed by dimethyl sulfate (0.776g, 0.0061 mole). The reaction mixture was stirred 12 hours at 25-30 °C. After completion, the product was isolated from dichloromethane (0.6g)

1H NMR (400 MHz, CDCl3–d6): d 0.80-0.95(6H, m), 1.40-1.55 (4H, m), 2.40-2.50(4H, m), 2.60-2.70(4H,m), 3.45(2H,s), 4.02(3H,s), 6.82(1H, d, J=7.6Hz), 6.90(1H, d, J=7.6Hz), 7.24(1H, m).

Mass: 291.0(M+1).

HPLC purity (Area %):-94.2%