WO2008075169A2

WO2008075169A2 - A process for the purification of ropinirole hydrochloride

Info

Publication number: WO2008075169A2
Application number: PCT/IB2007/003914
Authority: WO
Inventors: Vijaybaskar Veerappan; Sam Daniel Prabhu Devasitham; Seshukumar Arvapally; Susi Swaminathan; Mahender Rao Siripragada
Original assignee: Orchid Chemicals and Pharmaceuticals Ltd
Current assignee: Orchid Pharma Ltd
Priority date: 2006-12-15
Filing date: 2007-12-14
Publication date: 2008-06-26
Anticipated expiration: 2009-06-15
Also published as: WO2008075169A3

Abstract

The present invention relates to an improved process for the purification of Ropinirole hydrochloride of formula (I) using phosphorous containing reagent.

Description

A PROCESS FOR THE PURIFICATION OF ROPINIROLE HYDROCHLORIDE

Field of the Invention

(D

Background of the Invention

The chemical name of Ropinirole is 4-[2-(Dipropylamino)ethyl]-l, 3-dihydro- 2H-indol-2- one, formula Ci₆H₂₄N₂O and molecular weight is 260.37. Ropinirole is marketed in the form of its hydrochloride salt. The current pharmaceutical product containing this drug is being sold by Glaxosmithkline using the tradename Requip^®, in the form of tablets. The structural formula of Ropinirole hydrochloride is represented by formula (1):

(D

Ropinirole is useful in the treatment of Parkinsons disease. Ropinirole is a dopamine agonist and having selective affinity for dopamine D2-like receptors and little or no affinity for non-dopaminergic brain receptors. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson's disease. Also, recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson's disease.

During the synthesis of Ropinirole hydrochloride, a number of impurities are formed, of which 4-(2-(di-propyl amino)ethyl) isatin hydrochloride having the formula (II) is the most significant single impurity.

(")

The impurities, which are formed during the synthesis of Ropinirole hydrochloride including the contaminants of the reagents, get carried over till the final step of preparation of Ropinirole hydrochloride. In order to get the highly pure Active Pharmaceutical Ingredient (API) of Ropinirole, the purification step is very essential. The crude Ropinirole has impurities in the level of 0.5 to 0.6 % as single impurity and 1 % as total impurity. The purification by various solvents does not effectively lead to the purified Ropinirole to have single impurity content below 0.1 %.

EP 0300614A1, US 4997954, EP 113964 describe processes for reducing the number of steps, improving yields, or getting a commercially advantageous process. But, none of them address the problem of impurity level in the API.

Coufal, P., Stuli, K., Claessens, H. A., Hardy, M. J., Webb, M., J. Chromatog., B: Biomedical Sciences and Applications, Vol. 732 (2), 1999, pages 437-444 describes a capillary liquid chromatographic method for the separation and quantification of Ropinirole and its related impurities.

The separation and quantification of the single impurity requires complex analytical methods, which are expensive. Further, the isolation of the single impurity can be carried out only on a very small scale. Thus, there is no efficient chemical method for the purification of Ropinirole hydrochloride, wherein the single impurity is below 0.1% and total impurity is below 0.5%. There is an urgent need for the development of a purification procedure, which is cost-efficient, ecofriendly, less labour intensive, less time consuming as well as can be carried out on an industrial scale.

Ropinirole hydrochloride of formula (I) can be prepared by processes known in prior art. In one of the key processes (US Patent No. 4997954) 2-phenylethanol of formula (III) was reacted with phosphorous trichloride and paraformaldehyde to give the corresponding isochroman of formula (IV). The isochroman of formula (FV) on reaction with bromine gave the corresponding 2-(2'-bromoethyl)benzaldehyde of formula (V), which on reaction with nitromethane in the presence of sodium methoxide gave 2-(2'bromoethyl)beta-nitrostyrene of formula (VI). 2-(2'bromoethyl)- beta-nitrostyrene of formula (VI) on reaction with acetyl chloride and ferric chloride gave 4-2'-bromoethyl)-3-chloro-l,3-dihydro-2H-indole-2-one of formula (VII). 4-(2'- bromoethyl)-3-chloro-l,3-dihydro-2H-indole-2-one of formula (VII) was dehalogenated in presence of Palladium on carbon and sodium hypophosphite to give 4-(2'-bromoethyl)-l,3-dihydro-2H-indole-2-one of formula (VIII), which on further reaction with di-n-propylatnine in presence of water / acetonitrile and nitrogen gave Ropinirole hydrochloride of formula (T). The sequence of the synthetic steps followed is shown in Scheme 1.

During this reaction sequence, alongwith other impurity formation, especially oxidative impurities, possibly the oxidation at 3-position of indole-2-one moiety to give diketoindole (isatin derivative) might take place to give rise to the process impurity, as shown in Scheme -2.

PCT application WO2005080333 (henceforth '333) discloses an improved process for the purification of Ropinirole hydrochloride by dissolving or suspending crude Ropinirole base or its pharmaceutically acceptable salt in a suitable solvent (preferably isopropyl alcohol), reacting with a nitrogenous base (hydroxylamine hydrochloride, hydrazine hydrate, phenyl hydrazine) to form an imine derivative, optionally treating the reaction mixture with a base (preferably aqueous potassium hydroxide) to adjust the pH, and isolating purified Ropinirole hydrochloride of formula (I). The drawback of '333 publication is use of nitrogenous bases which are highly toxic and hazardous, hence industrially not viable and practically not safe.

Hydroxylamine hydrochloride is corrosive, causes burns to any area of contact.

It is harmful by inhalation, ingestion or skin absorption. It is extremely destructive of mucous membranes, upper respiratory tract, eyes and skin. It cause severe irritation and corneal damage to eye. On injestion, it converts hemoglobin to methemoglobin, producing cyanosis. It also cause nausea, vomiting, fall in blood pressure, headache, vertigo, ringing in the ears, shortness of breath, severe blood oxygen deficiency and convulsions. High concentrations cause coma and death from circulatory collapse. On chronic exposure it causes anemia, weight loss, nervous system affects, and kidney, liver and bone marrow damage.

Phenyl hydrazine is corrosive. It is harmful if swallowed, inhaled or absorbed through skin. It is suspected as carcinogen and cancer hazard. It is poisonous. On inhalation it causes irritation to respiratory tract. On skin contact, it causes burns to any area of contact and lead to dermatitis and skin sensitization. It affects blood, liver, kidneys and respiratory system. It may cause vomiting, dizziness, faintness, and jaundice.

PCT application WO2005105741 discloses a purification process for Ropinirole hydrochloride by treating Ropinirole freebase with a reducing agent and then converting it to pure Ropinirole hydrochloride. The reducing agent is selected from sodium metabisulfite, sodium hyposulfite, sodium hydrosulfite, hydroxylamine, hydrazine or mixtures thereof.

Sodium hyposulfite is harmful by ingestion, inhalation, or skin absorption. It is irritant on Acute Exposure. It may irritate or burn eyes and cause temporary conjunctivitis. It causes skin irritation. Dust or mist may cause severe irritation to the respiratory tract. Exposure may cause coughing, chest pains and difficulty in breathing. If it is heated to the point where sulfur dioxide gas is driven off, then this gas is highly irritating to the respiratory tract. It causes gastrointestinal irritation such as nausea, vomiting, purging and cyanosis. Hydrazine is toxic, and may be fatal, if inhaled, swallowed or absorbed through the skin. It is expected to be a human carcinogen. The substance is toxic to blood, kidneys, lungs, the nervous system, mucous membranes. Long-term exposure may cause CNS, lungs, blood, liver and kidney damage. It is highly corrosive and may produce tissue damage particularly on mucous membranes of eyes, mouth and respiratory tract. It is animal embryotoxic. Severe over-exposure can result in death.

Sodium metabisulfϊte is harmful if swallowed or inhaled. It causes irritation to skin, eyes and respiratory tract. It reacts with acids and water thereby releasing toxic sulfur dioxide gas which is harmful and deadly if inhaled which may cause severe or deadly allergic reactions in some asthmatics and sulfite sensitive individuals. Very large doses of intake may cause violent colic, nausea, vomiting, diarrhea, abdominal pains, circulatory disturbance, and central nervous system depression and even death. It may cause irreversible eye damage to eye such as stinging, tearing, redness, swelling, corneal damage and blindness.

We have further observed that the level of the diketoindole impurity in the API increases upon storage over extended periods irrespective of the pharmaceutical dosage form. Due to high initial levels of the diketoindole impurity in the API prepared by prior art processes; the impurity content exceeds the acceptable limits set forth by the regulatory authorities over a prolonged period of time. Thus, there is an urgent need to develop a process which removes the above mentioned deficits of prior art processes and provides an API containing insignificant initial amount of the diketoindole impurity, so that the content of the impurity can be kept within the acceptable levels throughout the shelf life of the product, while at the same time satisfying the regulatory requirements.

With reference to the above-discussed procedures, none of the prior art references disclosed or claimed the use of phosphorous containing reagents such as phosphorus trichloride (PCb), phosphorous pentachloride (PCI₅) and the like in the purification of a compound of formula (I), hence we focused our research to develop an improved and efficient process for the purification of a compound of formula (I) in substantially good yield and high chemical purity. Scheme - 1.

(III)

(IV) (V)

Methanol at Nitromethane / 0 to -5° C Sodium methoxide

(VII)

(VI)

Sodium hypophosphite / Pd /C (10%) Ethylacetate / Water at 65° to 70° C

(VIII)

(D

Scheme - 2.

(VII)

Sodium hypophosphite / Pd /C (10%) Ethylacetate / Water at 65° to 70° C

(VIII) (IX)

Di-n-propylamine Isopropyl alcohol / HCI Di-n-propylamine Isopropyl alcohol / HCI

Aqueous Acetonitrile at 65° to 70° C Aqueous Acetonitrile at 65° to 70° C

(I)

(H) Objectives of the Invention

The main objective of the present invention is to provide a process for the purification of Ropinirole hydrochloride of formula (I) in good yield and high chemical purity.

Another objective of the present invention is to provide a process for the purification of Ropinirole hydrochloride of formula (I), which would be simple and easy to implement on commercial scale and industrially viable.

Yet another object of the present invention is to provide an improved process for purification of Ropinirole hydrochloride of formula (I) which utilizes less hazardous reagents compared to the reagents used in prior art processes and gives Ropinirole hydrochloride with more than 99% purity.

Summary of the Invention

Accordingly, the present invention provides an improved process for the purification of Ropinirole hydrochloride of formula (I), comprising the steps of:

(D

a) dissolving or suspending crude Ropinirole or salt thereof in an organic solvent; b) treating the solution or suspension of step (a) with phosphorous containing reagent; c) extracting the reaction mixture with water; d) treating the reaction mixture of step (c) with a base and extracting Ropinirole base in an organic solvent; e) concentrating the organic layer and treating with an alcoholic solvent; f) treating the free base of Ropinirole with hydrochloric acid to get Ropinirole hydrochloride; g) isolating the Ropinirole hydrochloride; h) optionally purifying the Ropinirole hydrochloride by dissolving in an alcoholic solvent and precipitating using an anti-solvent; and i) isolating the Ropinirole hydrochloride of formula (I).

The process in the present invention is shown in the scheme given below:

HN[Propyl]_j

Water

(VIII) Ropinirole (Before Purification) (H)

Organic solvent Phosphoηating Reagent

Ropinirole Hydrochloride Ropinirole (After Purification)

(Pure)

Description of the Invention

Accordingly the term "treating" as used hereinabove refers to suspending, dissolving or mixing and contacting or reacting of Ropinirole hydrochloride with solvent (s) or reagent (s).

In an embodiment of the present invention, said organic solvent in step (a) is preferably selected from the group consisting of methylenedichloride, ethylenedichloride, carbon tetrachloride, chloroform or hydrocarbons like straight, branched or cyclo alkanes such as hexane, n-heptane, cyclohexane or aromatic hydrocarbons such as toluene, xylene and the like, most preferably methylenedichloride.

In another embodiment of the present invention, said phosphorous containing reagents in step (b) is preferably selected from phosphorous acid or halophosphorous compounds which is selected from the group consisting of phosphorous trichloride (PCl₃), phosphorous pentachloride (PCI₅), phosphorous oxy trichloride (POCI₃) and the like, most preferably phosphorous trichloride.

In another embodiment of the present invention, said base is selected from the group consisting of alkali hydroxide such as sodium hydroxide, potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, alkali bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like, most preferably aqueous sodium hydroxide.

In another embodiment of the present invention, said organic solvent in step (d) is preferably selected from hydrocarbons like straight, branched or cyclo alkanes such as hexane, n-heptane, cyclohexane or aromatic hydrocarbons such as toluene, xylene and the like alkanes, most preferably n-heptane.

In another embodiment of the present invention, said alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof, wherein in step (e) is most preferred alcoholic solvent is isopropyl alcohol and in step (h) most preferred alcoholic solvent is methanol.

In yet another embodiment of the present invention, anti-solvent employed for precipitating Ropinirole hydrochloride is selected form diethyl ether, isopropyl ether, methyl tertiary butyl ether, petroleum ether and the like or mixtures thereof, most preferably isopropyl ether. In still another embodiment of the present invention, the subjected purification process is carried out for the elimination of impurities particularly 4-(2-(di-propyl amino) ethyl) isatin hydrochloride impurity of formula (II).

In still another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 10⁰C to reflux temperature of the solvent used.

Starting materials of this invention are prepared according to the literature available in the prior art.

The present invention is illustrated with the following example, which should not be construed for limiting the scope of the invention.

(1) Preparation and Purification of Ropinirole hydrochloride

Water (1.0 L) and di-n-propylamine (456 mL) are placed in a reaction vessel and heated at 60⁰C under nitrogen purging for 1 hr., 4-(2-bromoethyl)-l,3-dihydro-2H- indol-2-one (80 gm) was added to the reaction mass at 35°C. Contents were stirred vigorously and heated to 80⁰C till the completion of the reaction and then reaction mass was cooled to 35°C, water layer was removed, organic layer was distilled out completely under vacuum below 7O⁰C to get dark oil.

Dichloromethane (800 mL) was added to this dark oil and extracted twice with aqueous HCl solution (10%), aqueous solution was washed with dichloromethane (400 mL x 3). The pH of the solution was adjusted to between 10 to 12 using 20% sodium hydroxide solution and extracted with dichloromethane (800 mL x 2). The organic layer was washed with water, separated and treated with phosphorus trichloride (7.6 mL) in dichloromethane (15 mL). The reaction was continued further for 1.5 hrs at 35°C and reaction mass was extracted with water (400 x 2), pH was adjusted to between 10 to 12 using 20% sodium hydroxide solution and extracted with n-heptane (400 mL x2), combined n-heptane layer and washed with water and distilled out under vacuum to get the dark red oil, isopropyl alcohol was added (480 mL) and adjusted the pH to 1.0 using HCl (35%) to obtain solid material. The material was filtered to obtain 4-[2-(dipropylamino)ethyl]-l,3-dihydro-2H-indole-2-one hydrochloride (Ropinirole hydrochloride). (52.8 gms, 53.3 % and Purity by HPLC 99.58 %)

Ropinirole hydrochloride was re-crystallized from methanol (250 mL) and isopropyl ether (500 mL) to get the highly pure crystals of Ropinirole hydrochloride (45.8 gm, 46% and Purity by HPLC 99.70 % ). Melting Point : 242 to 245⁰C.

Claims

We Claim:

(1) An improved process for the purification of Ropinirole hydrochloride of formula

(I), comprising the steps of;

(D

(2) A process according to claim no. 1, wherein crude Ropinorole contains impurities, particularly 4-(2-(di-propyl amino) ethyl) isatin hydrochloride impurity of formula (II).

(H)

(3) A process according to claim no. 1, wherein said organic solvent in step (a) is preferably selected from the group consisting of methylenedichloride, ethylenedichloride, carbon tetrachloride, hexane, n-heptane, cyclohexane, toluene, xylene, most preferably methylenedichloride.

(4) A process according to claim no. 1, wherein said phosphorous containing reagents in step (b) is preferably-selected from phosphorous acid or halophosphorous compounds which is selected from the group consisting of phosphorous trichloride (PCl₃₎, phosphorous pentachloride (PCI₅), phosphorous oxy trichloride (POCI₃), most preferably phosphorous trichloride.

(5) A process according to claim no. 1, wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, most preferably aqueous sodium hydroxide.

(6) A process according to claim no. 1, wherein said organic solvent in step (d) is preferably selected from hexane, n-heptane, cyclohexane, toluene, xylene, most preferably n-heptane.

(7) A process according to claim no. 1, wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n- butanol, isobutanol, tertiary butanol, and mixtures thereof.

(8) A process according to claim no. 1, wherein said anti-solvent employed for precipitating Ropinirole hydrochloride is selected form diethyl ether, isopropyl ether, methyl tertiary butyl ether, petroleum ether or mixtures thereof, most preferably isopropyl ether.

(9) A process according to claim no. 1, wherein all the steps are preferably performed at a temperature in the range of (-) 10⁰C to reflux temperature of the solvent used.

(10) An improved process for the purification of Ropinirole or its salt of formula (I) comprising treating crude Ropinirole or its salt thereof containing 4-(2-(di-propyl amino) ethyl) isatin hydrochloride as an impurity with halophosphorous compounds selected from group comprising of phosphorous trichloride (PCb), phosphorous pentachloride (PCI₅), phosphorous oxy trichloride (POCI₃).

(I)