WO2005105741A1 - Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur - Google Patents

Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur Download PDF

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Publication number
WO2005105741A1
WO2005105741A1 PCT/IN2005/000047 IN2005000047W WO2005105741A1 WO 2005105741 A1 WO2005105741 A1 WO 2005105741A1 IN 2005000047 W IN2005000047 W IN 2005000047W WO 2005105741 A1 WO2005105741 A1 WO 2005105741A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
substantially pure
ethyl
propylamino
Prior art date
Application number
PCT/IN2005/000047
Other languages
English (en)
Inventor
Hetalkumar Virendrabhai Patel
Jitendra Gopaldas Dipchandani
Raja Jyotir Jani
Rajamannar Thennati
Original Assignee
Sun Pharmaceutical Industries Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2005105741A1 publication Critical patent/WO2005105741A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin

Definitions

  • the present invention relates to substantially pure 4-[2-(di-n-propylamino)ethyl]-2(3H)- indolone hydrochloride, commonly lcnown as ropinirole hydrochloride (INN Name).
  • 4- [2-(Di-n-propylamino)ethyl] -2(3 H)-indo lone hydrochloride, compound of formula I, is used in treating Parkinson's disease.
  • United States Patent No. 4,452,808 discloses compound of formula I and the process of its preparation.
  • Example 1 isolates compound of formula I as a pale yellow crystalline solid whereas
  • Example 2 isolates as a white residue and then crystallizes with very large volumes of acetonitrile.
  • United States Patent No. 4,950,765 (assigned to SmitMdine) exemplifies a different process which furnishes an off-white solid.
  • United States Patent No. 4,997,954 (assigned to Smithkline) claims a novel process to prepare yellow coloured compound of formula I with HPLC purity 97.00% which on further purification by recrystallization from isopropanol or basification and re- acidification procedures gives 98 to 99% pure compound of formula I.
  • United States Patent No. 5,336,781 (assigned to Smithkline; referred to herein as '781) describes a variant of '954 process to yield off- white solid.
  • Our experience (see Comparative example 2) showed that the process results in variable impurity profile and color. Particularly, the product had a high color index and isatin impurity i.e. impurity of a compound of formula IL
  • the object of the present invention is to provide substantially pure compound of foraiula I having HPLC purity equal to or greater than 99.5%.
  • Yet another object is to provide process for the preparation of substantially pure compound of formula I having HPLC purity equal to or greater than 99.5%>.
  • the present invention provides substantially pure 4-[2-(Di-n-propylamino)ethyl] 2(3 H)- indolone hydrochloride having HPLC purity equal to or greater than 99.5%).
  • the substantially pure 4-[2-(Di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride has an HPLC purity equal to or greater than 99.5%> and less than 0.2% isatin impurity, compound of formula 2.
  • the substantially pure 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride has an HPLC purity equal to or greater than 99.5%> and a colour index less than 0.2 AU at 420 nm.
  • the present invention also provides a process for the preparation of substantially pure 4- [2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of foraiula I, said process comprising • HCI
  • substantially pure ropinirole hydrochloride 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride.
  • substantially pure 4-[2-(di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I is prepared by a process comprising
  • substantially pure compound of formula I may be prepared by dissolving compound of formula I, having
  • HPLC purity less than 99.5%> in water followed by addition of inorganic or organic alkali to generate the free base, compound of foraiula la, extracting the free base in suitable solvent(s), treating with a reducing agent and treating with hydrochloric acid, in gaseous or solution form, to yield substantially pure compound of formula I, having HPLC purity equal to or greater than 99.5%>.
  • crude free base, compound of formula la is dissolved in suitable solvent(s), treated with a reducing agent and then converted to substantially pure 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride.
  • the suitable solvent(s) that may be used for extraction or dissolution of free base, compound of foraiula la, may be selected from aliphatic or aromatic or cyclic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons, alkanols, ethers, esters and their mixtures.
  • the suitable solvent(s) may be aliphatic or aromatic or cyclic hydrocai'bon such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene and the like; alkanols such as methanol, ethanol, t-butanol, isopropanol, cyclohexanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; esters such as ethylacetate, butylacetate and the like.
  • the reducing agent may be selected from sodium metabisulf ⁇ te, sodium hyposulf ⁇ te, sodium hydrosulfite, hydroxylamine, hydrazine and the like or mixtures thereof.
  • the reducing agent may be used as dilute aqueous solutions ranging from 0.2 to 15.0 %w/v, preferably 1.0 to 10.0% w/v. Accordingly, the present invention provides substantially pure 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride having HPLC purity equal to or greater than 99.5%, preferably greater than 99.1% and the most preferred being 99.8%).
  • substantially pure 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride having HPLC purity equal to or greater than 99.5%> and less than 0.2% isatin impurity, compound of formula II.
  • substantially pure compound of formula I is prepared by dissolving compound of formula I in water, the clear solution is treated with ammonia followed by extraction with water immiscible organic solvent(s).
  • the organic phase containing compound of formula la is washed with dilute aqueous solution of moderately strong reducing agent w/v to obtain substantially pure compound of formula la.
  • the organic phase containing substantially pure compound of formula la is then washed with water, and alcoholic solution of hydrochloric acid added to get substantially pure compound of foraiula I.
  • the invention is further illustrated but not restricted by the description in the following examples. Examples Example 1
  • Example 2 Analytical Methods
  • Mobile phase Mix buffer solution (dissolve 1.36 g of potassium dihydrogen orthophosphate with water and make up lo 1000ml) in and dilute upto the mark., acetoiiitrile and triethylamine in the ratio of 850 : 150 : 2.0. Filter and degas prior to use. Finally adjust the pH of the solution to 3.5 ⁇ 0.1 with orthophosphoric acid.
  • Chromatog ayhic system The liquid chromatograph is equipped with a 250 ran TJV detector and 4.6 mm x 25 cm, 5 ⁇ column that contains LUNA C-18(2), (Phenomenex, UK). The flow rate is about 1.0 ml/min.
  • Example 3 The sample of Example 1 is stored under ambient conditions for a year in double polythene bags.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne un hydrochlorure de 4-[2-(Di-n-propylamino)éthyl]-2(3h)-indolone sensiblement pur, présentant une pureté HPLC égale ou supérieure à 99,5 % et le procédé de préparation dudit hydrochlorure.
PCT/IN2005/000047 2004-02-11 2005-02-11 Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur WO2005105741A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN154/MUM/2004 2004-02-11
IN154MU2004 2004-02-11

Publications (1)

Publication Number Publication Date
WO2005105741A1 true WO2005105741A1 (fr) 2005-11-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000047 WO2005105741A1 (fr) 2004-02-11 2005-02-11 Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur

Country Status (1)

Country Link
WO (1) WO2005105741A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007110880A2 (fr) * 2006-03-29 2007-10-04 Alembic Limited Procédé de purification du chlorhydrate de ropinirole
WO2007110879A2 (fr) * 2006-03-29 2007-10-04 Alembic Limited Procédé de purification du chlorhydrate de ropinirole
WO2008075169A2 (fr) * 2006-12-15 2008-06-26 Orchid Chemicals & Pharmaceuticals Limited Procédé de purification de chlorhydrate de ropinirole
WO2010134433A1 (fr) 2009-05-21 2010-11-25 久光製薬株式会社 Préparation transdermique

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452808A (en) * 1982-12-07 1984-06-05 Smithkline Beckman Corporation 4-Aminoalkyl-2(3H)-indolones
US4950765A (en) * 1986-08-30 1990-08-21 Smith Kline & French Laboratories Limited Process
US4997954A (en) * 1987-06-19 1991-03-05 Smith Kline & French Laboratories Limited Process for preparing substituted isoindolinone derivatives
WO1994015918A1 (fr) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Procede de preparation de derives de l'indolone substitues
US5336781A (en) * 1990-04-17 1994-08-09 Smithkline & French Laboratories Limited Process

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452808A (en) * 1982-12-07 1984-06-05 Smithkline Beckman Corporation 4-Aminoalkyl-2(3H)-indolones
US4950765A (en) * 1986-08-30 1990-08-21 Smith Kline & French Laboratories Limited Process
US4997954A (en) * 1987-06-19 1991-03-05 Smith Kline & French Laboratories Limited Process for preparing substituted isoindolinone derivatives
US5336781A (en) * 1990-04-17 1994-08-09 Smithkline & French Laboratories Limited Process
WO1994015918A1 (fr) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Procede de preparation de derives de l'indolone substitues

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007110880A2 (fr) * 2006-03-29 2007-10-04 Alembic Limited Procédé de purification du chlorhydrate de ropinirole
WO2007110879A2 (fr) * 2006-03-29 2007-10-04 Alembic Limited Procédé de purification du chlorhydrate de ropinirole
WO2007110880A3 (fr) * 2006-03-29 2007-11-29 Alembic Ltd Procédé de purification du chlorhydrate de ropinirole
WO2007110879A3 (fr) * 2006-03-29 2008-01-17 Alembic Ltd Procédé de purification du chlorhydrate de ropinirole
US7863462B2 (en) 2006-03-29 2011-01-04 Alembic Limited Process for the purification of ropinirole hydrochloride
US7968731B2 (en) * 2006-03-29 2011-06-28 Alembic Limited Process for the purification of Ropinirole hydrochloride
WO2008075169A2 (fr) * 2006-12-15 2008-06-26 Orchid Chemicals & Pharmaceuticals Limited Procédé de purification de chlorhydrate de ropinirole
WO2008075169A3 (fr) * 2006-12-15 2011-04-28 Orchid Chemicals & Pharmaceuticals Limited Procédé de purification de chlorhydrate de ropinirole
WO2010134433A1 (fr) 2009-05-21 2010-11-25 久光製薬株式会社 Préparation transdermique
KR20120024582A (ko) 2009-05-21 2012-03-14 히사미쓰 세이야꾸 가부시키가이샤 경피 흡수 제제
US9238025B2 (en) 2009-05-21 2016-01-19 Hisamitsu Pharmaceutical Co., Inc. Transdermal preparation comprising a ropinirole derivative

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