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WO1994015918A1 - Procede de preparation de derives de l'indolone substitues - Google Patents

Procede de preparation de derives de l'indolone substitues Download PDF

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Publication number
WO1994015918A1
WO1994015918A1 PCT/EP1993/003706 EP9303706W WO9415918A1 WO 1994015918 A1 WO1994015918 A1 WO 1994015918A1 EP 9303706 W EP9303706 W EP 9303706W WO 9415918 A1 WO9415918 A1 WO 9415918A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
compounds
formula
dihydro
indol
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1993/003706
Other languages
English (en)
Inventor
Andrew S. Wells
Norman John Lewis
Timothy Charles Walsgrove
Paul Oxley
Joseph Marian Fortunak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Ltd
SmithKline Beecham Corp
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 SmithKline Beecham Ltd, SmithKline Beecham Corp filed Critical SmithKline Beecham Ltd
Priority to PL93309645A priority Critical patent/PL176152B1/pl
Publication of WO1994015918A1 publication Critical patent/WO1994015918A1/fr
Priority to FI953361A priority patent/FI114094B/fi
Priority to NO952713A priority patent/NO305363B1/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention relates to an improved process for the preparation of substituted indolone derivatives.
  • substituted indolone derivatives are described in EP-113964-B as being useful in cardiovascular therapy, and in EP-299602-A as agents useful in the treatment of Parkinson's disease.
  • substituted indolone derivatives may be prepared in high yield and purity by reduction of the corresponding isatin precursor compounds.
  • High yields and purity in a process involving a number of reaction steps generally results in a much more efficient and cost-effective route to the end product.
  • the present invention therefore provides, in a first aspect, a process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof:
  • each group R is independently hydrogen or Cj ⁇ alkyl; and RMs hydrogen, hydroxy or Cj ⁇ alkoxy which comprises reduction of a compound of structure (II):
  • the reduction is carried out using Raney nickel in a suitable solvent, for example a C]_4 alcohol such as isopropanol at a temperature of between ambient and the reflux temperature of the solvent used.
  • a suitable solvent for example a C]_4 alcohol such as isopropanol
  • Raney nickel is used in relation to the compound of formula (II) and the mixture heated under reflux in isopropanol as solvent.
  • one of the groups R is hydrogen and the other is hydrogen or C ⁇ _4alkyl; preferably, both groups R are C] _4alkyl, in particular n-propyl.
  • n is 1 to 3; preferably n is 2.
  • R is hydrogen, hydroxy or C]_4alkoxy such as methoxy; preferably R is hydrogen.
  • Preferred salts of compounds of formula (I) include those described in
  • EP-113694-B particularly preferred are acid addition salts such as the hydrochloride salt.
  • the above method is particularly useful for the preparation of the compound 4-[2-(di-n- propylamino)ethyl]-l,3-dihydro-2H-indol-2-one hydrochloride salt (INN:ropinirole), a compound useful for the treatment of Parkinson's disease (EP-299-602-A).
  • Certain compounds of structure (I) can be converted into further compounds of structure (I).
  • compounds of structure (I) in which both R groups are hydrogen, or one R group is hydrogen and the other is Cj ⁇ alkyl can be converted to compounds of structure (I) in which both R groups are C]_4alkyl by conventional techniques known in the art such as reductive alkylation with aldehydes, for example using sodium cyanoborohydride or hydrogen gas as reducing agents.
  • Such procedure are particularly useful for preparing the compound 4-[2-(di-n-propylamino)ethyl]- 1 ,3-dihydro-2H-indol-2- one hydrochloride salt, as described in the following examples.
  • Compounds of structure (II) can be prepared using standard techniques well known to those skilled in the art. For example, compounds of formula (II) can be prepared as shown in the following scheme:
  • R* and n are as described for compounds of formula (I) and X is a leaving group or a group N(R)2 in which the groups R are as defined for formula (I).
  • Preferred leaving groups X include halogen, particularly bromo, and oxygen leaving groups such as p-toluenesulphonyloxy. It will be appreciated that when X is N(R)2 the resulting compounds of formula (III) are themselves compounds of formula (II).
  • the mixture was stirred with cooling to 0°C for several hours before collection of the product by filtration.
  • the product was dried in vacuo at 40 °C. to a constant weight, giving 2.40 g of the title compound, m.p. 228-229.5 °C.
  • the aqueous phase was basified with sodium hydroxide (6.0g, 0.15mol) in water (40ml) and the product extracted into dichloromethane (100ml and 2 times 50ml). The organic extracts were dried (MgSO4) and concentrated to an oil in vacuo. The oil was taken up in isopropanol (315ml) at 80°C and hydrochloric acid (SG 1.18, 12ml, 0.14mol) was added. The mixture was allowed to cool to 40°C and was then chilled at 0°C for 15 minutes. The resulting solid was filtered, washed with a little isopropanol, and then dried at 80°C for 24 hours to give the title compound as a pale yellow solid (31.3g, 90%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés de l'indolone possédant la formule générale (I) dans laquelle n vaut 1 à 3; chaque groupe R représente indépendamment hydrogène ou alkyle C1-4; et R1 représente hydrogène, hydroxy ou alkoxy C¿1-4?. La préparation se fait par réduction des composés précurseurs de l'isatine correspondants.
PCT/EP1993/003706 1993-01-08 1993-12-27 Procede de preparation de derives de l'indolone substitues Ceased WO1994015918A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PL93309645A PL176152B1 (pl) 1993-01-08 1993-12-27 Sposób wytwarzania podstawionych pochodnych indolonu
FI953361A FI114094B (fi) 1993-01-08 1995-07-07 Menetelmä substituoitujen indolonijohdannaisten valmistamiseksi
NO952713A NO305363B1 (no) 1993-01-08 1995-07-07 FremgangsmÕte for fremstilling av substituerte indolonderivater og forbindelsene derav

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939300309A GB9300309D0 (en) 1993-01-08 1993-01-08 Process
GB9300309.3 1993-01-08

Publications (1)

Publication Number Publication Date
WO1994015918A1 true WO1994015918A1 (fr) 1994-07-21

Family

ID=10728465

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/003706 Ceased WO1994015918A1 (fr) 1993-01-08 1993-12-27 Procede de preparation de derives de l'indolone substitues

Country Status (7)

Country Link
FI (1) FI114094B (fr)
GB (1) GB9300309D0 (fr)
HU (1) HUT72075A (fr)
MA (1) MA23081A1 (fr)
NO (1) NO305363B1 (fr)
PL (1) PL176152B1 (fr)
WO (1) WO1994015918A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080333A1 (fr) * 2004-02-19 2005-09-01 Torrent Pharmaceuticals Ltd Processus de purification de ropinirole
WO2005074387A3 (fr) * 2003-12-30 2005-10-06 Sun Pharmaceutical Ind Ltd Nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone
WO2005105741A1 (fr) * 2004-02-11 2005-11-10 Sun Pharmaceutical Industries Limited Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur
US7230118B2 (en) * 2003-10-14 2007-06-12 Urquima S.A. Process for the preparation of ropinirole
WO2008075169A3 (fr) * 2006-12-15 2011-04-28 Orchid Chemicals & Pharmaceuticals Limited Procédé de purification de chlorhydrate de ropinirole
WO2011030330A3 (fr) * 2009-09-09 2011-09-29 Taro Pharmaceutical Industries Ltd. Procédé pour la purification de chlorhydrate de ropinirole
WO2018227553A1 (fr) 2017-06-16 2018-12-20 浙江华海立诚药业有限公司 Procédé de purification de chlorhydrate de ropinirole

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3882236A (en) * 1973-12-26 1975-05-06 Lilly Co Eli Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension
EP0046666A1 (fr) * 1980-08-22 1982-03-03 Smithkline Beckman Corporation 2(3H)-Indolones, procédé de préparation et compositions les contenant
EP0113964A1 (fr) * 1982-12-07 1984-07-25 Smithkline Beckman Corporation 4-Aminoalkyle-2(3H)-indolones
EP0167288A2 (fr) * 1984-06-04 1986-01-08 Smithkline Beecham Corporation 4-[2-(amino-N,N-disubstitué)éthyl]isatines
EP0299602A2 (fr) * 1987-05-21 1989-01-18 Smith Kline & French Laboratories Limited L'emploi de dérivés de l'indolone pour la fabrication de médicaments pour le traitement du parkinsonisme
EP0300614A1 (fr) * 1987-06-19 1989-01-25 Smith Kline & French Laboratories Limited Procédé de préparation de dérivés substitués de l'indolinone
WO1991016306A1 (fr) * 1990-04-17 1991-10-31 Smith Kline & French Laboratories Limited Procede ameliore de preparation de derives d'indolene substitues

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3882236A (en) * 1973-12-26 1975-05-06 Lilly Co Eli Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension
EP0046666A1 (fr) * 1980-08-22 1982-03-03 Smithkline Beckman Corporation 2(3H)-Indolones, procédé de préparation et compositions les contenant
EP0113964A1 (fr) * 1982-12-07 1984-07-25 Smithkline Beckman Corporation 4-Aminoalkyle-2(3H)-indolones
EP0167288A2 (fr) * 1984-06-04 1986-01-08 Smithkline Beecham Corporation 4-[2-(amino-N,N-disubstitué)éthyl]isatines
EP0299602A2 (fr) * 1987-05-21 1989-01-18 Smith Kline & French Laboratories Limited L'emploi de dérivés de l'indolone pour la fabrication de médicaments pour le traitement du parkinsonisme
EP0300614A1 (fr) * 1987-06-19 1989-01-25 Smith Kline & French Laboratories Limited Procédé de préparation de dérivés substitués de l'indolinone
WO1991016306A1 (fr) * 1990-04-17 1991-10-31 Smith Kline & French Laboratories Limited Procede ameliore de preparation de derives d'indolene substitues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R.M. DEMARINIS ET AL.: "Synthesis and in vitro evaluation of 4-(2-aminoethyl)-2(3H)-indolones and related compounds as peripheral prejunctional dopamine receptor agonists.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 6, 1986, WASHINGTON US, pages 939 - 947 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7230118B2 (en) * 2003-10-14 2007-06-12 Urquima S.A. Process for the preparation of ropinirole
WO2005074387A3 (fr) * 2003-12-30 2005-10-06 Sun Pharmaceutical Ind Ltd Nouvelles formes cristallines d'hydrochlorure de 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone
WO2005105741A1 (fr) * 2004-02-11 2005-11-10 Sun Pharmaceutical Industries Limited Hydrochlorure de 4-[2-(di-n-propylamino)ethyl]-2(3h)-indolone sensiblement pur
WO2005080333A1 (fr) * 2004-02-19 2005-09-01 Torrent Pharmaceuticals Ltd Processus de purification de ropinirole
WO2008075169A3 (fr) * 2006-12-15 2011-04-28 Orchid Chemicals & Pharmaceuticals Limited Procédé de purification de chlorhydrate de ropinirole
WO2011030330A3 (fr) * 2009-09-09 2011-09-29 Taro Pharmaceutical Industries Ltd. Procédé pour la purification de chlorhydrate de ropinirole
WO2018227553A1 (fr) 2017-06-16 2018-12-20 浙江华海立诚药业有限公司 Procédé de purification de chlorhydrate de ropinirole
US10961194B2 (en) 2017-06-16 2021-03-30 Zhejiang Huahai Licheng Pharmaceutical Co., Ltd. Method for purifying ropinirole hydrochloride

Also Published As

Publication number Publication date
GB9300309D0 (en) 1993-03-03
NO305363B1 (no) 1999-05-18
FI953361L (fi) 1995-07-07
HUT72075A (en) 1996-03-28
NO952713D0 (no) 1995-07-07
FI953361A0 (fi) 1995-07-07
PL309645A1 (en) 1995-10-30
PL176152B1 (pl) 1999-04-30
MA23081A1 (fr) 1994-10-01
FI114094B (fi) 2004-08-13
NO952713L (no) 1995-07-07

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