|Title of Invention||
A PROCESS FOR THE PREPARATION OF 4-(2-DIPROPYLAMINOETHYL)-1,3-DIHYDRO-2H-INDOL-2- ONE HYDROCHLORIDE
|Abstract||The present invention discloses a novel process and novel intermediates for the preparation of 4-[2-(di-n-propyl amino)ethyl]-1,3-dihydro-2H-indol-2-one,commonly known as Ropinirole (I),being useful in cardiovascular therapy and an agent useful in treating Parkinson"s disease.|
|Full Text||FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
[See section 10; rule 13]
"Novel process and novel intermediates for the preparation of 4-(2-
(a) USV LIMITED
(b) B.S.D. Marg, Station Road, Govandi, Mumbai - 400 088, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:
60 MUM 2004
20 JAN 2004 Granted
Novel process and Novel intermediates for the preparation of) (2-DipropylaminoethyI)-1,3ihydro-2H-indol-2-.one-hydfochloride
Technical field of invention
The present invention relates to a novel process and novel intermediates for the preparation of4-[2-( di-n-propvl amino )ethyl 1-1 ,3-dihydro-2H-indol-one, commonly known as Ropiniroje.
Background and Prior Art:
Ropinirole is described in US 4,452,808 as being useful in cardiovascular therapy and in US 4,824,860 as an agent useful in treating Parkinson"s disease. The processes for the preparation of Ropinirole HCI & its derivatives have previously been described. US 4,452,808 describes the preparation of 4-aminoalkvl-2(3HVindolones starting from either 4-aminoalkyl-7hydroxy-2(3H)-indolones or 2-methyl -3-nitro-benzene acetic acid by two different processes. Particularly those processes involving reductive cyclization of nitrostyrene intermediates in presence of acetyl chloride and Iron (IIP) chloride described in EP 0300614 and WO 91/16306 are of particular relevance./Present invention discloses a novel route and novel intermediates for the preparation of Ropinirole. Present invention comprises of 6 steps leading to desired moiety.
US Patents namely US 4452808, US 5336781, US 4997954, US 4314944 deal with the molecule called Ropinirole. For the present purpose US 4452808 and US 4314944 are more relevant. Few patents deal with Ropinirole mainly from method of treatment point of view and therefore are not directly related to the present invention.
WO 91/16306 and EP 0300614 are relevant from the point of view of-reductive cyclization and are dealt at appropriate place hereafter.
The processes for the preparation of Ropinirole HCI & its derivatives have previously been described. US 4,452,808 describes the preparation of 4-aminoalkyl-2(3H)-indolones starting from either 4-aminoalkyl-7-hydroxy-2(3H)-indolones or 2-methyl -3-nitro-
C) Treating IV with FeCl3& R3COCI, in solvent like Dichloromethane, to form compound of formula V, wherein R3 is C1-4lkyl preferably butyl,
D) Treating compound V with a hydrogen donor in presence of reduction catalyst in ethyl acetate, to form a Compound of formula VI,
E) Treating compound VI with hydrazine hydrate or alkali metal hydroxide followed by aqueous halo acid such as hydrochloric acid to form a compound of
F) Treating compound VII with propionaldehyde under reducing conditions in presence of a reduction catalyst in solvent such as lower aliphatic alcohol to form a compound ot formula (1),
G) Conversion of I to its hydrochloride salt H) Purification of hydrochloride salt of I.
2. A process as per claim (A)wherein X is halo most preferred being bromo.
3. A process as claimed inclaim 1A1 Wherein the solvents are selected from dipolar
aprotic or a lower aliphatic alcohol or an aromatic hydrocarbon or aliphatic ketone or a mixture thereof.
4. A process as claimed in claim 1A wherein the selected solvent is DMSO.
5. A process as claimed in claim lA Wherein the selected solvent is DMF.
6. A process as claimed in claim 1A" wherein the selected solvent is acetone.
7. A process as claimed in claim 1A wherein the selected solvent is mixture of DMSO, DMF and acetone
8. A process as claimed in lA whefeln the selected solvent optionally is methanol, ethanol, propanol, isopropanol, n-butanol, iso-butanol or t-butanol.
9. A process as claimed in 1A wherein the selected "solvent optionally is toluene or benzene.
10. A process as claimed in 1A wherein the selected solvent optionally is ethylmethyl ketone.
11. A process as claimed in claim 1B wherein the selected solyent is from lower aliphatic alcohols.
12. A process as claimed in claim lB wherein the selected solvent is methanol or ethanolor mixture thereof.
13. A process as claimed in claim 1 C wherein the selected solvent is Chloroform or Carbon tetrachloride or Dichloroethane or a mixture thereof.
14. A process as per claim lDAvherein hydrogen donor is either hydrogen or sodium hypophosphite or formates like Ammonium formate. Sodium formate, or Formic acid or Hydrazine hydrate; and the catalyst is palladium., on charcoal where palladium percentage is 5% to 20%.
15. A process as claimed in claim 11 wherein preferred % of palladium on charcoal is 10%
16. An atemate proeess for the process claimed in claim ID wherein reduction catalyst is in DMF.
17. An altemate process for process as claimed in claim 1D wherein the catalyst is
5% to20% palladium on charcoal
18. An alternate_process for the process as claimed in claim ID wherein more preferfed Catalyst is 10 % palladium on charcoal.
19. A process as claimed in claim 1F wherein the solvent is methanol.
20. A process as claimed in claim 1F wherein the solvent is ethanol.
21. A process as per claim 1F where the catalyst is 5% to 20% palladium on charcoal.
22. A process as claimed in claim 18 wherein more preferred catalyst is 10 %
palladium on charcoal.
23.)A process as claimed in Claim 1F wherein the reducing conditions comprise of ydrogen under pressure in the range of 0 to 10kg/cm2.
24. A process as claimed in claim IF wherein more preferred hydrogen pressure conditions are in the range between 4 to 6 kg/ cm2.
25. A process as claimed in claim 1A wherein the alkali metal salt of an imide is rpotassiumphthalimide.
26 A process as claimed in claims 1 to 22 for preparation of compound VIII and the compound VIII
27 A process as claimed in claims 1 to 22 for preparation of compound IX and the compound IX
28 A process as claimed in claims 1 to 22 for preparation of compound X and the compound X
process as claimed in claims 1 to 22 for preparation of compound XI and the compound XI
30. A process of preparation of Ropinirole comprising condensation of 2-(2"-bromoethyl)benzaldehyde with Potassium Phthalimide to give 2-(2"-phthalimidoethyl) benzaldehyde (VIII as shown in claim 23), which is subjected to treatment with nitromethane to give 2-(2"- phthalimido ethyl) P- nitro styrene (IX as shown in claim 24) which is transformed to 4-(2" - phthalimidoethyl)-3 -chloro-l,3-dihydro-2H-indol-2-one (X as shown in claim 25) which is subjected to dechlorination to yield 4-(2"-phthalimido ethyl)-l,3-dihydro-2H-indol-2-one (XI as shown in claim 26) which is subjected to deorotection to eliminate phthalimide moiety to yield 4-f2"-aminoethv0-l .3-dihvdrQ-2H-indol-2-one hydrochloride (VII as shown in claim IE) which is subieated to converted to Ropinirole Hydrochloride (I as shown in claim IF).
31 A process for preparation of compound of structural formula (I)
and its acid addition salts, particularly hydrochloride salt are substantially described herein_wi.thxefere.nce to the foregoing-examples.
Dated this the 20th day of Jan 2004
Dr. Gopakumar G. Nair
Agent for the Applicant Gopakumar Nair Associates
1. A process for preparation of compound of structural formula (1)
and its acid addition salts, particularly hydrochloride salt, which comprises the steps of: A) Condensing a compound of formula II wherein X is a leaving group,
with any alkali metal salt of an imide. in a solvent to form compound of formula III
B) Treating III with nitromethane in presence of RCOOH, R1NH2 & HC(OR2)3 in a polar solvent to form a compound of formula IV, and wherein R is C1-4
preferably methyl, R is C1-4lkyl preferably butyl, R is C1-4lkyl preferably methvl,
|Indian Patent Application Number||60/MUM/2004|
|PG Journal Number||04/2008|
|Date of Filing||20-Jan-2004|
|Name of Patentee||USV LIMITED|
|Applicant Address||B.S.D.MARG,STATION ROAD,GOVANDI,MUMBAI-400 088,|
|PCT International Classification Number||C07D209/34 A61K31/404 A61K31/405|
|PCT International Application Number||N/A|
|PCT International Filing date|