Process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride
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) and pharmaceutical composition comprising the same. Further the present invention also discloses a method of treatment for cardiovascular disorders and Parkinson's disease.
1. A process for preparation of compound of structural formula (I)
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 alkali metal salt of an imide in a solvent to form compound of formula III
b) Treating compound of formula III with nitromethane in presence of RCOOH, R 1 NH 2 and HC(OR 2 ) 3 in a polar solvent to form a compound of formula IV, and wherein R is C 1-4 alkyl preferably methyl, R 1 is C 1-4 alkyl preferably butyl, R 2 is C 1-4 alkyl preferably methyl,
c) Treating compound of formula IV with FeCl3 and R 3 COCl, in solvent to form compound of formula V, wherein R 3 is C 1-4 alkyl preferably butyl,
d) Treating compound of formula V with a hydrogen donor in presence of reduction catalyst in ethyl acetate, to form a compound of formula VI,
e) Treating compound of formula VI with hydrazine hydrate or alkali metal hydroxide followed by aqueous halo acid to form a compound of formula VII,
f) Treating compound VII with propionaldehyde under reducing conditions
in presence of a reduction catalyst in solvent to form a compound of formula (I),
g) Conversion of compound of formula I to its hydrochloride salt,
h) Purification of hydrochloride salt of compound of formula I.
2. A process as per claim 1 where X is halo most preferred being bromo.
3. A process as claimed in claim 1 wherein the solvent used in step A is 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 1 wherein solvent used in step A is dimethyl sulphoxide.
5. A process as claimed in claim 1 wherein solvent used in step A is dimethyl formamide.
6. A process as claimed in claim 1 wherein solvent used in step A is acetone.
7. A process as claimed in claim 1 wherein solvent used in step A is mixture of dimethyl sulphoxide, dimethyl formamide and acetone.
8. A process as claimed in 1 wherein solvent used in step A is methanol, ethanol, propanol, isopropanol, r-butanol, iso-butanol, t-butanol.
9. A process as claimed in claim 1 wherein the solvent used in step A is toluene or benzene.
10. A process as claimed in claim 1 wherein the solvent used in step A is acetone or ethylmethyl ketone.
11. A process as claimed in claim 1 wherein the solvent used in step B is selected from lower aliphatic alcohols.
12. A process as claimed in claim 11 wherein said solvent is selected from methanol or ethanol or mixture thereof.
13. A process as claimed in claim 1 , wherein said solvent used in step C is Chloroform or Carbon tetrachloride or Dichloroethane or a mixture thereof.
14. A process as claimed in 1 wherein hydrogen donor used in step D is either hydrogen or sodium hypophosphite or a formate.
15. A process as claimed in claim 1 wherein said catalyst used in step D is 5% to 20% palladium on charcoal.
16. A process as claimed in claim 15 wherein the percentage for palladium on charcoal is 10%.
17. A process as claimed in claim 1 wherein said solvent used in step F is methanol.
18. A process as claimed in claim 1 wherein said solvent used in step F is ethanol.
19. A process as per claim 1 wherein the catalyst used in step F is 5% to 20% palladium on charcoal.
20. A process as claimed in claim 19 wherein the percentage for palladium on charcoal is 10%.
21. A process as claimed in claim 1 wherein the reducing conditions used in step F comprise of hydrogen under pressure in the range of 0 to 10 kg/cm 2 .
22. A process as claimed in claim 21 wherein the hydrogen pressure conditions is between 4 to 6 kg/cm 2 .
23. A process as claimed in claim 1 wherein the alkali metal salt of an imide used in step A is potassium phthalimide.
24. A process as claimed in claim 1 wherein said catalyst used in step D is Raney Nickel.