FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
PROCESS FOR PREPARATION OF 4-[2-(N,N-DI~N-PROPYLAMINO)ETRYL1-Z,3-DIHYDRO-1H-INDOL-2-ONE AND SALTS THEREOF,


SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA,
INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.


FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 4-[2-(N,N-di-n propylamino) ethyl]- 2,3-dihydro-lH-indol-2-one, commonly known as ropinirole (INN Name), a compound of the formula (I) .

formula 1
BACKGROUND OF THE INVENTION
Ropinirole and its salts are described in United States patent No.4452808 (referred to as '808 hereinafter) as being useful in cardiovascular therapy and in United States patent no. 4912126 as agents useful in the treatment of Parkinson's disease, based on its selective agonistic activity at the dopaminergic D2-receptors, The hydrochloride salt of ropinirole is approved in United States and several other countries worldwide for the treatment of Parkinson's disease. The '808 patent also describes different methods for preparing 4-[2-(N,N-di-n-propylamino)ethyl]-2.3-dihydro-1 H-indol-2-one and salts thereof.
Scheme B of the process described in '808 patent comprises the steps of
a. reaction of 2-methyl-3-nitropbenyiacetic acid, a compound of formula 2 with thiony]
chloride to give 2-methyl-3-nitro-phenylacetylchloride a compound of formula 3 .
b. The compound of formula 3 is reacted with N,N-di-n-propylamine to give 2-methyl-3-
nitrophenyl-N,N-di-n-propylacetarnide, a compound of formula 4 in the form of syrup.
c. The compound of formula 4 is reduced with borane in tetrahydrofuran and subsequently
treated with HCl/NaOH to give 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine, a
compound of formula 5.
?

d. The compound of formula 5 is treated with a metal ethanol and diethyl oxalate to
obtain ethyl 5-(2-(N,N-di-n-propylamino)ethy])-2-nitrophenyl pyruvate, a compound of
formula 6. which is further treated with hydrogen peroxide. NaOH and HC1 to prepare
6-(2-di-n-propy!aminoethyI)-2-nitro phenylacetic acid hydrochloride, a compound of
formula 7.
e. The compound of formula 7 undergoes reductive cyclization with hydrogen gas in
presence of Pd/C in ethanol to give ropinirole hydrochloride (la).The process is
outlined in Scheme 1 below.

CH, DPA, toluene
10 °C. Na,CO

COOH
CH.
SOCI-
75 °C
NO, reflux, 1 hr
Formula 2

NO,
Formula 3

Formula 4

THF, borane, reflux, 2 hr HCI; NaOH




Na metal, absolute EtOH
RT, diethyl oxalate, reflux N2 atmosphere
5% Pd /C , ethanol 5.5 hr

Formula 5

Formula 7

Formula 1

Scheme I

There are several limitations for using this process for large scale industrial use
• One of the major disadvantages of this process is very poor yield (7-10%) of the reaction of compound of formula 5 to obtain compound of formula 6. Further, one has to isolate product in lots, recover starting material and re-use for the next run, which is difficult for large scale manufacturing. It also involves use of sodium metal, which is pyrophoric and difficult to handle on large scale.
• The compound of formula 4 is converted to the compound of formula 5 using borane in tetrahydrofuran reagent, which is again highly pyrophoric. hazardous and difficult to handle on large scale. Also, when commercial borane in THF is used for the process. over reduction of compound of formula 4 to 2-methyl-3-amino-phenylethy!-N,N-di-n-propylamine is observed, Further, isolation of compound of formula 5 is difficult and requires use of special apparatus called Kugelrohr apparatus, which is not feasible for use in large scale production.
• Further, the 2-methyl-3-nitrophenyl-N,N-di-n-propylacetamide, the compound of formula 4 is prepared by a two step process, starting from 3-nitro-2-methylphenylacetic acid, the compound of formula 2. The first step of this two step process uses thionyl chloride which is toxic and produces harmful sulfur dioxide gas for preparing the compound of formula 3 which is then converted to compound of formula 4.
Thus there is a need for a simple and an economical process for preparation of 4-[2-(N,N-di-n-propylamino) ethyl]-2,j-dihydro-lH-indol-2-one, the compound of formula I or salts thereof, which is cost effective, uses easily available simple reagents, scalable with ease and suitable for commercial production.
We have now developed a new process for the preparation of 4-[2-(N,N-di-n-propylamino)ethyl]-2,3-dihydro-]H-indoi-2-orie, a compound of formula 1. The process of present invention uses a novel intermediate, a compound of formula 8, hitherto not reported in literature for preparation of compound of formula I.
4


Formula 8
(wherein Rl and R2 may be selected from lower alkyl group, or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
The present invention is advantageous as the preparation of novel intermediate, compound of formula 8 from compound of formula 5 does not require use of pyrophoric chemicals. Also the yield of this reaction is satisfactory as compared to the reaction to obtain compound of formula 6 of the prior art. Therefore overall yields of the process using novel intermediate are high. Also in the present invention the compound of formula 5 is prepared from compound of formula 4 without using borane in THF. In the present invention, a mixture of Sodium borohydride and Iodine is used to generate in-situ borane in required quantity for the reaction, thus, avoiding handling of borane solution on large scale. Both chemicals are easily available, cheap and easy to handle on large scale. Further the compound of formula 4 is directly obtained from the compound of formula 2 and without use of thionyl chloride. On the whole the process of the present invention is industrially feasible.
Object of the invention
One objective of the present invention is to provide a novel process for the preparation of 4-[2-(N,N-di-n-propylamino)ethyl]-2,3-dihydro-lH-indo]-2-one, a compound of formula 1 or salts thereof, which is feasible for large scale production.
Yet another objective of the present invention is to provide novel intermediate, compound of formula 8 useful for the preparation of 4-[2-(N,N-di-n-propylamino)ethyl]-2,3-dihydro-l H-indoI-2-one or salts thereof.
3

Still another objective of the present invention is to provide a process for the preparation of novel intermediate compound of the formula 8 useful for the preparation of 4-[2-(N,NA-di-n-propyiamino)ethyf]-2,3-dihydro-lH-indol-2-one, a compound of formula 1 or salts thereof.
Summary of the invention
The present invention in one aspect provides a process for preparing 4-[2-(N,N-d\-n-propylamino)ethyl]-2,3- dihydro-lH-indol-2-one, a compound of formula I or salts thereof comprising

formula 1 a. reacting a compound of formula 8 with hydroxylamine hydrochloride and formic acid to obtain 2-nitro-6-N,N-di-n-propylaminoethy[phenyl acetonitrile, a compound of formula 9; and



Formula 8 Formula 9
(wherein Rl and R2 may be selected from lower alkyl group, or
RI & R2 together with the nitrogen atom to which they are attached
form a morpholine, pyrrolidine, piperidine ring)

b. converting 2-nitro-6-N,N-di-n-propylaminoethylphenyl acetonitrile, the compound of formula 9 to the compound of formula 1 or salts thereof.
6

The present invention in one aspect provides a compound of formula 8

Formula 8 (wherein R1 and R2 may be selected from lower alkyl group or R1 & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
The present invention also provides a process for preparing the compound of formula 8 comprising reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, a compound of formula 5 with a dialkylformamide dialkylacetal.

Formula 5 Formula 8
(wherein Rl and R2 may be selected from lower
alkyl group)
The present invention also provides a process for preparing the compound of formula 8 comprising reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, a compound of formula 5 with dimethyl formamide dimethylacetal in presence of an amine.
7


Formula 5 Formula 8
( wherein Rl and R2 may be selected from lower alkyl group or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine
ring)
Description of the invention
The present invention provides an improved process for the preparation of 4-[2-(N,N-di-n-propylamino)ethy/]-2,3-dihydro-f H-indof-2-one, compound of formula (I) or salts thereof.
According to one embodiment the present invention provides a process for preparing a compound of formula 1 comprising

formula 1
(a) reacting a compound of formula 8 with hydroxylamine hydrochloride and formic acid to obtain 2-nitro-6-N,N-di-n-propylaminoethylphenyi acetonitrile a compound of formula 9: and
8



Formula 8 Formula 9
(wherein Rl and R2 may be selected from lower alkyl group, or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine
ring)
(b) converting 2-nitro-6-N.N-di-n-propyIaminoethylphenyl acetonitriie the compound of formula 9 to 4-[2-(N,N-di-n-propylamino)ethyl]-2,3-dihydro-lH-indol-2-one the compound of formula I or salts thereof.
The reaction of novel intermediate compound of formula 8 with hydroxylamine hydrochloride and formic acid may be effected in the presence or absence of an organic solvent. A suitable organic solvent when present in this reaction may be a water immiscible organic solvent which can form an azeotrope with water. The water immiscible organic solvent may be selected from toluene, xylenes, chlorobenzene and the like.
The reaction may be carried out at a temperature in the range of 80-120 °C. Preferably the reaction is carried out at 85-105 °C.
The compound of formula 9 obtained by the process of the present invention may be used as such for further conversion or maybe further converted to its salt for example the oxalate salt. The oxalate salt of compound of formula 9 may be obtained by any method known in the art.
Step (ii) as disclosed above involves converting 2-nitro-6-N,N-di-n-propylaminoethylphenyl acetonitriie, the compound of formula 9 or salt thereof to the compound of formula 1 or salts thereof.
9

2-nitro-6-N,N-di-n-propylarninoethylphenyl acetonitrile, compound of formula 9 or salt thereof is hydrolyzed to the 2-nitro 6-N,N-di-n-propylaminoethylphenyI acetic acid compound of formula 7.

Formula 9 Formula 7
which is then reductively cyclized to yield 4-[2-(N,N-di-n-propylamino) ethyl]-2,3-dihydro-l H-indol-2-one, compound of formula 1 or salts thereof.

Formula 7 Formula 1
The hydrolysis of 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetonitrile compound of formula 9 to yield 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetic acid compound of formula 7. may be carried out in presence of a mineral acid. A suitable mineral acid may be selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid. Preferably hydrochloric acid is used for the reaction.
The hydrolysis reaction may be conducted in the presence or absence of a solvent. Preferably the reaction is conducted in absence of a solvent. The hydrolysis reaction may be carried out at 80-100 °C.
10

The compound of formula 7 obtained by the process of the present invention may be used as such for further conversion or maybe further converted to its salt for example the hydrochloride salt. The salt of compound of formula 7 may be obtained by any method known in the art.
The reductive cyclization of 2-nitro 6-N,N-di-n-propylaminoethylphenylaceticacid, a compound of formula 7 or salt thereof to obtain compound of formula 1 is carried out in presence of a reducing agent.
The reducing agent for the reaction may be hydrogen or hydrazine hydrate or sodium hypophosphite using suitable hydrogenation metal catalysts, for example Raney nickel or platinum or palladium catalysts, for example platinum on active carbon or palladium on active carbon or may be metal (Fe or Sn) with aqueous hydrochloric acid and the like. Preferably the reductive cyclization may be carried out using any suitable hydrogen source, for example, hydrogen gas at a pressure between 0-20 bar in the presence of any suitable hydrogenation catalyst, for example. 5% palladium on charcoal.
The reductive cyclization reaction may be carried out in presence of solvent. The solvent may be selected from aqueous, or aqueous acidic solvent like acetic acid, alkanols, polar aprotic solvents, or mixture there of and the like. Preferably the reaction is carried out in methanol.
The compound of formula 1 obtained by following the process of the present invention may be converted to its salt. The pharmaceutically acceptable salt of compound of formula J may be selected from hydrochloride; hydrobromide, sulfate, nitrate, acetate: fumarate, maleate, citrate and the like.
According to another embodiment, the present invention provides novel intermediate, compound of formula 8. or salts thereof.
11


Formula 8 (wherein Rl and R2 may be selected from lower alkyl group, or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
The lower alkyl group from which Rl and R2 may be selected may be a Cl-C5 linear or branched alkyl chain such as methyl, ethyl, propyl, isopropyl, and the like.
According to one embodiment, the present invention provides a process for preparing the novel intermediate, the compound of formula 8 comprising reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, the compound of formula 5 with a dialkylformamide dialkylacetal to yield the compound of formula 8.

Formula 5 Formula 8
(wherein Rl and R2 may be selected from lower alkyl group)
The condensation of the compound of formula 5 with the dialkylfomiamide dialkylacetal can be effected in the presence or absence of an inert organic solvent. Preferably, the condensation is conducted in the presence of a polar aprotic solvent, such as. for example. N.N-
12

dimethylformamide (DMF), diethyleneglycol dimethyl ether (Diglyine).
hexamethylphosphortriamide (HMPT), and the like.
The condensation can be conducted at a temperature in the range of between about room temperature and the reflux temperature of the reaction mixture. Preferably, the reaction is conducted at a temperature in the range of 100°-160°. Most conveniently, the reaction is conducted at the reflux temperature of the reaction mixture.
According to yet another embodiment the compound of formula 8 wherein Rl and R2 may be selected from lower alkyl group, or R! & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring may be prepared by reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, a compound of formula 5 with dimethylformamide dimethylacetal in presence of an amine.

Formula 5 Formula 8
The amine used in the reaction may be selected from the group consisting of dialkylamine such as diethyl amine, diisopropyl amine and the like, or pyrrolidine, morpholine and piperidine to obtain compound of formula 8.
In a preferred embodiment the compound of formula 5 is reacted with a N.N-dimethylformamide dimethylacetal to yield β-dimethylamino-6-N,N-di-n-propylaminoethyl-2-nitrostyrene, a compound of formula 8a (compound of formula 8 wherein Rl and R2 are CHy
13


Formula 8a The novel intermediate compound of formula 8 may be isolated or may be used for further reaction without isolating.
According to a preferred embodiment of the invention, the preparation of the novel intermediate, compound of formula 8 and subsequent reaction of compound of formula 8 with hydroxylamiiie hydrochloride and formic acid is carried out in a single-pot, without isolation of novel intermediate.
According to another embodiment the present invention provides a novel process for preparing
the compound of formula 5 comprising
i) reacting 2-methyl-3-nitrophenyl acetic acid , a compound of formula 2 with N,N-di-n-propylamine in the presence of a carbodiimide and 1 -hydroxybenzotriazole to prepare 2-methyl -3-nitrophenyl-N,N-di-n-propyl acetamide, a compound of formula 4


'2 "^2
Formula 2 Formula 4
ii) reduction of 2-methyl -3-nitrophenyl-N,N-di-n-propyl acetamide, the compound of formula 4 to yield 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, the compound of formula 5
14

Formula 4

Formula 5

Suitable carbodiimides for the reaction of 2-methyl-3-nitrophenyl acetic acid, compound of formula 2 with N,N-di-n-propylamine which may be used according to the present inventions may be selected from N.N'-Dialkylcarbodiimide, N. N'-Dicycloheylcarbodiimide, preferably the carbodiimide is N.N'-dicyclohe.xylcarbodiimide.
The reaction may be carried out in an organic solvent. An organic solvent for the reaction may be selected from the group consisting of dichloromethane, THF, DMF, DMA, DMSO, NMP and like the like or mixture thereof. Preferably the solvent used is dichloromethane.
The reaction may be carried out in the temperature range of 25-150°C.
The reduction of 2-methy]-3-nitrophenyl-N,N-di-n-propylacetamide. the compound of formula 4 may be carried out with a suitable reducing agent in an organic solvent.
A suitable reducing agent for the reaction may be a hydride reducing agent with iodine. For example sodium borohydride may be a suitable reducing agent.
The organic solvent may be selected from the group consisting of tetrahydrofuran, diisopropyl ether and the like. Preferably the organic solvent is tetrahydrofuran.
The reaction may be carried out in the temperature range of -15 to 25° C, Preferably -5 to 5°C.
Further according to yet another preferred embodiment of the invention, the reaction of 2-methyl-3-nitrophenyl acetic acid of formula 2 with N,N-di-n-propylamine, which is carried out
15

in the presence of a carbodiimide and 1-hydroxybenzotriazole to prepare 2-methyl-3-nitrophenyl-A/,jV-di-n-propyl acetamide, compound of formula 4 and its subsequent reduction to form 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, compound of formula 5 may be carried out in a single pot. without isolation of the compound of formula 4.
According to preferred embodiment of the present invention, the process of preparing 4-[2-
(N,N-di-n-propylamino) ethyl]-2,3- dihydro-lH- indol-2-one, a compound of fomiula ] or salts
thereof, comprises
i) reacting 2-methyl-3-nitrophenyl acetic acid , compound of formula 2 with N,N-di-n-propylamine in the presence of a carbodiimide and 1-hydroxybenzotriazole to prepare 2-methyl -3-nitrophenyl-N,N-di-n-propyl acetamide, compound of formula 4



•2 -^2
Formula 2 Formula 4
ii) reduction of 2-methyl -3-nitrophenyl-N,N-di-n-propy| acetamide, compound of formula 4 to yield 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine compound of formula 5


-2 ..w2
Formula 4 Formula 5
iii) reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, the compound of formula 5 with a dialkylformamide dialkylacetal to yield the compound of formula
16


'2 —2
Formula 5 Formula 8
(wherein R i and R2 may be selected from lower alkyl group, or R1 & R2 together with
the nitrogen atom to which they are attached form a morphoiine. pyrrolidine, piperidine
ring.)
(iv) reacting a compound of formula 8 with hydroxylamine hydrochloride and formic acid to obtain a compound of formula 9.

Formula 8

Formula 9

v) hydrolysis of 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetonitrile of formula 6 to yield 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetic acid of formula 7

Formula 9 Formula 7
vi) reductive cyclization of 2-nitro 6-N,N-di-n-propylammoethylphenyl acetic acid of
17

formula 7 to yield 4-{2-(N,N-di-n-propylamino) ethyl]-2,3-dihydro-] H-indol-2-one of formula 1 or salts thereof.



formula 7

Scheme II outlines scheme of synthesis of ropinirole as provided by one ofthe embodiments of the invention.
18




Formula 2

Formula 4

COOH I COOH
HCI
COOH
Formula 9

Formula 8

■ HCI

Formula 1
Scheme II
The following examples illustrate the process of the present invention. It should be understood however that the invention is not limited solely to the particular examples given below.
19

Example 1 Preparation of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylammonium oxalate.
1.5 litres of dichloromethane was charged at 25-30°C under nitrogen atmosphere followed by 50 g of 2-Methyl-3-nitro phenyl acetic acid and stirred for 5-10 minutes. 56g of N.N-Dicyclohexyl carbodiimide (DCC) and 62.3 g of 1-Hydroxy benzotriazole (HOBT) were added and stirred for 15-30 minutes. The reaction mixture was refluxed for 4 hours. The heating was stopped, and the reaction mixture was cooled to I5-20°C, and 129.6 g of Di-n-propyl amine was added drop-wise maintaining the temperature between 15-20°C and stirred for 15-20 minutes after addition is over. The reaction mixture was again refluxed for 8.0-10.0 hours. Upon completion of the reaction, the reaction mixture was cooled to -5 to -3°C temperature and stirred for 2.0 hours. The solid was filtered at -5 to -3°C, and washed with chilled dichloromethane and the washings collected with the main filtrate. The dichloromethane was distilled out under vacuum. To the hot residue was added Toluene and distilled out under vacuum. This procedure was repeated one or two times. To the residue thus obtained was added toluene. The toluene layer was washed with aqueous sodium bicarbonate solution, aqueous Sodium chloride solution followed bylN Hydrochloric acid solution and finally with aqueous Sodium chloride solution. The toluene layer was filtered and was distilled out under vacuum to give the 37. 6 g of 2-methyl-3-nitrophenyl-N,N-n-propylacetamide.
To 37.6g of the hot residue of 2-methyl-3-nitrophenyl-N,N-di-n-propylacetamide was charged 350ml of tetrahydrofuran at 25-30°C under nitrogen and stirred for 5-10 minutes. The solution was cooled to 0-5°C, and 53.g Sodium borohydride was added and stirred for 15-30 minutes. A solution of 176g of iodine in 350 ml of tetrahydrofuran was prepared under nitrogen. This Iodine in Tetrahydrofuran solution was added drop wise to the reaction mixture at -7 to -2°C, and stirred at same temperature for 15-20 minutes. The reaction mixture was allowed to come to 5-10°C and stirred at the same temperature for 30 minutes. The reaction mixture was heated to 63-70°C and refluxed for 2.0 hours. The reaction mixture was cooled to -7 to -5°C and stirred for 10-15 minutes. To the reaction mixture was added 700ml of chilled Methanol (0-2°C) drop-wise below 5°C and stirred for 30-45 minutes after addition is over. To the reaction mixture water was added drop wise at 0-5°C and stirred. Hydrochloric acid was added till pH of the reaction mixture was between 1.0-2.0. The reaction mixture was heated to 65-70°C for 12.0 hours. Water was added to the reaction mixture and cooled the solution to 5-!0°C temperature
20

and stirred for 15-20 minutes. To the aqueous layer was charged toluene and cooled the solution to 5-10°C temperature. ~ 25 % Ammonia solution was added drop-wise to the reaction mixture at 5-10°C till pH of the reaction mixture was between 8.0-9.0. The lower layer was separated and extracted with toluene. The organic layers were combined and washed with water. The organic layer was distilled out completely under vacuum. The residue was degassed. To the hot residue was charged toluene and the solution was cooled to 25-30°C and stirred for 15-20 minutes. Water was added and cooled to 5-10cC and stirred for 10-15 minutes. Hydrochloric acid was added to adjust pH of aqueous layer to 1.0-1.5 and stirred for 15-30 minutes. The aqueous layer was separated and extracted with toluene and cooled to 15-20°C temperature. 25% Ammonia solution was added to adjust pH of aqueous layer to 8.0 to 8.5. The stirring was stopped and aqueous layer and organic layer were separated. The aqueous layer was extracted with toluene. The toluene layer was distilled out to get approximately 55g of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine.
To the above residue was added lsopropyl alcohol, and cooled to 25-30°C and stirred for 10-15 minutes to get clear solution. A solution of 31.5 g of Oxalic acid dihydrate tn isopropyl alcohol was prepared and added drop wise to the reaction mixture at 25-30°C, and stirred for 10-15 minutes. The solution was heated to 70-80°C and refluxed for 1.0 hour. The slurry was cooled to 0-5°C, and stirred for 1.0 hour at same temperature. The solid was filtered and washed with chilled isopropyl alcohol and dried to get 61.2 g of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylammonium oxalate.
Example 2 Preparation of 2-(cyanomethyl)-3-nitrophenyl-N,N-di-n-propypethylammonium oxalate.
a) 2-methyl-3-nitrophenyI-N,N-di-n-propylethy(ammonium oxalate (250 g), DM water (2 L) and dichloromethane (1.5 L) were added to a flask to form a suspension. The suspension was cooled to I0-15°C and 2N aqueous sodium hydroxide solution was added to it in a drop wise manner until pH is between 9.0-10.0. maintaining the temperature of the flask to 10-15°C. The temperature of the flask was allowed to increase to 20-30 °C and the product enriched organic layer was separated. The organic layer was washed with DM water (4 x 1.0 L) and subjected to distillation under vacuum at a temperature below 40-42°C and subsequently degassed to obtain 2-methyl-3-nitrophenyl-N.Ndi-n-propyl ethylamine.
21

(b) To the residue of 2-methyl-3-nitrophenyI-N,N-di-n-propyl ethylamine obtained in step (a) above. DMF (1.12L) and N,N'-dimethyl formamide dimethylacetal (372.0ml) was added and the mixture stirred for 5-10 minutes. The reaction mixture was then heated to 120-135 "C in a fractionating column distillation assembly for 12-15 hrs. After the completion of the reaction (confirmed with TLC) heating was stopped and the reaction mixture cooled to 90-100 °C. The solvents, N,N-dimethylformamide and N,N-dimethyl formamide acetal were distilled out below 100 °C under vacuum and the residue was degassed under high vacuum to obtain [3-dimethylamino -6-N,N-di-n-propylamino ethyl-2-nitro styrene, compound of formula 8a.
OR
(b) To the residue of 2-methyl-3-nitrophenyl-N,N-di-n-propyl ethylamine obtained in step (a)
above. N,N-dimethyl formamide dimethylacetal (120.0ml) and Pyrrolidine ( 75.0 ml ) were
added and the mixture stirred for 5-10 minutes. The reaction mixture was then heated to 80 -
100°C for 12-15 hrs. After monitoring reaction ( with TLC) heating was stopped and the
reaction mixture cooled to 60-70 °C. The solvents, Pyrrolidine and A;,7V-dimethyl formamide
acetal were distilled out below 100 °C under vacuum and the residue was degassed under high
vacuum to obtain a mixture of B-pyrrolidin -6-N,N-di-n-propylamino ethyl-2-nitro styrene and
B-dimethylamino -6-N,N-di-n-propylamino ethyl-2-nitro styrene.
(c) The residue obtained in step (b) above was cooled to 0-10 °C and chilled formic acid (0.42L.
98-100 % ) was added to it in a drop wise manner over a period of 15-30 minutes. The reaction
mixture was stirred for 10-15 minutes and hydroxylamine hydrochloride (59.5 g) was added to
it. The reaction mixture was heated to 90-98 °C and maintained at this temperature with stirring
for 4hrs. After completion of the reaction, the flask was cooled to I5-20°C and DM water
(1.25L) followed by MDC (1.25 L) was added to it. The reaction mixture was basifled by
addition of ammonia solution (25%) until pH is 8.0-9.0, maintaining the temperature below
15°C. The lower organic layer was separated, organic layer distilled under vacuum at a
temperature below 42"C and degassed. Acetone (250mL) was added to the hot residue and was
distilled out under vacuum below 60 °C to remove traces of MDC. Further quantity of acetone
(1.5L) was added to. the hot residue and solution was allowed to cool to 25-30°C. The solution
was charcoalised, filtered and washed with acetone. The filtrate was collected and 101.6 g of
oxalic acid was added to it with stirring to obtain a clear solution. The solution was heated to
55-60 °C and refluxed for 30-45 min. The solution was cooled to 25-30 °C and the slurry
obtained was further cooled to -2 to 2°C and stirred at this temperature for ! hr. The solid
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obtained was filtered and washed with chilled acetone (2 x 0.25 L). The wet cake thus obtained was slurried in 1.5 L DM water and the slurry was heated to 70-85 °C to obtain a clear solution. The solution was cooled to 25-30°C and further to 0-5°C and stirred for another 2 hrs. the solid obtained was filtered and washed with DM water (2x 0.15 L ) and dried to obtain 2-(cyanomethyl)-3-nitrophenyl-N,N-di-n-propypethy]ammonium oxalate, (about 55 % Theory yield)
Example 3 Preparation of 2-(Carboxymethyl)-3-nitrophenyl-N,N-di-n-propyl amine hydrochloride In a 10.0 L RBF 242 ml of hydrochloric acid was charged at 25-30˚C followed by 1 lOg of 2-(cyanomethyl)-3-nitrophenyl-N,N-di-n-propypethylammonium oxalate and stirred for 10-15 minutes. The solution was heated to 85-95°C for 3.0-4.0 hours at same temperature. The reaction mixture was cooled to 60-70°C. To the reaction mixture was added at 60-7O°C Isopropyl alcohol within 5-10 minutes and stirred for 15-30 minutes. The slurry was cooled to -5 to 0°C temperature and stir at same temperature for 1.5-2.0 hours for complete precipitation. The solid, was filtered and wash with chilled Isopropyl alcoho! (-5 to 0°C) and dried. This was followed by slurrying the wet cake with acetone and stirring for 10-15 minutes. The slurry was heated to 55-65°C and refluxed for 15-30 minutes. It was cooled and stirred at same temperature for 2.0 hour and filtered to obtain lOOg of 2-(Carboxymethyl)-3-nitrophenyl-N,N-di-n-propyl amine hydrochloride, (about 90-95 % Theory yield)
Example 4 Preparation of 4-[2-(di-n-propylamino)ethyl]-2,3-dihydro-lH-indol-2-one hydrochloride
A mixture of Methanol (280mL) and 40g 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetic acid hydrochloride were charged in an autoclave maintained at a temperature of 25-30°C. 2.0 g of 5 % Pd/C was charged to the autoclave and the resulting mixture stirred for another 5-10 minutes. 3.5 Kg pressure of hydrogen gas at 25-30°C was applied to the autoclave and the conditions maintained for 4 hrs. After completion of the reaction, hydrogen pressure was released and the solution was cooled to 18-22°C. Isopropyl alcohol hydrochloride (IPA.HCI., 40-60 g) was added to the reaction mixture to adjust pH between 1.0-1.5. The Reaction mixture was filtered under nitrogen and washed with methanol (2 x 80 mL). Methanol was distilled out completely under vacuum to obtain a residue. The residue was subjected to addition of isopropyl alcohol and subsequent distillation to remove the solvent, twice. To the hot residue
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obtained after distillation of isopropyl alcohol, isopropyl alcohol (280mL) was added and the flask heated to 65-75˚C for 30-60 minutes. The slurry thus obtained was cooled to 25-30°C. The solid was collected by filtration and dying.
The crude product was charged in a RBF containing toluene (280mL ) and DM water (200mL) and the flask was cooled to 15-20˚C. Liquor ammonia solution was added to the suspension to adjust the pH 8.5-9.5. The flask was maintained with stirring for 30-45 min. The organic layer was then separated and washed sequentially with 200mL DM water, 200 mL brine solution, 80 mL 0.2 % w/v sodium metabisulphite solution. 200 mL DM water and 200mL saturated brine solution. The organic layer was filtered and to it was added isopropyl alcohol hydrochloride to adjust pH of solution between 1.0-1.5. The slurry obtained was heated and the solvents distilled out under vacuum below 75°C to obtain a residue, the hot residue was then subjected twice, to addition of isopropyl alcohol and subsequent distillation. The residue was then mixed with isopropyl alcohol (400 mL) and heated to 65-75°C for 30-60 minutes to obtain free flowing slurry which was cooled to 25-30°C and stirred for 2 hrs for complete precipitation. The solid was filtered and washed with 2x 80 mL isopropyl alcohol and dried under nitrogen to obtain 4-[2-(di-n-propylamino)ethyi]-2,3-dihydro-IH-indol-2-one hydrochloride as white to off-white solid.
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claim
1. A process for preparing 4-[2-(N,N-dr-n-propylamino)ethyl]-2,3- dihydro-lH-indol-2-one, a compound of formula 1 or salts thereof comprising

formula 1
a. reacting a compound of formula 8 with hydroxylamine hydrochloride and formic acid to obtain 2-nitro-6-N.N-di-n-propylaminoethylphenyl acetonitrile,. a compound of formula 9; and

Formula 8

Formula 9

(wherein Rl and R2 may be selected from lower alkyl group or Rl & R2 together with the nitrogen atom to which they are attached form a morpboline, pyrrolidine, piperidine ring)
b. converting 2-nitro-6-N.N-di-n-propytaminoethylphenylacetonitrile, the compound of formula 9 to the compound of formula I or salts thereof.
A process as claimed in claim 1 wherein the compound of formula 9 is converted to compound of formula 1 comprising
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a. hydrolyzing 2-nitro-6-N,N-di-n-propylaminoethylphenyl acetonitrile, the compound of formula 9, to yield 2-nitro 6-N,N-di-n-propyl aminoethyl phenyl acetic acid, a compound of formula 7; and


COOH

Formula 9 Formula 7
b. reacting 2-nitro 6-N,N-di-n-propylaminoethyl phenyl acetic acid, a compound of formula 7, with a reducing agent to yield 4-[2-(N,N-di-n-propylamino) erhyl]-2.3-dihydro-lH-indol-2-one, compound of formula 1 or salts thereof.
3. Compound of formula 8

(wherein Rl and R2 may be selected from lower alkyl group like methyl, ethyl, or
R1 & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
4. A process for preparing a compound of formula 8 comprising reacting 2-methyl-3-nitro
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phenylethyl- N,N-di-n-propylamine, a compound of formula 5 with a dialkylformamide dialkylacetal.

Formula 5

Formula 8 (wherein Rl and R2 may be selected from lower alkyl group)

5. A process for preparing a compound of formula 8 comprising reacting 2-methyl-3-nitro phenylethyl-N,N-di-n-propylamine, a compound of formula 5 with dimethyl formamide dimethylacetal in presence of an amine.

Formula 5 Formula 8
( wherein Rl and R2 may be selected from lower alkyl group or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
6. A process for the preparation of 4-[2-(N,N-di-n-propylamino) ethyl]-2,3-dihydro-1 H-indol-2-one. a compound of formula 1 or salts thereof comprising
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formula 1
reacting 2-methyl-3-nitrophenyl acetic acid , compound of formula 2 with N,N-di-n-propylamine in presence of a carbodiimide and 1-hydroxybenzotriazole to obtain 2-methyl -3-nitrophenyl-N,N-di-n-propyl acetamide, a compound of formula 4 ;


■2 ■-'2
Formula 2 Formula 4
reacting 2-methyl-3-nitrophenyl-N,N-di-n-propyl acetamide, the compound of formula 4 with a reducing agent to yield 2-methyl-3- nitrophenylethyl-N,N-di-n-propylamine. a compound of formula 5;


2 "~2
Formula 4 Formula 5
reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine, the compound of formula 5 with a dialkylformamide dialkylacetal to yield, a compound of formula 8;
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Formula 5 Formula 8
(wherein RI and R2 may be selected from lower alkyl group, or Rl & R2 together with the nitrogen atom to which they are attached form a morpholine, pyrrolidine, piperidine ring)
reacting the compound of formula 8 with hydroxylamine hydrochloride and
formic acid to obtain a compound of formula 9 ;

Formula 8 Formula 9
hydrolyzing 2-nitro 6-N,N-di-n-propylaminoethyL phenyl acetonitrile. a compound of formula 9 to yield 2-nitro 6-N,N-di-n-propylaminoethyl phenyl acetic acid of formula 7; and



Formula 9

Formula 7

treating 2-nitro 6-N,N-di-n-propylaminoethylphenyl acetic acid, compound ol formula 7 with a reducing agent to yield 4-[2-(N,N-di-n-propylamino) ethyl]-2,3-dihydro-lH-indol-2-one of formula 1 or salts thereof.
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Dated this J211' Day of August, 2008

DILIP SHANGHVI CHAIRAMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LTD
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