Title of Invention

PROCESS FOR THE PREPARATION OF (S)-ROPIVACAINE HYDROCHLORIDE MONOHYDRATE

Abstract Process for preparation of Ropivacaine hydrochloride monohydrate comprising resolution of racemic pipecoloxylidide in non-ketonic solvents to give (S)-pipecoloxylidide followed by N-propylation to in water ass reaction medium give (S)-Ropivacaine base; converting the said (S)-Ropivacaine base to (S)-Ropivacaine hydrochloride monohydrate in one step and recrystallizing the same from isopropanol. The non-ketonic etheric solvents used are preferably water-soluble cyclic ethers selected from tetrahydrofuran and 1,4-dioxan.
Full Text FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF (S)-ROPIVACAINE HYDROCHLORIDE MONOHYDRATE"
2. APPLICANT(S):
(a) NAME: Goel, Ramniwas
(b) NATIONALITY: Indian
(c) ADDRESS: 'Shivashish', 565/6B, Golf View Park, Dr. Soares Marg,
Cham bur, Mumbai - 400 071, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to a process for the preparation of (S)-Ropivacaine base and (S)-Ropivacaine Hydrochloride monohydrate comprising resolution of racemic pipecoloxylidide using resolving agent with Etheric solvent system to give (S)-pipecoloxylidide followed by N-propylation of (S)-pipecoloxylidide to form (S)-Ropivacaine base. (S)-Ropivacaine base is further converted to (S)-Ropivacaine Hydrochloride monohydrate.
Background of Invention:
A variety of N-alkyl-pipecolic acid amides are used as local anesthetics, such as Mepivacaine, as racemate of N-methylpipecolic--acid-2,6-xylidide and Bupivacaine, as racemate of N-butylpipecolic- acid-2,6-xylidide. Ropivacaine, chemically named as (2S)-N-n-propylpipecolic acid-2,6-xylidide or (2S)-N-(2,6-dimethylphenyl) (N-propyl)-piperidine-2-carboxamide; is also of the same class and was developed after bupivacaine. Ropivacaine is the first local anesthetic, which is in (S)-enantiomeric form while mepivacaine and bupivacaine are in racemic form. Ropivacaine hydrochloride is marketed under trade name Naropin. It is found to be less cytotoxic than bupivacaine in animal models.

Ropivacaine - (2S)-N-n-propylpipecolic acid-2,6-xylidide
The process for the preparation of (S)-pipecoloxylidide, starting material of ropivacaine hydrochloride, is described in EP 0 151 110.
EP 0239710 describes the preparation of Ropivacaine hydrochloride monohydrate from Ropivacaine base. The process involves the addition of water and hot acetone to ropivacaine hydrochloride followed by crystallization. This solvent combination involving ketonic solvent such as acetone, brings in the 'F' impurity which is not
2

acceptable for pharmacopeal standards. To meet the desired impurity profile, the resultant product requires to be subjected to extra purification processes.
US patent no.l,180,712 discloses a process for the preparation of levo-l-n-butyl-2',6'-pipecoloxylidide i.e. bupivacaine. Said process involves resolving dl-2',6'-pipecoloxylidide by reacting with 0,0-dibenzoyl-d-tartaric acid and thereafter, the resulting mixture of diastereoisomeric 0,0-dibenzoyl-d-tartrates is reacted with boiling acetone, the acetone-insoluble dextro-2',6'-pipecoloxylidide salt is separated and the levo-2',6'-pipecoloxylidide salt is isolated from the acetone solution. However, the described process is intricate and includes isolating the product from hot acetone.
In WO8500599, preparation of Ropivacaine hydrochloride is disclosed involving resolution of Pipecolic acid. HC1 to get leavo-pipecolic acid HC1 followed by chlorination to give L-pipecolic acid chloride HC1. L-pipecolic acid chloride HC1 is reacted with 2, 6-xylidine to give L-pipecolic acid-2,6-xylidide hydrochloride.
WO9636606 discloses a process for the preparation of Ropivacaine Hydrochloride monohydrate. In the process, pipecoloxylidide is resolved by crystallization with a resolving agent forming a stable crystallization system with water followed by alkylation of S-pipecoloxylidide with a 1 -halopropane, preferably 1-bromopropane or 1-iodopropane. Preferred solvent for resolution are ketones such as acetone or ethyl methyl ketone forming a stable crystallization system together with water.
The processes described in WO'606 for preparation of ropivacaine hydrochloride are either carried out by two phase reaction system by longer extraction procedure or by using solvents such as ketones selected from acetone and ethyl methyl ketone preferably, acetone. Also, without any further purification Ropivacaine base is converted to Ropivacaine HC1 thereby, giving low yield and optical purity of final product.
In the Acta Chem Scand B41: 757-761, 1987, isopropanol is used in the different ratios with water for the resolution step. These different ratios of isopropanol and water gave varying yield and quality of the product. Also, the combination of isopropanol and water gave a crystallization system not enough stable for production on commercial level.
3

To overcome the above stated drawbacks there is a need of a cost-effective process for preparation of Ropivacaine HC1 monohydrate with high chiral purity in high yield which can be easily carried out on industrial scale in a reproducible manner.
Summary of the Invention:
According to the present invention, the process for preparation of Ropivacaine Hydrochloride monohydrate of formula (I) in one step, starting from ropivacaine free base, without the use of ketonic solvents such as acetone, to obtain ropivacaine hydrochloride monohydrate in high yield with high chiral purity and low impurity profile, wherein said process comprises;
flf I i^ xHCIxH20 (I) VA. O k.
i) resolving racemic pipecoloxylidide of formula (II)
rVv9
Kj?K^ o
(ii)
by employing a resolving agent in a non-ketonic solvents optionally in combination with water; ii) liberating (S)-pipecoloxylidide of formula (III) by hydrolyzing its salt using
diluted inorganic base;
4


iii) reacting (S)-pipecoloxylidide (III) with propyl halide in the presence of an inexpensive inorganic base in water, with out using any organic solvent at temperature of 75 to 80°C to obtain crude (S)- Ropivacaine base (IV)with high chiral purity;
I K
(IV)
iv) purifying the crude (S)-Ropivacaine base (IV) treating with activated carbon
in ester solvent at 60 - 65°C; followed by chilling to 0 - 5 °C to obtain (S)-
Ropivacaine base (IV); v) treating pure (S)-Ropivacaine base with Hydrochloric acid in water to obtain
directly (S)-Ropivacaine hydrochloride monohydrate of formula (I) in one
step; and vi) recrystallizing said Ropivacaine hydrochloride monohydrate is done by
distilling water and adding isopropanol.
In the preferred embodiment of the invention, the resolution of pipecoloxylidide is carried out using resolving agent such as (L)-tartaric acid derivatives in a stable non-ketonic crystallization solvent system followed by hydrolysis of corresponding tartrate salt using inorganic base to give (S)-N-(2,6)-Dimethyl phenyl-2-piperidine carboxamide i.e. (L)-pipecoloxylidide. The non-ketonic solvents used in the resolution process are selected from water soluble cyclic ethers.
5

The prior art process taught the propylation of (L)-pipecoloxylidide in organic solvent media as the propyl halide as well as the (L)-pipecoloxylidide are poorly soluble in water. However, the inventor had carried out the propylation reaction in water medium, green solvent, using excess amounts of alkali. Presumably, the reaction proceeds via water soluble sodium salt of (L)-pipecoloxylidide which is generated insitu in the reaction medium, facilitates the propylation reaction to completion to obtain (S)-N-n-propyl-(2,6)-Dimethyl phenyl-2-piperidine carboxamide (ropivacaine base) directly as solid from the reaction medium.
Crude (S)-Ropivacaine base is purified using ester solvents followed by charcoal treatment to obtain pure (S)-Ropivacaine base. The chiral purity of the (S)-Ropivacaine base is checked by HPLC.
The (S)-Ropivacaine base thus obtained is directly converted into (S)-Ropivacaine hydrochloride monohydrate salt without isolating its hydrochloride salt by treating with Hydrochloric acid in water in one step. The product formed is isolated by distilling water and adding isopropanol.
Description of drawings:
Fig 1 depicts chiral HPLC chromatogram of ropivacaine base
Fig 2 depicts chiral HPLC chromatogram of ropivacaine hydrochloride monohydrate
Detailed Description:
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated.
The present invention provides a cost effective, high yielding, reproducible method for
the preparation of (S)-Ropivacaine hydrochloride monohydrate, from (S)-Ropivacaine
Base, without isolating the corresponding Hydrochloride.
The invention provides an industrial manufacturing method for the preparation of Ropivacaine and it's hydrochloride salt directly in the form of monohydrate using
6

inexpensive and readily available reagents. Further, the invention provides an eco-friendly process by using Class III solvents which are less toxic and consequently having lower risk to human health.
According to one embodiment, the resolution of pipecoloxylidide is carried out using non-ketonic solvent. Preferably, the resolution is carried out by employing a resolving agent in water soluble etheric solvent optionally using water. The pipecoloxylidide is dissolved in etheric solvent optionally with water and solution is heated upto 40°C -45°C. The etheric solvent used for resolution is selected from water soluble cyclic ether such as, tetrahydrofuran or 1, 4-dioxan. The resolving agent used is tartaric acid derivative, preferably L-(-) dibenzoyl tartaric acid, which is dissolved separately in etheric solvent and added to the pipecoloxylidide solution at a temperature of 25- 30C to obtain di benzoly tartarate salt of (S)-pipecoloxylidide.
In another embodiment, the hydrolysis of (S)-pipecoloxylidide dibenzoyl tartrate salt (DBTA salt) is carried out using diluted inorganic base. The pH was adjusted to 10 using the inorganic base and the reaction mixture is stirred overnight at 25-30°C. The solid separated is filtered, washed and dried to give (S)-pipecoloxylidide base. The inorganic base used for hydrolyzing the di benzoly tartarate salt of (S)-pipecoloxylidide is selected from sodium carbonate, potassium carbonate and like.
In a further embodiment of the invention, the (S)-pipecoloxylidide formed is further converted to (S)-Ropivacaine base by N-propylation employing a propylating agent. The propylating agent used is propyl halide selected from propyl chloride, propyl bromide and propyl iodide, preferably propyl bromide.
The prior art process taught the propylation reaction of (L)-pipecoloxylidide in organic solvent media as the propyl halide as well as the (L)-pipecoloxylidide are poorly soluble in water. However, the inventor had achieved the propylation reaction in water medium, a green solvent, using excess amounts of alkali. Presumably, the reaction proceeds via water soluble sodium salt of (L)-pipecoloxylidide, which is formed insitu in the reaction medium. The sodium salt formed continuously in the reaction reacts with propyl halide to precipitate out the product, thus also acts as self-promoter in facilitating the propylation
7

reaction towards completion. The progress of the reaction is monitored by TLC. Here, the propylation reaction preferentially follows the first order kinetics as the reaction kinetics depends on the insitu generation of the sodium salt of (L)-pipecoloxylidide. The beauty of the reaction is that the product, ropivacaine base, with high chiral purity, comes out directly from the reaction medium as a solid.
The addition of (L)-pipecoloxylidide to alkali is carried out at a temperature of 25 to 30°C. Further, the addition of propyl halide is also carried out slowly at the same temperature to avoid any possible exotherm. The reaction mixture is heated slowly upto 75 - 80°C and maintained at the same temperature upto 7 to 10 hrs. After completion of the reaction, DM water(demineralized water) is added to the reaction mass and cooled the reaction mass to 5-10°C and maintained at the same temperature for one hour to obtain a precipitate of ropivacaine base. The precipitate is filtered and washed with DM water(demineralized water) till the pH of the washings are between 7.0 to 7.5 to remove the inorganic salts such as sodium hydroxide and sodium bromide. The solid separated is dried to give crude (S)-Ropivacaine base. The crude base thus obtained is tested for its sulphated ash, which is less than 0.1%. The chiral purity by HPLC of the crude ropivacaine base is 99.75%. The alkali used for the propylation reaction is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide. One preferred alkali is sodium hydroxide.
The above N- propylation reaction can be further extended to the preparation of Bupivacaine, by reacting the (L)-pipecoloxylidide with butyl halide under similar reaction conditions.
In yet another embodiment of the invention, the crude (S)-Ropivacaine base formed is further purified by giving charcoal treatment in ester solvent at a temperature of 60 to 65°C; filtered hot; collected the filtrate and reduced the volume of the filtrate to approx. 50%. The concentrate is cooled to 25-30°C and chilled to 0-5°C to yield crystallized product, i.e.pure ropivacaine base. The ester solvent used for purification of crude (S)-Ropivacaine base is selected from methyl acetate, ethyl acetate, propyl acetate and butyl acetate preferably ethyl acetate.
8

In a further embodiment of the present invention, the said dried pure Ropivacaine base is suspended in distilled water and hydrochloric acid is added carefully adjusting the pH to 3-3.5 and the base completely dissolves. This is followed by treatment with activated carbon at 70-80°C for 30 min under stirring. The solution is filtered and the filtrate is concentrated to one volume under vacuum to obtain (S)-Ropivacaine hydrochloride monohydrate. To this, isopropanol is added and the reaction mixture is cooled to 25-30°C followed by chilling at 5-10°C for about 2 hour to precipitate pure (S)- Ropivacaine HC1 monohydrate.
The advantages of the present invention involves in use of Class-Ill solvents, especially water or water miscible solvents thereby, making the said process eco-friendly. The invention thus provides cost-effective, high yielding method to obtain highly purified (S)-Ropivacaine hydrochloride monohydrate. The process involves use of distilled water and Class III solvents which helps to overcome problems arising from restrictions on residual solvents, thereby meeting regulatory requirements.
Another advantage of the present invention involves in the use of non-ketonic solvents in the entire process eliminates completely the acetone impurity (impurity 'F') which is recognized as an avoidable impurity in pharmacopeal standards from the finished product, thereby obtaining the Ropivacaine hydrochloride monohydrate in high purity with regulatory compliant impurity profile.
Thus, ropivacaine hydrochloride monohydrate obtained by the inventive process is devoid of ketonic impurity, (8a, S)-2-(2,6-dimethyl phenyl-3,3-dimethylhexahydro-imidazo(l,5-a)pyridine-l(5H)-one (acetone adduct, impurity'F').
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
9

Examples
Example 1:
Preparation of (2S)-N-(2,6-dimethyl Phenyl) Piperidine-2-Carboxamide ((2S)-pipecoloxylidide):
1000 gm of N-(2,6-dimethyl Phenyl) Piperidine-2-Carboxamide i.e. racemic pipecoloxylidide base was charged in a clean and dry glass assembly. 3.7 It of Tetrahydrofuran and 0.86 It of water were added to it and the solution was stirred for 30 min. till clear solution was obtained. 0.045 kg activated carbon was added to the solution and was heated to 40°C-45°C and was filtered. To the filtrate, a solution of Di-benzoyl Tartaric acid 0.790 kg in 3.6 It. of tetrahydrofuran was added over a period of one hour at 25°C-30°C. The reaction mass was stirred and cooled to 5°C -10°C and the mixture was kept at the same temperature for 30 minutes. The solid obtained was filtered, washed with chilled tetrahydrofuran to obtain (S)-pipecoloxylidide DBTA salt and dried. The Chiral purity obtained was 97% by HPLC. The (S)-Pipecoloxylidide DBTA salt was charged in the reactor, 2.5 It of water was added and pH was adjusted to 10 with dilute Sodium Carbonate solution. The solution was stirred for overnight at 25°C-30°C. The separated (2S) 'N-(2,6) Dimethyl Phenyl-2-Piperidine Carboxamide was filtered. The cake was washed with DM water (demineralized water) and dried at 50°C-60°C till moisture content is Yield: 0.360kg.
Example 2:
Preparation of (2S)-N-(2,6-dimethyl Phenyl) Piperidine-2-Carboxamide ((2S)-pipecoloxylidide):
To a clean and dry glass assembly, 1000 gm of N-(2,6-dimethyl Phenyl) Piperidine-2-Carboxamide i.e. racemic pipecoloxylidide base was charged. To this, 3.7 It. of 1,4-Dioxan was added and the solution was stirred for 30 min. till clear solution was obtained. 0.045 kg activated carbon was added to the solution, was heated to 40°C-45°C and was filtered. To the filtrate, a clear solution of 0.790 kg Di-benzoyl Tartaric acid
10

dissolved in 3.6 It. of tetrahydrofuran was added over the period of one hour at 25°C-30°C. The reaction mass was stirred and cooled to 5°C -10°C and the mixture was kept at the same temperature for 30 minutes. The solid obtained was filtered, washed with chilled Dioxan and dried. The Chiral purity obtained was 97% by HPLC. The (S)-Pipecoloxylidide DBTA salt formed was charged in the reactor, 2.5 It water was added and pH was adjusted to 10 with dilute Sodium Carbonate solution. The solution was stirred overnight at 25°C-30°C. The separated (S)-Pipecoloxylidide i.e. N-(2,6) Dimethyl Phenyl-2-Piperidine Carboxamide was filtered. The cake was washed with DM water(demineralized water). The product was dried at 50°C-60°C till moisture content Yield: 0.350kg.
Example 3:
Preparation of (S)-Ropivacaine Base-crude:
8.0 It of distilled water was charged to a clean and dry 100 It. capacity glass assembly with accessories and was cooled to 8-10°C by circulating chilled water in the jacket. 0.90 kg Sodium hydroxide pellets were slowly added to the glass assembly under stirring maintaining the temperature between 25°C -30°C. 4.0 kg of (2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide was added slowly in portions of 500 gm in about one hour by maintaining the temperature of the reaction mixture between 25°C-30°C. To the reaction mixture, 3.40 kg of n-propyl bromide was added slowly in about one hour at 25°C-30°C. The solution was heated slowly till the temperature raised to 75 -80°C and the temperature was maintained for seven hours. The reaction mass was allowed to cool to 30- 35°C, and was checked for the complete conversion of (2S)-pipecoloxylidide to Ropivacaine base by TLC. If the reaction was incomplete, the solution was refluxed at 75-80°C for additional one hour. After completion of reaction, 4 It of DM water (demineralized water) was added to the reaction mass and was cooled to 5-10°C and the temperature was maintained at 5-10°C for 1 hour to obtain precipitate. The precipitate was filtered and the cake was washed with chilled DM water(demineralized water) to remove inorganic salts such as sodium hydroxide and sodium bromide, till the
11

pH of the washings was between 7 - 7.5. The precipitate was tested for sulphated ash,(less than 0.1%) dried at 50-55°C till moisture was less than 0.5%. Yield: 4.0 - 4.4 kg; Chiral Purity HPLC: 99.75%
Example 4:
Purification of (S)-Ropivacaine base crude:
32.0 It of ethyl acetate and 0.120 kg of Activated carbon were charged with a clean and dry 50 It glass assembly. 4 kg of (S)-Ropivacaine base-crude was added to the same glass assembly and the temperature was slowly raised to 60-65°C by circulating hot water in the jacket. The reaction mass was heated at 60 to 65°C under stirring till the reaction was complete. The solution was filtered hot through Buchner funnel at 60-65°C and the filtrate was collected in a clean and dry 100 It glass assembly. The charcoal bed was washed with 1 to 2 It of ethyl acetate and approx 50% v/v of ethyl acetate (about 16 to 17 It) was distilled out by circulating steam in the reactor jacket and water in the condenser. The mixture was cooled to about 25-30°C by circulating water in the jacket and condenser, was chilled to about 0 - 5°C by circulating brine in the jacket and allowed to crystallize for 3 hrs at 0-5°C by maintaining the brine circulation. The precipitate was filtered through Nutch filter, washed with 2 It of ethyl acetate and was dried for 30 minutes under vacuum initially at 30 - 35°C for 3 hrs and then, at 50 - 55°C for 3 hrs in a tray dryer with air circulation to give pure (S)-Ropivacaine Base. Yield 3.6-3.8 kg.
Example 5:
Preparation of (S)-Ropivacaine hydrochloride monohydrate:
To a clean and dry 50 ltr glass assembly, 24 It of distilled water was charged at 25-30°C.
4 kg of Ropivacaine base (pure) under stirring was added. The solution was stirred for 15
to 20 minutes at 25 - 30°C. 1.25 It of Hydrochloric acid LR was added to adjust the pH
between 3-3.5. 0.080 kg of activated carbon was added and heated at 70 - 80°C under
stirring. The temperature was maintained at 70 - 80°C for 30 minutes. The hot solution
was filtered through Buchner funnel and the filtrate was collected in a clean and dry 100
It. glass assembly. Carbon bed was washed with hot distill water and the water was
distilled out from the filtrate till the volume of filtrate was reduced to one volume i.e. 4 It.
The thick slurry was added in 20 It. of isopropanol and was cooled to 25-30°C by
12

circulating water in the jacket. The reaction mixture was cooled to 5-10°C for 2 hours. The slurry was filtered through Nutch filter, washed with chilled isopropanol (about 1 It.) and was dried in vacuum dryer at 45-50°C about 2 hrs to 3 hrs till the water content obtained was 5% - 6% to give pure (S)-Ropivacaine hydrochloride monohydrate. Yield: 3.8-4.2 kg; Chiral purity: >99.85%; Optical rotation: -64 to -74°C.
It will be evident to those skilled in the art that the invention is not limited to the details of the here fore mentioned illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
13

I claim:
1. A process for the preparation of Ropivacaine hydrochloride monohydrate of the formula (I) in one step, starting from ropivacaine free base, without the use of ketonic solvents such as acetone, to obtain ropivacaine hydrochloride monohydrate in high yield with high chiral purity and low impurity profile, wherein said process comprises;



i) resolving racemic pipecoloxylidide of formula (II)


by employing a resolving agent in non-ketonic solvent optionally with
water;
ii) liberating (S)-pipecoloxylidide of formula (III) by hydrolyzing its diastereomeric salt using diluted inorganic base;

(in)
14

iii) reacting (S)-pipecoloxylidide (III) with propyl halide in the presence of an inexpensive inorganic base in water, without using any organic solvent at temperature of 75 to 80°C to obtain crude (S)-Ropivacaine base (IV);

(IV)
iv) purifying the crude (S)-Ropivacaine base by treating with activated
carbon in ester solvent at 60 to 65°C; followed by chilling to 0 to 5°C
to obtain (S)-Ropivacaine base (IV);
v) treating pure (S)-Ropivacaine base with Hydrochloric acid in water to
give (S)-Ropivacaine hydrochloride Monohydrate directly in one
step(I); and
vi) recrystallizing (S)-Ropivacaine hydrochloride monohydrate (I) using
isopropanol.
2. The process according to claim 1, wherein the said non-ketonic solvent is etheric solvent selected from water soluble cyclic ethers such as tetrahydrofuran and 1,4-dioxan.
3. The process according to claim 1, wherein the said resolving agent used in step (i) is L-(-) dibenzoyl tartaric acid.
4. The process according to claim 1, wherein the hydrolysis, in step (ii) further involves a step of adjusting pH to 10 using inorganic base followed by stirring the reaction mixture overnight at 25°C - 30°C.
5. The process according to claim 4, wherein the said diluted inorganic base in step (ii) is Sodium Carbonate.
6. The process according to claim 1, wherein in step (iii), the addition of propyl halide is carried out at 25 to 30°C for 7 to 10 hrs by maintaining the temperature.
15

7. The process according to claim 1, wherein the said propyl halide in step (iii) is selected from propyl chloride, propyl bromide and propyl iodide.
8. The process according to claim 1, wherein the said propyl halide in step (iii) is propyl bromide.
9. The process according to claim 1, wherein the said inorganic base in step (iii) is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide; preferably sodium hydroxide.
10. The process according to claim 1, wherein said ester solvent used in step (iv) is selected from methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
11. The process according to claims 1 and 10, wherein said ester solvent in step (iv) is ethyl acetate.
12. The process according to claim 1, wherein step (v) is carried out at a temperature of 70-80°C.
13. The process according to claim l(vi), wherein crystallization is effected at a temperature of 5-10°C.
14. The process as claimed in claim 1, wherein, the Ropivacaine Hydrochloride Monohydrate in step (v) is prepared directly from Ropivacaine base in one step.
15. The process as claimed in any of the preceding claims 1 to 14, wherein the use of non-ketonic solvents in the entire process eliminates completely the acetone impurity (impurity 'F') which is recognized as an avoidable impurity in pharmacopeal standards from the finished product, thereby obtaining the Ropivacaine hydrochloride monohydrate in high purity with regulatory compliant impurity profile.
16. The process as claimed in claim 1, wherein said ropivacaine hydrochloride monohydrate obtained is devoid of ketonic impurity, (8a, S)-2-(2,6-dimethyl phenyl-3,3-dimethylhexahydro-imidazo(l,5-a)pyridine-l(5H)-one (acetone adduct, impurity'F').
Dated this 1st day of October 2007


16

Abstract:
Process for preparation of Ropivacaine hydrochloride monohydrate comprising resolution of racemic pipecoloxylidide in non-ketonic solvents to give (S)-pipecoloxylidide followed by N-propylation to in water ass reaction medium give (S)-Ropivacaine base; converting the said (S)-Ropivacaine base to (S)-Ropivacaine hydrochloride monohydrate in one step and recrystallizing the same from isopropanol. The non-ketonic etheric solvents used are preferably water-soluble cyclic ethers selected from tetrahydrofuran and 1,4-dioxan.
19

Documents:

1942-mum-2007-abstract(granted)-(3-1-2011).pdf

1942-mum-2007-abstract.doc

1942-mum-2007-abstract.pdf

1942-mum-2007-cancelled pages(3-12-2009).pdf

1942-MUM-2007-CLAIMS(AMENDED)-(3-12-2009).pdf

1942-mum-2007-claims(granted)-(3-1-2011).pdf

1942-mum-2007-claims.doc

1942-mum-2007-claims.pdf

1942-MUM-2007-CORRESPONDENCE(13-1-2009).pdf

1942-MUM-2007-CORRESPONDENCE(15-11-2010).pdf

1942-mum-2007-correspondence(5-10-2007).pdf

1942-mum-2007-correspondence(ipo)-(4-1-2011).pdf

1942-mum-2007-correspondence-received.pdf

1942-mum-2007-description (complete).pdf

1942-mum-2007-description(granted)-(3-1-2011).pdf

1942-mum-2007-diagram.doc

1942-mum-2007-drawing(1-10-2007).pdf

1942-MUM-2007-DRAWING(3-12-2009).pdf

1942-mum-2007-drawing(granted)-(3-1-2011).pdf

1942-mum-2007-drawings.pdf

1942-mum-2007-form 18(5-10-2007).pdf

1942-mum-2007-form 2(granted)-(3-1-2011).pdf

1942-mum-2007-form 2(title page)-(1-10-2007).pdf

1942-mum-2007-form 2(title page)-(granted)-(3-1-2011).pdf

1942-mum-2007-form 3(1-10-2007).pdf

1942-MUM-2007-FORM 3(13-1-2009).pdf

1942-MUM-2007-FORM 3(3-12-2009).pdf

1942-mum-2007-form 9(5-10-2007).pdf

1942-mum-2007-form-1.pdf

1942-mum-2007-form-2-1.doc

1942-mum-2007-form-2.doc

1942-mum-2007-form-2.pdf

1942-mum-2007-form-26.pdf

1942-mum-2007-form-3.pdf

1942-MUM-2007-OTHER DOCUMENT(13-1-2009).pdf

1942-MUM-2007-PCT-ISA-237(13-1-2009).pdf

1942-MUM-2007-PETITION UNDER RULE 137(15-11-2010).pdf

1942-MUM-2007-REPLY TO EXAMINATION REPORT(3-12-2009).pdf

abstract1.jpg


Patent Number 245102
Indian Patent Application Number 1942/MUM/2007
PG Journal Number 01/2011
Publication Date 07-Jan-2011
Grant Date 03-Jan-2011
Date of Filing 01-Oct-2007
Name of Patentee GOEL RAMNIWAS
Applicant Address SHIVASHISH, 565/6B, GOLF VIEW PARK, DR.SOARES MARG, CHAMBUR,MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 GOEL RAMNIWAS SHIVASHISH, 565/6B, GOLF VIEW PARK, DR.SOARES MARG, CHAMBUR,MUMBAI - 400071
PCT International Classification Number C07B57/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA