FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NOVEL METHOD FOR ENANTIOMERIC ENRICHMENT OF 2',6'-
PIPECOLOXYLIDIDE"'
2. APPLICANT:
(a) NAME: NEON LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 140, Damji Shamji Industrial Complex, Mahakali Caves
Road, Andhert (East), Mumbai - 400093, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

TECHNICAL FIELD:
The present invention relates to a novel process for enantiomeric enrichment of 2',6'-pipecoloxylidide using a chiral carbamoyl benzoic acid (hereafter referred to as CCBA). The invention further relates to a novel process for synthesis of CCBA and alkylation of 2',6'-pipecoIoxylidide.
BACKGROUND AND PRIOR ART:
N-alkyl-piperidine-2-carboxamides of formula (A)

where R' is methyl (mepivacaine), propyl (d/1-ropivacaine) or butyl (bupivacaine) are local anaesthetics. Biological studies reveal that the (S)-enantiomers of bupivacaine and ropivacaine exhibit lower cardiotoxicity than the corresponding racemates while possessing the same anaesthetic activity and are therefore more advantageous for clinical purpose.
Compared to bupivacaine, levobupivacaine has a longer duration of action. It is approximately 13 percent less potent (by molarity) than racemic bupivacaine.
Thus there is a requirement for efficient process to manufacture ropivacaine and bupivacaine in the form of (S)-isomer.
(S)-2',6'-pipecoloxylidide of formula (IV) is a valuable intermediate for the preparation of (S)-isomer of N-propylpipecolic acid-2',6'-xylidide (ropivacaine), (S) isomer of mepivacaine and (S)-isomer of N-butylpipecolic acid-2',6'-xylidide (levobupivacaine).


Ropivacaine and its preparation have been described for the first time in the PCT publication WO8500599. However it has been reported in the US patent No. 4870086 that ropivacaine hydrochloride described in PCT application WO8500599 contains 10% of the D-(+) enantiomer of N-n-propylpipecolic acid-2',6'-xylidide hydrochloride as an impurity. In addition, the product is hygroscopic, contains 2% water and is physically unstable.
U.S. publication No. 20040210057 discloses a method for separation of racemic ropivacaine using L-(+)-tartaric acid. However, the overall yield of (S)-enantiomer is low which makes the process quite expensive.
Levobupivacaine and its preparation have been disclosed for the first time in the patent No. GB1180712. The process includes following steps:
resolving dl-2',6'-pipecoloxyIidide using 0,0-dibenzoyI-d-tartaric acid; reacting resulting mixture of diastereoisomeric 0,0-dibenzoyl-d-tartrate salts with boiling acetone; separating acetone-insoluble dextro-2',6'-pipecoloxylidide salt; and isolating levo-2',6'-pipecoloxylidide salt from the acetone solution.
However, the process is intricate and provides levo-2',6'-pipecoloxylidide in lower yield. Further the process includes isolating the product from hot acetone i.e. it is a plain method for laboratories which could not be used for production in the plant.
J. Med. Chem. Volume 14, issue 9, pages 891 to 892 (1971) describes optical resolution method to obtain a single enantiomer of mepivacaine and levobupivacaine. The process includes following steps:
treatment of 2',6'-pipecoloxylidide with dibenzoyl-L-tartaric acid monohydrate; addition of isopropanol to separate isopropanol-insoiuble enantiomer; and isolation of the desired enantiomer.
The U.S. Publication No. 20090187024 teaches that use of isopropanol in above mentioned J. Med. Chem. article for resolution of 2',6'-pipecoloxylidide with dibenzoyl-

L-tartaric acid monohydrate, does not give a crystallisation system which is stable during the time required for production in the plant. This is because the solution is supersaturated with the undesired enantiomer, and thus crystallization of the wrong shape could easily be started by small disturbances, which means that resolution process using dibenzoyl-L-tartaric acid or its hydrate in isopropanol is not suitable to use for production in large scale.
Acta. Chem. Scand. B41, pages 757 to 761 (1987) discloses resolution of 2',6'-pipecoloxylidide using (-)-0,0'-dibenzoyI-L-tartaric acid in a mixture of isopropanol and water. The combination of isopropanol and water gave a crystallization system resulting in only 48% isolation yield of desired diastereomeric salt. Also (-)-0,0'-dibenzoyI-L-tartaric acid is a costly reagent.
The U.S. Patent No. 5959112 discloses optical resolution of 2',6'-pipecoloxylidide using L-(-)-dibenzoyl tartaric acid or L-(-)-ditoluoyI tartaric acid in presence of acetone, water and sodium hydroxide. However enantiomeric purity of the product is not mentioned in the patent.
The PCT publication WO2009044404 discloses enantiomeric separation of 2',6'-pipecoloxylidide using L-(-)-dibenzoyl tartaric acid in non-ketonic etheric solvents such as water-soluble cyclic ethers (e.g. tetrahydrofuran or 1,4-dioxane). The process provides {S)-2',6'-pipecoloxylidide in 99.2% enantiomeric purity but in relatively low yield.
The prior art search reveals that L-(-)-dibenzoyl tartaric acid and L-(-)-ditoluoyl tartaric acid are the only reagents used for resolution of 2',6'-pipecoloxylidide and the resolution is efficiently carried out only in isopropanol. The main drawback of theses resolving agents is that their recovery and reuse are not feasible due to their solubility in water.
Thus, the search for a suitable manufacturing process for (S)-2',6'-pipecoloxylidide remains undoubtedly of interest.
In the course of this, various chiral acids known in the prior art were investigated for their suitability in enantiomeric enrichment of 2',6'-pipecoloxylidide. Numerous chiral acids

mentioned in the prior art for the resolution of amines were unsuitable for achieving the resolution of 2',6'-pipecoloxylidide to provide (S)-enantiomer in high yield and high enantiomeric purity. Finally an economical and industrially applicable process for the enrichment of 2',6'-pipecoloxylidide was found which uses chiral carbamoyl benzoic acid (CCBA) as a chiral reagent.
The inventors have found very few references for optical resolution of amines using CCBA as resolving agents.
Helvetica Chimica Acta, volume 52, Issue 1, pages 329 - 333 (1969) discloses use of enantiomorphs of N-(l-phenylethyl)succinamic acid and N-(l-phenylethyl)phthalamic acid for optical resolution of (l-phenylethyl)amine, 2-aminobutane-l-ol, threo-l-(4-nitrophenyl)-2-aminopropane-l, 3-diol and l-phenyl-2-aminopropane.
U.S. patent No. 3576854 discloses resolution of 1-phenyl-2-aminopropane, 2-aminobutanol, threo-l-(4-nitrophenyl)-2-aminopropane-l, 3-diol and (1-phenylethyl)amine using enantiomorphs of N-(l-phenylethyl)succinamic acid and N-(l-phenylethyl)phthalamic acid.
Chirality, volume 6, Issue 4, pages 314 - 320 (1994) discloses use of (R)-N-(l-phenylethyl) phthalamic acid for optical resolution of l-phenyl-2-aminopropane.
The present invention is based on the surprising discovery that hardly any literature discloses use of CCBA for optical resolution of xylidide compounds.
Due to limited use, availability of CCBA is also restricted. Therefore to make the process more economical it is essential to synthesise CCBA.
U.S. patent No. 3576854 and Helvetica Chimica Acta, volume 52, Issue 1, pages 329 -333 (1969) disclose preparation of (S)-N-(l-phenylethyl)phthalamic acid by reacting phthalic anhydride with (S)-alpha-methylbenzylamine in benzene which is classified as human carcinogen. Also there is a need for recrystallization of the crude material to obtain the desired purity.

Journal of the Chemical Society (1947), pages 505 - 513 and Journal of the Chemical Society (1957), pages 2828-30 disclosed the preparation of chiral N-(l-phenylethyl)phthalamic acid by refluxing phthalic anhydride and chiral 1-phenylethylamine in diethyl ether which is highly inflammable and hence cannot be used in plant scale.
Needless to say it is advantageous to develop a process for preparation of CCBA, which eliminates the necessity of hazardous substances.
OBJECT OF THE INVENTION:
An object of the invention is to overcome or ameliorate atleast one disadvantage of the prior art or to provide a useful alternative.
Another object of the invention is to provide a novel process for enantiomeric enrichment of 2',6'-pipecoloxylidide to provide (S)-enantiomer which is an intermediate of ropivacaine and levobupivacaine, in high yield and high enantiomeric purity.
Yet another object of the invention is to provide a commercially viable and industrially applicable enantiomeric separation process which enables easy recovery of the resolving reagent.
Yet another object of the invention is to provide a novel and concise process for preparation of CCBA, which eliminates the necessity of hazardous substances.
Finally the object of the invention is to convert (S)-2',6'-pipecoloxylidide, which is obtained by the present method, into highly pure ropivacaine and levobupivacaine having desirable pharmacological activity, broad safety margins, without toxicity or unfavourable side effects.

SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention provides a novel process for enantiomeric enrichment of 2',6'-pipecoIoxylidide using CCBA. Chiral carbamoyl benzoic acid as used according to the invention is selected from N-substituted amidic acids of formula (IIc).

Wherein, R is phenyl, phenyl substituted by halogen or alkyl containing I to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; R' is alkyl containing 1 to 5 carbon atoms; and R" is 2-carboxyphenyl, CH2CH2COOH or CH=CHCOOH.
N-substituted amidic acids of the present invention encompasses N-((R)-1-phenylethyl)phthalamic acid; N-((S)-l-phenyIethyl)succinamic acid and N-((R)-1-phenylethyl)maleinamic acid.
In another aspect the present invention provides novel intermediates formed in the enantiomeric enrichment process of 2',6'-pipecoloxyIidide.
In a further aspect the invention provides a novel process for synthesis of N-substituted amidic acids and alkylation of 2',6'-pipecoloxylidide resulting in ropivacaine, bupivacaine and levobupivacaine.
DETAILED DESCRIPTION OF THE INVENTION:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any method and material or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred

methods and materials are described. To describe the invention, certain terms are defined herein specified as follows:
Unless stated to the contrary, any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims.
Accordingly, the present invention provides a novel process for enantiomeric enrichment of 2',6'-pipecoloxylidide. The process comprises:
reacting a mixture of enantiomer of 2',6'-pipecoloxylidide of formula (I) with CCBA in presence of a solvent.

Formula (I)
Preferably the enantiomeric enrichment of 2',6'-pipecoloxylidide is carried out by reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I) with CCBA of formula (II) in presence of a solvent to provide a mixture of chiral salts of formula (Ilia); and isolating a salt of formula (Illb) from the salt mixture of formula (Ilia).



Wherein R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing \ to 5 carbon atoms.
Alternatively the enantiomeric enrichment of 2',6'-pipecoloxylidide is carried out by reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I) with CCBA of formula (Ha) in presence of a solvent to provide a mixture of chiral salts of formula (IIIc); and isolating a salt of formula (Hid) from the salt mixture of formula (IIIc).


Where R is phenyl, phenyl substituted by halogen or alky] containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
In a preferred embodiment R is phenyl and R' is methyl.
The solvent used in the process of enantiomeric enrichment is a polar solvent selected from the group consisting of alcohol, nitrile, ester, ketone or mixture thereof. The preferred solvents for enantiomeric enrichment are selected from isopropanol, acetone, ethyl acetate or acetonitrile.
Hence unlike prior art, the process of enantiomeric enrichment of 2',6'-pipecoloxylidide using CCBA can be carried out in plurality of solvents.
The process of enantiomeric enrichment may be carried out at suitable temperature. To minimise the decomposition of products and impurity formation the reaction is carried out at 0 to 80°C. The preferred temperature is 30 to 70°C. The most preferred range of temperature is 55 to 65°C.
The reaction normally completes in I to 10 hours, preferably within 2 to 3 hours.
The CCBA is conveniently used in an amount, relative to 2',6'-pipecoloxyIidide of formula (I) in a range between 0.25 to 1.5 equivalents. The preferred amount of CCBA is 0.5 to 1.0 equivalent.
The process of enantiomeric enrichment of 2',6'-pipecoloxylidide of formula (I) further comprises releasing (S)-2',6'-pipecoloxylidide of formula (IV) from the 2',6'-pipecoloxylidide-amide chiral salt of formula (IIIb) or (IIId) using a base.


The base which may be used for releasing (S)-2',6'-pipecoloxyIidide of formula (IV) is organic or inorganic. Examples of organic base include tertiary amines such as trialkyl amine. Examples of inorganic base include ammonia, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate and mixture thereof. The alkali metal carbonates are selected from sodium carbonate and potassium carbonate. The alkali metal bicarbonates are selected from sodium bicarbonate and potassium bicarbonate. The alkaline earth metal carbonates are selected from calcium carbonate and magnesium carbonate. Examples of alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate. The preferred base for releasing (S)-2',6'-pipecoloxylidide of formula (IV) from the 2',6'-pipecoloxylidide-amide chiral salt of formula (III) or (Ilia) is sodium carbonate.
(S)-2',6'-pipecoloxylidide prepared according to prior art processes contains extraneous compounds or impurities that can come from any source. The impurities can be in the form of unreacted starting materials, by-products of the reaction, products of side reactions or degradation products. (S)-2',6'-pipecoloxylidide containing impurities can lead to impure ropivacaine, levobupivacaine or their salts. Impurities in ropivacaine, levobupivacaine or their salts are undesired and might even be harmful to a patient being administered with a dosage form containing the same. Therefore known processes for preparation of (S)-2',6'-pipecoloxylidide need a step of purification, making the process expensive.
However, the process of the invention provides highly pure (S)-2',6'-pipecoloxylidide with more than 99% enantiomeric purity, and can be alkylated directly avoiding the step of purification. Hence the process is quite economical.
In the second embodiment, the present invention provides novel intermediates of formula (IIIb), (IIId), (IIIe) and (IIIf) formed in the process of enantiomeric enrichment of 2',6'-pipecoloxylidide.



Formula (IIIe) Formula (IIIf)
Where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms; formed in the enantiomer enrichment process of 2',6'-pipecoloxylidide of formula (I).
The salts of formula (IIIb), (IIId), (IIIie) and (IIIf) are further processed to recover CCBA.
In the third embodiment the present invention describes a novel method for preparation of N-substituted amidic acids of formula (IIc) or enantiomers thereof;

Formula (IIc)
Where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; R' is alkyl containing 1 to 5 carbon atoms; and R" is 2-carboxyphenyl, CH2CH2COOH or CH=CHCOOH;

Formula (V)
comprising: reacting phthalic anhydride, succinic anhydride or maleic anhydride with amines of formula (V) or enantiomers thereof in presence of a polar aprotic solvent;

where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
In the preferred embodiment R is phenyl and R' is methyl.
The polar aprotic solvents used for preparation of N-substituted amidic acids are selected from carboxylic acid ester, ketone, halogenated hydrocarbon or mixture thereof. The preferred solvent is ethy! acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone, dichloromethane, chloroform or mixture thereof. The most preferred polar aprotic solvent for the reaction is ethyl acetate.
The amine of formula (V) is conveniently used in an amount, relative to anhydride, preferably in a range between 0.5 to 2.0 equivalents, more preferably 0.7 to 1.5 equivalents. The most preferred quantity of the amine of formula (V) is 1.0 equivalent.
The reaction is carried out at 25 to 120°C, more preferably at 40 to 100°C. The most preferred temperature for the reaction is 60 to 90°C.
The reaction normally completes in 0.25 to 3 hours, more preferably 0.5 to 2.0 hours, most preferably 1.0 to 1.5 hours.
The process provides N-substituted amidic acids with required optical purity, avoiding need for further purification. Hence the method is economical. As the process is carried out in non-toxic solvent, it is non-hazardous.
(R)-2',6'-pipecoloxylidide obtained from hydrolysis of the salts of formula (Ille) and (Illf) is racemized. The racemic 2',6'-pipecoloxylidide is either alkylated to provide bupivacaine or mepivacaine; or resolved using CCBA.
In the fourth embodiment, the present invention provides a novel process for preparing alkylated 2',6'-pipecoloxylidides or acid addition salt thereof. The process comprises

reacting 2',6'-pipecoIoxylidide or its enantiomer with alkylating reagent using a base in presence of aromatic solvent; and optionally reacting the resulting product with acid,
The solvent used for alkylation is selected from toluene, tetralene, o-xylene, m-xylene, p-xylene or mixture thereof. The preferred solvent used for alkylation is toluene. The base used for alkylation is inorganic base selected from alkali metal carbonates, alkali metal hydroxides or mixture thereof. The preferred base for alkylation of 2',6'-pipecoloxylidide or its enantiomer is potassium carbonate.
Alkylation of 2',6'-pipecoloxylidide or its enantiomer is advantageously carried out under phase transfer catalyst selected from tetraalkylammonium halides, tetraalkylammonium hydroxides, tetraalkylammonium sulphates, tetraalkylammonium nitrates or mixture thereof. Preferably the phase transfer catalyst is tetrabutylammonium bromide.
The alkylating reagent is selected from alkyl halides, dialkyl sulphates, alkyl sulphonates or mixture thereof. Preferably the alkylating agent is dimethyl sulphate, propyl bromide or butyl bromide.
The pure Mepivacaine, bupivacaine, ropivacaine or levobupivacaine thus achieved may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques.
The course of the reactions can be represented by the following equations:


The process of racemization and reuse of (R)-2',6'-pipecoloxylidide; and easy recovery of chiral reagent make the invention further economical.
Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

Examples: Example 1
A clean and dry four neck round bottom flask was charged with 2',6'-pipecoloxyIidide (400 gm) and isopropanol (2 lit, 5 volumes). The reaction mixture was heated to 45°C to 50°C and N-((S)-l-phenylethyl)phthalamic acid (352 gm, 0.75 eq.) was added to it. The reaction mass was maintained at 45°C for 15 to 20 min, cooled to 15°C to 20°C and maintained at room temperature for one hour to obtain a precipitate. The reaction mass was filtered and the precipitate was dried to obtain corresponding (S)-(-)-2',6'-pipecoloxylidide-phthalamic acid salt (443 gm).
IR:- 3300.5, 3033.5, 1677.3, 1657.8, 1629.6, 1583.5, 1529.1, 1475.3, 1444.6, 1377.7, 1241.8, 1094.7, 947.9, 835.4, 756.8, 699.9 CM"1.
*H NMR:- 5 = 1.39(d, J = 4.0Hz, 3H), 1.50-1.70(m, 4H), 2.14(s, 7H), 2.83(dd, J = 2.8Hz, 11.6Hz, 16.6Hz, 1H), 3.14(d, J= 12.4Hz, 1H), 3.83(dd, J= 2.8Hz, 2.8Hz, U.OHz, 1H), 5.06(pen, 1H), 7.09(d, J= 4.0, 3H), 7.20-7.24(m, 4H), 7.31(t, J = 8.0Hz, 8.0Hz, 2H), 7.35-7.45(m, 4H), 7.58(t, J= 8.0Hz, 8.0Hz, 2H), 9.68(s, 1H), 10.27(s, 1H).
The mother liquor was further processed to obtain (R)-2',6'-pipecoloxylidide.
The (S)-(-)-2',6'-pipecoloxylidide-phthalamic acid salt was hydrolysed with 7% sodium
carbonate (7 lit) for two hours at room temperature to obtain a solid. The solid was
filtered and dried to obtain (S)-2',6'~pipecoloxylidide.
Yield - 162.8 gm (81.4%)
Enantiomeric purity - 97.66%
The filtrate was further processed to recover N-((S)-1 -phenylethyl)phthalamic acid.
Example 2
(S)-2',6'-pipecoloxylidide was prepared according to the example 1 using N-((S)-1-
phenylethyl)phthalamic acid (0.75 eq.) in isopropanol (25 volumes).
Yield - 83%
Enantiomeric purity - 99.1%

Examples 3 to 6
Resolution of 2',6'-pipecoloxylidide was carried out using N-((S)-1-phenylethyl)phthalamic acid in various solvents. The results are mentioned in the following table.

2\6'-
pipecoloxylidi de (gm) N-((S)-1-
phenylethyl)phthalam ic acid (gm) Solvent used (ml) Yield of S-(-)-2',6'-
pipecoloxylidid e Optica 1
purity (%)
25 29.0 Isopropanol (200) 8.0 gm, 64% 96.8
5 5.8 Ethanol (30) 1.64 gm, 65.6% 99.4
3.8 2.0 Ethyl
acetate (15) 1.28 gm,
67.3% 97.76
5.0 5.8 Acetone (60) 1.8 gm, 72% 96.5
Example 7
A clean and dry four neck round bottom flask was charged with N-((R)-1-phenylethyl)phthalamic acid (28.9 gm), isopropanol (300 ml) and 2',6'-pipecoloxylidide (25 gm). The reaction mixture was stirred at 25°C to 30°C for one hour. The reaction mass was cooled to 10°C to 15°C to get a precipitate of corresponding (R)-(-)- 2',6'-pipecoloxylidide-phthalamic acid salt (27.30 gm) which was separated by filtration to afford white crystalline solid.
IR:- 3300.8, 3032.8, 1677.2, 1629.7, 1583.4, 1529.8, 1444.7, 1378.4, 1244.8, 1037.7, 947.9, 835.5, 699.9 CM-1
1H NMR:- 8 = 1.39(d, J = 4.0Hz, 3H), 1.50-1.70(m, 4H), 2.13(s, 7H), 2.82(dd, J = 2.8Hz, 5.8Hz, 16.4Hz, 1H), 3.13(d, J= 12.4Hz, 1H), 3.79(dd, J = 2.8Hz, 2.8Hz, 11.0Hz, 1H), 5.06(pen, 1H), 7.04-7.10(m, 3H), 7.21(t, J= 7.2Hz, 7.2Hz, 1H), 7.31(t, J= 7.6Hz, 7.6Hz, 2H), 7.30-7.43(m, 4H), 7.57(d, J = 6.4Hz, 2H), 9.68(s, 1H), 10.27(s, 1H).
The filtrate was concentrated under vacuum, treated with 10% sodium carbonate (500 ml)
and stirred the reaction mass at room temperature for 1.5 hours to get a solid. The solid
was collected by filtration, washed with water and dried to get (S)-2',6'-pipecoloxylidide.
Yield - 12gm(96%)

Enantiomeric purity - 96.66%
(R)-(-)-2',6'-pipecoloxylidide-phthalamic acid sait was hydrolyzed with 10% sodium
carbonate (520 ml) and stirred the reaction mass at room temperature for one hour to get a
solid. The solid washed with water and dried to get (R)-2',6'-pipecoloxylidide.
Yield - 9.3 gm (74.4%)
Enantiomeric purity - 95.95%
Example 8
A clean and dry four neck round bottom flask was charged with ethyl acetate (2 lit) and
phthalic anhydride (552 gm). The reaction mixture was heated to 75°C to 80°C. S-(-)-
alpha-methylbenzyl amine (423 gm) was added to the reaction mixture and stirred the
mixture at 80oC for 10 min. The reaction mixture was cooled to 0 - 5°C to get a solid.
The solid was collected by filtration, washed with ethyl acetate and dried to obtain N-
((S)-l-phenylethyl)phthalamicacid.
Yield - 760 gm (81%)
[a]D25- -48.30(c = 2ethanol)
Example 9
N-((R)-l-phenyIethyI)phthalamic acid was prepared according to the example 8 using
phthalic anhydride (28.9 gm) and R-(+)-alpha-methylbenzyl amine (25 gm) in ethyl
acetate (100 ml).
Yield - , 38gm(68%)
[a]D25 - +45.98 (c = 2 ethanol)
Example 10
N-((S)-l-phenylethyl)succinamic acid was prepared according to the example 8 using
succinic anhydride (20.62 gm) and S-(-)-alpha-methylbenzyl amine (25 gm) in ethyl
acetate (100 ml).
Yield - 44 gm (96.4%)
[a]D25- -115.0 (c = 2 ethanol)

Example 11
N-((R)-l-phenylethyl)succinamic acid was prepared according to the example 8 using
succinic anhydride (20.62 gm) and R-(-)-alpha-methylbenzyl amine (25 gm) in ethyl
acetate (100 ml).
Yield - 43 gm (94.2%)
[a]D25- +114.0(c = 2ethanol)
Example 12
The mother liquor obtained in the example 1 was concentrated under reduced pressure to
obtain oily residue which was hydrolysed with 7% sodium carbonate (7 lit) for two hours
at room temperature to obtain a solid. The solid was collected by filtration and dried to
obtain (R)-2',6'-pipecoloxylidide.
Enantiomeric purity - 85.23%
The filtrate was further processed to recover N-((S)-l-phenylethyl)phthalamic acid.
(R)-2',6'-pipecoloxylidide (100 gm) obtained above was charged in water (1 lit) and
NaOH (100 gm); and heated to reflux for 36 hours. The reaction mass was cooled to 0°C
and stirred for 2 hours. The resulting solid was collected by filtration, washed with water
and dried under vacuum at 50°C to obtain racemic 2',6'-pipecoloxylidide as white
crystalline solid.
Yield - 90gm(90%)
Enantiomeric purity- R : S = 49.6 : 50.4 (by chiral HPLC)
Example 13
A clean and dry four neck round bottom flask was charged with (S)-2',6'-
pipecoloxylidide (20 gm), tetrabutylammonium bromide (2 gm), butyl bromide (20 ml),
potassium carbonate (26.4 gm), water (12.8) and toluene (200 ml). The reaction mixture
was heated at 80 - 85°C for 8.5 hours and cooled to room temperature. Water was added
to the reaction mixture. The organic layer was separated, washed with water and dried
over sodium sulphate. Acetone (60 ml) and 20% hydrochloric acid in isopropanol (18.70
ml) were added to the organic layer at 40°C. The mixture was cooled to 0 to 5°C and
maintained for an hour at same temperature to obtain a solid. The solid was collected by
filtration, dried to obtain levobupivacaine hydrochloride.
Yield - 21.5 gm (77%)

Enantiomeric purity - 99.98%
HPLC purity - 99.8%
Example 14
Bupivacaine hydrochloride hydrate was prepared according to the example 13 using
2',6'-pipecoloxyIidide and cone, hydrochloric acid instead of (S)-2',6'-pipecoloxylidide
and 20% hydrochloric acid in isopropanol.
Yield - 92%
HPLC purity- 99.84%
Example 15
Ropivacaine hydrochloride hydrate was prepared according to the example 13 using
propyl bromide and cone, hydrochloric acid instead of butyl bromide and 20%
hydrochloric acid in isopropanol.
Yield - 88%
Enantiomeric purity - 99.99%
HPLC purity - 99.92%

WE CLAIM.
1. A process for enantiomeric enrichment of 2',6'-pipecoloxyIidide comprising: reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I)

with a chiral carbamoyl benzoic acid in presence of a solvent.
2. The process as claimed in claim 1, wherein enantiomeric enrichment is carried out by reacting a mixture of enantiomers of 2',6'-pipecoloxylidide of formula (I) with a chiral carbamoyl benzoic acid of formula (II) in presence of a solvent to provide a salt mixture of formula (IIIa); and isolating a salt of formula (IIIb) from the salt mixture of formula (IIIa);

Formula (IIIb) where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 caTbon
atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon
atoms; and R' is alkyl containing 1 to 5 carbon atoms.

3. The process as claimed in claim I, wherein enantiomeric enrichment is carried out by reacting a mixture of enantiomers of 2',6'-pipecoIoxylidide of formula (I) with a chiral N-substituted amidic acid of formula (IIa) in presence of a solvent to provide a salts mixture of formula (IIIc); and isolating a salt of formula (IIId) from the salt mixture of formula (IIIc);

where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
4. The process as claimed in claims 2 and 3, wherein R is phenyl and R' is methyl.
5. The process as claimed in claims 1, 2 and 3, wherein the solvent is selected from polar solvents.
6. The process as claimed in claim 5, wherein the solvent is selected from the group consisting of alcohol, nitrile, ester, ketone or mixture thereof.
7. The process as claimed in claim 6, wherein the solvent is selected from the group consisting of isopropanol, ethanol, ethyl acetate or acetone.


8. The process as claimed in claims 2 and 3 further comprising releasing (S)-2',6'-pipecoloxylidide of formula (IV);
Formula (IV) from the chiral salt of formula (IIlb) and (IIIc) using a base.
9. The process as claimed in claim 8, wherein the base is selected from organic base or inorganic base.
10. The process as claimed in claim 9, wherein the base is selected from the group consisting of ammonia, tertiary amine, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate.
11. The process as claimed in claim 10, wherein the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, calcium bicarbonate or magnesium bicarbonate.
12. The process as claimed in claim 11, wherein the base is sodium carbonate.
13. The process as claimed in any one of the preceding claims, wherein the process provides (S)-2',6'-pipecoloxylidide of formula (IV) with more than 96% enantiomeric purity.
14. Salts of formula (IIIb), (IIId), (IIIe) and (IIIf)



Formula (IIIe) Formula (IIIf)
where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.
15. The salts as claimed in 14, wherein R is phenyl and R' is methyl.
16. A process for preparation of N-substituted amidic acid of formula (IIIe) or enantiomers thereof

where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; R' is alkyl containing 1 to 5 carbon atoms; and R" is 2-carboxyphenyl, CH2CH2COOH or CH=CHCOOH; comprising reacting phthalic anhydride, succinic anhydride or maleic anhydride with amines of formula (V) or enantiomers thereof in presence of atleast one polar aprotic solvent;

where R is phenyl, phenyl substituted by halogen or alkyl containing 1 to 5 carbon atoms, naphthyl or naphthyl substituted by halogen or alkyl containing 1 to 5 carbon atoms; and R' is alkyl containing 1 to 5 carbon atoms.

17. The process as claimed in claim 16, wherein the solvent is selected from carboxylic acid ester, ketone, halogenated hydrocarbon or mixture thereof.
18. The process as claimed in claims 16 and 17, wherein the solvent is selected from the group consisting of ethyl acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone, dichloromethane, chloroform or mixture thereof.
19. The process as claimed in claim 18, wherein the solvent is ethyl acetate.
20. Process for preparing alkylated 2',6'-pipecoloxylidides, enantiomers or acid addition salts thereof comprising reacting 2',6'-pipecoloxylidide or its enantiomers with alkylating reagent using a base in presence of atleast one aromatic hydrocarbon solvent; and optionally reacting the resulting product with an acid.
21. The process as claimed in claim 20 wherein the solvent is selected from toluene, tetralene, o-xylene, m-xylene, p-xylene or mixture thereof.
22. The process as claimed in claim 21, wherein the solvent is toluene.
23. The process as claimed in claim 20 wherein the base is inorganic base.
24. The process as claimed in claim 23, wherein the base is selected from alkali metal carbonates, alkali metal hydroxides or mixture thereof.
25. The process as claimed in claim 24, wherein the base is potassium carbonate.
26. The process as claimed in claim 20, wherein the alkylating reagent is selected from the group consisting of alkyl halides, dialkyl sulphates, alkyl sulphonates or mixture thereof.
27. The process as claimed in claim 26, wherein the alkylating reagent is selected from the group consisting of dimethyl sulphate, propyl bromide or butyl bromide.

28. The process as claimed in claim 20, wherein alkylation is carried out under phase transfer catalyst.
29. The process as claimed in claim 28, wherein the phase transfer catalyst is selected from the group consisting of tetraalkylammonium halides, tetraalkylammonium hydroxides, tetraalkylammonium sulphates, tetraalkylammonium nitrates or mixture thereof.
30. The process as claimed in claims 28 and 29, wherein the phase transfer catalyst is tetrabutylammonium bromide.