FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, RULE 13)
"PROCESS FOR PREPARATION AND ISOLATION OF
ROPIVACAINE BASE & ROPIVACAINE HYDROCHLORIDE
ANHYDROUS WITH HIGH PURITY CHIRAL FORMS"
DISHMAN PHARMACEUTICALS AND CHEMICALS LIMITED,
" Bhadr-Raj Chambers, C.G. Road,
Navrangpura, Ahmedabad-380 009,
Gujarat State, India
The following specification particularly describes the nature of this
invention and ma.nner in which it is to be performed: -


Field of Invention
The present invention relates to a process for preparation and Isolation
of Ropivacaine base and Ropivacaine hydrochloride with high purity
Chiral forms.

Prior Art
US 5,929,242 discloses the process, which comprises the prior steps of
diazotisation-solvolysis of .alpha.-N-blocked-L-lysine; condensation of
the resultant (S)-2-(blocked amino)-6-acetoxyhexanoic acid with 2,6-
dimethylaniline; cleavage of the o-acetyl group, by methanolysis.
U.S.Patent 5,959,112 discloses the preparation of ropivacaine base
and ropivacaïne hydrochloride, wherein racemic 2-pipecolinoxylidide
hydrochloride is converted to its base form and resolved by the
resolving agent L-(-)-dibenzoyl tartaric acid gave the (S)-
pipecoloxylidide in a solvent MIBK (Methyl Isobutyl Ketone), which is
alkylated with a 1-bromopropane, in the presence of a potassium
carbonate base, water and sodium iodide catalyst, the reaction is
completed at reflux temperature by 6 hrs. and the product isolated
after work up as a ropivacaine hydrochloride with the chiral purity of
about 90 %. To get ropivacaine hydrochloride monohydrate with
>99.5 % chiral purity extra purification is required using aqueous
2

acetone. Further, in thïs patent there is no isolation of ropivacaine
base.
This demands a cost effective process for preparation of to isolate the
ropivacaine base and hydrochloride with a high chïral purity without
any additional purïfication. By the present invention the ropivacaine
hydrochloride is in the anhydrous form.
The main object of the invention is to provide cost effective process for
preparation of isolatë the ropivacaine base and hydrochloride with a
chiral purity of > 99.5 %.
Further object of the present invention is to provide process for isolatë
the ropivacaine base and hydrochloride with a chiral purity of > 99.5
% without any additional purification, means less number of steps are
required.
DETAILED DESCRIPTIQN OF THE INVENTION:
The racemic 2-pipecoloxylïdide is resolved by using resolving agent L-
(-)-dibenzoyl tartaric acid in presence of isopropyl alcohol to form (S)-
pipecoloxylidide, which is alkylated with 1-bromo propane using phase
transfer catalyst tetra butyl ammonium iodide (TBAI) to have the
ropivacaine base with high enantiomeric purity > 99.5 %. This is
converted to ropivacaine hydrochloride using IPA.HCI in MIBK with a
Chiral purity >99.5%.
3

Advantages of the present invention
1. Isolation of Ropivacaine base with more than 99.5 % Chiral
purity.
2. Isolation in the form of Ropivacaine hydrochloride anhydrous
with the Chiral purity more than 99.5 %.
3. As the product of the present invention is anhydrous form 20-
25° C less temperature is required. Further, monohydrate
contains a mole of water which takes more material, whereas
in case of anhydrous, the intake of the material is less as
there is no water molecule
4. This is a Phase transfer catalyst based reaction.
5. There is less number of steps and hence less time is required.
4

5
Synthetic flow diagram of Ropivacaine Hydrochloride


The invention will now be described in more detail by the
following preparatory examples.
Exampfe - 1:
Step - 1:
Dissolve 70.0 gm (0.3 mole) 2-pipecolinoxylidide in 350.0 ml IPA
at RT. Filter through hiflow bed. Wash with 2 X 49.0 ml IPA.
Heat filtrate up to 80°C. Add solution of dibenzoyl-L-(-)-tartaric
acid [59.5 gm (0.16 mole) dibenzoyl-L-(-)-tartaric acid in 170.0
ml IPA] at 80°C in l hrs. Maintain reaction for l hrs at 80°C.
Cool to RT and stir for l hrs. Filter the solid. Wash with 3 X 25.0
ml IPA. Dry the solid. Dry weight 58.6 gm.
Step - 2:
Stir 40.0 gm (0.048 mole) dibenzoyl-2-pipecolinoxyiidïde-L-
tartrate, 160.0 ml DM water, 240.0 ml toluene at RT. Heat up to
60°C. Add 13.12 ml caustic lye at 60°C in Vi hrs. Stïr reaction
mixture at 60°C for Vz hrs. Separate the organic layer and
discard aqueous layer. Add 11.6 gm (0.145 mole) sodium
hydroxide solution (50%w/w), catalyst (TBAI), 17.8 gm (0.144
mole) n-propyl bromide at RT. Heat reaction mixture to 70°C and
stir for 1-2 hrs. Cool to 60°C. Add 120.0 ml DM water and Stir
for 1/2 hrs. Separate the organic layer and discard aqueous layer.
Dry organic layer over sodium sulfate, filter and concentrate the
reaction mass and cool to 0-5°C. Stir for l hrs and filter the
slurry. Dry the solid. Dry weight 21.0 gm. Chiral purity > 99.5%,
SOR [α]D25 -82.0° to -84.0° (C=2 in methanol).
6

Step - 3:
Stir 10.0 gm (0.03 mole) Ropivacaine base and 130.0 ml MIBK
at RT. Heat up to 40°C. Slowly add 8.5 gm (0.04 mole) IPA.HCI
(20%w/w) at 40°C in 1/2 hrs. Stir for 15 min. Cool to RT and stir
for l hrs. Filter the solid. Dry the solïd. Dry weight 11.2 gm.
Chiral purity 2:99.5%.
Example - 2:
Step - 1:
Dissolve 1000.0 gm (4.3 mole) 2-pipecolinoxylidide in 5000.0 ml
IPA at RT. Filter through hiflow bed. Wash with 2 X 700.0 ml
IPA. Heat filtrate up to 80°C. Add solutïon of dibenzoyl-L-(-)-
tartaric acid [850.0 gm (2.37 mole) dibenzoyl-L-(-)-tartaric acid
in 2420.0 ml IPA] at 80°C in 2 hrs. Maintain reactïon for l hrs at
80°C. Cool to RT and stir for l hrs. Filter the solid. Wash with 3 X
350.0 ml IPA. Dry the solid. Dry weight 859.1 gm.
Step - 2:
Stir 855.0 gm (1.04 mole) dibenzoyl-2-pipecolinoxylidide-L-
tartrate, 3420.0 ml DM water, 5130.0 ml toluene at RT. Heat up
to 60°C. Add 280.44 ml caustic lye at 60°C in Vi hrs. Stir reaction
mixture at 60°C for 1/2 hrs. Separate the organic layer and
discard aqueous layer. Add 247.65 gm (3.09 mole) sodium
hydroxide solution (50%w/w), catalyst (TBAI), 380.7 gm (3.09
mole) n-propyl bromide at RT. Heat reaction mixture to 70°C and
stir for 1-2 hrs. Cool to 60°C. Add 2565.0 ml DM water and Stir
for 1/2 hrs. Separate the organic layer and discard aqueous layer.
Dry organic layer over sodium sulfate, filter and concentrate the
7

reaction mass and cool to 0-5°C. Stir for l hrs and filter the
slurry. Dry the solid. Dry weight 444.6 gm. Chiral purity >
99.5%, SOR [α]D25 -82.0° to -84.0° (C=2 in methanol).
Step - 3:
Stir 419.0 gm (1.53 mole) Ropivacaine base and 5447.0 ml
MIBK at RT. Heat up to 40°C. Slowly add 355.0 gm (1.94 mole)
IPA.HCI (20%w/w) at 40°C in V/2 hrs. Stir for 15 min. Cool to RT
and stir for l hrs. Filter the solid. Dry the solid. Dry weight 470.0
gm. Chiral purity > 99.5%.
claim,
1. Process for preparation and isolation of ropivacaine base and
hydrochloride with a chiral purity of > 99.5 %.
2. Process for preparation of ropivacaine base and hydrochloride
with a chiral purity of > 99.5 %, whereïn racemic 2-
pipecoloxylidide is resolved by using resolving agent L-(-)-
dibenzoyl tartaric acid in presence of isopropyl alcohol to form
(S)-pipecoloxylidide, which is alkylated with 1-bromo propane
using phase transfer catalyst tetra butyl ammonium iodide
(TBAI) to have the ropivacaine base with high enantiomeric
purity > 99.5 % and then the same is converted to ropivacaine
rydrochloride using IPA.HCI in MIBK with a Chiral purity >99.5%.
3. Process for preparation and isolation of,ropivacaine base and
hydrochloride with a chiral purity of > 99.5 % as shown in the
flow diagram below:
8


9

4. The process as claimed in claim 1 to 3 is a Phase transfer
catalyst based reaction.
5. The process as claimed in claim 1 to 3 does not require any
additional purification.
6. Process for preparation and isolation of ropivacaine base and
hydrochloride with a chiral purity of > 99.5 % is substantially as
herein described with reference to the foregoing examples.
Dated this 25th day of October,2004.

To,
The Controller of Patents,
Patent Office.
10
Mumbai.