FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

A PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE 1,2,3,4-
TETRAHYDROISOQUINOLINE-3-CARBOXYLIC ACID DERIVATIVES
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office al ACME PLAZA,
ANDHER1-KURLA ROAD, ANDHER1 (E), MUMBA1-40Q059, MAHARASHTRA, INDIA.
The following specification particularly describes the 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 substantially pure
K2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives, compound of formula 1 and
pharmaceutical ly acceptable salt thereof wherein Et represents ethyl group; and X and Y
are independently selected from the group consisting of hydrogen. (C1-C3)-alkyl or 0-(C1-
C3)-alkyl. The compound of formula I is useful in therapy for the treatment of
hypertension.

Particularly, the present invention relates to a process for the preparation of compound of
formula la. wherein X and Y, both are H, commonly known as quinapril and compound
of formula lb, wherein X and Y both are OCH3. commonly known as moexipril.

BACKGROUND OF THE INVENTION:
United States Patent No. 4,344,949 (the 949 patent; Indian reference not available)
discloses compound of formula I and process for preparation thereof from its esters.
2

namely lower alkyl esters, arylmethyl ester or trimethylsilyl ester. The preparation of
compound of formula I from its arylmethyl ester, compound of formula II wherein Ar
represents phenyl: Et X and Y are as defined above, is carried out by catalytic
hydrogenolysis of the hydrochloride salt of compound of formula 11 with 20% palladium
on charcoal in tetrahydrofuran. After completion of the reaction the compound of formula
1 is precipitated by addition of 10 fold quantities of ether.

The process of the '949 patent has several disadvantages which makes it commercially
unviable.
(a) It requires high concentration of palladium (20%) on charcoal which is expensive
and uses large quantities of inflammable solvents like letrahydrofuran and ether.
(b) The yield of the compound la is only 56%. and the purity of the compound is not
disclosed.
(c) The preparation of hydrochloride salt of compound of formula II requires the use
of dry HCI gas which is not convenient for large scale preparations.
United States Patent No 4,761,479 (the '479 patent; Indian reference not available)
discusses the preparation of quinapril; the synthetic step involving removal of ester group
results in impurity formation to the extent of 10-30%, namely the diketopiperazine
impurity and two other unidentified impurities. The diketopiperazine impurity, a
compound of formula A,
3


Formula A
is difficult to remove and the crude quinapril is not purifiable by conventional organic
chemistry techniques. The '479 patent teaches the preparation of crystalline quinapril
hydrochloride from its corresponding 1.1-dimethylethyl ester, making acetonitrile solvate
thereof as an intermediate.
United States Patent No. 6,617,457 (the '457 patent; Indian reference not available)
discloses process for preparation of compound of formula la by hydrogenolysis of
compound of formula II (X and Y are both H) with Pd/C in an alcoholic solvent in the
presence of concentrated hydrochloric acid. In the workup of the reaction, the catalyst is
filtered off. solvent is removed by distillation followed by repeated addition of toluene
and removal of solvent by vacuum distillation. The quinapril hydrochloride is isolated in
the form of a toluene solvate. The toluene solvate is treated with a class 3 solvent to get
the corresponding solvate which is then dried to obtain quinapril hydrochloride.
PCT publication Number WO 2004/054980 (the 980 application) discJoses process for
preparation of compound of formula la by hydrogenolysis of compound of formula II (X
and Y are both H) with Pd/C in an alcoholic solvent in the presence of 35% hydrochloric
acid. After completion of reaction the catalyst is filtered off and the filtrate is evaporated
to give crude quinapril hydrochloride. It is then subjected to further purification by
repeated extractions with dichloromethane and concentration followed by formation of a
nitroalkane solvate and drying to give quinapril hydrochloride. reportedly in 65 % yield
only.
4

UK Patent application No. GB 2095252 A discloses catalytic hydrogenolysis of compound
of formula II (X and Y are both H) with hydrogen and Pd/C in ethanol. After completion
of reaction the catalyst is filtered, the solvent concentrated in vacuo. and the product
partitioned between ether and 2N HC1 followed by lyophilization. This process has the
disadvantage that the compound of formula I formed in this reaction as free base is
unstable and partially converts to the diketopiperazine impurity, a compound of formula
A. This results in quinapril in yield of only 37 %. Further, lyophilization on industrial
scale being energy intensive renders the process economically unviable.
5
These prior art processes reveal that the synthesis as well as isolation of compound of
formula I is a difficult process since the product as well as the starling material.
compound of formula II are prone to degradation to give impurities, namely,
diketopiperazine impurity, a compound of formula A; diacid impurity, a compound of
formula B and ethyl diester impurity, a compound of formula C.


wherein Et represents ethyl group, X and Y are independently selected from the group
consisting of hydrogen, (C1-C3)-alkyl or 0-(C1-C3)-alkyl and other uncharacterized
impurities.
Once formed, these impurities are difficult to remove by conventional separation
techniques, including fractional crystallization, thereby reducing the yield and purity of
final product. The key to tackle this problem would be to employ conditions for reaction
and product isolation which would minimize the formation of key impurities i.e.
compounds of formulae A. B and C.
The impurities diketopiperazine. compound of formula A. the diacid. compound of
formula B and ethyl diester, compound of formula C, may be formed due to various
reaction conditions used in the synthesis and isolation process.
The compound of formula I is a sensitive molecule and is unstable in its free base form.
When the side chain nitrogen is unprotonated it undergoes facile intramolecular
cyclization to give diketopiperazine impurity, compound of formula A. Therefore the
arylmethyl ester,, compound of formula II is First protonated by converting into
hydrochloride with concentrated HC1 and then subjected to hydrogenolysis in an alcoholic
solvent in some of the prior art processes described vide-supra. However since the
hydrochloride salt of compound of formula 1 is soluble in water as well as in alcohol, the
process of isolation of the compound of formula I in prior art processes involves removal
of these solvents from the reaction mixture by the process of distillation. This workup
procedure is time consuming and energy intensive because of the composition of the
reaction mixture. The generated product, compound of formula 1 is thus subjected to
thermal conditions in aqueous-alcoholic acidic medium for long durations, especially on
commercial scale preparations. Heating under aqueous acidic condition can partially
hydrolyze the side chain ester moiety of compound of formula 1. to give the diacid
impurity, compound of formula B. Also the other impurity, viz. ethyl diester. compound
6

of formula C. forms during removal of alcohol from the hydrogenolysis medium by
distillation, by esterification of compound of formula 1. in presence of acid.
In these prior art processes, after initial removal of the hydrogenolysis solvent system by
distillation, another solvent like dichloromethane or toluene is added followed by
distillation. This process is repeated number of times so that the water and alcohol traces
are completely removed, thus subjecting the product to further heating. These prolonged
thermal conditions during concentration of solution or thermal drying of solvates may
lead to increased formation of the diketopiperazine impurity, compound of formula A.
Moreover, when we repeated the hydrogenolysis reaction of formula II (X and Y are both
H) in ethanoi on a few kilogram scale in a reactor, we observed that stripping of solvent
system containing some amount of water from the added concentrated hydrochloric acid
was time consuming thereby leading to the formation of significant amounts of the
diketopiperazine impurity, compound of formula A; diacid impurity, compound of
formula B and ethyl diester impurity, compound of formula C. along with other
impurities as compared to when the reaction was carried out on a few gram scale in
laboratory. Thus we find that the processes of '457 and '980 are not really viable for
commercial scale preparations.
The reported methods of synthesis of compound of formula I involving hydrogenolysis of
compound of formula II in alcohol and acid when carried on an industrial scale lead lo the
formation of significant amount of diketopiperazine impurity, compound of formula A;
diacid impurity, compound of formula B and ethyl diester impurity, compound of formula
C. and are low yielding, time consuming and involve use of inflammable solvents.
Thus there is a need in the state of art for a process that would minimize the formation of
impurities and provides substantially pure l,2.3,4-tetrahydroisoquinoline-3-carboxylic
acid derivatives, compound of formula I or a pharmaceutically acceptable salts thereof
besides circumventing the other drawbacks of the prior art.
7

We have now developed a safe, high yielding, commercially viable process for the
preparation of substantially pure compound of formula 1.
As used herein, the term substantially pure compound of formula I or pharmaceutically
acceptable salts thereof means a compound of formula 1 or pharmaceutically acceptable
salts thereof, which has impurity A in less than 0.5%, impurity B in less than 0.5% and
impurity C in non-detectable amounts; preferably impurity A is less than 0.2%. impurity
B is less than 0.2% and 0% impurity C, as measured by HPLC (high performance liquid
chromatography) analysis.
The present invention provides a safe and convenient process for the preparation of
compound of formula I or a salt thereof by hydrogenolysis of compound of formula JJ or
acid addition salt thereof in an aqueous medium, in presence of acid. Typically, after
hydrogenolysis the catalyst is filtered off and product is extracted from the reaction
mixture with water immiscible organic solvent, thereby avoiding removal of
hydrogenolysis solvent system by heating. Thus the process avoids conditions that are
detrimental to the product quality, i.e. heating of the reaction mixture with a potentially
pro-impurity forming composition of acid, alcohol and water. The end result is
minimization of the formation of impurities, especially compounds of formulae A & B,
and prevention of impurity C. to obtain substantially pure compound of formula I or a salt
thereof.
The process of the present invention thus has several advantages
(a) It isolates the compound of formula I by extracting in an organic solvent and thereby
avoiding the step of heating the reaction mixture containing the product in an aqueous
acidic medium. This leads to the formation of substantially pure compound of formula
I, which is substantially free of diketopiperazine impurity, compound of formula A;
diacid impurity, compound of formula B and ethyl diester impurity, compound of
8

formula C.
(b) It gives high yield of compound of formula I.
(c) The workup is simple and less time consuming, as it does not involve stripping of
hydrogenolysis solvent system,
(d) Hydrogenolysis is carried out in aqueous medium hence large scale handling of
palladium is safe.
(e) The process is more robust and is especially suitable for commercial scale
manufacture.
SUMMARY OF THE INVENTION
The present invention in one aspect provides a process for preparation of substantially
pure 1.2.3,4-tetrahydroisoquinoline-3-carboxyiic acid, compound of formula 1 or its
pharmaceutically acceptable salt comprising:
a) subjecting compound of formula 11 or acid addition salt thereof to
hydrogenolysis in aqueous medium in the presence of an acid;

wherein Et represents ethyl group: Ar represents phenyl or substituted phenyl
group; and X and Y are independently selected from the group consisting of
hydrogen, (C1-C3)-alkyl or 0-(C1-C3)-alkyl or X and Y can be linked together
to form a cyclic group -O(CH2)n-0-, wherein n =1 or 2.
9

b) extracting the product from the reaction mixture with water immiscible
organic solvent to form an organic extract.
The present invention in one aspect provides a process for industrial scale preparation
of substantially pure l,2.3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of
formula 1 or pharmaceutically acceptable salt thereof comprising:
a) subjecting compound of formula II or acid addition salt thereof to
hydroge no lysis in aqueous medium in the presence of an acid;

Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl
group; and X and Y are independently selected from the group consisting of
hydrogen, (C1-C3)-alkyl or 0-(C1-C3)-alkyl or X and Y can be linked together
to form a cyclic group -O(CH2)n-O-, wherein n =l or 2.
b) extracting the product from the reaction mixture with water immiscible
organic solvent and
c) isolating the compound of formula I or its solvate as a pharmaceutically
acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a safe and convenient process for the preparation of
substantially pure 1.2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of
formula 1 or pharmaceutically acceptable salt thereof from compound of formula II or
acid addition salt thereof.
10


Formula I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl group
wherein phenyl ring is substituted with one or more halogen, O-(C1-C4)-alkyl or
haloatkoxy group containing(C1-C4)alkyl. for example. -OC3} group and the like and X
and Y are independently selected from the group consisting of hydrogen, (C1-C4)-alkyl or
O-(C1-C3)-alkyl or X and Y can be linked together to form a cyclic group -O(CHi)n-O-.
wherein n =1 or 2.
In one embodiment, the present invention provides a process for preparation of
substantially pure 1.2.3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of
formula I or its pharmaceutically acceptable salt comprising:
a) subjecting compound of formula II or acid addition salt thereof to
hydrogenolysis in aqueous medium in the presence of an acid;

wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl
group and X and Y are independently selected from the group consisting of
11

hydrogen, (C1-C3)-alkyl or O-(C1-C3)-alkyl or X and Y can be linked together
to form a cyclic group -0(CH2)n-O-; wherein n =lor 2.
b) extracting the product from the reaction mixture with water immiscible organic
solvent to form an organic extract.
In a preferred embodiment the compound of formula 1 or its solvate is isolated as a
pharmaceutically acceptable salt thereof by removing the solvent from said organic
extract by any method known in the art like removal of solvent by heating.
In another embodiment the present invention provides a process for industrial scale
preparation of substantially pure l,2,3,4-tetrahydroisoquinolineo-carboxylic acid
compound of formula 1 or pharmaceutically acceptable salt thereof comprising
a) subjecting compound of formula 11 or acid addition salt thereof to hydrogenolysis
in aqueous medium in the presence of an acid;

ForjnuJa I Formula II
wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl
group and X and Y are independently selected from the group consisting of
hydrogen, (C1-C3)-alkyi or O-(C1-C3)-alkyl;
b) extracting the product from the reaction mixture with water immiscible organic
solvent and
c) isolating the compound of formula I or its solvate as a pharmaceutically
acceptable salt thereof.
12

The batch size for industrial scale is preferably at least about 0.5 kg. Example 1 illustrates
such an industrial process, which prepares the compound of formula I in a batch having
about 10 kg.
In one preferred embodiment the present invention provides a process for the preparation
of substantially pure l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of
formula 1 or pharmaceutically acceptable salt thereof, wherein X and Y both are H.
In one preferred embodiment the present invention provides a process for the preparation
of substantially pure 1,2.3,4-tetrahydroisoquinoIine-3-carboxyiic acid, compound of
formula I or pharmaceutically acceptable salt thereof, wherein X and Y both are OCH3.
The aqueous medium for hydrogenolysis maybe selected from water or a mixture thereof
with a solvent selected from ketones such as acetone, methyl ethyl ketone and the like;
amides such as dimethylformarnide, dimethyiacetamide, N-methy! pyrrolidone, ureas and
the like, nitriles such as acetonitrile and the like.
In a preferred embodiment, the hydrogenolysis medium is water and acetone mixture.
Any suitable volume ratio of water and acetone may be used depending on the amount of
the compound of formula II to be subjected to hydrogenolysis. A suitable quantity and
composition of water and acetone solvent mixture to be used for hydrogenolysis may be
determined by one skilled in the art. The quantity and composition is chosen such that the
compound of formula II that is to be subjected to hydrogenolysis dissolves to form a
homogeneous solution at the temperature at which the hydrogenolysis reaction is carried
out.
In one preferred embodiment the present invention provides a process for preparation of
substantially pure 1.2,3,4-tetrahydroisoquinoline-3-carboxylic acid, compound of
formula 1 or pharmaceutically acceptable salt thereof, wherein X and Y both are H.
comprising subjecting a compound of formula I) or acid addition salt thereof, wherein X
13

and Y both are H, to hydrogenolysis in aqueous medium in the presence of an acid.
wherein the aqueous medium comprises of water and acetone mixture in the volume ratio
of 1:1.
The hydrogenolysis of compound of formula II in aqueous medium may preferably be
carried out in presence of concentrated HC1 or solution of hydrogen chloride in a suitable
solvent.
The hydrogenolysis in aqueous medium may be carried out using any suitable hydrogen
source, for example, hydrogen gas at a pressure between 0-20 bar and at a temperature
between -20 to 50°C in the presence of any suitable hydrogenation catalyst, for example.
10% palladium on charcoal.
Any suitable water immiscible organic solvent can be used for (he extraction of
compound of formula I obtained by hydrogenolysis of compound of formula II.
Preferably; a non-protic and volatile organic solvent for example, aliphatic halogenated
hydrocarbons such as dichloromethane, ethylene dichloride or chloroform may be used.
The pharmaceutically acceptable salt of compound of formula I may be selected from
hydro chloride, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the
like. The acid addition salts of compounds of formula II may be selected from
hydrochloride, maleate. hydrobromide, sulfate, nitrate, acetate, fumarate, maleate. citrate
and the like.
In a preferred embodiment the present invention provides substantially pure 1,2,3.4-
tetrahydroisoquinoIine-3-carboxylic acid, compound of formula I which is substantially
free of impurities represented by formulae A, B and C and solvates and salt thereof.
In one preferred embodiment the present invention provides substantially pure \23A-
tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a
14

compound of formula A in less than 0.5%. a compound of formula B in less than 0.5%
and compound of formula C is in non-detectable amount as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1.2.3.4-
tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a
compound of formula A in less than 0.5%, a compound of formula B in less than 0.5%
and compound of formula C is 0% as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1.2.3,4-
tetrahydroisoquinoline-3-carboxylic acid, compound of formula I which contains a
compound of formula A in less than 0.2%, a compound of formula B in less than 0.2%
and compound of formula C is in non-detectable amount as measured by HPLC analysis.
In one preferred embodiment the present invention provides substantially pure 1.2,3,4-
tetrahydroisoquinoline-3-carboxyiic acid, compound of formula 1 which contains a
compound of formula A in less than 0.2%, a compound of formula B in less than 0.2%
and compound of formula C is 0% as measured by HPLC analysis.
In a typical work up, after completion of hydrogenolysis the catalyst is removed by
filtration. The reaction mixture is then extracted with a water immiscible organic solvent.
The compound of formula 1 or its solvate or a pharmaceutically acceptable salt thereof,
may be isolated by removing the organic solvent from the extract, preferably under
vacuum at the temperature preferably below 50°C. If desired the isolated compound of
formula I or a pharmaceutically acceptable salt thereof can be dissolved in another
organic solvent and crystallized out as a solvate thereof, for example, acetone solvate or
acetonitrile solvate, optionally by seeding if required, which may then be converted to a
compound of formula 1 or a pharmaceutically acceptable salt thereof by drying the
product, preferably under vacuum at a temperature preferably below 50°C. The step of
formation of solvate of compound of formula 1 may be repeated if desired.
15

In a preferred embodiment, a compound of formula la, quinapril or a pharmaceutically
acceptable salt is prepared by subjecting the compound of formula II (wherein X and Y
are both H) to hydrogenolysis in an aqueous medium containing acetone in the presence
of a hydrogenation catalyst like palladium on carboy (Pd/C). hydrogen source like
hydrogen gas and hydrochloric acid at a temperature of about 40°C. After completion of
the reaction, the catalyst is removed by filtration and the aqueous reaction mixture is
extracted with a water immiscible organic solvent like dichloromethane. The organic
solvent is removed by heating under vacuum, preferably at / below 40°C. The residue is
dissolved in acetone and the product is crystallized out, preferably by cooling to about 0
to about 10°C; filtered and dried under vacuum, preferably below a temperature of 50°C
to obtain quinapril or a pharmaceutically acceptable salt thereof.
The process of the present invention provides substantially pure 1.2.3.4-

greater than 98%, as determined by HPLC.
The compound of formula II may be prepared by a method known to those skilled in the
art such as United States Patent No. 4.344949, which is incorporated herein by reference.
Throughout the specification and the claims which follow, unless the context requires
otherwise, the phrase 'compound of formula I' and 'compound of formula II will be
understood to include their respective pharmaceutically acceptable salts or acid .addition
salts.
The examples that follow do not limit the scope of the present invention and are included
as illustrations.
16

EXAMPLES:
Example I
Preparation of compound of formula I (wherein X and Y are H)
The maleate salt of compound of formula II. 10 kg (wherein Ar represents phenyJ, Et
represents ethyl group; and X and Y are both hydrogen) was suspended in DM water, and
its free base was extracted into dichloromethane after adjusting pH to 8.0 to 8.5 with 10%
sodium carbonate solution. The dichloromethane extract was concentrated under reduced
pressure and degassed under vacuum. The residue was taken up in a mixture of 20 litres
of DM water and 20 litres of acetone and 1.0 kg 5%Pd/C (50% wet) and 4 litres of 35%
hydrochloric acid were added. The reaction mass was subjected to catalytic
hydrogenolysis with hydrogen gas for 5.0 hours at 35-40°C at 0.5 kg/sq.cm pressure, and
the catalyst was filtered. The filtrate was extracted with dichloromethane. the extract
concentrated at below 35°C under reduced pressure, and resulting residue was stripped
with acetone under vacuum. The residue thus obtained was stirred with acetone, and
cooled to 5-10°C. The crystallized product was filtered and dried at 45°C in a vacuum
oven to obtain 6.22 kg of quinapril hydrochloride, compound of formula I wherein Et
represents ethyl group; and X and Y are hydrogen, as a solvate of acetone, having purity
98.93% as determined by HPLC. and containing 0.09% of compound of formula A.
0.11% of compound of formula B. and compound of formula C was not detected.
HPLC analysis method for compound of formula I (wherein X and Y arc H) and
related substances
Buffer:
Transfer 0.92 g of heptanesulphonic acid sodium salt into a 1000 ml volumetric flask.
Dissolve in and dilute upto mark with HPLC grade water. Add 1 ml of triethylamine and
mix well. Adjust the pH of the solution to 2.0 ± 0.1 with perchloric acid.
Mobile phase:
Mix buffer solution and acetonitrile in the ratio of 6 : 4. Filter and degas prior to use.
17

Diluent:
Transfer 2.88 g of ammonium dihydrogenorthophosphate into a 1000 ml volumetric flask,
dissolve in and dilute up to mark with HPLC grade water. Adjust pH to 6.5 with
ammonia solution. Mix 300 ml of this solution mix with 200 ml of acetonitrile. Filter and
degas prior to use.
Sample preparation :
Transfer about 20 mg accurately weighed sample into a 10 ml volumetric flask. Dissolve
in and dilute up to mark with diluent.
System suitability solution ;
Transfer about 10 mg of accurately weighed sample into a 100 ml volumetric flask.
Dissolve in and dilute up to mark with diluent.
Chromatographic system :
The liquid chromatograph is equipped with a 214 nm UV detector and 25cm x 4,0mm, 5µ,
column that contains Superspher R.P8. The flow rate is maintained at about 1.0 ml/min.
Procedure:
Inject 10 µl of the system suitability solution into the system and record the
chromatograms upto 80 min. Calculate the tailing factor of quinapril peak. It should not
be more than 2 and number of theoretical plates should not be less than 2000.
Inject 10 µl of the sample preparation into the system and record the chromatogram upto
80 min. The retention time of quinaprii is about 21.5min. Retention times of impurities A,
B and C are about 30.6. 8.61 and 69.3 min, respectively. The amount of related
substances are calculated by area normalization method.
18

Comparative Example
Preparation of compound of formula I (wherein X and Y are H) (Hydrogenolysis in
ethanol)
The maleate salt of compound of formula II. 20 kg, (wherein Ar represents benzyl, Et
represents ethyl group; and X and Y are both hydrogen) was suspended in DM water and
its free base was extracted into dichloromethane after adjusting the pH to 8.0-8.5 with
liquor ammonia. The dichloromethane layer was washed with water, charcoalized.
concentrated and the residue stripped off with ethanol. The residue was taken up in 80 1
of ethanol. and 4.3 1 of concentrated hydrochloric and 4 kg of 5%Pd/C (50% wet) were
added. The mixture was subjected to catalytic hydrogenolysis with hydrogen gas for 5.0
hours at 35-40°C at 0.5 kg/sq.cm of pressure, cooled and the catalyst was filtered. The
filtrate was charcoalized and subjected to distillation at 45-50°C under reduced pressure
to remove ethanol. The residue was repeatedly stripped with dichloromethane until the
water content of the residue was below ].0 %. The residue was finally degassed and
stripped with acetone. To the residue thus obtained was added acetone and the mixture
stirred at 25-30°C for 30 minutes and seeded with pure quinapril hydrochloride. The mass
was cooled to 5-l0°C then filtered and dried at 45-50°C in vacuum oven at 45°C to
obtain 8.3 kg of compound of formula I (wherein X and Y are H) associated with a
solvate of acetone, having purity 93.51% as determined by HPLC and 0.3% of compound
of formula A, 2.16% of compound of formula B, and 1.87% compound of formula C.
The HPLC analysis was carried out by using HPLC method as described above.

19
19


We claim
1. A process for preparation of substantially pure l;2.3.4xtetrahydroisoquinoline-3-
carboxylic acid, compound of formula 1 or its pharmaceutically acceptable salt
comprising:
a. subjecting compound of formula II or acid addition salt thereof to hydrogenolysis in
aqueous medium in the presence of an acid;

wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl
group and X and Y are independently selected frrom the group consisting of
hydrogen,(C1-C3)-alkyl or 0-(C1-C3)-alkyl or x and y can be linked together
to form a cyclic group -O(CH2)n-O, wherein n = 1 or 2,
b. extracting the product from the reaction mixture wjt]-, Water immiscible organic
solvent to form an organic extract.
2. The process as claimed in claim ], wherein the compound of formula I or its solvate is
isolated as a pharmaceutically acceptable salt thereof by removing the solvent from
said organic extract.
3. The process as claimed in claim I. wherein X and Y both are H.
4. The process as claimed in claim 1, wherein X and Y both are OCH3-
20

5, The process as claimed in claiml. wherein the resultarit substantially pure 1.2,3.4-
tetrahydroisoquinolineo-carboxylic acid, compound of formula I is substantially free
of impurities represented by formulae A. B and C:

and solvates or salts thereof.
6. The process as claimed in claim 5, wherein the resultant substantially pure 1,23.4-
tetrahydroisoquinoline-3-carboxylic acid, compound ot formula I or
pharmac-eutically acceptable salts thereof contains a compound of formula A in less
than 0.5%. a compound of formula B .in less than 0.5% and compound of formula C
is in non-detectable amount as measured by HPLC analysis.
7. The process as claimed in claim 5. wherein the resultant substantially pure 1,2,3,4-
21

tetrahydroisoquinoline-3-carboxylic acid, compound of formula 1 or
pharmaceutically acceptable salts thereof contains a compound of formula A in less
than 0.2%. a compound of formula B in less than 0.2% and compound of formula C
is in non-detectable amount as measured by HPLC analysis.
8. The process for industrial scale preparation of substantially pure 1,2,3.4-
telrahydroisoquinoline-3-carboxylic acid compound of formula 1 or pharmaceutically
acceptable salt thereof comprising
a) subjecting compound of formula II or acid addition salt thereof to hydrogenolysis
in aqueous medium in the presence of an acid;

wherein Et represents ethyl group; Ar represents phenyl or substituted phenyl
group and X and Y are independently selected from the group consisting of
hydrogen. (C1-C3)-alkyl or O-(C1-C3)-alky] or X and Y can be linked together
to form a cyclic group -0(CH2)n-O-. wherein n =l or 2.
b) extracting the product from the reaction mixture with water immiscible organic
solvent and
c) isolating the compound of formula I or its solvate as a pharmaceutically
acceptable salt thereof.
9. The process as claimed in claim 8, wherein X and Y both are H.
22

10. The process as claimed in claim 8, wherein X and Y both are OCH3.

11. The process as claimed in claim 8, wherein the resultant substantially pure
1.2.3;4-tetrahydroisoquinoline-3-carboxylic acid, compound of formula 1 is
substantially free of impurities represented by formulae A, B and C:

12. The process as claimed in claim 11, wherein the resultant substantially pure 1.2.3,4-
tetrahydroisoquinoline-3-carboxylic acid compound of formula 1 or
pharmaceutically acceptable salts thereof contains impurity A in less than 0.5%.
impurity B in less than 0.5% and impurity C in non-detectable amount as measured by
HPLC analysis..
13. The process as claimed in claim 11, wherein the resultant substantially pure 1.2.3,4-
23

tetrahydroisoquinolineo-carboxylic acid compound of formula I or pharmaceutically
acceptable salts thereof contains impurity A in less than 0.2%. impurity B in less
than 0.2% and impurity C in non-detectable amount as measured by HPLC analysis.
24
Dated this 12th day of October, 2006