FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
THE PATENTS RULES, 2003
COMPLETE
Specification
(See section 10 and rule 13)
A PROCESS FOR THE PREPARATION OF 4-FLUOROISOQUINOLINE
INNOVASSYNTH TECHNOLOGIES (INDIA) LTD.,
an Indian Company
of Paragon Condominium, 3rd floor, Pandurang Budhkar Marg,
Mumbai 400 013, Maharashtra, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Title:
An Imporoved Process For The Preparation Of 4-Fluoroisoquinoline
Field Of Invention
This invention relates to an improved process for the preparation of 4-Fluoroisoquinoline.
Definitions
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
"Ammonolysis" means a process analogous to hydrolysis, but in which ammonia takes the place of water, resulting in attachment of (or replacement by) an amino group, NH 2.
"Bromination" means a chemical reaction that replaces a hydrogen atom with Bromine.
"Carcinogen" means a chemical known or believed to cause cancer in mammals.
"GC" means Gas Chromotography.
Background Introduction
4-Fluoroisoquinoline ( CAS No.394-67-2), molecular formula C9H6FN is an important intermediate in fine chemical and pharmaceutical industry.
2

Chemical structure:

4-Fluoroisoquinoline
The known processes for preparation of 4-Fluoroisoquinoline
involve multiple purification steps, making them uneconomical.
This invention relates to the process for preparation of 4-Fluoroisoquinoline with improved purity and improved yield. Furthermore this process is carried out at low temperature making it less energy intensive.
Prior Art
The known process for prepartion of 4-Fluoroisoquinoline involves brominating isoquinoline hydrobromide salt to get 4-bromoisoquinoline which on ammonolysis results in 4-aminoisoquinoline.
4-Aminoisoquinoline on further reaction with fluoroboric acid and sodium nitrite results in fluoroborate diazonium salt, which on decomposition gives 4-fluoroisoquinoline.
However the bromination of isoquinoline hydrobromide salt is carried out at 180- 190°C,which is undesirable and makes the process very energy intensive.
Secondly, Benzene which is known to be highly carcinogenic, is used as a solvent in the process of the prior art.
3

Summary
The present invention provides for an improved process for the preparation of of 4-Fluorisoquinoline wherein the drawbacks of prior art processes mentioned hereinabove are minimized.
This invention provides an improved process for prepartion of 4-Fluorisoquinoline in which bromination of hydrobromide salt is carried out at low temperature and hence by a less energy intensive manner.
Further object of this invention is to provide a safer method for preparation of 4-Fluorisoquinoline using a non-carcinogenic solvent.
Another object of this invention is to provide an economical process for preparation of 4-Fluorisoquinoline with better purity and better yield.
In accordance with this invention there is provided an improved process for prepartion of 4-Fluorisoquinoline, said process comprising the following steps:
step (a) preparing hydrobromide salt of Isoquinoline by treating isoquinoline with Hydrobromic acid, followed by isolation of said salt by filtration
step (b) subjecting isolated isoquinoline hydrobromide salt to bromination, to result in a brominated reaction mixture
step(c) adding water to the brominated reaction mixture resulting in the formation of an aqueous layer and a charred sticky organic mass
4

step(d) separating the organic mass and treating the aqueous layer with a first water immiscible solvent and separating the water immiscible solvent solution from the aqueous layer
step(e) combining the water immiscible solvent solution with the organic mass to form a mixture
step(f) decanting the mixture to obtain a supernatant and settled organic mass;
step(g) removing and treating said supernatant with Hydrobromic acid to result in a solution of 4-bromoisoquinoline
step(h) distillating the solution of 4—bromoisoquinoline with to obtain 4-bromoisoquinoline residue
step(i) ammonolysis of 4-bromoisoquinoline residue to obtain 4-aminoisoquinoline followed by isolation using a second solvent
step (j) reacting said isolated 4-aminoisoquinoline with fluoroboric acid and sodium nitrite to obtain a diazonium fluoroborate salt
step (k) decomposing the diazonium fluoroborate salt with a third solvent to obtain crude 4-Fluoroisoquinoline and
step(l) purifying the crude 4-Fluoroisoquinoline with a fourth solvent followed by further purification with Hydrochloric acid.
5

Typically, bromination is carried out at a temperature in the range of 125 to l30°C.
Typically, Hexane is used as the first water immiscible solvent.
Typically, 5% Hydrobromic acid is used for purification of 4— bromoisoquinoline solution.
Typically, ammonolysis reaction is carried out in an autoclave at a temperature in the range of 155-160°C.
Typically, Dichloromethane is used as the second solvent.
Typically, isolation of 4-aminoisoquinoline is carried out at a temperature in the range of 0 to 5 °C.
Typically, decomposition of diazonium fluoroborate is carried out at a temperature in the range of 45-70°C.
Typically, the third solvent is Toluene.
Typically, a mixture of Hexane and Ethylacetate is used as the fourth solvent
Typically, the fourth solvent consists of Hexane and Ethylacetate in the ratio 8:2.
Typically, 1% aqueous Hydrochloric acid is used for purification of crude crude 4-Fluoroisoquinoline.
6

Detailed Description
Synthetic Reaction Parameters
For step (b):
This step is carried out at temperature ranging between 115 to 150 °C, more
preferably 120 to 135 °C.
For step (d):
Typically, Hexane , is used as solvent for this step.
For step (g):
Typically hydrobromic acid is used for further purification of 4-
Bromoisoquinoline.
For step(i):
Ammonalysis is carried out at temperature in the ranging between
130 to 180°C, more preferably 155 to 160°C.
Typically, Dichloromethane is used for separation of the amino compound.
Isolation of 4-aminoisoquinoline using Dichloromethane is carried out at
temperature ranging between -10 to 30°C more preferably 0 to 5 °C.
For Step(k):
The decomposition step is carried out temperature ranging between 35 to
80°C, more preferably at 45 to70°C.
Typically, Toluene is used for decomposing the fluoroborate complex.
For step (1):
Typically, Hexane :Ethyl Acetate and 1% aqueous Hydrochloric acid is
used for purification
7

Details Of The Processes
In accordance with this invention, there is provided a process for the synthesis of 4-Fluoro-Isoquinoline comprising the steps: ( Scheme-1)
Br


NH3 A


Aq. HBr .N

SCHEME-1
Step (a) preparing hydrobromide salt of Isoquinoline by treating isoquinoline with Hydrobromic acid, followed by isolation of said salt by filtration.
Step (b) subjecting isolated isoquinoline hydrobromide salt to bromination, to result in a brominated reaction mixture.
This step is typically carried out at temperature ranging between 120-135 °C by drop wise addition of bromine.
step(c) adding water to the brominated reaction mixture resulting in the formation of an aqueous layer and a charred sticky organic mass This step is typically carried out at 80 to 100 ° C.
8

step(d) separating the organic mass and treating the aqueous layer with a first water immiscible solvent and separating the water immiscible solvent solution from the aqueous layer;
step(e) combining the water immiscible solvent solution with the organic mass to form a mixture;
step(f) decanting the mixture to obtain a supernatant and settled organic mass;
step(g) removing and treating said supernatant with Hydrobromic acid to result in a solution of 4-bromoisoquinoline;
step(h) distillating the solution of 4-bromoisoquinoline with to obtain 4-bromoisoquinoline residue
Typically, Hexane, is used as the first water immiscible solvent for this step.
Typically 5 % Hydrobromic acid solution is used for purification of 4-Bromoisoquinoline.
step(i) ammonolysis of 4-bromoisoquinoline residue to obtain 4-
aminoisoquinoline followed by isolation using a second solvent
Ammonalysis is carried out at temperature in the range of 155-
160°C.
Typically, Dichloromethane is used for separation of the amino compound.
9

Isolation of 4-aminoisoquinoline is typically carried out at temperature in the range of 0 to 5 °C.
step (j) reacting said isolated 4-aminoisoquinoline with fluoboric acid and
sodium nitrite to obtain a diazonium fluoroborate salt
step (k) decomposing the diazonium fluoroborate salt with a third solvent
to obtain crude 4-Fluoroisoquinoline.
The decomposition step is carried out temperature in the range of 45-70°C.
Typically, Toluene is used for decomposing the fluoroborate complex.
step(l) purifying crude 4-Fluoroisoquinoline with a fourth solvent followed
by further purification by treatment with Hydrochloric acid.
Typically, mixture of Hexane:Ethyl Acetate in the ratio of 8:2 is used as the
fourth solvent.
Typically, 1% aqueous Hydrochloric acid is used for purification.
The contents are then subjected to single vacuum distillation resulting in
pure 4-Fluoro-Isoquinoline.
The following specific examples are presented to illustrate the preferred mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the forgoing description.
Examples
Preparation of 4-BomoisoquinoIine
Isoquinoline (1280g, 9.92moles) was added to a solution of 48% hydrobromic acid(1320 ml), under stirring at 25-30°
10

The reaction mass was heated to 60- 65 0°C and 30% of total volume of
water was distilled applying a vacuum of 100mm of Hg. The reaction mass
was cooled to 10°C.
The precipitated product was filtered. Bromine 1222 g (7.637 moles) was
added drop wise over a period of two hours to the dry 1458g of
isoquinoline hydrobromide salt, under stirring, below 70°C.
The reaction mass was heated to 130° C and temperature was maintained
in the range of 125 to 130°C for 24 hours. Subsequently this mass was
cooled to 25°C.
A second lot of bromine(610gms) was added drop-wise over a period two hours below 70°C. The reaction mass was heated at 125-130°C for 48 hours. Temperature of reaction mixture was lowered to 100°C.
Water(2600ml) was added to this reaction mixture at 80-100°C. Temperature was further lowered to 50°C and pH was adjusted to 8.0 to 8.5 with 20% NaOH solution. Organic layer was separated and aqueous layer was extracted with 2X6 Litres of Hexane. The main organic layer and Hexane layers were combined and stirred for one hour.
The content was allowed to settle. The lower charred sticky mass was removed. The Hexane layer was further stirred with 5 % Hydrobromic acid solution(67.1 g). The resulting layers were separated and Hexane layer was distilled further to get 890 g of 4- bromoisoquinoline .
This crude material was again distilled at 120 - 125 °C at 4 mm Hg of vacuum to give 810 g of 4-bromo-isoquinoline.
11

Preparation of 4-Aminoisoquinoline
4-bromoisoquinoline 810g(3.88 moles) and 48.5g of copper sulphate pentahydrate were added to 25% aqueous ammonia solution(2630 ml) in autoclave. The contents of the autoclave were heated under stirring at 155°C. The temperature was maintained between 155 - 160°C for 8 hours at the Pressure in the range of 16- 25 Kg/cm .
A sample was taken to check the completion of the reaction by GC. After completion of the reaction, the mass was cooled to 25°C. After releasing the pressure from the autoclave, the reaction mass was extracted with 3 x 2000 ml of dichloromethane. All the dichloromethane layers were combined and washed with 6000 ml of water. After separation of the layers, the organic layer was distilled off to remove 75% of dichloromethane.
The remaining contents were cooled to 0-5°C. The product was filtered and dried under vacuum at 30°C. The dried product was then mixed with 1000 ml of Hexane at 25-30°C, and was stirred for one hour followed by and filtration in vacuum.
This process was repeated once and the product was filtered and dried at 25-30°C for 4-5 hours to give 420 g of 4-aminoisoquinoline.
Preparation of 4-Fluoro- Isoquinoline
4-Aminoisoquinoline (420g, 2.909moles) was added to 1890 ml of 40% fluoroboric acid under stirring at 25-30°C. The reaction mixture was stirred to get a clear solution.
12

Cool the solution to -10 to -15 C and 231 g (3.346 moles) of sodium nitrite was added in 20 lots with stirring between -10 to -15°C over period of 1 hr. After complete addition of sodium nitrite, stir the resulting mixture for 1 hourat-15°C.
The diazonium fluoroborate salt was filtered and washed with 2 x 500 ml of chilled diisopropyl ether and suck dried. Diazonium fluoroborate salt was added to 2000 ml of toluene under stirring and heated to 45 -50°C. The temperature increases to 60-70°C. After completion gaseous evolution ceases, the upper toluene layer was separated.
Lower oily layer was made basic with 5000 ml of saturated sodium bicarbonate solution (pH - 7.5 to 8.0) The product liberated was extracted with 3 x 1500 ml of 8:2 mixture of hexane and ethyl acetate.
Layers are separated and the organic layer was washed twice with 200 ml of 1% aqueous hydrochloric acid solution till absence of isoquinoline. Layers are separated and the organic layer was distilled off to give 110 g crude product.
This crude 4-fluoroisoquinoline was distilled at 0.2 mm Hg of vacuum at 70-75°Cto give lOOg of 4-fluoroisoquinoline.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention.
13

These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
The isolation and purification procedures described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or preparative chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can, of course, also be used.
14


We Claim:
1. A process for the preparation of 4-Fluoroisoquinoline, said process
comprising the following steps:
Step (a) preparing hydrobromide salt of Isoquinoline by treating
isoquinoline with Hydrobromic acid, followed by isolation of said salt by
filtration;
Step (b) subjecting isolated isoquinoline hydrobromide salt to bromination,
to result in a brominated reaction mixture;
step(c) adding water to the brominated reaction mixture resulting in the
formation of an aqueous layer and a charred sticky organic mass;
step(d) separating the organic mass and treating the aqueous layer with a
first water immiscible solvent and separating the water immiscible solvent
solution from the aqueous layer;
step(e) combining the water immiscible solvent solution with the organic
mass to form a mixture;
step(i) decanting the mixture to obtain a supernatant and settled organic
mass;
step(g) removing and treating said supernatant with Hydrobromic acid to
result in a solution of 4-bromoisoquinoline;
step(h) distilling the solution of 4-bromoisoquinoline with to obtain 4-
bromoisoquinoline residue;
step(i) ammonolysis of 4-bromoisoquinoline residue to obtain 4-
aminoisoquinoline followed by isolation using a second solvent;
step (j) reacting said isolated 4-aminoisoquinoline with fluoroboric acid
and sodium nitrite to obtain a diazonium fluoroborate salt;
step (k) decomposing the diazonium fluoroboric salt with a third solvent
to obtain crude 4-Fluoroisoquinoline; and
15

step(l) purifying the crude 4-Fluoroisoquinoline with a fourth solvent followed by further purification with Hydrochloric acid.
2. A process as claimed in Claim 1, wherein bromination is carried out at a temperature in the range of 125-130°C.
3. A process as claimed in Claim 1, wherein said first water immiscible solvent is Hexane.
4. A Process as claimed in claim 1, wherein Hydrobromic acid is used in a 5% concentration.
5. A process as claimed in Claim 1, wherein ammonolysis reaction is carried out in an autoclave at a temperature in the range of 155-160°C.
6. A process as claimed in Claim 1, wherein said second solvent is Dichloromethane.
7. A process claimed in Claim 5, wherein isolation of 4-
aminoisoquinoline is carried out at a temperature in the range of 0 to
5°C.
8. A process as claimed in Claim 1, wherein, the decomposition of diazonium fluoroborate is carried out at a temperature in the range of 45 to 70°C.
9. A process as claimed in Claim 1, wherein, the third solvent is Toluene.
16

10. A process as claimed in Claim 1, wherein, the fourth solvent is a mixture of Hexane and Ethylacetate.
11. A process as claimed in Claim 9, wherein, said fourth solvent consists of Hexane and Ethylacetate in the ratio 8:2.
12. A process as claimed in claim 1, wherein, aqueous Hydrochloric acid is used in a 1% concentration.
Dated this 29th day of March,2006
MOHAN DE WAN
OF R.K. DEWAN & COMPANY
APPLICANTS' PATENT ATTORNEY