DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Tipiracil. More, particularly the present invention relates to improved process for the preparation of Tipiracil in pure form and Crystal II of Tipiracil HCl.
BACKGROUND OF THE INVENTION
Tipiracil hydrochloride is chemically described as 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride or 2,4(1H,3H)-pyrimidinedione, 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-, hydrochloride (1:1), having the structural Formula I.

Tipiracil hydrochloride, a thymidine phosphorylase inhibitor and trifluridine, an antineoplastic thymidine-based nucleoside analogue, is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

There are many prior art the processes which discloses the preparation of Tipiracil hydrochloride such as US5,744,475, nucleosides, nucleotides, and nucleic acids, 24 (5-7): 367 - 373, (2005) and CN103980253 B. However, prior art processes are silent about the purity of the product.

Tipiracil hydrochloride known to exist in three different polymorphic forms, viz. Crystal I, Crystal II, and Crystal III as disclosed in WO2014203877.

US 5,744,475 disclose a process for the preparation of Tipiracil in example-6, wherein the process involves distillation of aqueous solution of Tipiracil hydrochloride followed by addition of ethanol. Applicant found that following this process yields Crystal II of Tipiracil HCl. As this process warrants complete distillation of aqueous solution to dryness level this process is not suitable in manufacturing point of view.

US 9,527,833 B2 discloses a process for the preparation of Crystal II of (Tipiracil hydrochloride) in which the Crystal II is obtained by dissolving Tipiracil hydrochloride at 60° C and adding into cooled ethanol. The said process is commercially not suitable as the process yields mixture of polymorphs.

Considering the importance of Tipiracil hydrochloride in the pharmaceutical field, the present inventors focused in the preparation of Tipiracil hydrochloride, in particular Crystal II of Tipiracil hydrochloride and identified an improved process for the same.

Therefore, it would be desirable to provide a simplified process which is safe and can also be carried out advantageously on an industrial scale and which supports an active compound in high yield and high purity in pharmaceutically acceptable quality.

SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided an improved process for the preparation of Crystal II of Tipiracil hydrochloride comprising steps of:
a) obtaining a solution of Tipiracil in a suitable acid in presence of water;
b) adding HCl to the reaction mass of step (a) or vice versa; and
c) isolating Crystal II of Tipiracil hydrochloride.
In another aspect, the invention provides an improved process for the purification of Tipiracil which comprises the steps of:
a) treating of the Tipiracil with a suitable acid in a suitable solvent;
b) neutralizing the acid addition salt of Tipiracil with a suitable base; and
c) isolating highly pure Tipiracil.
In yet another aspect the invention provides an improved process for the preparation of Crystal II of Tipiracil hydrochloride comprising steps of:
a) treating acid addition salt of Tipiracil in suitable acid in a suitable solvent;
b) adding HCl to the reaction mass of step (a); and
c) isolating Crystal II of Tipiracil HCl.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: shows the X-ray powder diffraction pattern of Tipiracil Base.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment of the present invention provides an improved process for the preparation of Crystal II of Tipiracil hydrochloride comprising steps of:
a) providing a solution of Tipiracil in a suitable acid in presence of water;
b) adding HCl to the reaction mass of step (a) or vice versa; and
c) isolating Crystal II of Tipiracil hydrochloride.
In another embodiment of the present invention, the step a) solution of Tipiracil is obtained by 1) dissolving Tipiracil in suitable acid such as acetic acid, formic acid and the like that may optionally contain water; 2) to the reaction of mixture of Tipiracil in water, acid was added; 3) Tipiracil acid addition salt is dissolved in an acid or in water or mixture of water and acetic acid. The dissolution can be achieved at about 20° C to 60° C. The step (a) solution may optionally contain other organic solvent that does not alter the scope of the invention.
In another embodiment of the present invention, the HCl used in step (b) is in the gaseous form or dissolved in a solvent. Preferably aqueous HCl is employed in the reaction.
In yet embodiment of the present invention, the Crystal II of Tipiracil hydrochloride is isolated from the reaction mass by conventional methods such as; by addition of suitable solvent; by cooling the reaction mass; by distilling the solvent or by combination of any of the said method in any order.
In another embodiment of the present invention provides an improved process for the purification of Tipiracil which comprises the steps of:
a) treating of the Tipiracil with a suitable acid in a suitable solvent;
b) neutralizing the acid addition salt of Tipiracil obtained in step a) with a suitable base; and
c) isolating highly pure Tipiracil.
In yet another embodiment of the present invention suitable acid is selected from the group comprising of maleic acid, acetic acid, propionic acid and formic acid, adipic acid, benzoic acid, fumaric acid, malic acid, malonic acid, mandelic acid, succinic acid, tartaric acid, salicyclic acid, hydrobromic acid, phosphoric acid, sulphuric acid and nitric acid. More preferably maleic acid and acetic acid.
In yet another embodiment of the present invention suitable solvent is selected from the group comprising of water, alcohols, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof.
In another embodiment of the present invention alcohol solvents include ethanol, n-propanol, 2-propanol and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate, ketones include acetone, methyl ethyl ketone ,methyl isobutyl ketone and the like, ethers include tetrahydrofuran, MTBE and the like, polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, and N-methylpyrrolidone. More preferably water.
In yet another embodiment of the present invention, suitable base is selected from the group comprising of inorganic base or organic base such as carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals and the like, carbonates such as sodium carbonate, potassium carbonate, ammnonium carbonate, cesium carbonate. Organic base is selected from the group comprising of diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-butylamine, piperidine, pyridine and N,N-diethylaniline. More preferably potassium carbonate.
In yet another embodiment, the present invention provides Tipiracil hydrochloride having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
Tipiracil HCl obtained according to the present invention is converted in to Crystal III of Tipiracil HCl as shown in the examples.
The staring material i.e. Tipiracil used in the present invention is prepared by the method known in the literature.
The prior art process fails to provide a robust process for preparation of Crystal II of Tipiracil hydrochloride in pure form on the contrary the Crystal II of Tipiracil hydrochloride obtained according to the present invention is robust and consistently produce the Crystal II in significantly pure form.
In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

EXAMPLES
Example 1: Preparation of Crystal II of Tipiracil Hydrochloride
To the solution of acetic acid (100 ml) in water (200 mL) Tipiracil base (100 g) was added at room temperature. To the resulting reaction HCl solution (90 ml) was added at room temperature. The reaction mixture was stirred and acetone (1000 ml) was added. The resulting solid material was filtered and washed with acetone then suck dried to obtain Crystal II of Tipiracil hydrochloride. (100 gm).
Example 2: Preparation of Crystal II of Tipiracil hydrochloride
To the solution of water (50 ml) and acetic acid (25 ml) Tipiracil (25 gm) was added at room temperature. The reaction mixture was filtered and filtrate was distilled out under reduced pressure. Hydrochloric acid (22.5 ml) was added to the residue at room temperature. Acetone was added and allowed to stir at room temperature for 2-3h. Solid was filtered and washed with acetone to obtain Crystal II of Tipiracil hydrochloride. (18 gm).
Example 3: Process for the purification of Tipiracil base
To the solution of 5-Chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione (100 gm) (HPLC purity : <98) in methanol (1000 ml), maleic acid (52.58 gm) in methanol was added with heating. The reaction mixture was cooled, stirred; solid is filtered and washed with methanol. The obtained wet solid was stirred with a mixture of methanol and Water (1:1) and heated till clear solution. Activated carbon was added to the above solution and heated for 1h. The solution was filtered through hyflo bed. To the filtrate, aqueous solution of potassium carbonate was added and stirred. The precipitates were filtered and washed with methanol, which was further purified with a mixture of methanol and water (1:1) to obtain Tipiracil base (85 gm). (HPLC purity >99.5).
Example 4: Preparation of Crystal III of Tipiracil hydrochloride
Tipiracil hydrochloride Crystal II (15 gm) was heated in ethanol (75 ml) with stirring. The reaction mixture was cooled to room temperature and allowed to stir at room temperature. The solid was filtered and washed with ethanol to obtain Crystal III of Tipiracil hydrochloride. (12gm).
Example 5: Preparation of Crystal III of Tipiracil hydrochloride
Tipiracil hydrochloride Crystal II (20 gm) was stirred in ethanol (100 ml) at room temperature. The reaction mixture was filtered and washed with ethanol to obtain Crystal III of Tipiracil hydrochloride. (17 gm).
Example 6: Preparation of Crystal III of Tipiracil hydrochloride
Tipiracil (10 gm) was stirred in acetic acid (40 ml) at room temperature. The reaction mixture was filtered and hydrochloric acid (5 ml) was added followed by addition of ethanol (100ml). The mixture was allowed to stir for 2-3 hours .Solid was filtered and washed with ethanol to get Tipiracil hydrochloride Crystal III as a white solid. (10 gm).
,CLAIMS:WE CLAIM:
1. A process for the preparation of Crystal II of Tipiracil hydrochloride comprising steps of:
a) providing a solution of Tipiracil in a suitable acid in presence of water;
b) adding HCl to the reaction mass of step (a) or vice versa; and
c) isolating Crystal II of Tipiracil hydrochloride.

2. A process as claimed in claim 1 wherein suitable acid is selected from acetic acid and formic acid.

3. A process for the purification of Tipiracil which comprises the steps of:
a) treating Tipiracil with a suitable acid in a suitable solvent;
b) neutralizing the acid addition salt of Tipiracil obtained in step a) with a suitable
base; and
c) isolating Tipiracil.

4. The process as claimed in claim 3 which comprises isolation of acid addition salt of Tipiracil followed by neutralization.

5. The process as claimed in claim 3, wherein suitable acid is selected from the group comprising of maleic acid, acetic acid, propionic acid and formic acid, adipic acid, benzoic acid, fumaric acid, malic acid, malonic acid, mandelic acid, succinic acid, tartaric acid, salicyclic acid, hydrobromic acid, phosphoric acid, sulphuric acid and nitric acid.

6. The process as claimed in claim 3, wherein suitable solvent is selected from group comprising of ethanol, n-propanol, 2-propanol ,butanol, ethyl acetate, n-propyl acetate, isopropyl acetate,. acetone, methyl ethyl ketone , methyl isobutyl ketone, tetrahydrofuran, MTBE , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, and N-methylpyrrolidone.

7. The process as claimed in claim 3, wherein suitable base is selected from group comprising of sodium carbonate, potassium carbonate, ammnonium carbonate, cesium carbonate, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-butylamine, piperidine, pyridine and N,N-diethylaniline.

Dated this 28th day of June, 2018
Dr. Subramaniam Ganesan