FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Tipiracil hydrochloride of Formula (I) and intermediates thereof.



BACKGROUND OF THE INVENTION

Tipiracil hydrochloride is chemically known 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) of Formula (I). Tipiracil hydrochloride has an inhibitory action on human thymidine phosphorylase and an enhancing action on the antitumor effect of Trifluridine. An antitumor agent “TAS-102” composed of a mixture of Trifluridine and Tipiracil hydrochloride with a molar ratio of 1 to 0.5. Combination of Trifluridine and Tipiracil hydrochloride was approved in 2016 by EMEA and also approved in 2015 by USFDA. It is marketed in the form of oral tablets under the brand name Lonsurf® by Taiho Pharma. U.S. Pat. No. 5,744,475 discloses Tipiracil and its pharmaceutically acceptable salts.

U.S. Pat. No. 5,744,475 discloses a process for the preparation of Tipiracil hydrochloride of Formula (I) by reaction of 6-(chloromethyl)uracil of Formula (II) with sulfuryl chloride in acetic acid to produce 5-chloro-6-chloromethyluracil of Formula (III). Further, compound of Formula (III) is reacted with 2-iminopyrrolidine of Formula (IV) in the presence of sodium ethoxide base in N,N-dimethylformamide solvent followed by treating with HCl to produce Tipiracil Hydrochloride of Formula (I).

The synthetic procedure is illustrated as in Scheme-I below:



The process disclosed in U.S. Pat. No. 5,744,475 suffers from the following disadvantages outlined below:

Step-I: chlorination on 6-(chloromethyl)-2,4(1H,3H)-pyrimidinedione(i) Purity of compound of Formula (III) obtained in step-I is 95% (Reference: Referential Example-01 of US '475);(ii) Yield of compound of Formula (III) obtained in step-I is 92%. (Reference: Referential Example-01 of US '475);

Step-II: coupling of 5-chloro-6-chloromethyluracil with 2-iminopyrrolidine hydrochloride.(i) No purity/impurity profile is disclosed in the process.(ii) For isolation of the product, solvent distillation process is required, which is not capable to remove impurities.(iii) Overall yield of Tipiracil hydrochloride produced with the above disclosed process is only 38% (Reference: Example-06)(iv) Purity of Tipiracil Hydrochloride compound of Formula (I) obtained in step-II is 95%.

Shingo Yano et al., (Bioorganic&Medicinal Chemistry2004, 12, 3443-3450) disclosed a process for the preparation of Tipiracil hydrochloride of Formula (I) by reaction of 4-chlorobutanenitrile of Formula-(V) with ammonia in methanol to produce 2-iminopyrrolidine hydrochloride of Formula (IVa), which is further reacted with 5-chloro-6-chloromethyluracil of Formula (III) in presence of 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) base followed by treating with Aq.HCl to produce Tipiracil HCl of Formula (I).

The synthetic procedure is illustrated in Scheme-II as below:



The process disclosed inBioorganic&Medicinal Chemistry2004, 12, 3443-3450 suffers from the following disadvantages outlined below:

Step-I: Synthesis of 2-iminopyrrolidine hydrochloride by using 4-chlorobutyro nitrile and ammonia(i) This step performed at temperature 100-120° C. in a sealed tube under pressure of ammonia, which is not viable in commercial scale.(ii) Expensive 4-chlorobutyronitrile of Formula (V) is used in the process which is not viable on commercial scale.(iii) No purity/impurity profile is disclosed in the process.

Step-II: Coupling of 5-chloro-6-chloromethyluracil with 2-iminopyrrolidine hydrochloride(i) Expensive reagent DBU is used in the process which is not viable on commercial scale.(ii) Impurity profile is not disclosed in the process.(iii) Purity of Tipiracil Hydrochloride compound of Formula (I) obtained in step-II is 95%. (Reference: page no 3450 and paragraph: 5.1.24)

Petersen et al., (Chemische Berichte,90, 909-21; 1957) and Shridhar et al., (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry,1985, 24B(6), 693-4) disclosed a process for the preparation of 2-iminopyrrolidine hydrochloride of Formula (IVa) by reaction of 2-pyrrolidinone of Formula (VI) with dimethyl sulfate in benzene to produce 2-methoxy-1-pyrroline of Formula (VII), which is further reacted with ammonium chloride in ethanol to produce 2-iminopyrrolidine hydrochloride of Formula (IVa).

The synthetic procedure is illustrated in Scheme-III as below:



The process disclosed inChemische Berichte,90, 909-21; 1957 andIndian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry,1985, 24B(6), 693-4 suffers from the following disadvantages outlined below:(i) Class-1 solvent Benzene (carcinogenic solvent) is used in the process;(ii) No purity/impurity profile is disclosed in the process.(iii) Purification method is not given.

Hence, there exists a need to have simple, scalable, easy to handle and cost effective process for the preparation of Tipiracil HCl of Formula (I) and intermediate thereof with high chemical purity and high yield.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of Tipiracil HCl of Formula (I) and intermediate thereof with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of Tipiracil HCl of Formula (I),

comprising the steps of:a) reacting 5-chloro-6-chloromethyluracil of Formula (III),

with 2-iminopyrrolidine hydrochloride of Formula (IVa)

in presence of sodium methoxide in a solvent to produce Tipiracil free base of Formula (Ia).

b) treating the Tipiracil free base of Formula (Ia) with hydrochloric acid to produce Tipiracil HCl of Formula (I).c) purifying the Tipiracil HCl of Formula (I) from a ketone solvent.wherein the obtained Tipiracil HCl of Formula (I) hasa) more than 99.5% of purity; andb) more than 65% of overall yield.

The present invention further provides a process for preparation of 5-chloro-6-chloromethyluracil of Formula (III),


comprising the steps of:a) reacting 6-(chloromethyl)uracil of Formula (II),

with sulfuryl chloride in the presence of acetic acid to produce 5-chloro-6-chloromethyluracil of Formula (III).b) purifying the 5-chloro-6-chloromethyluracil of Formula (III) from a suitable solvent.

The present invention further provides a process for preparation of 2-iminopyrrolidine hydrochloride of Formula (IVa),


comprising the steps of:a) reacting 2-Pyrrolidone of Formula (VI),

with dimethyl sulfate to produce 2-methoxy-1-pyrroline of Formula (VII)

b) reacting the compound of Formula (VII) in-situ with ammonium chloride in a suitable solvent to produce 2-iminopyrrolidine hydrochloride of Formula (IVa).

c) purifying the 2-iminopyrrolidine hydrochloride of Formula (IVa) from a solvent selected from alcohol or ketone or a mixture thereof.

