WO2019002407A1

WO2019002407A1 - Process for the preparation of tipiracil hydrochloride

Info

Publication number: WO2019002407A1
Application number: PCT/EP2018/067322
Authority: WO
Inventors: Abhay Subodhbhai MAHETA; Ankur Amrutlal KANERIA; Kapil Dhanjibhai BHESANIYA; Bhavesh Laljibhai SAVALIYA; Joseph Prabahar Koilpillai; Virendra Kumar Agarwal; Rahul Baburao CHAVAN; Mohsin Razakbhai ARABIANI; Kalpesh Ratilal HEDAPARA; Lalit Keshav KATARIYA; Vijay Premajibhai PATEL; Mahesh Kurajibhai THUMMAR; Rahul Harsukhlal BHALODIYA
Original assignee: Amneal Pharmaceuticals Co GmbH
Current assignee: Amneal Pharmaceuticals Co GmbH
Priority date: 2017-06-28
Filing date: 2018-06-27
Publication date: 2019-01-03
Anticipated expiration: 2019-12-28

Abstract

The present invention relates to a process for preparation of tipiracil of formula (I) or salt thereof.

Description

Process for the preparation of tipiracil hydrochloride

Field of Invention

The present invention relates to the novel polymorphs of tipiracil hydrochloride and process for the preparation thereof. The present invention also relates to the process for preparation of tipiracil of formula (I) or salt thereof which involves novel intermediates.

Background of Invention

Tipiracil is an anticancer molecule and indicated for the treatment of patients with metastatic colorectal cancer. Tipiracil is known by chemical name 5-chloro-6-[(2- iminopyrrolidin- 1 -yl) methyl]pyrimidine-2,4-(lH,3H)-dione monohydrochloride or 2,4(1H,3H)- Pyrimidinedione, 5-chloro-6-[(2-imino-l-pyrrolidinyl)methyl]-, hydrochloride (1 : 1). Tipiracil is marketed in USA by Taiho Pharmaceutical Co., Ltd. under trade name LONSURF® which is a combination of tipiracil HC1 and trifiuridine in the form of oral tablet of EQ 6.14MG BASE; 15MG and EQ 8.19MG BASE; 20MG strength. It is represented by following structure.

U.S. patent no. 5,744,475 first disclosed tipiracil HCI and process for its preparation.

Reference example 1 and example 6 of the said patent disclose a method for producing a 5- chloro-6-chloromethyluracil intermediate and tipiracil HCI respectively as shown in scheme 1.

Nucleosides, Nucleotides, and Nucleic Acids, 2005, Vol 24 (5-7), page 367-373, discloses process for the preparation of 6-chloromethyluracil which can be used for the preparation of tipiracil as shown in scheme 2. However, the first step in the route of the oxidation reaction use toxic selenium dioxide, which is a strong irritant.

Synthetic Communications, 2002, Vol 32(6), page 851-855, provides process for the preparation of 6-chloromethyluracil starting from β-diketone as shown in Scheme 3.

Various processes for the preparation of tipiracil HC1 and its intermediates were disclosed in CN103980253, CN104945384, CN106317028, CN104725324, CN105906573 and CN106366073.

The above synthetic processes suffer from one or more drawbacks. For this reason, there is need for the development of novel methods for producing tipiracil hydrochloride. The present application covers novel processes for preparation of tipiracil of formula (I) or salt thereof involving novel intermediates.

The occurrence of different solid forms is possible for some compounds. A single compound can give rise to a variety of solid forms having distinct physical properties. This variation in solid forms can be significant and can result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because solid forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all possible solid forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.

The existence and possible number of solid forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare solid forms of a substance. However, new forms of a pharmaceutically useful compound can provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug can exhibit very different solubility and dissolution rates. The discovery of new solid forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics.

U.S. patent no. 9,527,833 discloses three crystalline form of tipiracil HCl namely Crystal I, Crystal II and Crystal III. It has been reported in the patent that Crystal II of tipiracil HCl is unstable.

CN103788075, CN104744443, CN104945385, CN105859691, CN107216314 are the applications disclosing different polymorphic form of tipiracil HCl and the process for its preparation.

Discovering new polymorphic forms of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, dissolution rate, ease of purification. Such properties may significantly influence the processing, shelf life, and commercial acceptance of a polymorph.

There remains a need to provide new polymorphic forms of Tipiracil HCl and processes for making the new polymorphic forms.

Brief description of the drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of a dimethyl sulfoxide (DMSO) solvate of tipiracil HCl.

Figure 2 is a differential scanning calorimetry (DSC) curve of a dimethylsulfoxide (DMSO) solvate of tipiracil HCl.

Figure 3 is a thermogravimetric analysis (TGA) curve of a dimethylsulfoxide (DMSO) solvate of tipiracil HCl.

Figure 4 is an X-ray powder diffraction (XRPD) pattern of a N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl.

Figure 5 is an X-ray powder diffraction (XRPD) pattern of a N-methyl-2-pyrrolidone

(NMP) solvate of tipiracil HCl.

Figure 6 is an X-ray powder diffraction (XRPD) pattern of crystalline form-A of tipiracil

HCl.

Figure 7 is an X-ray powder diffraction (XRPD) pattern of a Crystal II of tipiracil HCl produced as per example 14.

Figure 8 is an X-ray powder diffraction (XRPD) pattern of amorphous tipiracil HCl. Figure 9 is an X-ray powder diffraction (XRPD) pattern of amorphous solid dispersion of tipiracil HCl together with polyvinylpyrrolidone (PVP). Figure 10 is an X-ray powder diffraction (XRPD) pattern of amorphous solid dispersion of tipiracil HC1 together with hydroxypropylmethylcellulose (HPMC).

Summary of the Invention

The present invention relates to the novel polymorphs of tipiracil hydrochloride and process for the preparation thereof.

The present invention also relates to the process for preparation of tipiracil of formula (I) or salt thereof which involves novel intermediates.

In first embodiment, the present invention relates to tipiracil HC1 solvate and process for the preparation thereof.

In second embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide

(DMSO) solvate.

In third embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide (DMSO) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 8.0°, 11.6°, 16.0°, 17.0°, 22.5°, 22.7°, 24.0°, 24.3°, 26.4°, 27.5°, 27.9°, 30.1°, 31.6° and 38.1 ± 0.2° 2Θ.

In fourth embodiment, the present invention relates to process for the preparation of tipiracil HC1 dimethylsulfoxide (DMSO) solvate comprising steps of:

a) addition of tipiracil base in dimethylsulfoxide solvent;

b) adding concentrated HC1 in step a; and

c) isolating tipiracil HC1 dimethylsulfoxide solvate.

In fifth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride dimethylsulfoxide (DMSO) solvate and one or more pharmaceutically acceptable excipient.

In sixth embodiment, the present invention relates to tipiracil HC1 , N-dimethylacetamide (DMAc) solvate.

In seventh embodiment, the present invention relates to tipiracil HC1 N, N- dimethylacetamide (DMAc) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 8.9°, 9.0°, 11.6°, 13.0°, 13.7°, 16.5°, 16.7°, 16.9°, 17.0°, 18.7°, 19.2°, 21.2°, 22.3°, 22.4°, 22.8°, 23.5°, 24.3°, 24.4°, 25.6°, 26.1°, 26.3°, 26.6°, 27.9°, 28.2°, 28.6°, 28.7°, 29.1°, 29.4°, 29.7°, 31.0°, 32.1°, 35.3° and 39.6 ± 0.2° 2Θ.

In eighth embodiment, the present invention relates to process for the preparation of tipiracil HC1 N, N-dimethylacetamide (DMAc) solvate comprising steps of:

a) addition of tipiracil base in water;

b) adding concentrated HC1 in step a; c) adding N, N-dimethylacetamide in step b; and

d) isolating tipiracil HC1 , N-dimethylacetamide solvate.

In ninth embodiment, the present invention relates to process for the preparation of tipiracil HC1 N, N-dimethylacetamide (DMAc) solvate comprising steps of:

a) addition of tipiracil HC1 in water;

b) adding N, N-dimethylacetamide in step a; and

c) isolating tipiracil HC1 N, N-dimethylacetamide solvate.

In tenth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride N, N-dimethylacetamide (DMAc) solvate and one or more pharmaceutically acceptable excipient.

In eleventh embodiment, the present invention relates to tipiracil HC1 N-methyl-2- pyrrolidone (NMP) solvate.

In twelfth embodiment, the present invention relates to tipiracil HC1 N-methyl-2- pyrrolidone (NMP) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 7.1°, 8.9°, 11.4°, 11.5°, 12.8°, 13.7°, 14.3°, 16.4°, 16.8°, 17.1°, 17.8°, 18.8°, 19.3°, 19.5°, 21.3°, 21.5°, 22.1°, 23.0°, 23.2°, 23.6°, 24.4°, 24.6°, 25.0°, 25.7°, 26.0°, 26.4°, 27.0°, 27.4°, 27.9°, 28.4°, 29.2°, 29.6°, 30.4°, 31.7°, 32.7°, 33.4° and 38.0 ± 0.2° 2Θ.

In thirteenth embodiment, the present invention relates to process for the preparation of tipiracil HC1 N-methyl-2-pyrrolidone (NMP) solvate comprising steps of:

a) addition of tipiracil HC1 in water;

b) adding N-methyl-2-pyrrolidone in step a;

c) optionally seeding the solution of step b; and

d) isolating tipiracil HC1 N-methyl-2-pyrrolidone solvate.

In fourteenth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride N-methyl-2 -pyrrolidone (NMP) solvate and one or more pharmaceutically acceptable excipient.

In fifteenth embodiment, the present invention relates to crystalline form-A of tipiracil

HC1.

In sixteenth embodiment, the present invention relates to crystalline form-A of tipiracil HC1 characterized by X-ray diffraction pattern having characteristic peaks at about 9.4°, 9.9° and, 10.5± 0.2° 2Θ.

In seventeenth embodiment, the present invention relates to process for the preparation of crystalline form-A of tipiracil HC1 comprising steps of:

a) adding tipiracil HC1 in pre-heated methanol; b) adding water in step a; and

c) isolating crystalline form-A of tipiracil HC1.

In eighteenth embodiment, the present application provides pharmaceutical composition comprising crystalline form-A of tipiracil hydrochloride and one or more pharmaceutically acceptable excipient.

In nineteenth embodiment, the present invention relates to novel process for the preparation of stable Crystal II of tipiracil HC1 comprising steps of:

a) adding tipiracil HC1 in pre-heated ethanol;

b) adding water in step a;

c) slowly evaporating ethanol at room temperature; and

d) isolating Crystal II of tipiracil HC1.

In twentieth embodiment, the present invention provides a process for preparation of tipiracil of formula (I) or salt thereof:

which comprises,

a) chlorinating compound of formula (II) with a chlorinating agent to give compound formula(III)

wherein Ri is acid protecting group and R₂ is alcohol protecting group;

b) reacting compound of formula (III) with urea to obtain compound of formula (IV);

c) deprotecting compound of formula (IV) to obtain compound of formula (V);

d) chlorinating compound of formula (V) with chlorinating agent to obtain compound of formula (VI); and

e) reacting compound of formula (VI) with 2-iminopyrrolidine or salt thereof to obtain tipiracil of formula (I) or salt thereof.

In twenty first embodiment, the present invention provides a process for preparation of tipiracil of formula (I) or salt thereof

which comprises,

a) reacting compound of formula (II) with urea to give compound of formula (VII)

wherein Ri is acid protecting group and R₂ is alcohol protecting group;

b) chlorinating compound of formula (VII) with a chlorinating agent to obtain compound of formula (IV);

(IV)

c) deprotecting compound of formula (IV) to obtain compound of formula (V);

(V)

(VI )

In twenty second embodiment, the present invention provides an amorphous form of tipiracil hydrochloride.

In twenty third embodiment, the present invention provides a process for the preparation of amorphous form of tipiracil hydrochloride, comprising:

a) providing a solution of tipiracil hydrochloride in a solvent; and

b) isolating amorphous form of tipiracil hydrochloride.

In twenty fourth embodiment, the present invention provides pharmaceutical composition comprising amorphous form of tipiracil hydrochloride and one or more pharmaceutically acceptable carriers.

In twenty fifth embodiment, the present invention provides amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers.

In twenty sixth embodiment, the present invention provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing tipiracil hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and

b) isolating an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers.

In twenty seventh embodiment, the present invention provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of: a) dissolving or dispersing tipiracil hydrochloride under heating in one or more pharmaceutically acceptable carriers; and

b) cooling down the mixture.

In twenty eighth embodiment, the present invention provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

b) spray drying the mixture to obtain the said amorphous solid dispersion.

In twenty ninth embodiment, the present application provides pharmaceutical composition comprising amorphous solid dispersion of tipiracil hydrochloride and one or more pharmaceutically acceptable carriers.

In thirtieth embodiment, the present invention provides novel intermediates of formula Ila, Ilia, Illb, IIIc, Hid, IVa, IVb, IVc, IVd, IVe, Vila, Vllb and Vila

Detail Description of Invention

As used herein, the term "alkyl" by itself or as part of another substituent, means, a saturated straight or branched chain, or cyclic hydrocarbon radical, or combination thereof having the number of carbon atoms designated (e.g. Ci_io means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, (cyclopropy)methyl, homo logs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, the term "aryl" by itself or as part of another substituent, means, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently. "aryl" includes, but is not limited to, heteroaryl groups. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl and quinolyl.

The term "substituted" as used herein means that the groups in question are substituted with one or more of the substituents selected from nitro, hydroxy, cyano, sulfanyl, oxo, halogen, amino, sulfo, alkyl, alkenyl, aryl and heteroaryl. When the groups in question are substituted with more than one substituent, the substituents can be the same or different. The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

As used herein, the term "chlorinating agent" includes, but are not limited to, pivaloyl chloride, thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, N-chlorosuccinimide, N-chlorobenzotriazole, sulfuryl chloride, phosgene, liquid chlorine, chlorine gas, anhydrous hydrogen chloride, aqueous solution of hydrogen chloride, triphosgene, diphosgene, hypochlorous acid, hydrochloric acid in the presence of hydrogen peroxide, methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl 1 -chloride, 1- butanesulfonyl chloride, trifiuoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4- methoxybenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, methyl chlorooxoacetate, 4-chlorobenzoyl chloride, 4-nitrobenzoyl chloride, 3- (chloromethyl)benzoyl chloride, and methyl chloroformate.

As used herein, the term "acid protecting group" by itself or as part of another substituent, means, substituted or unsubstituted, linear or branched alkyl, aryl, heteroaryl, alkylaryl, silyl. Examples of acid protecting group include, but are not limited to, methyl, ethyl, propyl, isopropyl, t-butyl, 2-alkyl-l,3-oxazoline, benzyl, 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-tert-butylphenol, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), 2- (trimethylsilyl)ethyl, and diphenylmethyl.

As used herein, the term "alcohol protecting group" by itself or as part of another substituent, means, substituted or unsubstituted, linear or branched alkyl, alkanoyl, aryl, heteroaryl, alkylaryl. Examples of alcohol protecting group include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, benzyl, β-methoxyethoxymethyl (MEM), dimethoxytrityl, [bis-(4- methoxyphenyl)phenyl methyl] (DMT), methoxymethyl (MOM), methoxytrityl [(4- methoxyphenyl)diphenylmethyl] (MMT), p-methoxybenzyl (PMB), methylthiomethyl, pivaloyl, tetrahydropyranyl, tetrahydrofuran, trityl, trimethylsilyl (TMS), trimethylsilyl (TES), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS), methyl, ethyl, propyl, tert-butyl, ethoxyethyl, 2- naphthylmethyl (Nap), methoxypropyl (MOP), Benzyloxymethyl acetal (BOM), Tetrahydropyranyl acetal (THP), and 2,2,2-Trichloroethyl carbonate (Troc). As used herein, the term "cyclizing agents" includes, but are not limited to, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulphuric acid, concentrated sulphuric acid - silica, polyphosphoric acid, sulphuryl chloride, p- toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, and acetic anhydride.

As used herein, the term "deprotecting agents" includes, but are not limited to, hydrogen and palladium on carbon (H2, Pd/C), ammonium formate and palladium on carbon (NH4HC02, Pd/C), hydrogen and palladium hydroxide on carbon (H2, Pd(OH)2/C), combination of Pd/C and Pd(OH)2/C, lithium 4,4'-Di-tert-butylbiphenylide (Li.DTBBP), sodium, 2,3-dichloro-5,6- dicyano-l,4-benzoquinone (DDQ), and trimethylsilyl chloride - sodium iodide (TMSC1, Nal).

As used herein, the term "base" in any reaction step of present invention is selected from following base as single or in any combination or in aqueous form depending upon the kind and nature of the reaction. Base used in the present invention can be inorganic or organic base. Inorganic base are alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal. The metal alkoxide alkyl groups, either alone or with the various substituents defined hereinabove are preferably alkyl containing one to six carbon atoms in the principal chain. They can be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like. Examples of metal alkoxide include, but are not limited to, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert- butoxide, magnesium methoxide, magnesium ethoxide and magnesium tert-butoxide. Examples of metal carbonates include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate and calcium carbonate. Examples of metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate and lithium bicarbonate. Examples of metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, barium hydroxide, lithium hydroxide, cesium hydroxide and strontium hydroxides. Examples of metal hydride include, but are not limited to, sodium hydride, potassium hydride and calcium hydride. Examples of metal amide include, but are not limited to, lithium amide and sodium amide. Examples of metal phosphates include, but are not limited to, potassium phosphate and sodium phosphate. Examples of organic bases include, but are not limited to, triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, Ν,Ν-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1- azabicyclo[2.2.2]octane (ABCO), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), N-methylpyrrolidine, ammonia, sodium hexamethyldisilazide (NaHMDS), N methyl 2-pyrrolidone (NMP), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.

As used herein, "solvent" used in any reaction step of present invention is selected from following solvent as single solvent or mixture thereof. The selection of solvent depends upon the nature of the reaction. Solvents used in the present invention is selected from halogenated hydrocarbons such as dichloromethane, trichloromethane, dichloroethane, chloroform, dibromochloromethane, dibromodifluoromethane, chlorobenzene, bromobenzene or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethylene glycoldimethylether, diethyl ether, diisopropyl ether, dimethoxyethane, diethyl glycol dimethylether; nitrile such as acetonitrile or propionitrile; ester such as ethylacetate, propyl acetate, isopropyl acetate, butyl acetate; ketone such as acetone, methyl isobutyl ketone (MIB ), methyl ethyl ketone (MEK), diethyl ketone; polar aprotic solvents such as amides including, but are not limited to N,N- dimethylformamide (DMF), formamide, dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP), hexamethyl phosphoric triamide; sulfoxides such as dimethyl sulfoxide (DMSO); polar pro tic solvents such as alcoholic solvent Ci_s linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol; formic acid, acetic acid and the like; water or mixtures thereof.

As used herein, the term "salt" includes pharmaceutically acceptable acid addition salts formed with organic or inorganic acids. Inorganic salts is selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; or organic salts is selected from maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-toulenesulfonic acid, p- aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids.

As used herein, the term "room temperature" refers to 'the temperatures of the thing close to or same as that of the space, example, the room or fume hood, in which the thing is located'. Typically, room temperature can be from about 20°C. to about 30° C, about 22°C to about 27°C, or about 25°C. As used herein, the term "drying" in any reaction step of present invention can be carried out in a tray dryer, vacuum oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or any other suitable dryer. The drying can be carried out at temperatures less than about 100° C, less than about 80° C, less than about 60° C, less than about 50° C, less than about 30° C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the product is not degraded in its quality. Optionally drying can be carried out using an inert gas such as nitrogen or argon. The drying can be carried out for any desired times until the required product quality is achieved. The dried product can optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization can be performed before drying, or after the completion of drying of the product. Techniques that can be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling.

As used herein, the term "spray drying technique" in any reaction step of present invention involves dissolving tipiracil hydrochloride in suitable solvent or mixtures thereof. The solution can be spray dried at 40 to 100° C. inlet temperature, at a feed rate of 3 ml/min. to 15 ml/minute, at a flow rate of 5-50 rpm, and at 1.5 to 6.5 kg/cm² atomization pressure.

As used herein, the term "pharmaceutically acceptable carriers" include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, maltose, raffmose, α-, β- and γ-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl β-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co- (lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene- /polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and copolymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silicon dioxide, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like.

In all the embodiments, the progress of the reaction is monitored by thin layer chromatography (TLC) or by gas chromatography (GC) or any customary method known in the art of chemistry.

Customary work up includes quenching of the reaction generally by means of addition of water, extraction of the product in organic solvent, optionally washing of the organic phase containing product with water to remove impurities or inorganic salts soluble in water. Finally, the product is isolated by means of removal of solvent from organic phase or adding anti-solvent to solution containing product so as to induce precipitation or crystallization. In other method wherein reaction solvent is polar solvent miscible in water, the reaction is quenched with water so as to precipitation of product in water.

A solid that is in the "amorphous" solid state form means that it is in a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as are found in crystalline solids. The solid state form of amorphous solid can be determined by X-Ray Powder Diffraction (XPRD), or other standard techniques known to those skilled in the art.

In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.

The term "amorphous solid dispersion" as used herein, refers to solid dispersion which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form as determined by X-Ray Powder Diffraction (XPRD). Tipiracil hydrochloride used for the preparation of amorphous solid dispersion can be crystalline or amorphous.

Particle size of tipiracil hydrochloride can have impact on content uniformity of tablets. In an embodiment, tipiracil hydrochloride of present invention has average particle size of particles between 1 to 100 μηχ, less than 90 μιτι, less than 80 μιη, less than 60 μιη, less than 50 μιτι, less than 40 μιτι, less than 30 μηι, less than 20 μιη, less than 10 μιη, less than 5 μιη or any other suitable particle sizes. In another embodiment, tipiracil hydrochloride of present invention can have particle size distribution: D₁₀ of particles smaller than 20 μηι, smaller than 15 μιη, smaller than 10 μηι, or smaller than 5 μιτι; Dso of particles smaller than 100 μιη, smaller than 90 μιη, smaller than 80 μηι, smaller than 70 μπι, smaller than 60 μιη, smaller than 50 μιη, smaller than 40 μιη, smaller than 30 μιτι, smaller than 20 μιη, smaller than 10 μιη; Dgo of particles smaller than 200 μιη, smaller than 175 μιη, smaller than 150 μιη, smaller than 140 μιτι, smaller than 130 μηι, smaller than 120 μηι, smaller than 110 μιη, smaller than 100 μιη, smaller than 90 μηι, smaller than 80 μηχ, smaller than 70 μιη, smaller than 60 μιτι, smaller than 50 μηι, smaller than 40 μηι, smaller than 30 μιη, smaller than 20 μηι, smaller than 10 μηι. Particle size distributions of tipiracil hydrochloride particles can be measured using any techniques known in the art. For example, particle size distributions of tipiracil hydrochloride particles can be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term "Dio" in the context of the present invention is 10% of the particles by volume are smaller than the D₁₀ value and 90% particles by volume are larger than the D₁₀ value. "D50" in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. "D90" in the context of the present invention is 90%> of the particles by volume are smaller than the D 0 value and 10% particles by volume are larger than the D90 value.

The term "solvate" as used herein refers to a compound which contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. It also means that the solvent is bound with a target compound in a reproducible molar ration, such as 0.5: 1 or 1 : 1.

According to first embodiment, the present invention relates to tipiracil HC1 solvate and process for the preparation thereof.

According to second embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide (DMSO) solvate.

In the present invention, tipiracil HC1 dimethylsulfoxide solvate is substantially crystalline in nature. By substantially crystalline it is meant that at least about 80%>, more preferably, at least about 90%), more preferably, at least about 95%, more preferably, at least about 99% to 100% of the material is crystalline on a weight per total weight basis (w/w).

According to third embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide (DMSO) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 8.0°, 11.6°, 16.0°, 17.0°, 22.5°, 22.7°, 24.0°, 24.3°, 26.4°, 27.5°, 27.9°, 30.1°, 31.6° and 38.1 ± 0.2° 2Θ.

In the present invention tipiracil HC1 dimethylsulfoxide (DMSO) solvate is characterized by XP D pattern as shown in figure 1.

In the present invention, the tipiracil HC1 DMSO solvate is characterized by differential scanning calorimetry (DSC) thermogram having an endotherm peak in the range between about 165°C and about 180°C and in the range between about 245°C and about 260°C substantially as depicted in figure 2.

The tipiracil HC1 DMSO solvate is also characterized by TGA thermogram substantially in accordance with figure 3.

According to fourth embodiment, the present invention relates to process for the preparation of tipiracil HC1 dimethylsulfoxide (DMSO) solvate comprising steps of:

a) addition of tipiracil base in dimethylsulfoxide solvent;

b) adding concentrated HC1 in step a; and

c) isolating tipiracil HC1 dimethylsulfoxide solvate. In step (a), tipiracil free base is added in dimethylsulfoxide (DMSO) solvent. Any physical form of tipiracil free base can be utilized for providing the solution or suspension of tipiracil free base in step (a). Although the temperature is not particularly limited, preferably it is between 10° C and 70° C, more preferably between 20° C and 50° C, more preferably between 25° C and 40° C. The solution or suspension of step (a) is maintained at a temperature for a sufficient period of time. Typically, the time can vary from about few minutes to several hours. For example the maintenance time can be from about 10 minutes to about 24 hours, or any other suitable time period. Step (a) can be done with or without stirring. Amount of DMSO solvent used in step (a) can vary from about 5 volumes, about 10 volumes, about 15 volumes, about 20 volumes per one mole of tipiracil free base.

In step (b), hydrochloric acid is added in the solution or suspension obtained from step (a). Concentration of hydrochloride acid used can vary from 20%w/v, 30%w/v, 40%w/v, 50%w/v and 60%w/v. Although the temperature is not particularly limited, preferably it is between 10° C and 70° C, more preferably between 20° C and 50° C, more preferably between 25° C and 40° C.

The solution of step (b) is maintained at a temperature for a sufficient period of time so as to enhance the crystal formation, as is commonly known to one skilled in the art. Typically, the time can vary from about few minutes to several hours. For example the maintenance time can be from about 10 minutes to about 24 hours, or any other suitable time period. Step (b) can be done with or without stirring.

In step (c), tipiracil hydrochloride DMSO solvate is isolated using the techniques commonly known to one skilled in the art. For example, tipiracil HC1 DMSO solvate may be isolated with filtration by gravity or by suction, centrifugation, decantation, and the like. The crystals of DMSO solvate of tipiracil hydrochloride can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Crystals of DMSO solvate of tipiracil HC1 can be dried at room temperature or at elevated temperature. Elevated temperature can be from about 50°C to about 100° C, about 55°C to about 70°C, or about 55°C to about 65°C. After isolation, the solid may optionally be washed with a suitable solvent such as DMSO, optionally in combination with a co-solvent, when desired.

According to fifth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride dimethylsulfoxide (DMSO) solvate and one or more pharmaceutically acceptable excipients.

According to sixth embodiment, the present invention relates to tipiracil HC1 N, N- dimethylacetamide (DMAc) solvate. In the present invention, tipiracil HC1 DMAc solvate is substantially crystalline in nature. By substantially crystalline it is meant that at least about 80%, more preferably, at least about 90%, more preferably, at least about 95%, more preferably, at least about 99% to 100% of the material is crystalline on a weight per total weight basis (w/w).

According to seventh embodiment, the present invention relates to tipiracil HC1 N, N- dimethylacetamide (DM Ac) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 8.9°, 9.0°, 11.6°, 13.0°, 13.7°, 16.5°, 16.7°, 16.9°, 17.0°, 18.7°, 19.2°, 21.2°, 22.3°, 22.4°, 22.8°, 23.5°, 24.3°, 24.4°, 25.6°, 26.1°, 26.3°, 26.6°, 27.9°, 28.2°, 28.6°, 28.7°, 29.1°, 29.4°, 29.7°, 31.0°, 32.1°, 35.3° and 39.6 ± 0.2° 2Θ.

In the present invention tipiracil HC1 N, N-dimethylacetamide (DMAc) solvate is characterized by XPRD pattern as shown in figure 4.

According to eighth embodiment, the present invention relates to process for the preparation of tipiracil HC1 N, N-dimethylacetamide (DMAc) solvate comprising steps of:

a) addition of tipiracil base in water;

b) adding concentrated HC1 in step a;

c) adding N, N-dimethylacetamide in step b; and

d) isolating tipiracil HC1 N, N-dimethylacetamide solvate.

In step (a), tipiracil free base is added in water. Any physical form of tipiracil free base can be utilized for providing the solution or suspension of tipiracil free base in step (a). Amount of water used in step (a) can vary from about 5 volumes, about 10 volumes, about 15 volumes, about 20 volumes per one mole of tipiracil free base.

In step (b), hydrochloric acid is added in the solution or suspension obtained from step (a). Concentration of hydrochloride acid used can vary from 20%w/v, 30%w/v, 40%w/v, 50%w/v and 60%w/v. The solution of step (b) can be filtered to remove any insoluble particles.

In step (c), dimethylacetamide solvent is added in solution of step (b). Amount of DMAc solvent used in step (c) can vary from about 10 volumes, about 20 volumes, about 25 volumes, about 30 volumes per one mole of tipiracil free base.

In step (d), tipiracil hydrochloride DMAc solvate is isolated using the techniques commonly known to one skilled in the art.

According to ninth embodiment, the present invention relates to process for the preparation of tipiracil HC1 , N-dimethylacetamide (DMAc) solvate comprising steps of:

a) addition of tipiracil HC1 in water;

b) adding N, N-dimethylacetamide in step a; and

c) isolating tipiracil HC1 N, N-dimethylacetamide solvate. In step (a), tipiracil HCl is added in water. Any physical form of tipiracil HCl can be utilized for providing the solution or suspension of tipiracil HCl in step (a). Amount of water used in step (a) can vary from about 5 volumes, about 10 volumes, about 15 volumes, about 20 volumes per one mole of tipiracil free base.

In step (b), dimethylacetamide solvent is added in solution of step (a). Amount of DMAc solvent used in step (b) can vary from about 10 volumes, about 20 volumes, about 25 volumes, about 30 volumes per one mole of tipiracil HCl.

In step (c), tipiracil hydrochloride DMAc solvate is isolated using the techniques commonly known to one skilled in the art.

According to tenth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride N, N-dimethylacetamide (DMAc) solvate and one or more pharmaceutically acceptable excipient.

According to eleventh embodiment, the present invention relates to tipiracil HCl N-methyl- 2-pyrrolidone (NMP) solvate. In the present invention, tipiracil HCl NMP solvate is substantially crystalline in nature. By substantially crystalline it is meant that at least about 80%, more preferably, at least about 90%, more preferably, at least about 95%, more preferably, at least about 99% to 100% of the material is crystalline on a weight per total weight basis (w/w).

According to twelfth embodiment, the present invention relates to tipiracil HCl N-methyl- 2-pyrrolidone (NMP) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 7.1°, 8.9°, 11.4°, 11.5°, 12.8°, 13.7°, 14.3°, 16.4°, 16.8°, 17.1°, 17.8°, 18.8°, 19.3°, 19.5°, 21.3°, 21.5°, 22.1°, 23.0°, 23.2°, 23.6°, 24.4°, 24.6°, 25.0°, 25.7°, 26.0°, 26.4°, 27.0°, 27.4°, 27.9°, 28.4°, 29.2°, 29.6°, 30.4°, 31.7°, 32.7°, 33.4° and 38.0 ± 0.2° 2Θ.

In the present invention, tipiracil HCl N-methyl-2-pyrrolidone (NMP) solvate is characterized by XPRD pattern as shown in figure 5.

According to thirteenth embodiment, the present invention relates to process for the preparation of tipiracil HCl N-methyl-2-pyrrolidone (NMP) solvate comprising steps of:

a) addition of tipiracil HCl in water;

b) adding N-methyl-2-pyrrolidone in step a;

c) optionally seeding the solution of step b; and

d) isolating tipiracil HCl N-methyl-2-pyrrolidone solvate.

In step (a), tipiracil HCl is added in water. Any physical form of tipiracil HCl can be utilized for providing the solution or suspension of tipiracil HCl in step (a). Amount of water used in step (a) can vary from about 5 volumes, about 10 volumes, about 15 volumes, about 20 volumes per one mole of tipiracil free base. In step (b), N-methyl-2-pyrrolidonesolvent is added in solution of step (a). Amount of NMP solvent used in step (b) can vary from about 10 volumes, about 20 volumes, about 25 volumes, about 30 volumes per one mole of tipiracil HCl.

In step (c), optionally the seeding of tipiracil HCl NMP solvate is done in the solution of step (b). Seed of NMP solvate of tipiracil HCl can be obtained by performing the entire steps without seeding. The crystals of NMP solvate of tipiracil HCl is obtained by performing step (a), step (b) and step (d) stated above. The crystals thus obtained can be used as a seed to enhance the crystal growth of NMP solvate of tipiracil HCl in further batches.

In step (d), tipiracil hydrochloride NMP solvate is isolated using the techniques commonly known to one skilled in the art.

According to fourteenth embodiment, the present application provides pharmaceutical composition comprising tipiracil hydrochloride N-methyl-2-pyrrolidone (NMP) solvate and one or more pharmaceutically acceptable excipients.

According to fifteenth embodiment, the present invention relates to crystalline form- A of tipiracil HCl.

According to sixteenth embodiment, the present invention relates to crystalline form- A of tipiracil HCl characterized by X-ray diffraction pattern having characteristic peaks at about 9.4°, 9.9° and, 10.5 ± 0.2° 2Θ. More preferably, substantially pure form-A has an X-ray powder diffraction pattern containing specific peaks at 6.5°, 9.2°, 9.4°, 9.9°, 10.5°, 11.7°, 12.7°, 13.4°, 16.9°, 17.9°, 18.2°, 19.0°, 19.5°, 20.4°, 20.6°, 21.4°, 22.1°, 23.5°, 23.7°, 24.0°, 24.7°, 25.1°, 25.5°, 25.7°, 26.1°, 26.4°, 26.6°, 26.9°, 28.4°, 29.7°, 30.2°, 31.8°, 32.8°, 33.5° and 40.2± 0.2° 2Θ

In the present invention, crystalline form-A of tipiracil HCl is characterized by XPRD pattern as shown in figure 6.

According to seventeenth embodiment, the present invention relates to process for the preparation of crystalline form-A of tipiracil HCl comprising steps of:

a) adding tipiracil HCl in pre-heated methanol;

b) adding water in step a; and

c) isolating crystalline form-A of tipiracil HCl.

In step (a), methanol is heated before the addition of tipiracil HCl. Although the temperature is not particularly limited, preferably it is between 40 and 60° C, and more preferably 50° C. Tipiracil HCl is added in pre-heated methanol with or without stirring. Any physical form of tipiracil hydrochloride can be utilized for providing the solution of tipiracil hydrochloride in step (a). In step (b), water is added drop wise in step (a) comprising of tipiracil HCl and methanol. Water is added in an amount preferably to make a clear solution of tipiracil HCl. The ratio of methanol: water can be about 2:0.1 to about 2: 1, preferably 2:0.5, more preferably 2:0.75 and still more preferably 2: 1. Step (b) is performed with or without stirring. Although the temperature is not particularly limited, preferably it is between 40 and 60° C, and more preferably 50° C.

The solution of step (b) is maintained at a temperature for a sufficient period of time so as to enhance the crystal formation, as is commonly known to one skilled in the art. Typically, the time can vary from about few minutes to several hours. For example the maintenance time can be from about 10 minutes to about 24 hours, or any other suitable time period.

In step (c), the novel crystalline form-A is isolated using the techniques commonly known to one skilled in the art. The solution of step (b) can be filtered to remove any insoluble particles. The insoluble particles can be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Depending upon the equipment used, concentration and temperature of the solution, the filtration apparatus can be preheated to avoid premature precipitation.

The filtrate obtained can be kept at room temperature to crystallize tipiracil HCl form-A from the filtrate. The crystals of novel form-A of tipiracil HCl can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Crystals of form-A of tipiracil HCl can be dried at room temperature.

According to eighteenth embodiment, the present application provides pharmaceutical composition comprising crystalline form-A of tipiracil hydrochloride and one or more pharmaceutically acceptable excipient.

According to nineteenth embodiment, the present invention relates to novel process for the preparation of stable Crystal II of tipiracil HCl comprising step of:

a) adding tipiracil HCl in pre-heated ethanol;

b) adding water in step a;

c) slowly evaporating ethanol at room temperature; and

d) isolating Crystal II of tipiracil HCl.

In step (a), ethanol is heated before the addition of tipiracil HCl. Although the temperature is not particularly limited, preferably it is between 40 and 60° C, and more preferably 50° C. Tipiracil HCl is added in pre-heated ethanol with or without stirring. Any physical form of tipiracil hydrochloride can be utilized for providing the solution of tipiracil hydrochloride in step (a).

In step (b), water is added drop wise in step (a) comprising of tipiracil HCl and ethanol. Water is added in an amount preferably to make a clear solution of tipiracil HCl. The ratio of ethanol: water can be about 2:0.1 to about 2: 1, preferably 2:0.5, more preferably 2:0.75 and still more preferably 2: 1. Step (b) is performed with or without stirring. Although the temperature is not particularly limited, preferably it is between 40 and 60 °C, and more preferably 50 °C.

The solution of step (b) can be filtered to remove any insoluble particles. The insoluble particles can be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Depending upon the equipment used, concentration and temperature of the solution, the filtration apparatus can be preheated to avoid premature precipitation.

In step (c), the filtrate obtained can be kept at room temperature to crystallize tipiracil HCl Crystal II. The stable Crystal II of tipiracil HCl is obtained due to the slow evaporation of ethanol which helps in the stabilization of Crystal II as compared to the fast cooling reported in US 9,527,833.

In step (d), the Crystal II of tipiracil HCl can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Crystals II of tipiracil HCl can be dried at room temperature.

In the present invention, Crystal II of tipiracil HCl is characterized by XPRD pattern as shown in figure 7.

According to twentieth embodiment of the present invention, a process for the preparation of tipiracil of formula (I) or salt thereof comprising steps of:

a) chlorinating compound of formula (II) with a chlorinating agent to give compound of formula

(in);

c) deprotecting compound of formula (IV) to obtain compound of formula (V);

In step (a), compound of formula (II) is chlorinated with a chlorinating agent to give compound of formula (III), wherein Ri is acid protecting group selected from substituted or unsubstituted, linear or branched alkyl, aryl, heteroaryl, and alkylaryl. R2 is alcohol protecting group selected from substituted or unsubstituted, linear or branched alkyl, alkanoyl, aryl, heteroaryl and alkylaryl. Preferably, compound of formula (II) includes, methyl 4-(benzyloxy)-3- oxobutanoate, ethyl 4-(benzyloxy)-3-oxobutanoate, propyl 4-(benzyloxy)-3-oxobutanoate, isopropyl 4-(benzyloxy)-3-oxobutanoate, tert-butyl 4-(benzyloxy)-3-oxobutanoate, benzyl 4- (benzyloxy)-3-oxobutanoate, ethyl 4-methoxy-3-oxobutanoate, ethyl 4-ethoxy-3-oxobutanoate, and ethyl 4-isopropoxy-3-oxobutanoate. More preferably, compound of formula (II) can be ethyl 4-(benzyloxy)-3-oxobutanoate. Preferably, compound of formula (III) includes, methyl 4-(benzyloxy)-2-chloro-3- oxobutanoate, ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, propyl 4-(benzyloxy)-2-chloro-3- oxobutanoate, isopropyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, tert-butyl 4-(benzyloxy)-2- chloro-3-oxobutanoate, benzyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, ethyl 2-chloro-4- methoxy-3-oxobutanoate, ethyl 2-chloro-4-ethoxy-3-oxobutanoate, and ethyl 2-chloro-4- isopropoxy-3-oxobutanoate. More preferably, compound of formula (III) can be ethyl 4- (benzyloxy)-2-chloro-3-oxobutanoate.

In the present invention, the compound of formula (II) is chlorinated in the presence of chlorinating agent selected from the agents listed above; preferably the chlorinating agent is thionyl chloride.

Optionally, the chlorination of compound of formula (II) can be done in the presence or absence of a chlorination catalyst which is selected from, but not limited to, pyridine, alkyl substituted pyridine and tertiary amides such as dimethylalkylamide and dialkylformamide. Preferably, the chlorination catalyst is selected from the group consisting of N, N- dimethylformamide, Ν,Ν-diethylformamide and pyridine; and more preferably is N,N- dimethylformamide .

Optionally, chlorination of compound of formula (II) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar pro tic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of chlorinating agent with respect to the compound of formula (II) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, or about 2 mole per mole of the compound of formula (II), or any other suitable mole ratio.

The reaction is advantageously conducted with the application of heat as, for example, by heating the reaction mixture under reflux.

The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.

In step (b), compound of formula (III) is reacted with urea to obtain compound of formula (IV), wherein ₂ is alcohol protecting group selected from substituted or unsubstituted, linear or branched alkyl, alkanoyl, aryl, heteroaryl, alkylaryl, Preferably, compound of formula (III) includes methyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, ethyl 4-(benzyloxy)-2-chloro-3- oxobutanoate, propyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, isopropyl 4-(benzyloxy)-2-chloro- 3-oxobutanoate, tert-butyl 4-(benzyloxy)-2-chloro-3-oxobutanoate, benzyl 4-(benzyloxy)-2- chloro-3-oxobutanoate, ethyl 2-chloro-4-methoxy-3-oxobutanoate, ethyl 2-chloro-4-ethoxy-3- oxobutanoate, and ethyl 2-chloro-4-isopropoxy-3-oxobutanoate. More preferably, compound of formula (III) can be ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate.

Preferably, compound of formula (IV) includes 5-chloro-6-(methoxymethyl)pyrimidine- 2,4(lH,3H)-dione, 5-chloro-6-(ethoxymethyl) pyrimidine-2,4(lH,3H)-dione, 5-chloro-6- (isopropoxymethyl)pyrimidine-2,4(lH,3H)-dione, 6-((benzyloxy)methyl)-5-chloropyrimidine- 2,4(lH,3H)-dione. More preferably, compound of formula (IV) can be 6-((benzyloxy) methyl)- 5-chloropyrimidine-2, 4(1H, 3H)-dione.

In the present invention, compound of formula (III) is cyclized in the presence of cyclizing agent selected from the agents listed above; preferably the cyclizing agent is polyphosphoric acid.

Optionally, cyclization of compound of formula (III) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of urea with respect to the compound of formula (III) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, or about 2 mole per mole of the compound of formula (III), or any other suitable mole ratio.

In step (c), compound of formula (IV) is deprotected to obtain compound of formula (V). In the present invention, compound of formula (IV) is deprotected in the presence of deprotecting agent selected from the agents listed above; preferably the deprotecting agent is ammonium formate and palladium on carbon (NH₄HCO₂, Pd/C). Compound of formula (IV) includes 5-chloro-6-(methoxymethyl)pyrimidine-2,4(lH,3H)-dione, 5-chloro-6-(ethoxymethyl) pyrimidine-2,4( 1 H,3H)-dione, 5-chloro-6-(isopropoxymethyl)pyrimidine-2,4( 1 H,3H)-dione, and 6-((benzyloxy)methyl)-5-chloropyrimidine-2,4(lH,3H)-dione. Preferably, compound of formula (IV) can be 6-((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione.

Optionally, deprotection of compound of formula (IV) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of deprotecting agent with respect to the compound of formula (IV) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, about 2, about 2.5, or about 3 mole per mole of the compound of formula (III), or any other suitable mole ratio.

In step (d), compound of formula (V) is chlorinated with chlorinating agent to obtain compound of formula (VI). In the present invention, the compound of formula (V) is chlorinated in the presence of chlorinating agent selected from the agents listed above; preferably the chlorinating agent is sulfuryl chloride.

Optionally, the chlorination of compound of formula (V) can be done in the presence or absence of a chlorination catalyst which is selected from, but are not limited to, pyridine, alkyl substituted pyridine and tertiary amides such as dimethylalkylamide and dialkylformamide. Preferably, the chlorination catalyst is selected from the group consisting of N, N- dimethylformamide, N, N-diethylformamide and pyridine; and more preferably is N, N- dimethylformamide .

Optionally, chlorination of compound of formula (V) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of chlorinating agent with respect to the compound of formula (V) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, or about 2 mole per mole of the compound of formula (II), or any other suitable mole ratio. The reaction is advantageously conducted with the application of heat as, for example, by heating the reaction mixture under reflux for several hours.

In step (e), compound of formula (VI) is reacted with 2-iminopyrrolidine or salt thereof to obtain tipiracil of formula (I) or salt thereof. In the present invention, the compound of formula (VI) can be reacted with 2-iminopyrrolidine or salt thereof in presence of base. The base that can be used for the said reaction is selected from alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal or organic base.

Optionally, condensation of compound of formula (VI) with 2-iminopyrrolidine or salt thereof can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of 2-iminopyrrolidine or salt thereof with respect to the compound of formula (IV) can be derived by a person skilled in the art. For example, the said mole ratio can be about 1.0, about 1.5, about 2, about 2.5, or about 3 mole per mole of the compound of formula (VI), or any other suitable mole ratio.

The conversion of the compound of formula (VI) to the compound of formula (I) can take place at a temperature of about 10° C. to about 100° C, about 20° C. to about 50° C, about room temperature, about reflux temperature of the solvent used in the reaction, or any other suitable temperature, which facilitates the desired reaction to happen without substantially negatively affecting the quality of the substrates or the reaction product.

According to twenty first embodiment of the present invention, a process for the preparation of tipiracil of formula (I) or salt thereof comprising steps of:

a) reacting compound of formula (II) with urea to give compound of formula (VII);

b) chlorinating compound of formula (VII) with a chlorinating agent to obtain compound formula (IV);

c) deprotecting compound of formula (IV) to obtain compound of formula (V);

(V)

(VI )

In step (a), compound of formula (II) is reacted with urea to give compound of formula (VII), wherein Ri is acid protecting group selected from substituted or unsubstituted, linear or branched alkyl, aryl, heteroaryl, alkylaryl. ₂ is alcohol protecting group selected from substituted or unsubstituted, linear or branched alkyl, alkanoyl, aryl, heteroaryl, alkylaryl. Preferably, compound of formula (II) includes methyl 4-(benzyloxy)-3-oxobutanoate, ethyl 4- (benzyloxy)-3-oxobutanoate, propyl 4-(benzyloxy)-3-oxobutanoate, isopropyl 4-(benzyloxy)-3- oxobutanoate, tert-butyl 4-(benzyloxy)-3-oxobutanoate, benzyl 4-(benzyloxy)-3-oxobutanoate, ethyl 4-methoxy-3-oxobutanoate, ethyl 4-ethoxy-3-oxobutanoate, and ethyl 4-isopropoxy-3- oxobutanoate. More preferably, compound of formula (II) can be ethyl 4-(benzyloxy)-3- oxobutanoate.

Preferably, compound of formula (VII) includes 6-(methoxymethyl)pyrimidine- 2,4(lH,3H)-dione, 6-(ethoxymethyl)pyrimidine-2,4(lH,3H)-dione, 6-

(isopropoxymethyl)pyrimidine-2,4( 1 H,3H)-dione, and 6-((benzyloxy)methyl)pyrimidine- 2,4(lH,3H)-dione. More preferably, compound of formula (VII) can be 6-((benzyloxy) methyl) pyrimidine-2, 4(1H, 3H)-dione.

In the present invention, compound of formula (II) is cyclized in the presence of cyclizing agent selected from the agents listed above; preferably the cyclizing agent is polyphosphoric acid. Optionally, cyclization of compound of formula (II) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The reaction is advantageously conducted with the application of heat as, for example, by heating the reaction mixture under reflux for several hours.

In step (b) compound of formula (VII) is chlorinated with a chlorinating agent to obtain compound of formula (IV), wherein R₂ is alcohol protecting group selected from substituted or unsubstituted, linear or branched alkyl, alkanoyl, aryl, heteroaryl, alkylaryl. Preferably, compound of formula (VII) includes 6-(methoxymethyl)pyrimidine-2,4(lH,3H)-dione, 6- (ethoxymethyl)pyrimidine-2,4(lH,3H)-dione, 6-(isopropoxymethyl)pyrimidine-2,4(lH,3H)- dione, and 6-((benzyloxy)methyl)pyrimidine-2,4(lH,3H)-dione. More preferably, compound of formula (VII) can be 6-((benzyloxy) methyl) pyrimidine-2, 4(1H, 3H)-dione. Preferably, compound of formula (IV) includes 5-chloro-6-(methoxymethyl)pyrimidine- 2,4(lH,3H)-dione, 5-chloro-6-(ethoxymethyl) pyrimidine-2,4(lH,3H)-dione, 5-chloro-6- (isopropoxymethyl)pyrimidine-2,4(lH,3H)-dione, or 6-((benzyloxy)methyl)-5-chloropyrimidine- 2,4(lH,3H)-dione. More preferably, compound of formula (IV) can be 6-((benzyloxy) methyl)- 5-chloropyrimidine-2, 4(1H, 3H)-dione.

In the present invention, the compound of formula (VII) is chlorinated in the presence of chlorinating agent selected from the agents listed above; preferably the chlorinating agent is thionyl chloride. Optionally, the chlorination of compound of formula (VII) can be done in the presence or absence of a chlorination catalyst which is selected from, but are not limited to, pyridine, alkyl substituted pyridine and tertiary amides such as dimethylalkylamide and dialkylformamide. Preferably, the chlorination catalyst is selected from the group consisting of N, N-dimethylformamide, N, N-diethylformamide and pyridine, and more preferably is N, N- dimethylformamide .

Optionally, chlorination of compound of formula (VII) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof.

The molar ratio of chlorinating agent with respect to the compound of formula (VII) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, or about 2 mole per mole of the compound of formula (VII), or any other suitable mole ratio.

Chlorination of the compound of formula (VII) to obtain compound of formula (IV) can take place at a temperature of about 0° C. to about 100° C, about 20° C. to about 50° C, about room temperature, about reflux temperature of the solvent used in the reaction, or any other suitable temperature, which facilitates the desired reaction to happen without substantially negatively affecting the quality of the substrates or the reaction product.

In step (c), compound of formula (IV) is deprotected to obtain compound of formula (V). In the present invention, compound of formula (IV) is deprotected in the presence of deprotecting agent selected from the agents listed above; preferably the deprotecting agent is ammonium formate and palladium on carbon (NH4HCO2, Pd/C).

Compound of formula (IV) includes 5-chloro-6-(methoxymethyl)pyrimidine-2,4(lH,3H)- dione, 5-chloro-6-(ethoxymethyl) pyrimidine-2,4(lH,3H)-dione, 5-chloro-6- (isopropoxymethyl)pyrimidine-2,4(lH,3H)-dione, and 6-((benzyloxy)methyl)-5- chloropyrimidine-2,4(lH,3H)-dione. Preferably, compound of formula (IV) can be 6- ((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione.

The molar ratio of deprotecting agent with respect to the compound of formula (IV) can be easily derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, about 2, about 2.5, or about 3 mole per mole of the compound of formula (III), or any other suitable mole ratio.

In step (d), compound of formula (V) is chlorinated with chlorinating agent to obtain compound of formula (VI). In the present invention, the compound of formula (V) is chlorinated in the presence of chlorinating agent selected from the agents listed above; preferably the chlorinating agent is sulfuryl chloride. Optionally, the chlorination of compound of formula (V) can be done in the presence or absence of a chlorination catalyst which is selected from, but not limited to, pyridine, alkyl substituted pyridine and tertiary amides such as dimethylalkylamide and dialkylformamide. Preferably, the chlorination catalyst is selected from the group consisting of N, N-dimethylformamide, N, N-diethylformamide and pyridine; more preferably is N, N- dimethylformamide.

Optionally, chlorination of compound of formula (V) can be carried out in the presence or absence of a solvent. The solvents that can be used in the said reaction is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof. The molar ratio of chlorinating agent with respect to the compound of formula (V) can be derived by a person skilled in the art. For example, the said mole ratio can be about 0.01, about 0.02, about 0.05, about 0.1, about 0.2, about 0.5, about 1.0, about 1.5, or about 2 mole per mole of the compound of formula (II), or any other suitable mole ratio.

The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.In twenty second embodiment, the present invention provides an amorphous form of tipiracil hydrochloride. The present invention provides an amorphous form of tipiracil HC1, which may be characterized by its X-ray powder diffraction (XRD) pattern, as well as using thermal techniques such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

In embodiments, the amorphous form of the present application may be in a pure amorphous form, however, in certain embodiments, there is provided an amorphous enriched form, wherein the amorphous content in the solid tipiracil HC1 is about 60% or more by weight. It may be substantially pure amorphous form, which has about 90% by weight or more of the amorphous form. Also, it may be pure amorphous form, which has about 98% by weight or more of the amorphous form.

Amorphous form and amorphous solid dispersions, unless stated otherwise, may be characterized by their X-ray powder diffraction patterns, differential scanning calorimetry curves, thermogravimetric analysis curves and infrared absorption spectra.

The present invention provides an amorphous form of tipiracil hydrochloride characterized by X-ray diffraction pattern substantially similar to the XRD as illustrated in figure 8.

In the present invention an amorphous form of tipiracil hydrochloride is produced which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form.

a) providing a solution of tipiracil hydrochloride in a suitable solvent or mixtures thereof; and

b) isolating amorphous form of tipiracil hydrochloride.

Providing a solution of tipiracil hydrochloride in step (a) includes:

i. direct use of a reaction mixture containing tipiracil hydrochloride that is obtained in the course of its synthesis; or

ii. dissolving tipiracil hydrochloride in a solvent.

Any physical form of tipiracil hydrochloride can be utilized for providing the solution of tipiracil hydrochloride in step (a). The dissolution temperatures can range from about 0° C to about the reflux temperature of the solvent, or less than about 60° C, less than about 50° C, less than about 40° C, less than about 30° C, less than about 20° C, less than about 10° C, or any other suitable temperatures, as long as a clear solution of tipiracil hydrochloride is obtained without affecting its quality. Preferably, temperature is 60° C. The solution can optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflo) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles can be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyfio. Depending upon the equipment used, concentration and temperature of the solution, the filtration apparatus can be preheated to avoid premature precipitation.

In the present invention, tipiracil hydrochloride can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. The solvents that can be used is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof. Preferably, the solvent used is a mixture of methanol and water at the ratio of 2:1, more preferably 1.5:1 and most preferably 1 :1.

In step (b) amorphous form of tipiracil hydrochloride is isolated from the solution obtained in step (a). Isolation of amorphous form of tipiracil hydrochloride in step (b) can involve methods including removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying or any other suitable technique. Preferably, spray drying technique can be used for the isolation of amorphous tipiracil hydrochloride. The spray drying technique involves dissolving tipiracil hydrochloride in suitable solvent or mixtures thereof, preferably mixture of methanol and water at 1 : 1 ratio. The solution can be spray dried at 100° C, at a flow rate of 10 rpm, and at 2 kg/cm² atomization pressure. The amorphous form of tipiracil hydrochloride as isolated can carry some amount of occluded mother liquor and can have higher than desired levels of impurities. If desired, this amorphous form can be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation can be less than about 120° C, less than about 80° C, less than about 60° C, less than about 40° C, less than about 30° C, less than about 20° C, less than about 10° C, less than about 0° C, less than about -10° C, less than about -40° C. or any other suitable temperatures.

The recovered solid can optionally be dried. In twenty fourth embodiment, the present invention provides pharmaceutical composition comprising amorphous form of tipiracil hydrochloride and one or more pharmaceutically acceptable carriers.

In the present invention, any pharmaceutical acceptable carrier can be used; the most preferable pharmaceutical acceptable carrier used is polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC).

The use of mixtures of more than one of the pharmaceutical acceptable carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

Any suitable quantity of pharmaceutical acceptable carriers can be used for the preparation of the said amorphous solid dispersion. For example, about 0.1, about 0.5, about 1.0, about 2.0, about 3.0, about 4.0, about 5.0, about 6.0, about 7.0, about 8.0, about 9.0 or about 10.0 portions by weight of pharmaceutical acceptable carriers can be used per one portion by weight of tipiracil hydrochloride. Preferably about 1.0 portion by weight of pharmaceutically acceptable carrier can be used per one portion by weight of tipiracil hydrochloride.

In the present invention the amorphous solid dispersion of tipiracil hydrochloride with PVP is prepared which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form as characterized by X-ray diffraction pattern substantially similar to the XRD as illustrated in figure 9.

In the present invention the amorphous solid dispersion of tipiracil hydrochloride with hydroxypropylmethylcellulose (HPMC) is produced which is substantially amorphous, that is, at least 75%, preferably at least 80%, most preferably at least 85%, is in amorphous form as characterized by X-ray diffraction pattern substantially similar to the XRD as illustrated in figure 10. In twenty sixth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing tipiracil hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixtures thereof; and

b) isolating an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers. Tipiracil hydrochloride used in step (a) includes, direct use of a reaction mixture containing tipiracil hydrochloride obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers. Optionally, tipiracil hydrochloride can be dissolved or dispersed in a suitable solvent or mixture of solvent, either alone followed by addition of one or more pharmaceutically acceptable carriers, or in combination with one or more pharmaceutically acceptable carriers. Optionally, auxiliaries such as diluents or disintegrant can be added during dissolution or dispersion.

Any physical form of tipiracil hydrochloride, such as crystalline, amorphous or their mixtures can be utilized in step (a).

The dissolution temperatures can range from about 0° C. to about the reflux temperature of the solvent, less than about 100° C, less than about 90° C, less than about 80° C, less than about 70° C, less than about 60° C, less than about 50° C, less than about 40° C, less than about 30° C, less than about 20° C, less than about 10° C, or any other suitable temperatures, as long as a clear solution of tipiracil hydrochloride is obtained without affecting its quality. The solution can optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflo) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above can be filtered to remove any insoluble particles. The insoluble particles can be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution can be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus can need to be preheated to avoid premature precipitation.

When the solution or dispersion of tipiracil hydrochloride is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order can be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Tipiracil hydrochloride or pharmaceutically acceptable carrier can be completely soluble in the solvent or they can form dispersion. In embodiments, tipiracil hydrochloride and the pharmaceutically acceptable carrier can be separately dissolved either in the same solvent or in different solvents, and then combined to form a mixture.

The solvent that can be used in step (a) is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof. Isolation of an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers in step b) can involve methods including removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique. An amorphous solid dispersion as isolated can carry some amount of occluded mother liquor and can have higher than desired levels of impurities. If desired, amorphous solid dispersion can be washed with a solvent or a mixture of solvents to wash out the impurities.

Isolation can be carried out by freeze drying (lyophilization) the solution at low temperatures and reducing the pressure to remove the solvent from the frozen solution. Temperatures that can be required to freeze the solution, depending on the solvent chosen to make the solution, can range from about -80° C. to about 20° C. Temperatures that can be required to remove the solvent from the frozen solution can be less than about 20° C, less than about 0° C, less than about -20° C, less than about -40° C, less than about -60° C, less than about -80° C, or any other suitable temperatures.

Optionally, isolation can be effected by combining a suitable anti-solvent with the solution obtained in step (a). Anti-solvent as used herein refers to a liquid in which tipiracil hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti- solvents that can be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, CI to CIO hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.

The recovered solid can optionally be dried.

In twenty seventh embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing tipiracil hydrochloride under heating in one or more pharmaceutically acceptable carriers; and

b) cooling down the mixture. The methods for dissolving or dispersing tipiracil hydrochloride include stirring by heating up to or higher than the melting point or the softening point of tipiracil hydrochloride or pharmaceutically acceptable carrier(s). Optionally, pressure can be applied using kneading machine along with heating. Plasticizers such as, polyethyleneglycol, sucrose fatty acid ester, glycerine fatty acid ester, propylene glycol, triethyl citrate, castor oil and triacetin; and surfactants, e.g. sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxy ethylene 60 hydrogenated castor oil, sorbitan monostearate, and sorbitan monopalmitate can be added as additives.

The amorphous solid dispersion by the melt method can be produced using agitation granulators with heating, for example. More concretely, a mixture of tipiracil hydrochloride and one or more pharmaceutically acceptable carriers can be prepared in advance. The above plasticizers or surfactants can be added to the mixture, if necessary. The conditions such as the treatment temperature and time vary depending on pharmaceutical carrier(s), additives and the like. The treatment temperature can be within the range of room temperature to about 300° C; and the treatment time can be within the range of a few minutes to several hours. The cooling temperature can be within the range of about -100° C. to room temperature.

In twenty eighth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising tipiracil hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing tipiracil hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents;

b) spray drying the mixture to obtain the said amorphous solid dispersion.

In the present invention, the pharmaceutically acceptable carrier is polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) that can be dissolved in any suitable solvent.

In step (b) amorphous solid dispersion of tipiracil hydrochloride with polyvinylpyrrolidone is isolated from the solution obtained in step (a). Isolation of amorphous solid dispersion of tipiracil hydrochloride and polyvinylpyrrolidone in step (b) can involve methods including removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying or any other suitable technique. Preferably, spray drying technique can be used for the isolation of amorphous solid dispersion of tipiracil hydrochloride and pharmaceutically acceptable carrier. The spray drying technique involves dissolving tipiracil hydrochloride and pharmaceutically acceptable carrier in suitable solvent or mixtures thereof. The solution can be spray dried at 100° C, at a feed rate of 3 ml/min. to 15 ml/minute, at a flow rate of 10 rpm, and at 2 kg/cm2 atomization pressure. The amorphous solid dispersion of tipiracil hydrochloride and pharmaceutically acceptable carrier as isolated can carry some amount of occluded mother liquor and can have higher than desired levels of impurities. If desired, this amorphous form can be washed with a solvent or a mixture of solvents to wash out the impurities.

The recovered solid can optionally be dried.

Suitable solvents include any solvents that have no adverse effect on the compound as well as pharmaceutically acceptable carrier and can dissolve them to a useful extent. The solvents that can be used during spray drying is selected from, but is not limited to, nitriles, ketones, ethers, esters, alcohols, amides, sulfoxides, aromatic hydrocarbons, halogenated hydrocarbons, polar protic solvents, polar aprotic solvents or mixtures thereof. Preferably, the solvent used is a mixture of methanol and water at the ratio of 2: 1 , more preferably 1.5:1 and most preferably 1 : 1.

In twenty ninth embodiment, the present invention provides pharmaceutical composition comprising amorphous solid dispersion of tipiracil hydrochloride and pharmaceutically acceptable carriers. In the present invention, the pharmaceutically acceptable carrier is polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC).

Amorphous form of tipiracil hydrochloride or amorphous solid dispersion comprising tipiracil hydrochloride can be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations can be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions can be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that can comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The formulation can be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation can be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

All PXRD data reporting is carried out using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper a radiation wavelength 1.5418 A.

For XRD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 2-theta values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus about 0.2°.

Differential scanning calorimetric analyses were carried out in a Mettler Toledo DSC 1 system operating with STAR⁶ with a ramp of 10° C. /minute. The starting temperature was 25° C. and ending temperature was 300° C.

According to thirtieth embodiment, the present invention provides novel intermediates used in preparation of tipiracil HC1:

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

Example 1

Preparation of ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate from ethyl 4-(benzyloxy)-3- oxobutanoate To a solution of ethyl 4-(benzyloxy)-3-oxobutanoate (10.0 g 0.04232 moles) and catalytic amount of N, N-dimethylformamide in dichloromethane, thionyl chloride (6.04 g, 0.05078 moles) was added drop wise. Reaction mixture was stirred at reflux temperature. The progress of reaction was monitored by TLC. After completion of the reaction water (50 ml) was added. Product was extracted with dichloromethane (25 ml X 2) and washed with 10% potassium bicarbonate solution (50 ml). Finally organic layer was washed with water (50 ml), sodium chloride solution (50 ml) and dried over sodium sulfate. Organic layer was distilled under vacuum to give ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate (9.8 g).

Yield: 85.58%

Example 2

Preparation of 6-((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione from ethyl 4- (benzyloxy)-2-chloro-3-oxobutanoate

A mixture of ethyl 4-(benzyloxy)-2-chloro-3-oxobutanoate (9.0 g, 0.03324 moles) and urea (2.0 g, 0.03324 moles) in polyphosphoric acid (45 ml) was heated under reflux temperature for 24 h. After the completion of reaction, the mixture was cooled and poured into ice-cold water (450 ml) and stirred for lh at 0-10°C. The obtained solid was filtered and further washed with cold water (18 ml X 2). The product was dried in air tray dryer at 45-55°C for 6-8 hours to give 6- ((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione as brown solid (6.2 g).

Yield: 69.97%

Example 3

Synthesis of 5-chloro-6-(hydroxymethyl) pyrimidine-2, 4(1H, 3H)-dione from 6- ((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione

To a solution of 6-((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione (5.0 g, 0.01874 moles) in ethanol (50 ml), 10% Pd/C (0.5 g) and ammonium format (2.36 g, 0.03748 moles) was added. The reaction mixture was stirred at reflux temperature and completion of reaction was monitored with TLC. After completion of reaction, reaction mass was filtered through hyflo bed and washed with ethanol (5 ml X 2). Solvent was distilled under vacuum to give the solid residue. Obtained solid residue was dissolved in water and was extracted with ethyl acetate (25 ml X 3). Organic layer was separated with the aqueous layer and further washed with water (25 ml) and sodium chloride solution (25 ml) and was dried over sodium sulphate and finally distilled under vacuum. The crude product obtained was purified in acetone (50 ml) to give 5- chloro-6-(hydroxymethyl) pyrimidine-2, 4(1H, 3H)-dione as white solid (4.2 g).

Yield: 70.51 %

Example 4 Synthesis of 5-chloro-6-(chloromethyl) pyrimidine-2, 4(1H, 3H)-dione from 5-chloro-6- (hydroxymethyl) pyrimidine-2, 4(1H, 3H)-dione

To a solution of 5-chloro-6-(hydroxymethyl)pyrimidine-2,4(lH,3H)-dione (4.0 g, 0.02265 moles) and catalytic amount of N,N-dimethylformamide in dichloromethane (40 ml), thionyl chloride (3.23 g, 0.02718 moles) was added drop wise. The reaction mixture was stirred at reflux temperature and completion of reaction was monitored by TLC. After completion of reaction water (40 ml) was added in the reaction mixture and the product was extracted with dichloromethane (20 ml X 2) which was further washed with 10% potassium bicarbonate solution (20 ml). Organic layer was separated from the aqueous layer and further washed with water (20 ml) and sodium chloride solution (20 ml) and dried over sodium sulfate and finally distilled under vacuum to give 5-chloro-6-(chloromethyl) pyrimidine-2, 4(1H, 3H)-dione as brown solid (3.8 g).

Yield: 85.97%

Example 5

Preparation of 6-((benzyloxy) methyl) pyrimidine-2, 4(1H, 3H)-dione from ethyl 4- (benzyloxy)-3-oxobutanoate.

A mixture of ethyl 4-(benzyloxy)-3-oxobutanoate (25 g, 0.1519 moles) and urea (9.12 g, 0.1519 moles) in polyphosphoric acid (75 ml) was heated under reflux for 24 h. After completion of reaction, the mixture was cooled and poured into ice-cold water (450 ml) and was stirred for lh at 0-10°C. Obtained solid was filtered and washed with cold water (25 ml X 2). The product was dried in air tray dryer at 45-55°C for 6-8 hours to give 6-((benzyloxy)methyl)pyrimidine- 2,4(lH,3H)-dione compound as brown solid (15.0 g).

Yield: 60.19%

Example 6 Preparation of 6-((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione from 6- ((benzyloxy) methyl) pyrimidine-2, 4(1H, 3H)-dione

To a suspension of 6-((benzyloxy)methyl)pyrimidine-2,4(lH,3H)-dione (15 g, 0.06458 mole) in acetic acid (75 ml), sulfuryl chloride was added (10.46 g, 0.07751 moles) at 50°C. The progress of reaction was monitored by TLC. After completion of reaction, reaction mass was cooled to 0- 10°C and cold (0-10°C) water (75 ml) was added to the reaction mixture. The solid was filtered and washed with water (15 ml x 2) followed methanol (15 ml X 2) wash. The solid was dried at 50-60°C in air tray drier for 3 h to give 6-((benzyloxy)methyl)-5-chloropyrimidine-2,4(lH,3H)- dione compound as white solid (16.2 g).Yield: 94.02%

Example 7 Synthesis of 5-chloro-6-(hydroxymethyl) pyriniidine-2, 4(1H, 3H)-dione from 6- ((benzyloxy) methyl)-5-chloropyrimidine-2, 4(1H, 3H)-dione

To a solution of 6-((benzyloxy)methyl)-5-chloropyrimidine-2,4(lH,3H)-dione (10.0 g, 0.03749 moles) in ethanol (100 ml), 10% Pd/C (1 g) and ammonium format (4.72 g, 0.07499 moles) was added at room temperature. The reaction mixture was stirred at reflux temperature and completion of reaction was monitored with TLC. After completion of reaction, reaction mass was filtered through hyflo bed and washed with ethanol (10 ml X 2). Solvent was distilled under vacuum to give the solid residue. Obtained solid residue was dissolved in water (50 ml) and was extracted with ethyl acetate (50 ml X 2). Organic layer was separated with the aqueous layer and further washed with water (25 ml) and sodium chloride solution (25 ml) and was dried over sodium sulphate and finally distilled under vacuum. The crude product obtained was purified in acetone (50 ml) to give 5-chloro-6-(hydroxymethyl) pyrimidine-2, 4(1H, 3H)-dione (5.5 g). Yield: 75.52%

Example 8

Preparation of 5-chloro-6-((2-iminopyrrolidin-l-yl) methyl) pyrimidine-2, 4(1H, 3H)-dione hydrochloride (Tipiracil HC1)

To a suspension of 5-chloro-6-(chloromethyl)pyrimidine-2,4(lH,3H)-dione (25 g, 0.1282 mole) in Ν,Ν-dimethyl formamide (250 ml), 2-amino-l-pyrroline hydrochloride (30.91 g, 0.2564 mole) and sodium ethoxide (26.17 g, 0.3846 mole) was added. The reaction was stirred at room temperature for 18 hours. The progress of reaction was monitored by TLC. After completion of reaction the solid was filtered to give a pale brown cake. 75 ml of water was added to the wet cake and pH=7 was adjusted with acetic acid. Solid was filtered and the wet cake obtained was dissolved in 125 ml of aqueous hydrochloric acid solution at 60°C, to which activated carbon was added and stirred for 30 minute at 60°C. The mass was filtered on hyflo bed and washed with water (25 ml). Filtrate obtained was cooled to 0-10°C and acetone (750 ml) was added drop wise under stirring. The reaction mass was stirred for 2 hours at 0-10°C. The solid was filtered and washed with mixture of acetone: water (6: 1) (5 ml X 2) which was further dried at 50°C for 10 hours to give white product (18.5 g). Yield: 51.70%

Example 9

Preparation of dimethylsulfoxide (DMSO) solvate of tipiracil hydrochloride

Tipiracil free base (50 g) was added in dimethylsulfoxide solvent (DMSO) (500 ml) and was stirred for 10 min. 40 %w/v of hydrochloric acid (22.6 ml) was added slowly in the reaction mixture and was stirred for 6 hours. The solid obtained was filtered and dried using vacuum try drier at 55-65°C. Yield: 70.7%. The XRPD pattern, DSC curve and TGA curve are substantially in accordance with figure 1 , 2 and 3 respectively.

Example 10

Preparation of N, N-dimethylacetamide (DMAc) solvate of tipiracil hydrochloride

Tipiracil free base (65g) was added in water (325 ml) and was stirred for 10 min. 40 %w/v of hydrochloric acid (48.9 ml) was added slowly in the reaction mixture and the reaction mixture was heated at 85-95°C. The solution obtained was filtered. DMAc (1300 ml) was added slowly in the solution of the reaction mixture and the reaction mass was further cooled to room temperature. The solid obtained was filtered and washed with DMAc solvent and dried at 45- 55°C.

Yield: 73.35%. The XRPD pattern is substantially in accordance with figure 4.

Example 11

Preparation of N, N-dimethylacetamide (DMAc) solvate of tipiracil hydrochloride

Tipiracil HC1 (5g) was added in water (25 ml) and was stirred for 10 min. The reaction mixture was heated at 55-65°C and stirred for 15 min. DMAc solvent (100 ml) was slowly added within 15-20 min. The reaction mass was further cooled to room temperature and stirred for 12 hr. The solid obtained was filtered and washed with DMAc solvent and dried at 45-55°C.

Yield: 54.96%. The XRPD pattern is substantially in accordance with figure 4.

Example 12

Preparation of N-methyl-2-pyrrolidone (NMP) solvate of tipiracil hydrochloride

5g of tipiracil HC1 was added in water (30 ml) and stirred for 10 min. the reaction mixture was heated to 65°C and was stirred for 15 min. N-methyl-2-pyrrolidone (100 ml) was slowly added in the reaction mixture within 15-20 min. The reaction mass was cooled along with stirring. Reaction mass was further cooled to 0-10°C. Seeds of NMP solvate was added and stirred for 2 hours. The solid obtained was filtered and washed with NMP solvent (5 ml). The solid was dried at 45-55°C.

Yield: 42.64%. The XRPD pattern is substantially in accordance with figure 5.

Example 13

Preparation of Form-A of tipiracil hydrochloride

500 mg of tipiracil was added in pre-heated 20 ml of methanol at 50 °C. Water was added drop wise to methanol till the formation of clear solution. Intermittently solution was shaken to dissolve drug into the solvent. The solution was maintained at 50 °C for 10 min. The solution was filtered and kept for drying at room temperature.

Yield: 88.24%. The XRPD pattern is substantially in accordance with figure 6. Example 14

Preparation of Crystal II of tipiracil hydrochloride

500 mg of tipiracil HCl was added in pre-heated 20 ml of ethanol at 50 °C. Water was added drop wise to ethanol till the formation of clear solution. Intermittently the solution was shaken to dissolve the drug into the solvent. The solution was maintained at 50 °C for 10 min. The solution was filtered and kept for drying at room temperature.

Yield: 86.13%. The XRPD pattern is substantially in accordance with figure 7.

Example 15

Preparation of amorphous tipiracil hydrochloride

Tipiracil HCl (2g) was added in 100 ml of methanol and water (50:50) mixture. The reaction mixture was heated at 60°C to make a clear solution. Once the clear solution was obtained then it was spray dried to obtain amorphous tipiracil hydrochloride. Parameters for spray drying: Inlet temperature was kept 100°C and the outlet temperature was 40°C, aspirator speed was kept at 1350 rpm, atomization pressure was kept at 2 kg/cm2 and flow rate at 10 rpm.

The XRPD pattern is substantially in accordance with figure 8.

Example 16

Preparation of amorphous solid dispersion of tipiracil hydrochloride with polyvinylpyrrolidone (PVP)

Tipiracil HCl (2g) and polyvinylpyrrolidone (PVP) (2g) was added in 100 ml of methanol and water (50:50) mixture. The reaction mixture was heated at 60°C to make a clear solution. Once the clear solution was obtained then it was spray dried to obtain amorphous tipiracil hydrochloride. Parameters for spray drying: Inlet temperature was kept 100°C and the outlet temperature was 40°C, aspirator speed was kept at 1350 rpm, atomization pressure was kept at 2 kg/cm2 and flow rate at 10 rpm.

The XRPD pattern is substantially in accordance with figure 9.

Example 17

Preparation of amorphous solid dispersion of tipiracil hydrochloride with hydroxypropylmethylcellulose (HPMC)

Tipiracil HCl (2g) and hydroxypropylmethylcellulose (HPMC) (2g) was added in 100 ml of methanol and water (50:50) mixture. The reaction mixture was heated at 60°C to make a clear solution. Once the clear solution was obtained then it was spray dried to obtain amorphous tipiracil hydrochloride. Parameters for spray drying: Inlet temperature was kept 100°C and the outlet temperature was 40°C, aspirator speed was kept at 1350 rpm, atomization pressure was kept at 2 kg/cm2 and flow rate at 10 rpm. The XRPD pattern is substantially in accordance with fig

Claims

v We claim:

1) A crystalline dimethylsulfoxide (DMSO) solvate of tipiracil HCl.

2) The crystalline dimethylsulfoxide (DMSO) solvate of tipiracil HCl according to claim 1, having an X-ray diffraction pattern comprising characteristic peaks at 20 value of about 8.0°, 11.6°, 16.0°, 17.0°, 22.5°, 22.7°, 24.0°, 24.3°, 26.4°, 27.5°, 27.9°, 30.1°, 31.6° and 38.1 ± 0.2°.

3) The crystalline dimethylsulfoxide (DMSO) solvate of tipiracil HCl according to claim 1, having an X-ray diffraction pattern with peaks substantially in accordance with figure 1.

4) A pharmaceutical composition comprising the crystalline dimethylsulfoxide (DMSO) solvate of tipiracil HCl according to claim 1 and a pharmaceutically acceptable carrier.

5) A process for preparing crystalline dimethylsulfoxide (DMSO) solvate of tipiracil HCl, comprising:

d) addition of tipiracil base in dimethylsulfoxide solvent;

e) adding concentrated HCl in step a; and

f) isolating tipiracil HCl dimethylsulfoxide solvate.

6) A crystalline N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl.

7) The crystalline N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl according to claim 6, having an X-ray diffraction pattern comprising characteristic peaks at 2Θ value of about 8.9°, 9.0°, 11.6°, 13.0°, 13.7°, 16.5°, 16.7°, 16.9°, 17.0°, 18.7°, 19.2°, 21.2°, 22.3°, 22.4°, 22.8°, 23.5°, 24.3°, 24.4°, 25.6°, 26.1°, 26.3°, 26.6°, 27.9°, 28.2°, 28.6°, 28.7°, 29.1°, 29.4°, 29.7°, 31.0°, 32.1°, 35.3° and 39.6 ± 0.2°.

8) A pharmaceutical composition comprising the crystalline N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl according to claim 6 and a pharmaceutically acceptable carrier.

9) A process for preparing crystalline N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl according to claim 6, comprising:

a) addition of tipiracil base in water;

b) adding concentrated HCl in step a;

c) adding N, N-dimethylacetamide in step b; and

d) isolating tipiracil HCl N, N-dimethylacetamide solvate.

10) A process for preparing crystalline N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl according to claim 6, comprising:

a) addition of tipiracil HCl in water;

b) adding N, N-dimethylacetamide in step a; and

c) isolating tipiracil HCl N, N-dimethylacetamide solvate. 11) A crystalline N-methylpyrrolidine (NMP) solvate of tipiracil HCl.

12) The crystalline N-methylpyrrolidine (NMP) solvate of tipiracil HCl according to claim 11, having an X-ray diffraction pattern comprising characteristic peaks at 2Θ value of about 7.1°, 8.9°, 11.4°, 11.5°, 12.8°, 13.7°, 14.3°, 16.4°, 16.8°, 17.1°, 17.8°, 18.8°, 19.3°, 19.5°, 21.3°, 21.5°, 22.1°, 23.0°, 23.2°, 23.6°, 24.4°, 24.6°, 25.0°, 25.7°, 26.0°, 26.4°, 27.0°, 27.4°,

27.9°, 28.4°, 29.2°, 29.6°, 30.4°, 31.7°, 32.7°, 33.4° and 38.0 ± 0.2°.

13) A pharmaceutical composition comprising the crystalline N-methylpyrrolidine (NMP) solvate of tipiracil HCl according to claim 11 and a pharmaceutically acceptable carrier.

14) A process for preparing crystalline N-methylpyrrolidine (NMP) solvate of tipiracil HCl according to claim 11, comprising:

a) addition of tipiracil HCl in water;

b) adding N-methylpyrrolidine in step a;

c) optionally seeding the solution of step b; and

d) isolating tipiracil HCl N-methylpyrrolidine solvate.

15) A crystalline form-A of tipiracil HCl.

16) The crystalline form-A of tipiracil HCl according to claim 15, having an X-ray diffraction pattern comprising characteristic peaks at 2Θ value of about 9.4°, 9.9° and, 10.5 ± 0.2°.

17) A pharmaceutical composition comprising the crystalline form-A of tipiracil HCl according to claim 15 and a pharmaceutically acceptable carrier.

18) A process for preparing form-A of tipiracil HCl according to claim 15, comprising:

a) adding tipiracil HCl in pre-heated methanol;

b) adding water in step a; and

c) isolating crystalline form-A of tipiracil HCl.

19) The process according to claim 18, wherein the temperature of pre-heated methanol is 50° C.

20) A process for preparing Crystal II of tipiracil HCl, comprising:

a) adding tipiracil HCl in pre-heated ethanol;

b) adding water in step a;

c) slowly evaporating ethanol at room temperature; and

d) isolating Crystal II of tipiracil HCl.

21) Amorphous tipiracil HCl.

22) The amorphous tipiracil HCl according to claim 21, substantially in accordance with figure 8. 23) The pharmaceutical composition comprising the amorphous tipiracil HCl according to claim 21 and a pharmaceutically acceptable carrier.

24) A process for preparing an amorphous tipiracil HCl according to claim 21, comprising: c) providing a solution of tipiracil hydrochloride in a solvent; and

d) isolating amorphous form of tipiracil hydrochloride.

25) The process according to claim 24, wherein the solvent is mixture of methanol and water.

26) The process according to claim 24, wherein the solvent is a 50:50 mixture by volume of methanol and water.

27) An amorphous solid dispersion of tipiracil HCl comprising tipiracil HCl and a pharmaceutically acceptable carrier.

28) An amorphous solid dispersion of tipiracil HCl according to claim 27, comprising tipiracil HCl and polyvinylpyrrolidone (PVP).

29) A pharmaceutical composition comprising the amorphous solid dispersion of tipiracil HCl according to claim 27 together with one or more pharmaceutically acceptable carriers.

30) The pharmaceutical composition comprising the amorphous solid dispersion of tipiracil HCl according to claim 29 together with polyvinylpyrrolidone (PVP).

31) An amorphous solid dispersion of tipiracil HCl with polyvinylpyrrolidone (PVP) according to claim 28, substantially in accordance with figure 9.

32) An amorphous solid dispersion of tipiracil HCl according to claim 27, comprising tipiracil HCl and hydroxypropylmethylcellulose (HPMC).

33) The pharmaceutical composition comprising the amorphous solid dispersion of tipiracil HCl according to claim 29 together with hydroxypropylmethylcellulose (HPMC).

34) An amorphous solid dispersion of tipiracil HCl with hydroxypropylmethylcellulose (HPMC) according to claim 32, substantially in accordance with figure 10.

35) A process for preparing an amorphous solid dispersion of tipiracil HCl according to claim 27 together with one or more pharmaceutically acceptable carriers, comprising:

c) dissolving or dispersing the tipiracil hydrochloride and the one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and

d) spray drying the mixture to obtain the amorphous solid dispersion.

36) The process according to claim 35, wherein the one or more pharmaceutically acceptable carriers is selected from polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC).

37) The process according to claim 35, wherein the solvent is a mixture of methanol and water. 38) The process according to claim 37, wherein the solvent is a 50:50 mixture by volume of methanol and water.

39) A process for preparing an amorphous solid dispersion of tipiracil HC1 according to claim 27 together with one or more pharmaceutically acceptable carriers, comprising:

d) isolating the amorphous solid dispersion comprising the tipiracil hydrochloride and the one or more pharmaceutically acceptable carriers.

40) The process according to claim 39, wherein the one or more pharmaceutically acceptable carriers is selected from polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose

(HPMC).

41) The process according to claim 39, wherein the solvent is a mixture of methanol and water.

42) The process according to claim 41, wherein the solvent is a 50:50 mixture by volume of methanol and water.

43) A process for preparing an amorphous solid dispersion of tipiracil HC1 according to claim 27 together with one or more pharmaceutically acceptable carriers, comprising:

c) dissolving or dispersing the tipiracil hydrochloride under heating in the one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and d) cooling down the mixture.

44) The process according to claim 43, wherein the one or more pharmaceutically acceptable carriers is selected from polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC).

45) The process according to claim 43, wherein the solvent is a mixture of methanol and water.

46) The process according to claim 45, wherein the solvent is a 50:50 mixture by volume of methanol and water.

47) A process for preparing tipiracil of formula (I) or salt thereof:

which comprises, f) chlorinating compound of formula (II) with a chlorinating agent to give compound of formula (III)

(II) (ill) wherein Ri is acid protecting group and R2 is alcohol protecting group; g) reacting compound of formula (III) with urea to obtain compound of formula (IV);

h) deprotecting compound of formula (IV) to obtain compound of formula (V);

i) chlorinating compound of formula (V) with a chlorinating agent to obtain compound of formula (VI); and

j) reacting compound of formula (VI) with 2-iminopyrrolidine or salt thereof to obtain tipiracil of formula (I) or salt thereof.

48) The process according to claim 47, wherein Ri is an acid protecting group selected from methyl, ethyl, propyl and benzyl; and R2 is an alcohol protecting group selected from benzoyl, acetyl and trifluoroacetyl.

49) The process according to claim 47, wherein the chlorinating agent in step (a) and step (d) is selected from the group consisting of pivaloyl chloride, thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, N- chlorosuccinimide, N-chlorobenzotriazole and sulfuryl chloride. 50) The process according to claim 49, wherein the chlorinating agent in step (a) is thionyl chloride.

51) The process according to claim 49, wherein the chlorinating agent in step (d) is sulfuryl chloride.

52) The process according to claim 47, wherein step (a) and step (d) is optionally done in the presence of a chlorination catalyst selected from the group consisting of N, N- dimethylformamide, N, N-diethylformamide and pyridine.

53) The process according to claim 52, wherein the chlorination catalyst in step (a) and step (d) is N, N-dimethylformamide.

54) The process according to claim 47, wherein step (a) to step (e) is optionally done in the presence of a solvent selected from the group consisting of halogenated hydrocarbons, aromatic hydrocarbon, nitrile, ester, ketone, amides, sulfoxides, alcohols and water.

55) The process according to claim 47, wherein step (b) is optionally done in the presence of a cyclizing agent selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulphuric acid, concentrated sulphuric acid - silica, polyphosphoric acid, sulphuryl chloride, p- toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid and acetic anhydride.

56) The process according to claim 55, wherein the cyclizing agent is polyphosphoric acid.

57) The process according to claim 47, wherein step (c) is done in the presence of a deprotecting agent selected from the group consisting of hydrogen and palladium on carbon (¾, Pd/C), ammonium formate and palladium on carbon (NH₄HCO₂, Pd/C), hydrogen and palladium hydroxide on carbon (H₂, Pd(OH)₂/C), combination of Pd/C and Pd(OH)₂/C, lithium 4,4 '-Di- tert-butylbiphenylide (Li.DTBBP), sodium, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), and trimethylsilyl chloride - sodium iodide (TMSC1, Nal).

58) The process according to claim 57, wherein the deprotecting agent is palladium on carbon (¾, Pd/C) and ammonium formate.

59) The process according to claim 47, wherein step (e) is done in the presence of an inorganic base selected from the group consisting of metal alkoxide, metal carbonates, metal bicarbonates, metal hydroxides, metal hydride, metal amide and metal phosphates or in the presence of organic base.

60) The process according to claim 59, wherein the base in step (e) is metal alkoxide selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, magnesium methoxide, magnesium ethoxide and magnesium tert-butoxide.

61) The process according to claim 60, wherein the base is sodium ethoxide.

62) A process for preparing tipiracil of formula (I) or salt thereof:

which comprises, f) reacting compound of formula (II) with urea to give compound of formula (VII)

wherein Ri is acid protecting group and R2 is alcohol protecting group; g) chlorinating compound of formula (VII) with a chlorinating agent to obtain compound of formula (IV);

h) deprotecting compound of formu compound of formula (V);

(V) i) chlorinating compound of formula (V) with a chlorinating agent to obtain compound of formula (VI); and

63) The process according to claim 62, wherein Ri is an acid protecting group selected from methyl, ethyl, propyl and benzyl; and R₂ is an alcohol protecting group selected from benzoyl, acetyl and trifluoroacetyl.

64) The process according to claim 62, wherein step (a) is optionally done in the presence of a cyclizing agent selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulphuric acid, concentrated sulphuric acid - silica, polyphosphoric acid, sulphuryl chloride, p- toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid and acetic anhydride.

65) The process according to claim 64, wherein the cyclizing agent is polyphosphoric acid.

66) The process according to claim 62, wherein step (a) to step (e) is optionally done in the presence of a solvent selected from the group consisting of halogenated hydrocarbons, aromatic hydrocarbon, nitrile, ester, ketone, amides, sulfoxides, alcohols and water.

67) The process according to claim 62, wherein the chlorinating agent in step (b) and step (d) is selected from the group consisting of pivaloyl chloride, thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, N- chlorosuccinimide, N-chlorobenzotriazole and sulfuryl chloride.

68) The process according to claim 67, wherein the chlorinating agent in step (b) is thionyl chloride.

69) The process according to claim 67, wherein the chlorinating agent in step (d) is sulfuryl chloride.

70) The process according to claim 62, wherein step (b) and step (d) is done in the presence of a chlorination catalyst selected from the group consisting of N, N-dimethylformamide, N, N- diethylformamide and pyridine.

71) The process according to claim 70, wherein the chlorination catalyst in step (b) and step (d) is N, N-dimethylformamide. 72) The process according to claim 62, wherein step (c) is done in the presence of a deprotecting agent selected from the group consisting of hydrogen and palladium on carbon (¾, Pd/C), ammonium formate and palladium on carbon (NH₄HCO₂, Pd/C), hydrogen and palladium hydroxide on carbon (H₂, Pd(OH)₂/C), combination of Pd/C and Pd(OH)₂/C, lithium 4,4 '-Di- tert-butylbiphenylide (Li.DTBBP), sodium, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), and trimethylsilyl chloride - sodium iodide (TMSC1, Nal).

73) The process according to claim 72, wherein the deprotecting agent is palladium on carbon (¾, Pd/C) and ammonium formate.

74) The process according to claim 62, wherein step (e) is done in the presence of an inorganic base selected from the group consisting of metal alkoxide, metal carbonates, metal bicarbonates, metal hydroxides, metal hydride, metal amide and metal phosphates or in the presence of organic base.

75) The process according to claim 74, wherein the base in step (e) is metal alkoxide selected from the group consisting ofsodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, magnesium methoxide, magnesium ethoxide and magnesium tert-butoxide.

76) The process according to claim 75, wherein the base is sodium ethoxide.

77) A compound selected from:

