The following specification describes the nature of the invention:

PREPARATION OF PYRIMIDINE DERIVATIVES

INTRODUCTION

The present application concerns an improved process for the preparation of 5-aminopyrimidines which are useful intermediates in the preparation of pharmaceutically active triazolo[4 5-d]pyrimidine cyclopentanes.

The compound [1S-(1? 2? 3?(1S* 2R*) 5?)]-3-[7-[2-(3 4-difluorophenyl-cyclopropyl]amino]-5-(propylthio)-3H-1 2 3-triazolo[4 5-d]pyrimidin-3-yl)-5-(2-hydroxy ethoxy)-cyclopentane-1 2-diol (ticagrelor) and similar such compounds are disclosed in WO 00/34283 and WO 99/05143 as pharmaceutically active P2T (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as inter alia as inhibitors of platelet activation aggregation or degranulation. Compounds of Formula I are useful in the preparation of ticagrelor or analogues thereof. The present application provides a process for the preparation of the compounds of Formula I (amine) of high purity:

Formula I
wherein X is independently halogen.

Processes for the preparation of compound of Formula I and its precursor nitro compound are described in Patent Application Publications Larsson WO2005/095358A2 Quittmann WO2007/093368A1 Aufdenblatten WO2011/036479A2 Khile WO2011/101740A1 Hardern WO 99 /5142 A1 Rao WO 2011/017108 A2 and Ingall EP 0 508 687 A1. These publications involve use of reagents like zinc/acetic acid transition metal catalyst to materialize reduction of nitro group and/or purification of precursor nitro compound by column chromatography which is tedious and not feasible industrially. The methods described above give low yields or involves use of expensive reagents or do not directly result in desired purities of the intermediate compounds of Formula I. Since the purity of intermediate compound play a major role in deciding the efficiency of the process for final compound therefore there remains a need to prepare compounds of Formula I of high purity and in good yield. Despite the efforts of the research aimed at finding alternative routes it would be desirable to study methods for preparing intermediate compound of Formula I which allow overcoming the drawbacks presented by the processes described in the art in particular with the aim of by-passing the chromatographic step and alleviating the use of expensive reducing agents.

The present application provides a cost-effective process for preparation of compound of Formula I of high purity by employing inexpensive reagents removing/controlling the impurities by techniques at origin of the impurities.

SUMMARY

The present application provides a process for the preparation of the compounds of Formula I (amine)

Formula I
wherein X is independently halogen.

DETAILED DESCRIPTION

The present application provides a process comprising:

a) reaction of thiourea with diethylmalonate in presence of suitable base and solvent to afford 2-thiobarbituric acid of Formula II;

Formula II
b) alkylation of 2-thiobarbituric acid with a suitable alkylating agent in presence of a suitable base and solvent to afford the compound of Formula III;

Formula III
c) nitration of the compound of Formula III to afford the compound of Formula IV;

Formula IV
d) halogenation of the compound of Formula IV with a suitable halogenating agent to afford the compounds of Formula V:

Formula V
wherein X is independently halogen; and

e) reduction of the compounds of Formula V with a suitable reducing agent to afford a compound of Formula I

Formula I

Step a) involves condensation of thiourea and diethylmalonate in presence of suitable base and solvent to afford compound of Formula II. In embodiments methanol is employed. Suitable bases that may be employed include but are not limited to: inorganic bases such as for example sodium hydroxide potassium hydroxide sodium methoxide potassium tertiarybutoxide or sodium tertiarybutoxide.

Step b) involves alkylation of 2-thiobarbituric acid to afford compound of Formula III. The base employed in step b) include but are not limited to inorganic bases such as alkali metal hydroxides alkali metal carbonates alkaline metal hydroxides alkaline metal carbonates or ammonium hydroxide or organic bases such as N N-diethylaniline triethylamine 4-dimethylaminopyridine (DMAP) dicyclohexylamine or diisopropylethylamine. The base can be directly added as a solid or liquid or its mixtures with a solvent can be employed. In embodiments a mixture of water and N-methyl pyrrolidone is employed. The reaction can be efficiently conducted at room temperature or ambient temperature or if desired the reaction mass can be heated to elevated temperatures up to about the solvent reflux temperature. Suitable alkylating agents are any electrophile capable of delivering a propyl radical to a sulfur nucleophile. Examples of such suitable alkylating agents include but are not limited to propyl chloride propyl bromide propyl iodide propyl triflate propyl mesylate propyl tosylate or propyl acetate. In embodiments the suitable alkylating agent is propyl bromide or propyl iodide.

Step c) involves nitration of compound of Formula III. Conventional nitrating agents can be employed. In one embodiment mixture of fuming nitric acid and acetic acid is used. In embodiments the reaction of step c) include adding a precooled nitrating mixture to compound of Formula III or adding a compound of Formula III to a precooled nitrating mixture. After mixing of compound of Formula III with a nitrating mixture reaction can efficiently be conducted at room temperature or ambient temperature. Compound of Formula III can be added as a solid or by taking in a suitable solvent which is inert to the reaction conditions.

Step d) involves halogenation of the compound of Formula IV. X can be any halogen. In one embodiment X is chlorine. Conventional halogenating agents known in the art can be employed in step d) such as thionyl chloride phosphorus oxychloride phosphorus pentachloride dry hydrochloric acid gas etc. In one embodiment phosphorus oxychloride can be employed. The halogenation step can optionally be carried out in the presence of suitable solvent or else neat reaction can be performed. The mixing of compound of Formula IV with a halogenating agent is preferably done at room temperature or at a temperature less than ambient temperature. Suitable temperature for the reaction can be reflux temperature of the reaction mixture or any other suitable temperature. Suitable bases that can be employed in step d) include but are not limited to: organic bases such as N N-diethylaniline triethylamine 4-dimethylaminopyridine (DMAP) dicyclohexylamine diisopropylethylamine or the like; or inorganic bases such as metal hydroxides carbonates or bicarbonates. A specific example of a useful base is N N-diethylaniline. The reaction may be carried out for any desired time periods to achieve the desired product yield and purity.

Step e) involves reduction of compound of Formula V with a suitable reducing agent in a suitable solvent. Suitable reducing agents employed in step e) includes but not limited to dithionate sources like sodium- lithium- potassium- calcium- magnesium- a tetraalkylammonium- or a guanidinium-dithionate sodium hydrosulfite sodium sulfide iron in acidic media or the like known in the art. In embodiments sodium dithionate is employed. In embodiments 1 4-dioxane or its mixture with water is employed.

The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis said suitable solvents generally being any solvent which is substantially non-reactive with the starting materials (reactants) the intermediates or products at the temperature at which reactions are carried out i.e. temperatures which may range from the solvents freezing temperature to the solvents boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step suitable solvents for a particular reaction step may be selected.

Suitable solvents may include but are not limited to: alcohols such as for example methanol ethanol or 2-propanol; ethers such as for example diisopropyl ether methyl tert-butyl ether diethyl ether 1 4-dioxane tetrahydrofuran (THF) or methyl THF; esters such as for example ethyl acetate isopropyl acetate or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; halogenated hydrocarbons such as dichloromethane dichloroethane chloroform or the like; hydrocarbons such as toluene xylene or cyclohexane; nitriles such as acetonitrile; polar aprotic solvents such as N N-dimethylformamide N N-dimethylacetamide N-methyl pyrrolidone dimethylsulfoxide or the like; water; or any mixtures of two or more thereof.

The compounds at various stages of the process may be isolated using conventional techniques known in the art. For example useful techniques include but are not limited to decantation centrifugation gravity filtration suction filtration concentrating cooling stirring shaking combining a solution with an anti-solvent adding seed crystals evaporation flash evaporation simple evaporation rotational drying spray drying thin-film drying freeze-drying or the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and if desired the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely or almost completely at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including but not limited to tray drying spray drying fluidized bed drying or thin film drying under atmospheric or a reduced pressure.

The isolated solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer vacuum oven air oven fluidized bed dryer spin flash dryer flash dryer or the like at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C less than about 60°C less than about 40°C or any other suitable temperatures in the presence or absence of an inert atmosphere such as nitrogen argon neon or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product such as for example from about 1 hour to about 15 hours or longer.

Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents or by commonly known recrystallization techniques. The suitable recrystallization techniques include but are not limited to steps of concentrating cooling stirring or shaking a solution containing the compound combination of a solution containing a compound with an anti-solvent seeding partial removal of the solvent or combinations thereof evaporation flash evaporation or the like. An anti-solvent as used herein refers to a liquid in which a compound to be purified is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time until the desired purity is attained.

Compounds at various stages of the process may also be purified by slurrying from suitable solvents for example by providing a compound in a suitable solvent if required heating the resulting mixture to higher temperatures subsequent cooling and recovery of compound having a high purity. Optionally precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include but are not limited to: alcohols such as for example methanol ethanol or 2-propanol; ethers such as for example diisopropyl ether methyl tert-butyl ether diethyl ether 1 4-dioxane tetrahydrofuran (THF) or methyl THF; esters such as for example ethyl acetate isopropyl acetate or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; halogenated hydrocarbons such as dichloromethane dichloroethane chloroform or the like; hydrocarbons such as toluene xylene or cyclohexane; nitriles such as acetonitrile or the like; water; or any mixtures of two or more thereof. In one embodiment slurrying process with water is employed.

The present application provides a process comprising reduction of the compounds of Formula V with sodium dithionate (dithionate source) sodium hydrosulfite or sodium sulfide to afford a compound of Formula I

Formula V Formula I

wherein X is independently halogen.

The process further comprising halogenation of the compound of Formula IV:

Formula IV

with a suitable halogenating agent to afford the compounds of Formula V.

The process further comprising nitration of the compound of Formula III:

Formula III to afford the compound of Formula IV.

The process further comprising alkylation of 2-thiobarbituric acid of Formula II:

Formula II

with a suitable alkylating agent in presence of a suitable base and solvent to afford the compound of Formula III.

The process further comprising reaction of thiourea with diethylmalonate in presence of suitable base and solvent to afford 2-thiobarbituric acid of Formula II.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. All percentages and ratios used herein are by weight of the total composition unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and atmospheric pressure unless otherwise designated. All ranges recited herein include the endpoints including those that recite a range "between" two values. As used herein a "room” or “ambient” temperature includes temperature from about 15°C to about 35°C from about 20°C to about 30°C or about 25°C.

As used herein "comprising" means the elements recited or their equivalents in structure or function plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. Terms such as "about " "generally " "substantially " or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes at very least the degree of expected experimental error technique error or instrument error for a given technique used to measure a value.

An “alcohol” is an organic liquid containing a carbon bound to a hydroxyl group including but not limited to methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol i-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol C1-6 alcohols or the like.

An “ether” is an organic liquid containing an oxygen atom –O- bonded to two other carbon atoms including but not limited to diethyl ether diisopropyl ether methyl t-butyl ether glyme diglyme tetrahydrofuran 1 4-dioxane dibutyl ether dimethylfuran 2-methoxyethanol 2-ethoxyethanol anisole C2-6 ethers or the like.

"Halo" or “halogen” refers to fluorine chlorine bromine or iodine.

“Halogenating agent” refers to various inorganic and organic reagents having the functionality of an acid halide. Examples of a “halogenating agent” include but are not limited to oxalyl chloride phosphorus oxychloride phosphorus pentachloride phosphorus trichloride phosgene oxalyl bromide thionyl bromide oxalyl bromide phosphorus oxybromide phosphorus pentabromide phosphorus tribromide phosgene or oxalyl bromide.

A “halogenated hydrocarbon” is an organic liquid containing a carbon bound to a halogen including but not limited to dichloromethane 1 2-dichloroethane trichloroethylene perchloroethylene 1 1 1-trichloroethane 1 1 2-trichloroethane chloroform carbon tetrachloride or the like.

A “ketone” is an organic liquid containing a carbonyl group -(C=O)- bonded to two other carbon atoms including but not limited to acetone ethyl methyl ketone diethyl ketone methyl isobutyl ketone C3-6 ketones or the like.

A “hydrocarbon” is a liquid compound formed from carbon and hydrogen atoms and may be linear branched cyclic saturated unsaturated non-aromatic or aromatic. Examples include but are not limited to n-pentane isopentane neopentane n-hexane isohexane 3-methylpentane 2 3-dimethylbutane neohexane n-heptane isoheptane 3-methylhexane neoheptane 2 3-dimethylpentane 2 4-dimethylpentane 3 3-dimethylpentane 3-ethylpentane 2 2 3-trimethylbutane n-octane isooctane 3-methylheptane neooctane cyclohexane methylcyclohexane cycloheptane C5-C8 aliphatic hydrocarbons petroleum ethers benzene toluene ethylbenzene m-xylene o-xylene p-xylene indane naphthalene tetralin trimethylbenzene chlorobenzene fluorobenzene trifluorotoluene anisole C6-C10 aromatic hydrocarbons or the like.

The phrase "nitrating agent" refers to a compound that introduces a nitro group (O2N-) onto a carbon atom of another compound. Examples of a nitrating agent include tetranitromethane nitric acid; mixtures of nitric acid and another acid such as sulfuric acid or acetic acid; nitric acid and acetic anhydride; N2O5 in the presence of drying agent such as P2O5; esters of nitric acid including but not limited to methyl nitrate and ethyl nitrate in the presence of alkaline media a protic acid or a Lewis acid; metallic nitrites such as sodium nitrite or potassium nitrite in the presence of an acid such as trifluoroacetic acid or sulfuric acid; N2O4; or nitronium salts such as NO2+BF4- NO2+PF6- NO2+CF3SO3-. Other suitable nitrating agents are summarized in Schofield "Aromatic Nitration " (Cambridge University Press Cambridge 1980); and Hogget et al. "Nitration and Aromatic Reactivity " 122-145 163-222 (Cambridge University Press London 1971); each of which is incorporated herein by reference in its entirety.

A “nitrile” is an organic liquid containing a cyano -(C=N) bonded to another carbon atom including but not limited to acetonitrile propionitrile C2-6 nitriles or the like.

A “polar aprotic solvent” has a dielectric constant greater than 15 and includes: amide-based organic solvents such as hexamethyl phosphoramide (HMPA) or hexamethyl phosphorus triamide (HMPT) N-methyl pyrrolidone; nitro-based organic solvents such as nitromethane nitroethane nitropropane or nitrobenzene; ester-based organic solvents such as ?-butyrolactone ethylene carbonate propylene carbonate butylene carbonate dimethyl carbonate or propiolactone; pyridine-based organic solvents such as pyridine or picoline; or sulfone-based solvents such as dimethylsulfone diethylsulfone diisopropylsulfone 2-methylsulfolane 3-methylsulfolane 2 4-dimethylsulfolane 3 4-dimethylsulfolane 3-sulfolene or sulfolane.
Any organic solvents may be used alone or two or more of these or in combination with water in desired ratios could be employed.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES

EXAMPLE 1: PREPARATION OF 2-MERCAPTOPYRIMIDINE-4 6-DIOL (FORMULA II). Thiourea (20 g) methanol (300 mL) and diethyl malonate (39.5 mL) are charged in a round bottom flask and reaction mixture is heated to reflux further maintained at 60-65 oC for 3-4 hours. The reaction mixture is cooled to room temperature and the pH is adjusted to about 2 by addition of aqueous hydrochloric acid (10% 15 mL). The reaction mixture is further maintained at same temperature for 1-2 hours. The solid is isolated by filtration washed with methanol (20 mL) and dried under vacuum at 55-60 oC to afford the title compound in about 64% yield having HPLC purity of about 90%.

EXAMPLE 2: PREPARATION OF SODIUM SALT OF 2-MERCAPTOPYRIMIDINE-4 6-DIOL. Thiourea (20 g) methanol (300 mL) and diethyl malonate (39.5 mL) are charged in a round bottom flask and stirred. To the mixture sodium methoxide (15 g) is added the reaction mixture is heated to reflux and further maintained at 60-65 oC for 3-4 hours. The solid is isolated by filtration washed with methanol (20 mL) and dried under vacuum at 55-60 oC to afford the title compound.

EXAMPLE 3: PREPARATION OF 2-(PROPYLTHIO)-4 6-PYRIMIDINE-DIOL (FORMULA III). 2-Thiobarbituric acid (150 g) and water (500 mL) are charged in a round bottom flask and reaction mixture is subjected to cooling to 15-20 oC. To it aqueous sodium hydroxide solution (94.5 g in 750 mL of water) is added over a period of 1 hour followed by sequential and slow addition of N-methyl pyrrolidinone (310 mL) and propyl iodide (107 mL) at the same temperature in a period of 45 minutes and 20 minutes respectively. The reaction mixture is maintained at the same temperature for about 20-24 hours if required until completion of the reaction as verified by thin layer chromatography (TLC). Then 6M HCl (170 mL) is slowly added to the reaction mixture and the so formed solid is isolated by filtration washed with water (150 mL) and dried to give the title compound in about 79% yield having HPLC purity of about 90.5%.

EXAMPLE 4: PURIFICATION OF 2-(PROPYLTHIO)-4 6-PYRIMIDINE-DIOL (FORMULA III). 2-(Propylthio)-4 6-pyrimidine-diol (5 g) and water (50 mL) are charged in a round bottom flask. To this aqueous sodium hydroxide solution (3 g in 30 mL of water) is added and mixture is stirred for 5-10 minutes. The said mixture is washed with ethyl acetate (2 x 25 mL) and the aqueous layer is separated. The pH of the aqueous layer is adjusted to 2.0 by addition of aqueous hydrochloric acid (10% 15 mL) over a period of 50 minutes at which point a solid precipitated. The reaction mixture is further maintained at room temperature for 1-2 hours. The solid is isolated by filtration washed with water (10 mL) and dried under vacuum at 45-55oC to afford the title compound in about 72% yield having HPLC purity of about 97.5%.

EXAMPLE 5: PREPARATION OF 2-(PROPYLTHIO)-4 6-PYRIMIDINE-DIOL (FORMULA III). 2-Thiobarbituric acid (100 g) and water (350 mL) are charged in a round bottom flask and reaction mixture is subjected to cooling to about 20oC. To it aqueous sodium hydroxide solution (61 g in 500 mL of water) is added over a period of 15 minutes followed by sequential and slow addition of N-methyl pyrrolidinone (200 mL) and propyl bromide (65 mL) at the same temperature. The reaction mixture is maintained at the same temperature for about 20-24 hours if required until completion of the reaction as verified by thin layer chromatography (TLC). The reaction mixture is washed with ethyl acetate (3 x 150 mL). To the reaction mixture i.e. the aqueous layer 6M hydrochloric acid is added over a period of 20 minutes and is stirred for 3-4 hours. The formed solid is isolated by filtration washed with water (200 mL) and dried under vacuum at 55oC to give the title compound in about 69% yield having HPLC purity of about 93.0%.

EXAMPLE 6: PREPARATION OF 2-(PROPYLTHIO)-4 6-PYRIMIDINE-DIOL (FORMULA III). 2-Thiobarbituric acid (20 g) and water (70 mL) are charged in a round bottom flask. To it aqueous sodium hydroxide solution (5.3 g in 60 mL of water) is added over a period of 15 minutes followed by slow addition of propyl bromide (16.3 g) over a period of about 30 minutes at 25-30oC. The reaction mixture is maintained at the same temperature for about 22-24 hours if required until completion of the reaction as verified by thin layer chromatography (TLC). To the reaction mixture 6M aqueous hydrochloric acid (30 mL) is added over a period of 15 minutes and is stirred for 3-4 hours at 25-30oC. The solid is isolated by filtration washed with water (20 mL) and dried under vacuum at 50-55oC to give the title compound in about 72% yield.

EXAMPLE 7: PREPARATION OF 5-NITRO-2-(PROPYLTHIO)PYRIMIDINE-4 6-DIOL (FORMULA IV). 2-(Propylthio)-4 6-pyrimidine-diol (10 g) is slowly added to a mixture of acetic acid (25 mL) and fuming nitric acid (8.5 mL) at 25-35oC over a period of 20 minutes in a round bottom flask. The reaction mixture is maintained at same temperature for 1 hour if required until completion of the reaction as verified by thin layer chromatography (TLC). After completion of reaction reaction mass is poured into water (50 mL) and maintained for 30 minutes. The formed solid is isolated by filtration washed with water (10 mL) and dried to give the title compound in about 73% yield having HPLC purity of about 90.0%.

EXAMPLE 8: PREPARATION OF 4 6-DICHLORO-5-NITRO-2-(PROPYLTHIO)PYRIMIDINE (FORMULA V). 5-Nitro-2-(propylthio)pyrimidine-4 6-diol (8 g) and phosphorus oxychloride (24 mL) are charged in a round bottom flask. To this mixture N N-diethylaniline (11.1 mL) is slowly added at room temperature over a period of 25 minutes. Then the temperature of the reaction mass is raised to 100-110oC and mass is maintained at same for about 2-3 hours until completion of the reaction as verified by TLC. The reaction mixture is cooled to room temperature poured into water (120 mL) and followed by further addition of ethyl acetate (40 mL).The organic layer is separated and desired compound is extracted from aqueous layer using ethyl acetate (2x40 mL). The combined ethyl acetate layer is washed with water (40 mL) followed by its complete evaporation under vacuum at 60-65oC to afford the title compound in about 84% yield having HPLC purity of about 98%.

EXAMPLE 9: PREPARATION OF 4 6-DICHLORO-2-(PROPYLTHIO)PYRIMIDIN-5-AMINE (FORMULA I). 4 6-Dichloro-5-nitro-2-(propylthio)pyrimidine (100 g) 1 4-dioxane (500 mL) and water (500 mL) are charged in a round bottomed flask. To this mixture sodium dithionate (259.6 g) is added and reaction mass is heated to 40-45oCat which temperature it is stirred for 30 minutes until completion of the reaction as verified by TLC. The reaction mixture is cooled to 25-30oC followed by addition of water (500 mL) and ethyl acetate (500 mL). The ethyl acetate layer is separated and the aqueous layer is further extracted with ethyl acetate (500 mL). The combined organic layer is washed with water (500 mL) separated and then subjected to evaporation under vacuum at 60oC. To the obtained residue ethyl acetate (500 mL) is added followed by silica gel (50g). The mixture is filtered under vacuum and the silica gel bed is washed with ethyl acetate (100 mL). The filtrate is subjected to distillation under vacuum at 60oC to afford the title compound in about 77% yield having HPLC purity of about 97%.

EXAMPLE 10: PREPARATION OF 4 6-DICHLORO-2-(PROPYLTHIO)PYRIMIDIN-5-AMINE (FORMULA I). 4 6-Dichloro-5-nitro-2-(propylthio)pyrimidine (50 g) acetone (100 mL) are charged in a round bottomed flask. To this mixture sodium dithionate (130 g) is added and reaction mass is heated to 40-45oC followed by slow addition of water (250 mL) over a period of about 30 minutes. The reaction mass is stirred at the same temperature for 1-2 hour until completion of the reaction as verified by TLC. The reaction mixture is cooled to 25-30oC followed by addition of water (250 mL) and ethyl acetate (250 mL). The ethyl acetate layer is separated and the aqueous layer is further extracted with ethyl acetate (150 mL). The combined organic layer is washed with water (100 mL) separated and then subjected to evaporation under vacuum at 60oC to afford the title compound in about 92% yield having HPLC purity of about 86%.

EXAMPLE 11: PREPARATION OF 4 6-DICHLORO-2-(PROPYLTHIO)PYRIMIDIN-5-AMINE (FORMULA I). 4 6-Dichloro-2-(propylthio)pyrimidin-5-amine (39.6 g obtained in Example 10) and ethyl acetate (400 mL) are charged in a round bottomed flask and stirred until dissolution. Silica gel (78 g) is added to the mixture and the mixture is stirred for about 2 hours. The reaction mixture is subjected to filtration and the silica gel bed is washed with ethyl acetate (100 mL). The filtrate is subjected to evapoartion under vacuum at 60oC to afford the title compound in about 64% yield having HPLC purity of about 97%.

Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

CLAIMS:

1. A process for preparation of compound of Formula I comprising reduction of compound of Formula V with a suitable reducing agent selected from dithionate sources like sodium-, lithium-, potassium-, calcium-, magnesium-, a tetraalkylammonium- or a guanidinium-dithionate in a suitable solvent.

2. The process of claim 1 where reducing agent employed is sodium dithionate.

3. The process of claim 1 where solvent comprises alcohol, ketones, ethers, water and mixtures thereof.

4. The process of claim 1 where compound of Formula V is prepared by halogenation of compound of Formula IV.

5. The process'tfiJclaim 4 where compound of Formula IV is purified by slurrying with a suitable solvent.

6. The process of claim 5 where solvent employed for slurrying is water.