DESC:FIELD OF THE INVENTION
The present invention provides a process for preparation of 4,6-dihydroxy-5-halopyrimidines of formula I.

Formula I
wherein X is selected from chloro or fluoro.

BACKGROUND OF THE INVENTION
The present invention provides an economical and convenient process to produce 4,6-dihydroxy-5-halopyrimidines. The 4,6-dihydroxy-5-halopyrimidines are important raw material for preparing photosensitizer, medicine and pesticides, and find applications in pharmaceuticals and agrochemicals industries.
There are several methods known in the literature for production of 4,6-dihydroxy-5-halopyrimidines.
JP-A2-61205262 discloses a process for preparation of 4,6-dihydroxy-5-fluoropyrimidine by reacting a-fluoromalonic acid diethyl ester with formamidine hydrochloride. This process uses hydrochloride salt of formamidine, which is relatively expensive and highly hygroscopic.
US 6,255,486 describes a process for preparation of 4,6-dihydroxy-5-fluoropyrimidine by reacting ethyl fluoromalonate with formamide and sodium methoxide in methanol. The process involves generations of impurities that reduces the yield and purity of hydroxypyrimidine.
Thus, there is a need to develop a process, which can provide better yield and purity of 4,6-dihydroxy-5-halopyrimidines.
The present invention provides an alternate and industrially feasible process for preparation of 4,6-dihydroxy-5-halopyrimidine compounds.

OBJECT OF THE INVENTION
The present invention provides an alternate and convenient route for preparation of 4,6-dihydroxy-5-halopyrimidines of formula I from 2-halomalonamide.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein X is selected from chloro or fluoro.
comprising the steps of:
a) contacting a solution of a compound of formula II and a base with formamide to form a reaction solution;

Formula II
b) acidifying the reaction solution of step a) with an acid; and
c) isolating the compound of formula I from step b).
In another aspect, the present invention provides a process for preparation of the compound of formula I, comprising the steps of

Formula I
wherein X is selected from chloro or fluoro.
a) providing a solution of compound of formula II;
b) contacting the solution of step a) with formamide in a reactor to form a reaction slurry;
c) acidifying the slurry obtained in step b) with an acid to form a reaction mixture; and
d) isolating the compound of formula I from the reaction mixture of step c).

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the base is selected from a group consisting of an alkali metal hydroxides, an alkaline earth hydroxides, an alkali metal alkoxides, metal carbonates or the like.
The preferred base can be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, sodium methoxide, sodium ethoxide, sodium butoxide, sodium propoxide, potassium methoxide, potassium ethoxide, potassium butoxide, potassium propoxide or a mixture thereof.
As used herein, the alcohol is selected from a group consisting of methanol, ethanol, propanol, butanol, pentanol and hexanol or the like.
As used herein, the acid refers to an inorganic acid selected from a group consisting of hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid or an organic acid selected from a group consisting of glacial acetic acid, formic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid or the like.
As used herein, the term “isolate” refers to a method of chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or crystallization or a combination thereof.
In an embodiment, the compound of Formula II can be prepared by any known method in the literature.
In an embodiment, providing a solution of Formula II refers to a solution containing compound of formula II, a base and a solvent.
In a preferred embodiment, providing a solution of Formula II refer to a solution containing compound of formula II, sodium methoxide and methanol.
In an embodiment, the reaction of compound of formula II with a base in a solvent in step a) is carried out at a temperature of 10-15°C.
In another embodiment, the reaction of compound of formula II with a base in a solvent in step a) is carried out at a temperature of 10-15°C for a time period of 30 minutes to 1 hour.
In another embodiment, the step of contacting a solution of Formula II with formamide is carried out at a temperature of 65-90°C.
In another embodiment, the step of contacting a solution of Formula II in formamide is carried out at a temperature of 65-90°C for a time period of 2-4 hours.
In another embodiment of the present invention, the alcohol used or generated in the reaction is recovered and recycled for subsequent reactions.
The purity of isolated compound of formula I is between 95% to 99.89% and a yield of 60% to 80%.
In another embodiment, the reaction mixture is filtered to isolate a compound of formula I. The present invention is isolating a compound of formula I by simple filtration and eliminating multiple workup operation given in prior art for purification.
In another embodiment, a solvent is used in the reaction mixture to filter to obtain a compound of formula I. The solvent is selected from alcohol and importantly alcohol is used as a solvent throughout the process.
In a preferred embodiment, methanol is used in the reaction mixture to filter to obtain a compound of formula I.
In a specific embodiment, the present invention provides a process for preparation of 4,6-dihydroxy-5-fluoropyrimidine, comprising the steps of:
a) reacting a solution of 2-fluoromalonamide and sodium methoxide with formamide to obtain a reaction mixture;
b) acidifying the reaction mixture obtained in step a) with hydrochloric acid; and
c) isolating the 4,6-dihydroxy-5-fluoropyrimidine form step b).
In another specific embodiment, the present invention provides a process for preparation of 4,6-dihydroxy-5-fluoropyrimidine, comprising the steps of:
a) providing a solution of 2-fluoromalonamide, a base and a solvent;
b) contacting the solution of step a) with formamide in a reactor to form a reaction slurry;
c) acidifying the slurry obtained in step b) with hydrochloric acid to form a reaction mixture; and
d) isolating 4,6-dihydroxy-5-fluoropyrimidine from a reaction mixture of step c).
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 4,6-dihydroxy-5-fluoropyrimidine
Step-1: Preparation of a solution of 2-fluoromalonamide and sodium methoxide:
Methanol (430.0 g, 13.43 mol) was added into the reactor flushed with nitrogen at a temperature of 20°C and then sodium methoxide (192.0 g, 3.33 mol) powder was added lot-wise over a period of 30 minutes in the same reactor to form a reaction mixture. Thereafter, 2-fluoromalonamide (100.0 g, 0.83 mol) was added in 2-3 minutes to the reaction mixture at a temperature of 10-15°C. The reaction mixture was stirred until complete dissolution to obtain the clear yellow colour solution.
Step-2: Preparation of 4,6-dihydroxy-5-fluoropyrimidine
Formamide (150 g, 3.33 mol) was added into the reactor flushed with nitrogen at a temperature of 65°C and then a solution of 2-fluoromalonamide and sodium methoxide mixture (prepared in step-1) was added over a period of 3 hours in the same reactor to form a reaction mass, maintained the reaction mass for 1-2 hours at same temperature and then monitored by HPLC. After the completion of the reaction, the reaction mixture was cooled to 20-25°C and quenched with water (600.0 g, 33.33 mol). Thereafter the reaction mixture was acidified to 2-3 pH using hydrochloric acid (35%, 395.0 g, 3.79 mol) while maintaining the temperature between 20 and 25°C to form a slurry.
The acidified slurry was filtered washed with methanol (400.0 g, 12.5 mol) and then dried at a temperature of 60°C and 10 torr pressure over a period of 5 hours to obtain the target compound.
Purity: 99.9%
Yield: 72.45%

ABSTRACT
PROCESS FOR PREPARATION OF 4,6-DIHYDROXY-5-HALOPYRIMIDINES
In an aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein X is selected from chloro or fluoro.
The 4,6-dihydroxy-5-halopyrimidines are important raw material for preparing photosensitizer, medicine and pesticides, and find applications in pharmaceuticals and agrochemicals industries.

CLAIMS:WE CLAIM:
1. A process for preparation of a compound of formula I,

Formula I
wherein X is selected from chloro or fluoro.
comprising the steps of:
a) contacting a solution of a compound of formula II and a base with formamide to form a reaction solution;

Formula II
b) acidifying the reaction solution of step a) with an acid; and
c) isolating the compound of formula I from step b).
2. The process as claimed in claim 1 for preparation of the compound of formula I, further comprising the steps of

Formula I
wherein X is selected from chloro or fluoro.
a) providing a solution of compound of formula II;
b) introducing the solution of step a) in a reactor containing formamide to form a reaction slurry;
c) acidifying the slurry obtained in step b) with an acid to form a reaction mixture; and
d) isolating the compound of formula I from the reaction mixture of step c).
3. The process as claimed in claim 1, wherein the base is selected from a group consisting of an alkali metal hydroxide, an alkaline earth hydroxide, an alkali metal alkoxide and metal carbonate.
4. The process as claimed in claim 3, wherein the base is selected from a group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, sodium methoxide, sodium ethoxide, sodium butoxide, sodium propoxide, potassium methoxide, potassium ethoxide, potassium butoxide and potassium propoxide or a mixture thereof.
5. The process as claimed in claim 1, wherein the acid is an inorganic acid selected from a group consisting of hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide and sulfuric acid or an organic acid selected from a group consisting of glacial acetic acid, formic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid.
6. The process as claimed in claims 1 & 2, wherein the solution of compound of formula II refers to a solution containing compound of formula II, a base and a solvent.
7. The process as claimed in claims 1 & 2, wherein the solution of the compound of formula II with a base and a solvent is prepared at a temperature of 10-15°C.
8. The process as claimed in claims 1 & 2, wherein the step of contacting or introducing the solution of compound of Formula II in formamide is carried out at a temperature of 65-90°C.
9. The process as claimed in claims 1 & 2, wherein the solvent used or generated in the reaction is recovered and recycled for subsequent reactions.
10. The process as claimed in claim 9, wherein the solvent is alcohol selected from a group consisting of methanol, ethanol, propanol, butanol, pentanol and hexanol or a mixture thereof.