FORM 2
THE PATENTS ACT, 1970
As amended by the Patents (Amendment) Act, 2002
and
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules 2016
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
TITLE OF THE INVENTION
A ONE-POT PROCESS FOR THE PREPARATION OF A SUBSTITUTED
HYDROXYPYRIMIDINE
APPLICANT
LAXMI ORGANIC INDUSTRIES LIMITED of Chandermukhi, 3rd Floor, Nariman Point, Mumbai 400021, India.
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
[001] The present invention relates to a one-pot process for the preparation of a substituted hydroxypyrimidine. In particular, the present invention relates to a one-pot process for the preparation of 2-isopropyl-6-methyl-4-pyrimidinol.
BACKGROUND OF THE INVENTION
[002] Synthesis of substituted hydroxypyrimidine, in particular 2-isopropyl-6-methyl-4-pyrimidinol, is known in the art. In this regard, amide synthesis which is an intermediate for obtaining substituted hydroxypyrimidine is to be first obtained from a commercially viable route. One such route involves synthesis of carboxamide from carboxylic acid. For this, the carboxylic acid is first converted to acid chloride and the acid chloride is reacted with ammonia gas in a non-polar solvent such as toluene or xylene to obtain the carboxamide. Another route involves oxidation of nitriles using suitable oxidizing agents, such as hydrogen peroxide, in the presence of a strong base or strong anion exchanged resin and a catalytic quantity of quaternary ammonium salts in an aqueous or alcoholic solvent. Hydrolysis of aliphatic nitrile in the presence of metal oxides, thereby forming carboxylic acid amides is also a possible route for amide synthesis. Further, in situ conversion of aldehyde to nitrile and subsequent oxidation using t-butyl hydro peroxide results in corresponding acid amide.
[003] Amide synthesis can also be carried out by vapor phase reaction of an aldehyde with ammonia in the presence of alumina modified with an alkali at 350°C to 500°C in a flow method. Under optimum condition, wherein ammonia and aldehyde are reacted at a molar ratio of 2:1 in the presence of 2-3 mmol NaOH/g Al2O3 and at temperature ranging between 410°C to 430°C for about 10 seconds, 93 to 96% of nitrile, 1 to 2% of alkyl acrylonitrile and 1 to 2% of by¬products are formed. Controlled hydrolysis of nitrile yields the amide.
[004] Some of the routes for synthesis of substituted hydroxypyrimidine, in particular 2-isopropyl-6-methyl-4-pyrimidinol, and their derivatives via amide or

other starting materials are discussed herein. One such process is described in US 4163848 A. Herein, 2-alkyl- or cycloalkyl-4-methyl-6-hydroxypyrimidine are obtained by first neutralizing an alkyl imidate ester hydrochloride with a base in the presence of a water-immiscible solvent for the alkyl imidate ester to be freed thereby; condensing the alkyl imidate ester with diketene to form an oxazinone intermediate, which is then reacted in organic solution with gaseous ammonia and recovering the desired substituted 6-hydroxypyrimidine. Although, the process reports a yield of ~ 86%, the synthesis of 2-methyl propanimidamide requires dry HCl gas and condensation with aceto acetate ester, which require highly anhydrous and acidic conditions to be maintained. Thus, a need for specialized equipments to handle the process is inevitable and therefore, the overall cost of the product is always on the higher side.
[005] Another route involves ethylisobutyrimidate-hydrochloride which is a precursor of 2-methyl propanimidamide and requires highly acidic conditions during Pinner reaction of isobutyronitrile. However, free base of imidates or imidamide is not a stable moiety.
[006] US 4018771 A discloses production of 2-alkyl or 2-cycloalkyl-4-methyl-6-hydroxy pyrimidines by first reacting diketene and lower alkanoic or cycloalkanoic acid amides in the presence of catalytic amounts of Lewis bases or Lewis or Bronsted acids, followed by treating the N-acetoacetyl (lower) alkanoic or cycloalkanoic acid amide intermediates with ammonia in the presence of acid catalysts. The yield reported herein is only ~ 80 – 82%.
[007] The existing processes have several limitations. One such limitation is that carboxamide synthesis using reagents like acid chlorides, nitriles etc., generates huge amounts of salts, aqueous effluents and by products, mitigation of which is a challenging task. Continuous vapour phase processes from aldehyde and ammonia require special equipments and further control on hydrolysis or oxidation of nitrile to obtain required purity of carboxamide. These processes also require the recovery

and purification of the solvents before reuse. In this regard, an additional step of purification to achieve high purity, results in loss of the desired product yield.
[008] Thus, there is a need for a one-pot process for the preparation of a substituted hydroxypyrimidine with higher yield and purity, while at the same time being environment-friendly, less complex, economical, and minimizes or eliminates the generation of hazardous substances and troublesome effluents.
SUMMARY OF THE INVENTION
[009] In one aspect, the present invention provides one-pot process for the preparation of a substituted hydroxypyrimidine of formula (I) comprising reacting a carboxylic acid of formula (II) with ammonia to obtain an in-situ intermediate of formula (III) followed by reaction with diketene in the presence of a catalyst to obtain the substituted hydroxypyrimidine of formula (I):

wherein,
R represents an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to 6
carbon atoms.
DESCRIPTION OF THE INVENTION
[010] The present invention provides a one-pot process for the preparation of a substituted hydroxypyrimidine of formula (I) comprising reacting a carboxylic acid of formula (II) with ammonia to obtain an in-situ intermediate of formula (III) followed by reaction with diketene in the presence of a catalyst to obtain the substituted hydroxypyrimidine of formula (I):


wherein,
R represents an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to 6
carbon atoms.
[011] In an embodiment, the substituted hydroxypyrimidine of formula (I) obtained by reacting the carboxylic acid of formula (II) with ammonia to obtain the in-situ intermediate of formula (III) followed by reaction with diketene in the presence of the catalyst is referred to as scheme 1. Said otherwise, the scheme 1 discloses a one-pot reaction scheme wherein (i) the carboxylic acid of formula (II) is reacted with ammonia to obtain the in-situ intermediate of formula (III), and (ii) the in-situ intermediate of formula (III) is reacted with diketene in the presence of the catalyst to obtain the substituted hydroxypyrimidine of formula (I).
[012] In the present context, “one-pot” refers to the synthesis of substituted hydroxypyrimidine of formula (I), as above, in a series of steps that are performed in a single apparatus or reaction vessel. The one-pot procedure eliminates the need for isolation (e.g., purification) of the catalyst and/or intermediates, while reducing the number of synthetic steps and the production of waste materials and/or byproducts.
[013] In an embodiment, the present invention process is a green process or is environment friendly. In the present context, “environment-friendly” refers to the process being capable of substantially reducing the requirement of recovering the hazardous and troublesome effluents in comparison with the state-of-the-art or commercially used processes. In particular, the involvement of hazardous and troublesome effluents, such as but not limited to dry HCl gas, ammonia, etc. requires specialised equipments. On the contrary, the present invention requires a

single autoclave reactor thereby reducing the requirement of multiple equipments for the process. Further, in the present invention during the in-situ formation of the intermediate of formula (III), formation of salts does not occur, hence separation of pure compounds of formula (III) from the salts, as required in other commercial processes, is avoided.
[014] In another embodiment, the scheme 1 comprises the in-situ intermediate of formula (III) reacting with the diketene in the presence of the catalyst to obtain an in-situ intermediate of formula (IV). Subsequently, the in-situ intermediate of formula (IV) reacts with ammonia to obtain the substituted hydroxypyrimidine of formula (I), as above. The reaction scheme depicted herein can be referred to as scheme 1a shown below:

[015] In the scheme 1a, R represents an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms. In the present context, the term "alkyl" refers to an alkane absent hydrogen. Alkyl groups denoted by R are straight chain or branched chain groups having 1 to 4 carbon atoms selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, and tertiary butyl. Cycloalkyl groups denoted by R having 3 to 6 ring carbon atoms can be selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl.
[016] In an embodiment, the weight ratio between ammonia and the carboxylic acid of formula (II) is in the range of 0.18:1.0 to 2.0:1.0. In another embodiment, the weight ratio is in between 0.18:1.0 to 1.9:1.0, or 0.18:1.0 to 1.8:1.0, or 0.18:1.0 to 1.7:1.0. In still another embodiment, the weight ratio is in between 0.18:1.0 to 1.6:1.0, or 0.18:1.0 to 1.5:1.0, or 0.18:1.0 to 1.4:1.0. In yet another embodiment,

the weight ratio is in between 0.18:1.0 to 1.2:1.0, or 0.18:1.0 to 1.0:1.0, or 0.18:1.0 to 0.8:1.0, or 0.18:1.0 to 0.6:1.0, or 0.18:1.0 to 0.4:1.0.
[017] In another embodiment, the carboxylic acid of formula (II) is isobutyric acid. Accordingly, the in-situ intermediate of formula (III) is isobutyramide and the in-situ intermediate of formula (IV) is N-acetoacetyl acid amide.
[018] In an embodiment, the at least one of the reactions depicted in scheme 1 or 1a is carried out in the presence of a non-polar solvent. Suitable non-polar solvents include alkyl benzenes such as mono-alkyl, and di-alkyl benzenes; higher analogues of alkyl benzenes; halo benzenes such as mono-, di- and tri-halo benzenes; and fused hydrocarbons such as naphthalene. In an embodiment, the non-polar solvent is alkyl benzene, in particular toluene. In this regard, the weight ratio between the non-polar solvent and the carboxylic acid of formula (II) is in the range of 1.0:1.0 to 10.0:1.0.
[019] In an embodiment, the weight ratio between the non-polar solvent and the carboxylic acid of formula (II) is in the range of 1.0:1.0 to 9.0:1.0, or 1.5:1.0 to 9.0:1.0, or 1.5:1.0 to 8.0:1.0. In another embodiment, the weight ratio is in between 2.0:1.0 to 7.0:1.0, or 2.0:1.0 to 6.0:1.0, or 2.0:1.0 to 5.0:1.0. In still another embodiment, the weight ratio is in between 2.0:1.0 to 4.0:1.0, or 2.5:1.0 to 4.0:1.0.
[020] Suitable catalysts used in scheme 1 or 1a include an amine salt of general
formula R1-X, wherein X can be selected from:
(i) inorganic acids selected from phosphoric acid (H3PO4), hydrochloric acid
(HCl), per-chloric acid (HClO4), sulfuric acid (H2SO4), sulfurous acid (H2SO3),
chlorosulfuric acid (ClSO3H), nitric acid (HNO3), and nitrous acid (HNO2),
(ii) carboxylic acids of general formula formula R2-COOH, wherein R2 is
selected from aliphatic straight chain, branched alkyl groups having R2=H or C1 to
C8 or trihalo acetic acids including tri-chloro, tri-bromo, and tri-fluoro acetic acid;
and aromatic groups having C6 to C9; and

(iii) sulfonic acids of general formula R3-SO3H, wherein R3 represents aliphatic
straight chain, branched alkyl groups having C1 to C8 or aromatic groups having C6
to C9;
and wherein R1 can be selected from:
(i) aliphatic tertiary amines selected from tri alkyl amines (R4-N) and
derivatives thereof, wherein R4= aliphatic chain C1 to C6; or R4= cyclic aliphatic
chains, C3 to C6, and
(ii) heterocyclic tertiary amines selected from:
a. 5-membered cyclic, heterocyclic amines selected from N- methyl
pyrrolidine, N-methyl imidazole, thiazole and mixtures thereof;
b. 6-membered cyclic, heterocyclic amines such as pyridine, pyrazine,
pyrimidine, N-methyl piperidine, morpholine, ortho/para/meta picoline
and mixtures thereof;
c. 7-membered cyclic, heterocyclic amines such as azepine, 1,4-diazepine
and mixtures thereof; and
d. fused cyclic, heterocyclic amines such as quinolone, iso-quinoline,
pteridine, DABCO and mixtures thereof;
[021] In an embodiment, the weight ratio between the catalyst and the carboxylic acid of formula (II) is in the range of 0.1:1.0 to 1.0:1.0. In another embodiment, the range is in between 0.1:1.0 to 0.75:1.0.
[022] In an embodiment, the scheme 1 or 1a comprises of the following steps:
(A) reacting the carboxylic acid of formula (II) and ammonia in presence of the non-polar solvent at a temperature ranging between 120°C to 250°C and a pressure ranging between 10 kg/cm2 to 40 kg/cm2 to obtain a first reaction mass comprising the in-situ intermediate of formula (III),
(B) reacting the first reaction mass of step (A) with the diketene in presence of the non-polar solvent and the catalyst at a temperature ranging between 75°C to 95°C and a duration ranging between 1 h to 10 h to obtain a second reaction mass comprising the in-situ intermediate of formula (IV), and

(C) reacting the second reaction mass of step (B) with ammonia in the presence
of a buffer at a temperature ranging between 40°C to 70°C and a pH ranging
between 9 to 12 to obtain a mixture comprising the substituted hydroxypyrimidine
of formula (I).
[023] In another embodiment, the scheme 1 or 1a further comprises of the following steps:
(D) filtrating the mixture of step (C) to separate the non-polar solvent with a
wet residual mass of the substituted hydroxypyrimidine of formula (I), and
(E) washing and drying the wet residual mass of step (D) in the presence of a
nitrile to obtain the substituted hydroxypyrimidine of formula (I).
[024] In an embodiment, the temperature in step (A) is in the range of 120°C to 250°C, or 160°C to 250°C, or 160°C to 240°C, or 170°C to 240°C, or 180°C to 240°C. The duration over which the temperature is maintained is in between 1 h to 10 h, or 3 h to 9 h, or 6 h to 8 h. The pressure is maintained in between 10 kg/cm2 to 40 kg/cm2, 12 kg/cm2 to 38 kg/cm2, or 16 kg/cm2 to 40 kg/cm2 for a duration ranging between 5 h to 15 h, or 7 h to 13 h, or 10 h to 12 h.
[025] During the reaction progress in step (A) when the consumption of ammonia stops, the excess of ammonia can be either vented off or recovered using suitable means. Similarly, water formed during the reaction can also be recovered. In an embodiment, water is separated by azeotropic distillation prior to subjecting the first reaction mass to step (B). The first reaction mass obtained in step (A) comprises the in-situ intermediate of formula (III).
[026] In another embodiment, the temperature in step (B) is in the range of 75°C to 95°C, or 80°C to 95°C, or 80°C to 90°C, or 80°C to 85°C for a duration ranging between 1 h to 10 h, or 1 h to 8 h, or 2 h to 8 h, or 2 h to 6 h.

[027] With respect to specific reaction procedure and especially the order of addition of the reactants, it is advantageous to add diketene slowly to the reaction vessel containing the first reaction mass. Alternatively, diketene can be simply mixed with the first reaction mass at suitable temperatures. Further, the catalyst and/or non-polar solvent can be added to the first reaction mass in incremental amounts. The second reaction mass obtained in step (A) comprises the in-situ intermediate of formula (IV).
[028] In an embodiment, the weight ratio between diketene and the carboxylic acid of formula (II) in step (B) is in the range of 0.9:1.0 to 2.0:1.0. In another embodiment, the weight ratio is in between 0.9:1.0 to 1.8:1.0, or 0.9:1.0 to 1.6:1.0. In still another embodiment, the weight ratio is in between 0.9:1.0 to 1.5:1.0, or 0.9:1.0 to 1.2:1.0.
[029] The second reaction mixture obtained in step (B) is subjected to amination in step (C). Herein, the second reaction mass is reacted with ammonia, thereby accomplishing amination and cyclization of the in-situ intermediate of formula (IV) to obtain the substituted hydroxypyrimidine of formula (I). Suitable buffer is also added at this step. Examples of the buffer include such as ammonium acetate, ammonium formate, and ammonium citrate.
[030] In an embodiment, the temperature in step (C) is in the range of 45°C to 70°C, or 45°C to 65°C, or 50°C to 65°C, or 50°C to 60°C. The pH range is maintained in between 9 to 12, or 9 to 11 to obtain the mixture comprising the substituted hydroxypyrimidine of formula (I).
[031] The mixture obtained in step (C) includes the non-polar solvent along with the substituted hydroxypyrimidine of formula (I). To separate the substituted hydroxypyrimidine of formula (I) from the mixture, the mixture is subjected to filtration techniques. Such techniques are known to a person skilled in the art.

Subsequent to filtration of the mixture, the wet residual mass of the substituted hydroxypyrimidine of formula (I) is removed.
[032] Subsequent washing and drying of the wet residual mass in the presence of nitrile results in substituted hydroxypyrimidine of formula (I) with purity as high as 99.8% to 100% and with yields ranging between 90% to 92%. For this, suitable nitriles can be selected from acetonitrile, iso-butyronitrile, butyronitrile, propionitrile, isopropionitrile, and mixtures thereof.
[033] In an embodiment, the weight ratio between the nitrile and the carboxylic acid of formula (II) is in the range of 1.0:1.0 to 5.0:1.0. In another embodiment, the weight ratio is in between 1.0:1.0 to 4.5:1.0, or 1.0:1.0 to 4.0:1.0, or 1.0:1.0 to 3.5:1.0. In still another embodiment, the weight ratio is in between 1.5:1.0 to 3.5:1.0, or 1.5:1.0 to 3.0:1.0, or 1.5:1.0 to 2.5:1.0.
[034] During the present invention process, removal/recovery of water is essential. For this, azeotropic distillation is carried out from time to time. Further, the non-polar solvent is also recovered by subjecting the wet residual mass to solvent recovery under reduced pressure. Subsequently, the recovered non-polar solvent is recycled to step (B).
[035] Subsequent to washing the wet residual mass, a mother liquor is obtained. The mother liquor comprises the nitrile and/or the non-polar solvent which can be recycled back to step (D) and/or step (B) respectively.
[036] In an embodiment, the substituted hydroxypyrimidine of formula (I) is 2-isopropyl-6-methyl-4-pyrimidinol.
[037] Advantageously, the present invention process can be carried out in a single reactor vessel without isolation and recovery of the intermediates. Furthermore, it is also feasible to practice the present invention as a semi-continuous or continuous

process. Further, the process of the present invention is clean and environment friendly and can be carried out in a single reaction vessel, i.e., one-pot. Additionally, the process is less complex, economical with minimum generation of impurities.

EXAMPLES
[038] Preparation of 2-isopropyl-6-methyl-4-hydroxypyrimidine
[039] 85g of liquid/gas ammonia was injected at room temperature to an autoclave reactor containing solution of 400g of isobutyric acid in 1218g of toluene. The autoclave reactor was sealed and gradually heated to 180°C in 6 h to 8 h till it attained a pressure in the range of 20 kg/cm2 to 25 kg/cm2. Excess pressure above 25 kg/cm2 was carefully vented off in water. The reaction mass was maintained at a temperature of 180°C to 185°C and a pressure of 20 kg/cm2 to 25 kg/cm2 till the ammonia consumption was stopped practically. The reaction mass was subjected to azeotropic distillation for recovery/removal of water.
[040] Reaction mass was then cooled to 80°C to 90°C under inert atmosphere, toluene co-distilled was compensated and 45g catalyst of amine salt (quinoline hydrochloride) were charged to the autoclave reactor. 378g diketene was gradually added to the autoclave reactor maintaining the temperature below 85°C. The reaction mass thus obtained was maintained at 80°C to 85°C till completion of the reaction.
[041] Subsequently, the reaction mass was cooled to 60°C to 65°C and 170g ammonium acetate was added to the reaction mass and pH was maintained in the range of 10 to 11.
[042] Toluene was recovered and 802g acetonitrile was added to the residual mass at the temperature range of 80°C to 90°C and maintained for 3 h to 5 h. Subsequent filtration and washing resulted in white colored wet solids which were dried at 45°C to 50°C temperature under vacuum to yield 616 g of high purity 2-isopropyl-6-methyl-4-pyrimidinol with a molar yield of about 90% and 99.9+ % of purity.
[043] The foregoing description of the invention has been set merely to illustrate the invention and is not intended to be limiting. Since the modifications of the

disclosed embodiments incorporating the spirit and substance of the invention may occur to the person skilled in the art, the invention should be construed to include everything within the scope of the disclosure.

WE CLAIM
1. A one-pot process for the preparation of a substituted hydroxypyrimidine of
formula (I) comprising reacting a carboxylic acid of formula (II) with
ammonia to obtain an in-situ intermediate of formula (III) followed by
reaction with diketene in the presence of a catalyst to obtain the substituted
hydroxypyrimidine of formula (I):

wherein,
R represents an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to
6 carbon atoms.
2. The process as claimed in claim 1, wherein the in-situ intermediate of formula
(III) reacts with the diketene in the presence of the catalyst to obtain an in-
situ intermediate of formula (IV), the in-situ intermediate of formula (IV)
reacting with ammonia to obtain the substituted hydroxypyrimidine of
formula (I):

wherein,
R represents an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to
6 carbon atoms.
3. The process as claimed in claim 1 or 2, wherein the weight ratio between
ammonia and the carboxylic acid of formula (II) is in the range of 0.18:1.0 to
2.0:1.0.

4. The process as claimed in one or more of claims 1 to 3, wherein at least one of the reactions is carried out in the presence of a non-polar solvent.
5. The process as claimed in claim 4, wherein the weight ratio between the non-polar solvent and the carboxylic acid of formula (II) is in the range of 1.0:1.0 to 10.0:1.0.
6. The process as claimed in claim 5, wherein the non-polar solvent comprises toluene.
7. The process as claimed in one or more claims 1 to 6, wherein the catalyst is an amine salt of general formula R1-X, wherein X can be selected from:
(i) inorganic acids selected from phosphoric acid (H3PO4), hydrochloric
acid (HCl), per-chloric acid (HClO4), sulfuric acid (H2SO4), sulfurous acid (H2SO3), chlorosulfuric acid (ClSO3H), nitric acid (HNO3), and nitrous acid (HNO2),
(ii) carboxylic acids of general formula formula R2-COOH, wherein R2
is selected from aliphatic straight chain, branched alkyl groups having R2=H or C1 to C8 or trihalo acetic acids including tri-chloro, tri-bromo, and tri-fluoro acetic acid; and aromatic groups having C6 to C9; and
(iii) sulfonic acids of general formula R3-SO3H, wherein R3 represents
aliphatic straight chain, branched alkyl groups having C1 to C8 or aromatic groups having C6 to C9;
and wherein R1 can be selected from:
(i) aliphatic tertiary amines selected from tri alkyl amines (R4-N) and
derivatives thereof, wherein R4= aliphatic chain C1 to C6; or R4= cyclic aliphatic chains, C3 to C6, and
(ii) heterocyclic tertiary amines selected from:
a. 5-membered cyclic, heterocyclic amines selected from N- methyl pyrrolidine, N-methyl imidazole, thiazole and mixtures thereof;

b. 6-membered cyclic, heterocyclic amines such as pyridine,
pyrazine, pyrimidine, N-methyl piperidine, morpholine,
ortho/para/meta picoline and mixtures thereof;
c. 7-membered cyclic, heterocyclic amines such as azepine, 1,4-
diazepine and mixtures thereof; and
d. fused cyclic, heterocyclic amines such as quinolone, iso-
quinoline, pteridine, DABCO and mixtures thereof.
8. The process as claimed in one or more of claims 1 to 7 comprising the steps
of:
(A) reacting the carboxylic acid of formula (II) and ammonia in presence of the non-polar solvent at a temperature ranging between 120°C to 250°C and a pressure ranging between 10 kg/cm2 to 40 kg/cm2 to obtain a first reaction mass comprising the in-situ intermediate of formula (III),
(B) reacting the first reaction mass of step (A) with the diketene in presence of the non-polar solvent and the catalyst at a temperature ranging between 75°C to 95°C and a duration ranging between 1 h to 10 h to obtain a second reaction mass comprising the in-situ intermediate of formula (IV), and
(C) reacting the second reaction mass of step (B) with ammonia in the presence of a buffer at a temperature ranging between 40°C to 70°C and a pH ranging between 9 to 12 to obtain a mixture comprising the substituted hydroxypyrimidine of formula (I).

9. The process as claimed in claim 8, wherein the buffer is ammonium acetate.
10. The process as claimed in claim 8 or 9 further comprising the step of:
(D) filtrating the mixture of step (C) to separate the non-polar solvent
with a wet residual mass of the substituted hydroxypyrimidine of formula (I),
and

(E) washing and drying the wet residual mass of step (D) in the presence
of a nitrile to obtain the substituted hydroxypyrimidine of formula (I).
11. The process as claimed in claim 10, wherein the nitrile includes acetonitrile, iso-butyronitrile, butyronitrile, propionitrile, iso-propionitrile, and mixtures thereof.
12. The process as claimed in one or more of claims 8 to 11, wherein the first reaction mass of step (A) comprises water which is separated by azeotropic distillation prior to subjecting the first reaction mass to step (B).
13. The process as claimed in one or more of claims 1 to 12, wherein the weight ratio between diketene and the carboxylic acid of formula (II) is in the range of 0.9:1.0 to 2.0:1.0.
14. The process as claimed in one or more of claims 10 to 13, the weight ratio between the nitrile and the carboxylic acid of formula (II) is in the range of 1.0:1.0 to 5.0:1.0.
15. The process as claimed in one or more of claims 1 to 15, wherein the weight ratio between the catalyst and the carboxylic acid of formula (II) is in the range of 0.1:1.0 to 1.0:1.0.
16. The process as claimed in one or more of claims 1 to 15, wherein the carboxylic acid of formula (II) is isobutyric acid.
17. The process as claimed in one or more of claims 1 to 16, wherein the in-situ intermediate of formula (III) is isobutyramide.

18. The process as claimed in one or more of claims 1 to 17, wherein the substituted hydroxypyrimidine of formula (I) is 2-isopropyl-6-methyl-4-pyrimidinol.