The present invention concerns a process for making 4, 6-dihydroxypyrimidine. 4, 6-dihydroxypyrimidine is a useful chemical intermediate (especially in the agrochemical industry).
Various processes for making 4, 6-dihydroxypyrimidine, and substituted variants thereof, have been disclosed. See for example US4059696, GB1092144, Chem.Abs. (1963) 58 4565h, J.Med.Chem (1964) 7(6) 808-11, Bull.Soc.Chim.France (1959) 741-2, Collect. Cech. Chem. Commun (1967) 32 (12) 4241-59, Zhim. Farm. Zh (1974) 8(12) 28-31, BE-798724, CN1082031, EP-Al-0738717 and J.Chem.Soc (1951) 2214.
The process taught by CN 1082031, in which 4,6-dihydroxypyrimidine is prepared by reacting dimethyl malonate with sodium methoxide and formamide, is not suitable on a commercial scale. It has been found, however, that by adding water to the reaction mixture before removal of the solvent, not only is more organic material recovered at the solvent removal stage by virtue of the conversion of residual alkoxide to alcohol, but a more mobile mixture is obtained after solvent removal thereby facilitating work up. Similar advantages are obtained over the process taught by GB 1092144. Compared with the said British patent the present invention differs in two respects. First, water is added to the reaction mixture immediately after reaction of the formamide, malonate and alkoxide, and, second, the alcoholic solvent is removed before isolation of the DHP. The combination of the water addition and the solvent removal is crucial to the operation of a viable process on an industrial scale. Removal of

the alcohol solvent alone leaves a mixture which is difficult to stir and work up. Further, organic material in the form of alkoxide still remains in the mixture. However, by adding water before removing the alcohol, alkoxide is converted to alcohol enabling more organic material to be recovered. Also, the water addition produces a more mobile mixture which facilitates subsequent work up.
The present invention provides a process for preparing 4, 6-dihydroxypyrimidine comprising the steps:
(a) reacting formamide, an alkoxide of formula ROM and, at the same time or later reacting, a malonate of formula" -CH2(C02R2) in a solvent of formula ROH, the molar ratio of formamide:ROM:CH2(C02R2) being in the range (2.0-4.0):(3.0-4.0):(0.8-1.2);
(b) adding water to the'product of step (a) to dissolve all the solid;
(c) removing by distillation substantially all of the solvent of formula ROH from the product of step (b); and
(d) acidifying the product of step (c) to a pH in range 1-5 to form 4, 6-dihydroxypyrimidine
wherein R is C1-4 alkyl and M is an alkali metal.
The addition of water before the removal of the solvent of formula ROH enables more organic material to be recovered during step (c) because the following reaction takes place:

ROM + H2O -» ROH + MOH Wherein R and M are as defined above.
Alkyl groups contain from 1 to 4 carbon atoms and are straight or branched chain. Alkyl is, for example, methyl or ethyl, but is preferably methyl. Alkali metals are, for example, sodium or potassium. Step (a) of the process of the invention can be conducted in a number of ways but it is preferred that:
iii) formamide is contacted with a alkoxide of formula ROM in a solvent of
formula ROH; and iv) the product of (i) is contacted with a malonate of formula CH-(CO2R)2-
t is preferred that malonate of formula CH2(CO2R)2 is added to the product of (i) at an elevated temperature (such as a temperature in the range 40-80°C, especially 40-60°C).
It is preferred that the molar ratio of formamide:ROM:CH2(CO2R)2 in step (a) is in the range (2.0-4.0):(3.0-4.0):(0.8-1.2), especially in the range (3.0-3.2):(3.3-3.7):(0.9-l.l), more preferably about 3:3.5:1.
A preferred method for solvent removal (step (c) of the present invention) is distillation, especially distillation under reduced pressure. Substantially all of the solvent of formula ROH is removed when more than 95% (preferably more than 98%) is removed. When the solvent of formula ROH is removed water may also be removed to leave a solid residue, an aqueous slurry or a solution in water. (It is preferred that not all the water is removed, that is, that after removal of the solvent of formula ROH an aqueous slurry or a solution in water remains.) Water is added to the solid residue or aqueous slurry so that complete dissolution is achieved before step (d) is carried out.
Acidification (step (d)) of the product of step (c) of the present invention is preferably acidification to a pH in the range 1-5 (for example 1.5-4.0), especially in the range 2-3, particularly about 2.1. While acidification can be carried out using a suitable ion exchange resin it is preferred that a strong mineral acid (such as nitric acid, hydrochloric acid or sulphuric acid), or a suitable organic acid (such as acetic acid) is used.
When the product of step (c) is acidified 4,6-dihydroxypyrimidine precipitates. In order to reduce co-precipitation of inorganic materials it is preferred (especially when sulphuric acid is used for the acidification) to keep the temperature above 25°C (especially in the range 30-40"C). In this way, it is possible to obtain product that can be used as a chemical intermediate without the need for further purification.
The acidification in step (d) can be achieved by the addition of a suitable acid to the product of step (c) or, preferably, by the addition of the product of step (c) to a suitable acid.
In one aspect the present invention provides a process for preparing 4,6-dihydroxypyrimidine, the process comprising adding a malonate of formula CH2(CO2R)2 to a mixture of formamide and an alkoxide of formula ROM in a solvent of formula ROH at an elevated temperature and heating the resulting mixture at an elevated temperature (especially in the range 40-80°C). After a suitable length of time water is added to the resulting mixture and substantially all the solvent of formula ROH removed to leave an aqueous slurry. If
necessary water is added to the aqueous residue to ensure that all solids are in solution and the solution is acidified and 4,6-dihydroxypyrimidine precipitates out. The product can be collected by filtration.
The following Examples illustrate the invention. Where provided, nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm) from tetramethylsilane.
EXAMPLE 1
To a stirred solution of sodium methoxide (140g, 0.7mol of a 27% solution in methanol) under nitrogen was added formamide (27.0g, 0.6mol) over about 5 minutes. The resulting reaction mixture was heated to 50°C and then dimethyl malonate (26.4g, 0.2mol) added dropwise over 1 hour. The resulting white suspension was held at 50°C for a further hour and then cooled to ambient temperature. Water (100ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then the methanol was removed under vacuum (final pot at 50°C under l00mmHg vacuum). Water (40ml) was added and then 36% sulphuric acid (90g) added to give a final pH of 2.2. Once the acid had been added the temperature was kept at about 35°C. The yellow suspension was stirred for 1 hour, filtered and washed with water (2x25g). The water-wet paste was dried overnight under vacuum at 50°C to provide 4,6-dihydroxypyrimidine (16.2g, 70% yield, 96% strength).
EXAMPLE 2
To a stirred solution of sodium methoxide (63 g of a 30% solution in methanol containing 0.35 mol) under nitrogen was added formamide (13.5g, 0.3mol) over 5 minutes. The resulting reaction mixture was heated to 50°C and then dimethyl malonate (13.2g, 0.1 mol) added dropwise over 1 hour. The resulting white suspension was held at 50°C for a further hour and then cooled to ambient temperature. Water (50 ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then methanol was removed under vacuum (final pot at 50°C under 100 mmHg vacuum) until signs of solid could be seen. Water (20 ml) added and then 36% hydrochloric acid added to give a final pH of 2.1. The resulting yellow suspension was stirred for 1 hour, filtered and washed with water (2 x 15ml). The water-wet paste was dried overnight under vacuum at 50°C to provide 4,6-dihydroxypyrimidine (8.75g at 96.2% strength, 75.1% yield).
EXAMPLE 3
To a stirred solution of sodium methoxide (252g of a 30% solution in methanol containing 1.4 mol) under nitrogen was added formamide (54.Og, 1.2 mol) over 5 minutes. The resulting reaction mixture was heated to 50°C and then dimethyl malonate (52.8g, 0.4 mol) added dropwise over 1 hour. The resulting white suspension was held at 50°C for a further hour and then cooled to ambient temperature. Water (200ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then methanol was removed under vacuum (final pot at 40°C under 100 mmHg vacuum) until no further distillation was seen. Water (80 ml) was then added to leave a straw-coloured opaque solution (355.6g) which was used in Acidifications (a), (b) and (c) below. Acidification (a)
A sample of the straw-coloured opaque solution (118.8g, 0.134 mol based on dimethyl malonate starting material) was charged to a flask and the pH adjusted to 2.1 using 36% hydrochloric acid. The yellow slurry produced was agitated for an hour, filtered and washed with water (2 x 15ml). The water-wet paste was dried overnight under vacuum at 50°C to afford 4,6-hydroxypyrimidine (12.0g at 95.5% strength, 76.4% yield). Acidification (b)
A sample of the straw-coloured opaque solution (108. lg, 0.122 mol based on dimethyl malonate starting material) was charged to a flask and water (50ml) was added. The pH was then adjusted to 2.1 using 36% hydrochloric acid. The yellow slurry produced was agitated for an hour, filtered and washed with water (2 x 15ml). The water-wet paste was dried overnight under vacuum at 50°C to afford 4,6-dihydroxypyrimidine (10.4g at 98.3% strength, 74.8% yield). Acidification (c)
A sample of the straw-coloured opaque solution (127. lg, 0.143 mol based on dimethyl malonate starting material) was added dropwise to 36% hydrochloric acid (50 g) over 30 minutes. The pH at the end of addition was found to be 1.9. The very pale yellow slurry produced was agitated for an hour, filtered and washed with water (2 x 15 ml). The water-wet paste was dried overnight under vacuum at 50°C to afford 4,6-dihydroxypyrimidine (12.3g at >99% strength, 76.0% yield).

EXAMPLE 4 To a stirred solution of sodium methoxide in methanol (126.3g of a 30% solution containing 0.7mol) under nitrogen was added formamide (27.0g, 0.6mol) over 5 minutes. The resulting reaction mixture was heated to 50°C and then dimethyl malonate (26.4g, 0.2mol) was added dropwise over 1 hour. The resulting white suspension was held at 50°C for an hour and then cooled to ambient temperature. A white solid was isolated by filtration and was washed with methanol (50g). The solid was then dried under vacuum overnight. 1H NMR (D2O): δ 8.2, 7.7 and 4.9 ppm. 13C NMR(D2O): 5 174.7, 170.0, 155.3 and 90.5ppm.
The following preparations were conducted for comparative purposes.
A D2O solution of the disodium salt of 4,6-dihydroxypyrimidine was prepared by treating a sample of 4,6-dihydroxypyrimidine with a solution of a suitable amount of sodium hydroxide in D20. Proton NMR of the resulting solution showed peaks at 7.4(H-2) and 4.7(H-5) ppm.
A D20 solution of the dipotassium salt of 4,6-dihydroxypyrimidine was prepared by treating a sample of 4,6-dihydroxypyrimidine with a solution of a suitable amount of potassium hydroxide in D2O. 13C NMR of the resulting solution showed peaks at 179.2(C-4 & C-6), 160.9(C-2) and 93.8(C-5) ppm.
Proton NMR of a solution of 4,6-dihydroxypyrimidine in dimethylsulphoxide (DMSO) showed peaks at 8.0(H-2) and 5.2(H-5) ppm.

WE CLAIM:
1. A process for preparing 4,6-dihydroxypyrimidine comprising the steps:
(a) reacting formamide, an alkoxide of formula ROM and, at the same time or later reacting, a malonate of formula CH2(CO2R2) in a solvent of formula ROH, the molar ratio of formamide:ROM:CH2(C02R2) being in the range (2.0-4.0):(3.0-4.0):(0.8-1.2);
(b) adding water to the product of step (a) to dissolve all the solid;

c) removing by distillation substantially all of the solvent of formula ROH from the product of step (b); and
d) acidifying the product of step (c) to a pH in the range 1-5 to form 4,6-dihydroxypyrimidine;
wherein R is C1-4 alkyl and M is an alkali metal.
2. A process as claimed in claim 1 wherein R is methyl or ethyl.
3. A process as claimed in claim 1 or 2 wherein M is sodium or potassium.
4. A process as claimed in claim 1, 2, or 3 wherein the acid used in step (d) is sulphuric acid.
5. A process as claimed in any one of the preceding claims wherein the distillation in step (c) is carried out under reduced pressure.

6. A process for preparing 4, 6-dihydroxypyrimidine substantially as hereinbefore described with reference to the foregoing examples.