MXPA97006972A - Preparation of 4,6-dimetoxy-2 - ((fenoxicarbonil) amino) -pirimid - Google Patents

Abstract

The present invention describes a process for preparing 4,6-dimethoxy-2 - ((phenoxycarbonylamino) -pyrimidine, which comprises reacting 2-amino-4,6-dimethoxypyrimidine and phenyl chloroformate in an inert solvent, in the presence of a receptor deci

Description

PREPARATION OF 4,6-DIMETOXY-2- ((PHENOXYCARBONYL) AMINO) - PYRIMIDINE BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of an intermediate chemical compound, useful for preparing herbicides. More specifically, the present invention relates to an improved process for preparing 4,6-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine (hereinafter "DPAP"), which is useful as an intermediate for the preparation of sulfonylurea herbicides. The intermediates for herbicides are preferably free of substantial amounts of impurities, especially impurities which will be entrained to the final herbicide itself. Impurities in agricultural products are subject to careful regulatory inspection, and are subject to severe restrictions. Therefore, advantageous methods for making intermediates are not only advantageous for producing high yields, but are also advantageous for producing the intermediate in high purity "as prepared", so that a small purification, preferably no purification, is necessary. additional. Accordingly, an object of this invention is to provide a method for making DPAP in high yield and high purity. REF: 25303 References US 5,102,444 and US 5,017,212 describe the preparation of DPAP and the use thereof in the preparation of sulfonylurea herbicides, but do not describe the present invention. BRIEF DESCRIPTION OF THE INVENTION Now a process has been discovered that results in the preparation of 4, β-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine in high yields and high purity. Accordingly, the process of the invention for preparing 4, β-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine comprises reacting 2-amino-4, β-dimethoxypyrimidine and phenyl chloroformate in an inert solvent, in the presence of of an acid receptor, at a temperature of between 10 ° to 45 ° C. DETAILS OF THE INVENTION The process of the invention comprises reacting 2-amino-4,6-dimethoxypyrimidine and phenyl chloroformate in an inert solvent, selected from 1,4-dioxane and tetramethylurea, in the presence of N, N-dimethylaniline, at a temperature of 10 ° to 45 ° C. preferred solvent is 1,4-dioxane. The amount of phenyl chloroformate is generally at least stoichiometric. The preferred amount of phenyl chloroformate is 10-75% excess of the stoichiometric amount. The acid receptor, N, N-dimethylaniline, is generally present in a molar amount equal to that of the phenyl chloroformate. The preferred reaction temperature is in the range of 20 ° to 30 ° C. The pressure is not controlled, and it is the ambient atmospheric pressure. In a typical operation, 2-amino-4, β-dimethoxypyrimidine, the solvent and the acid receptor are mixed in a reactor equipped with a stirrer and means for cooling the reaction. Phenyl chloroformate is added to the stirred reaction mixture, which is maintained at the desired temperature. The rate of addition of the phenyl chloroformate is not critical, and can be any convenient rate that allows the desired reaction temperature to be maintained. The starting 2-amino-4,6-dimethoxypyrimidine and the DPAP product are not substantially dissolved in the solvent, and are present in the reaction medium as a slurry. Sometimes the DPAP forms a supersaturated solution, which can be induced to crystallize by introducing seed crystals of it. After the addition of all the ingredients, the reaction mixture is maintained at the reaction temperature, usually for about 4 to 24 hours, then quenched with water. The product is recovered by filtration, washed with water (and optionally isopropanol), and dried at an elevated temperature, usually around 55 ° C, under vacuum. The impurity, N, N'-bis (4,6-dimethoxy-2-pyrimidinyl) urea, is recovered with the DPAP product in the filtration step. The present process, however, it produces low levels of this impurity, so that a small purification is needed, if any further purification of the DPAP product is needed. Reducing the amount of, or eliminating the purification of the product is advantageous, because extra purification steps are avoided, and the loss of product therein. It has been found that the product yield, and the amount of impurity of N, N'-bis (4,6-dimethoxy-2-pyrimidinyl) urea formed are critically dependent on the selection of the solvent and the acid receptor. The present process, which employs 1,4-dioxane or tetramethylurea as solvents, and N, N-dimethylaniline as an acid receptor provides a substantially higher yield, and less impurity of N, N'-bis (4, β-dimethoxy- 2-pyrimidinyl) urea than the prior art processes of US 5,102,444 and US 5,017,212, wherein the solvent is tetrahydrofuran and the acid receptor is dimethylpyridine.

It is also believed that adding excess phenyl chloroformate is useful in keeping the concentration of the N, N'-bis (4, β-dimethoxy-2-pyrimidinyl) urea impurity low. It is believed that any benefit of adding the excess phenyl chloroformate is separate and in addition to any effect of the solvent and the acid receptor on the yield and purity. These following examples illustrate the present invention, and the advantages thereof. EXAMPLE 1 A 500 ml flask was charged with 23.8 g (0.154 mol) of 2-amino-4,6-dimethoxy-pyrimidine, 29.1 g (0.240 mol) of N, N-dimethylaniline, and 110 ml of 1,4- dioxane The mixture was cooled to 5 ° C with an ice bath. Then 37.58 g (0.24 mole) of phenyl chloroformate was added dropwise while maintaining the temperature of the reaction mixture below 20 ° C. The reaction mixture was stirred for 16 hours at room temperature (20 ° C). at 25 ° C), and then cooled again to 5 ° C. Water, 325 ml, was added to the reaction mixture; the temperature during the addition was kept below 20 ° C. The reaction mixture, a slurry, was filtered, and the solids were washed twice with an additional 50 ml of water. The solids were dried by suction through the filter. The weight of the recovered solids, which had a melting point of 117-120 ° C was 34.24 g, which gives a calculation of 81% yield, uncorrected for purity. EXAMPLE 2 The procedure of Example 1 was repeated, except that 110 ml of tetramethylurea was used instead of 1,4-dioxane.

The weight of the recovered solids, which had a melting point of 119-122 ° C was 35.77 g, which gives a calculation of 85% yield, uncorrected for purity. EXAMPLE A (COMPARATIVE) This demonstrates the use of tetrahydrofuran (THF) as a solvent, with N, N-dimethylaniline as the acid receptor. The yield was lower than in Examples 1 and 2. The purity of the product, judged by the lower melting point range, was also lower. A 500 ml flask was charged with 23.8 g of 2-amino-4, β-dimethoxypyrimidine, 29.10 g of N, N-dimethylaniline and 110 ml of THF. The mixture was cooled to 5 ° C with an ice bath, and 37.58 g of phenyl chloroformate were slowly added, while keeping the temperature below 20 ° C. After stirring 16 hours at room temperature (20 ° -25) ° C), the mixture was cooled to 5 ° C. Water, 360 ml, was slowly added to the reaction mixture while maintaining the temperature below room temperature. The reaction mixture, a slurry, was filtered, and the solids were washed with two aliquots of 50 ml of water. The solids were dried on the filter, then placed on a tray, to be air dried. The weight of the recovered solids, which had a melting point of 114-117 ° C was 22.93 g, which gives an estimate of 54% yield, uncorrected for purity. EXAMPLE 3 A 250 ml flask was charged with 15.6 g (0.101 g) of 2-amino-4,6-dimethoxy-pyrimidine, 20 ml (0.158 mol) of N, N-dimethylaniline, 50 ml of 1,4-dioxane. , and 20 ml (0.159 moles) of phenyl chloroformate. The mixture was stirred for 2 hours at room temperature (20-25 ° C), and then allowed to stand 16 hours at the same temperature. The reaction mixture was transferred to a separate flask, which contained 140 ml of water. An oil was formed, which crystallized eventually. The reaction mixture was filtered, and the solids were washed with three aliquots of 50 ml of water, and two aliquots of 25 ml of isopropanol. The solids were dried by sucking air through the filter. The melting point was 122-123 ° C. Assay of the solids: 96.9% of 4,6-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine, 1.54% of 2-amino-4,6-dimethoxypyridine and 0.20% N, N'-bis (4,6-dimethoxy-2-pyrimidinyl) urea. A total of 22.8 g of solids was recovered for a yield, corrected for purity, of 79.8%. EXAMPLE B (COMPARATIVE) This shows 2,6-dimethylpyridine as acid receptor, with 1, 4-dioxane as solvent. The yield and purity are lower than in Example 3. Example 3 was repeated, except that 19 ml (0.163 mol) of 2,6-dimethylpyridine were used instead of the 20 ml of N, N-dimethylaniline. The melting point of the product was 115 ° -117 ° C. The test was 85.7% of 4,6-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine, 0.47% of 2-amino-4,6- dimethoxypyridine and 1.14% of N, N'-bis (4,6-dimethoxy-2-pyrimidinyl) urea. A total of 24.8 g of solids was recovered for a yield, corrected for purity, of 76.8%. EXAMPLE 4 120 g of 1,4-dioxane, 59.1 kg (488 moles) of N / N-dimethylaniline, and 47.7 kg (308 moles) of 2-amino-4,6-dimethoxypyrimidine were charged to a 0.378 m 3 reactor ( 100 gallons). Phenyl chloroformate, 76.4 kg (488 moles), was added for 1.5 hours, while the temperature was maintained at 25 ° C by jacket cooling. Three hours after the completion of the addition of the phenyl chloroformate, the reaction mass was seeded with a small amount of previously prepared DPAP crystals. After another 30 minutes, the reaction mass was seeded again. Stirring was continued at 25 ° C for another 11 hours. The reaction slurry was then transferred to a 1,134 m3 (300 gallon) reactor, which already contained 159 kg of water; the temperature of this reactor was kept below 35 ° C by both measures, adjusting the transfer rate of the reaction paste, and cooling by a reactor jacket of 1,134 m3 (300 gallons). The 0.378 m3 (100 gallon) reactor and the transfer line were then rinsed with 11.4 kg of 1,4-dioxane. The resulting slurry was stirred for another 30 minutes before an additional 280 kg of water was added. Stirring was continued for 30 minutes, before the slurry was discharged to the filters. The reactor was rinsed with water, followed by isopropanol, and the rinses were used to wash the filter cakes. The product was then dried at 55 ° C under a vacuum of 0.136 kg / cm2 (100 mitiHg) or less. This procedure was followed for 23 batches, and the average purity of all batches was 97.1%. The total average yield, corrected for purity, was 88.3%.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (10)

1. CLAIMS 1. A process for the preparation of 4,6-dimethoxy-2- ((phenoxycarbonyl) amino) -pyrimidine, characterized in that it comprises reacting 2-amino-4,6-dimethoxy-pyrimidine and phenyl chloroformate in amounts of less stoichiometric, in an inert solvent selected from 1,4-dioxane and tetramethylurea, and at a temperature from 10 ° to 45 ° C.
2. 2. The process according to claim 1, characterized in that the solvent is 1,4-dioxane.
3. 3. The process according to claim 1, characterized in that the solvent is tetramethylurea.
4. 4. The process according to claim 1, characterized in that the temperature is 20 ° -30 ° C.
5. 5. The process according to claim 4, characterized in that the solvent is 1,4-dioxane.
6. 6. The process according to claim 4, characterized in that the solvent is tetramethylurea.
7. 7. The process according to claim 1, characterized in that the amount of phenyl chloroformate is 10-75% in excess of the stoichiometric amount.
8. 8. The process according to claim 7, characterized in that the temperature is 20 ° -30 ° C.
9. 9. The process according to claim 7, characterized in that the solvent is 1,4-dioxane.
10. 10. The process according to claim 1, characterized in that the solvent is tetramethylurea.