KR100411400B1 - Chemical method - Google Patents

Abstract

The present invention relates to a process for the preparation of 4, 6-dichloropyrimidine, consisting of treating 4, 6-dihydroxypyrimidine with phosgene in the presence of a suitable base and optionally a solvent.

Description

Chemical method

The present invention relates to a process for converting 4,6-dihydroxypyrimidine of formula (1) to 4,6-dichloropyrimidine of formula (2) using phosgene (COCl ₂ ) and a suitable base. . 4,6-Dichloropyrimidine is useful as a chemical intermediate in the pesticide industry.

It is particularly useful for the manufacture of ICIA5504.

For example, phosphoryl chloride (POCl ₃ ) in the presence of dimethylaniline can convert 4, 6-dihydroxypyrimidine to 4, 6-dichloropyrimidine (Journal Chemical Society (1943) 574-5, and East and West (1951) 2214 are known. The problem with this method is that on a large scale, a significant amount of phosphoric acid is produced as a by-product and must be treated in several ways.

The present invention provides a process for the preparation of 4, 6-dichloropyrimidine comprising treating 4, 6-dihydroxypyrimidine with phosgene in the presence of a suitable base.

4, 6-dihydroxypyrimidine (1) may also exist in the tautomeric form of the following formulas (A) and (B) so that all 4, 6-dihydroxypyrimidines are It includes.

Suitable bases include ^tertiary of the formula R ¹ R ² R ³ N, wherein R ¹ , R ² and R ³ are independently C _1-10 alkyl, aryl, heteroaryl or aryl (C _1-4 ) alkyl Heterocyclic amines optionally substituted with amines and C _1-10 alkyl. Examples of tertiary amines are triethylamine, 4- (N, N-dimethylamino) -pyridine, N, N-diisopropylethylamine and especially dimethylaniline. Examples of heterocyclic amines are pyridine, 2-methylpyridine, 4-methylpyridine, imidazole and N-alkyl pyrrolidine (such as N-methylpyrrolidine).

The base: phosgene molar ratio is preferably in the range of 1: 10-10: 1, in particular 1: 1-1: 4 (such as 2: 3 and 2: 4.5).

The alkyl group is straight or branched and preferably contains C _1-6 , especially C _1-4 unless otherwise indicated. Examples thereof are methyl, ethyl, iso-propyl, n-propyl, n-butyl and tert-butyl.

Aryl is preferably phenyl.

Heterocyclic amines are preferably saturated or unsaturated 3-7 membered carbon nitrogen rings. These are for example pyridine, imidazole, pyrrolidine or piperidine.

Heteroaryl is a 3-7 membered carbon nitrogen ring. These are for example pyridine, imidazole, pyrazole or pyrrolidine.

The method is preferably carried out in a solvent or solvent mixture. Chlorinated solvents (eg, dichloromethane, 1, 1, 2, 2-tetrachloroethane or chlorobenzene), ethers (eg, tetrahydrofuran, glyme, diglyme or triglyme), polar aprotic solvents [eg, Preference is given to esters (eg C _1-4 alkyl esters such as methyl formate or iso-propyl formate) or nitriles (eg propionitrile, butyronitrile, benzonitrile or acetonitrile). Solvent mixtures include, for example, mixtures of acetonitrile and dichloromethane.

The process is preferably carried out in a temperature range of -10 to 130 ° C, in particular 0 to 120 ° C, especially 10 to 90 ° C.

A first aspect of the invention provides a process for the preparation of 4, 6-dichloropyrimidine comprising adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a suitable base.

A second aspect of the present invention comprises adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a suitable base and adding all of the phosgene to be used in this method when the method is disclosed, 4,6-dichloropyri Provided are methods for preparing midines.

A third aspect of the present invention comprises adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a suitable base (such as dimethylaniline or diisopropylethylamine) in a chlorinated solvent. Dihydroxypyrimidine: a suitable base: phosgene molar ratio of 1: (0.8-2.5): (2.5-3.6), especially 1: (1.5-2.2): (2.9-3.3) Provided are methods for preparing midines.

A fourth aspect of the invention comprises adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a suitable base (such as dimethylaniline or diisopropylethylamine) in a nitrile solvent, 4, 6-dichloropyrimidine with a molar ratio of hydroxypyrimidine: suitable base: phosgene in the range of 1: (0.1-2.4): (4-9), especially 1: (0.1-2.1): (4.4-6.5) It provides a method of manufacturing.

A fifth aspect of the invention relates to adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a suitable base (such as dimethylaniline) in a suitable solvent (such as dichloromethane, acetonitrile or tetrahydrofuran) ( 4, 6 comprising heating all of the phosgene to be used in this process at the start of the process and the reaction mixture (preferably for 1-30, in particular for 1-6 or 15-24 hours). Provided is a process for the preparation of dichloropyrimidine. Suitable bases can be recovered and recycled (in the form of salts) upon product separation.

The following examples illustrate the invention. The apparatus used in the following examples was dried before use and the reaction was carried out under nitrogen atmosphere using anhydrous conditions.

Example 1

4, 6-Dihydroxypyrimidine (0.94 g) was suspended in dichloromethane, dimethylaniline (1.12 g) was added and the phosgene (5 g) was condensed into this mixture.

The resulting mixture was heated to reflux for 24 hours and then cooled and poured into water. High pressure liquid chromatography (hplc) analysis of the resultant organic layer showed a ratio of 4, 6-dihydroxypyrimidine: 4, 6-dichloropyrimidine at 39:58.

Example 2

4, 6-Dihydroxypyrimidine (20.5 g) was dispersed in dichloromethane (400 ml) with stirring. Dimethylaniline (40.4 g) was added to the stirred mixture (except for the vent line to the scrubber) and the system was sealed. Phosgene gas (56 g) was injected through the cylinder to condense in the cooling rods and collected in an equally dripping funnel. Upon collection, the phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and stirred at reflux (about 29 ° C.) for 17 hours, then cooled to room temperature and sparged with nitrogen to remove excess phosgene.

Water (400 ml) was slowly added to the stirred reaction mixture while cooling to maintain ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 100 ml). The collected extracts were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give 4, 6-dichloropyrimidine as an orange crystalline solid (27 g), corresponding to a yield of 80% (hplc analysis).

Example 3

4, 6-Dihydroxypyrimidine (2.0 g) was dispersed in acetonitrile (40 ml) with stirring, dimethylaniline (2.1 g) was added and the mixture was heated to 50 ° C. Phosgene gas (14.6 g) was added to the mixture over 1 hour (by bubbling phosgene gas through the mixture). The mixture was placed at 50 ° C. for 4.5 hours to cool to room temperature and then excess phosgene was removed by sparging with nitrogen. The resulting reaction was analyzed (hplc) and found to contain 4, 6-dichloropyrimidine (81% yield).

Example 4

To a mixture of imidazole (6.19 g, 2 equiv) and 4,6-dihydroxypyrimidine (5.14 g, 1 equiv) in acetonitrile (100 ml) was added phosgene (28 g, 6.2 equiv). The mixture thus obtained was stirred at room temperature for 2¼ hour and at 50 ° C for 1 hour. The reaction mixture was purged with nitrogen overnight and separated into water and dichloromethane. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic extracts were washed with water (twice), dried over magnesium sulfate and evaporated to dryness, leaving 4, 6-dichloropyrimidine as a pale yellow solid.

Example 5

To a stirring mixture of 4-(N, N-dimethylamino) pyridine (0.55 g, 0.1 equiv) and 4,6-dihydroxypyrimidine (5.18 g, 1 equiv) in acetonitrile (100 ml) , 19.7 ml, 6.2 equivalents) was added in two portions. The mixture thus obtained was stirred at room temperature for 10 minutes and then at 55 ° C. for 4 hours. The reaction mixture was purged with air and then water (200 ml) was added. The resulting mixture was extracted with dichloromethane (3 × 100 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated to dryness, leaving 4, 6-dichloropyrimidine (4.63 g).

Example 6

Phosgene (28 g, 19.7) in a stirred mixture of N, N-diisopropylethylamine (11.75 g, 2 equiv) and 4,6-dihydroxypyrimidine (5.18 g, 1 equiv) in acetonitrile (100 ml) ml, 6.2 equiv) was added in 2 portions. The mixture thus obtained was stirred at room temperature for 10 minutes and then at 55 ° C. for 4 hours. The reaction mixture was sparged with air overnight and then water (100 ml) was added. The resulting mixture was extracted with dichloromethane (3 × 100 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated to dryness, leaving 4, 6-dichloropyrimidine (6.35 g).

Claims (7)

A process for the preparation of 4,6-dichloropyrimidine comprising treating 4,6-dihydroxypyrimidine with phosgene in the presence of a base selected from the group consisting of the following amines or carbon nitrogen rings: Tertiary amines of the formula R ¹ R ² R ³ N [wherein R ¹ , R ² and R ³ are independently C _1-10 alkyl, phenyl, aromatic 3-7 membered carbon nitrogen ring or phenyl (C _1-4 ) Alkyl]: or A saturated C _1-10 alkyl optionally substituted with 3-7 won optionally substituted with unsaturated 3 carbon nitrogen ring or C _1-10 alkyl-7 member carbon nitrogen ring. The method of claim 1 wherein the base: phosgene molar ratio is in the range of 1: 10-10: 1. The process according to claim 1 or 2, wherein the process is carried out in a solvent or solvent mixture. The method of claim 1 wherein phosgene is added to a mixture of 4, 6-dihydroxypyrimidine and a base. The process of claim 1 wherein the method comprises adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a base in a chlorinated solvent, wherein the molar ratio of 4, 6-dihydroxypyrimidine: base: phosgene is 1: (0.8-2.5) :( 2.5-3.6). The process of claim 1 wherein the method comprises adding phosgene to a mixture of 4, 6-dihydroxypyrimidine and a base in a nitrile solvent, wherein the molar ratio of 4, 6-dihydroxypyrimidine: base: phosgene is 1 : (0.1-2.4): Method in the range of (4-9). The method of claim 1 wherein the base is dimethylaniline or diisopropylethylamine.