KR900002061B1 - Process for preparing 2,4-diamino-6-chloropyrimidine - Google Patents

Abstract

Pyrimidine derivs. (I) useful as an intermediate for antihypertensive compd., are prepd. by reaction of 2,4-diamino-6hydroxypyrimidine (II) and alkali metal or alkali metal hydroxide (IX) followed by reaction with III (M=K,Na,Li) and oxychlorophosphate in the presence of tertiary amine cat. The IV is one of NaOH, KOH, LiOH and alkali metal is Na and Li. The tertiary amine is one of pyridine, triethyl amine, N-methyl piperidine.

Description

Method for preparing 2,4-diamino-6-chloropyrimidine

The present invention relates to a novel process for the preparation of 2,4-diamino-6-chloropyrimidine, of formula (II), which is an intermediate compound for preparing a compound of formula (I), which is known to be an effective therapeutic agent for severe hypertension.

The compounds of the structural formulas (I) and (II) are known compounds, and conventional preparation methods thereof are described in US Pat. Nos. 3,382,247 and 3,644,364, German Patent Nos. 2,943,161 and J. Org. Chem. vol. 40, no. 22, 3304 (1975), J. Med. Chem. 7, 792 (1964). Conventional methods react 2,4-diamino-6-hydroxypyrimidine of formula (III) with an excess of phosphorus oxychloride to produce 2,4-diamino-6-chloropyrimidine of formula (II) It was how to do it.

However, this conventional method generates a maximum of 19.5 mol of toxic hydrogen chloride gas per kilogram of phosphorus oxychloride when hydrolyzed due to excess phosphorus oxychloride, which is very dangerous and requires a large amount of ammonia water used as a neutralizing agent. In addition, since the intermediate compound formed after neutralization is contained in a large amount of salt, it is cumbersome to extract and the yield is also low, and the highest yield reported in the literature is 71%. In order to remove the hydrogen chloride gas, a separate HOOD facility and an air purification facility are required, and excessive facility costs are invested.

In the present invention, to improve these disadvantages, the metal salt of formula (IV) is prepared by reacting the structure (III) 2,4-diamino-6-hydroxypyrimidine with a metal hydroxide to produce Only phosphorus oxychloride was reacted to prepare 2,4-diamino-6-chloropyrimidine as the target compound of formula (II).

As described above, the present invention uses an equivalent amount of phosphorus oxychloride instead of an excessive amount of phosphorus oxychloride, thus greatly reducing the amount of neutralizing agent used, thereby reducing the amount of salt generated and making it easier to extract. Not only is it increased to at least 80%, but also the amount of hydrogen chloride gas generated during hydrolysis is extremely small, thus providing a new technologically advanced manufacturing method which is economical and very useful in terms of work safety and pollution prevention.

Briefly describing the present invention, 2,4-diamino-6-hydroxypyrimidine of formula (III) prepared by a known method is reacted with a metal hydroxide to form a metal salt of formula (IV), which is formed under a tertiary amine catalyst. A method for producing 2,4-diamino-6-chloropyrimidine of formula (II) by reacting with an equivalent of phosphorus oxychloride.

Where M is K, Li or Na.

The present invention is described in more detail below.

First, 2,4-diamino-6-chloropyrimidine of formula (II) included in the characteristic synthetic route of the present invention is prepared from 2,4-diamino-6-hydroxypyrimidine of formula (III). Compounds of formula (III) are prepared in the presence of an equivalent sodium ethoxide from compounds of the structure of ethyl cyanate and guanidine, or the like, according to known methods. The compound of formula (III) is made into metal salt (IV) by reaction with an equivalent amount of metal hydroxide, that is, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and water is evaporated to make anhydride.

At this time, since the consumption of phosphorus oxychloride increases due to moisture, it is dried in a vacuum dryer at a temperature of 80-120 ° C. to make completely anhydride. To get rid of this difficulty, it is better to use metal as it is.

By reacting the metal salt of formula (IV) prepared by the method as described above with phosphorus oxychloride to prepare 2,4-diamino-6-chloro pyrimidine of formula (II), wherein a hydroxyl group is used as a reaction solvent. Missing polar organic solvents such as dimethyl sulfoxide or hexamethyl phosphate are mainly used, and nonpolar solvents which do not react with phosphorus oxychloride, such as carbon tetrachloride dichloroethane and chloroform, may also be used. The reaction proceeds ideally under anhydrous conditions.

At this time, in order to promote the progress of the reaction, it is good to use various amines as a catalyst. This catalyst promotes the reaction well, especially in the case of tertiary amines. Tertiary amines that can be used include triethylamine, pyridine, 4-methylpyridine, N-methylpiperidine and the like. This reaction is almost quantitative in less than one hour in a temperature range of -20-20 ° C. in an organic solvent that does not contain water.

When the substituent of the intermediate compound of formula (IV) is able to react with phosphorus oxychloride, the protecting group does not participate in the reaction by using a protecting group before adding phosphorus oxychloride, which does not affect the method of the present invention.

Recrystallization of the compound of formula II is anhydrous organic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dioxane, tetrahydrofuran, ethyl acetate, ethanol, methanol, 2-propanol, 1-butanol and the like, or It is preferable to carry out in their two or more mixed solvents.

Disadvantages of the present invention for preparing and extracting compounds of formula II include low yields due to the use of excess raw materials and salt generation resulting from the use of excess raw materials, and cumbersome lighting during purification and separation. Not only is the economically and technically improved manufacturing method free of waste, but also excellent in pollution prevention.

A feature of the present invention is to prepare a compound of formula (IV) using a low-cost compound such as sodium hydroxide, potassium hydroxide and the like and reacting it with an equivalent phosphorus oxychloride in the presence of an amine catalyst to give 2,4-dia of formula (II). It is an economical and technically advanced method that greatly reduces raw material usage and improves yield by preparing mino-6-chloropyrimidine.

Example 1

144 g of 2,4-diamino-6-hydroxypyrimidine hydrate is placed in 1 L of 1N sodium hydroxide solution, and the solid obtained by evaporation under reduced pressure is dispersed in 2 l of dichloroethane, and then 155 g of phosphorus oxychloride is slowly added at room temperature. 24 ml of pyridine was slowly added thereto, stirred for 30 minutes, and heated to reflux for 2 hours. The solid obtained by evaporation under reduced pressure was dissolved in 1 L of water, neutralized with ammonia water, cooled to obtain a solid, dried, extracted with acetone and concentrated to give 127 g of 2,4-diamino-6-chloropyrimidine (yield 88%).

Melting Point: 199-200 ℃

Elemental Analysis: C ₃ H ₅ N ₄ Cl (144.57)

Theoretical value (%): C; 24.92 H; 3.49 N; 38.75

Found (%); C; 24.95 H; 3.54 N; 38.70

Example 2

144 g of 2,4-diamino-6-hydroxypyrimidine hydrate was dissolved in 1 L of 1N potassium hydroxide, and the solid obtained by evaporation under reduced pressure was reacted in the same manner as in Example 1 and separated and purified to obtain 2,4-diamino-6. 123 g of -chloropyrimidine was obtained (yield 85%).

Example 3

63 g of 2,4-diamino-6-hydroxypyrimidine anhydride was dissolved in 250 ml of a 2N lithium hydroxide solution, and the dried solid was treated as in Example 1 to obtain 61 g of 2,4-diamino-6-chloropyrimidine. (84% yield)

Example 4

After dissolving 63 g of 2,4-diamino-6-hydroxypyrimidine anhydride in 500 ml of 1N sodium hydroxide and evaporating under reduced pressure, the solid obtained was dispersed in 1.4 L of carbon tetrachloride, cooled to -20 ° C, and 77 g of phosphorus oxychloride was gradually added thereto. 14 ml of ethylamine was added, and then gradually warmed up, stirred at room temperature for 1 hour, heated to reflux for 30 minutes, reduced pressure to evaporate carbon tetrachloride, and the remaining solid was dissolved in water and separated in the same manner as in Example 1 to obtain 2,4-diamino- 60 g of 6-chloropyrimidine was obtained. (Yield 83%)

Example 5

63 g of 2,4-diamino-6-hydroxypyrimidine anhydride was reacted with 11.5 g of sodium metal, followed by reaction with 77 g of phosphorus oxychloride, and 20 g of N-methylpiperidine was slowly added, followed by separation in the same manner as in Example 4. 58 g of 2,4-diamino-6-chloropyrimidine was obtained (yield 80%).

Claims (3)

The 2,4-diamino-6-hydroxypyrimidine of formula (III) is reacted with an alkali metal hydroxide or an alkali metal to make a metal salt of formula (IV), and the compound of formula (IV) is oxygenated in the presence of a tertiary amine catalyst. A process for preparing 2,4-diamino-6-chloropyrimidine of formula (II) for reacting with phosphorus chloride.

M in the formula (IV) is K or Na or Li. The method of claim 1, wherein the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and the alkali metal is sodium or lithium. The method of claim 1, wherein the tertiary amine is selected from pyridine, triethylamine, N-methylpiperidine.