DK160270B - METHOD OF PREPARING 2,4- OR 2,4,5-SUBSTITUTED 6-HYDROXYPYRIMIDINES - Google Patents

Description

DK 160270 B

The present invention relates to a novel process for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines of the general formula I

R3

5 2 I

Vv “I I 1 v R1

10 R

wherein R 1 represents alkyl [preferably CH 3, C 2 H 5, n-C 3 H 7, CH (CH 3) 2 or n-C 4 H 9] or R 7 n /, R 2 represents alkyl, aryl or aralkyl [preferably CH 3, C 2 H 5, n-C 3 H 7, CH (CH3) 2, n-C4H9, C (CH3) 3, C6H5 or CH2CH2C6H5], and R3, R7 and R8 each represent hydrogen, alkyl or aralkyl [preferably H, CH3, C2Hg, n-C3H7, CH (CH3) 2, 20 n-C4Hg, C (CH3) 3, CH2C6H5 or CH2CH2C6H5], or salts thereof with a salt-forming cation, and the process is characterized by reacting a 3- or 2,3-substituted 3-aminoacrylic acid derivative with the general formula II R3

r2 \ A '° II

I I

H7N X

Wherein R 2 and R 3 have the above meanings, and X is OR 4 or R 5 is R 6 wherein R 4 is alkyl, aryl or aralkyl [preferably 2

DK 160270B

CH3, C2H5, n-C3H7, CH (CH3) 2, n-C4H9, C (CH3) 3, C6H5 or CH2C6H5], and R5 and R3 each represent hydrogen, alkyl or aralkyl [preferably H, CH3, C2Hg , n-C 3 H 7, CH (CH 3) 2,

5, n-C4Hg, C (CH3) 3, CH2C6H5 or CH2CH2C6H5], with a nitrile of the general formula III

R1-C = N III

wherein R 1 has the aforementioned meaning, in the presence of a base and a solvent, after which, if desired, the salt formed is converted to the free pyrimidine of formula I by the addition of an acid.

This procedure can be reproduced by the following reaction scheme: 15 R3 3 2 1?

R \ 2 I

c 'c' R v .Cv ν · ΟΗ I j 1st Base

h2n X -> I II

20 + 2. Acid Nv N

Il Rl

R

25 wherein the various symbols have the above meanings.

The process can be described as the reaction between a 3-aminoacrylic acid ester or a 3-aminoacrylic acid amide and a nitrile under the decomposition of an alcohol or ammonia / amine, respectively. The reaction is general for the above starting materials, as well as for the tauomeric forms in which the starting materials may occur.

For example, the starting materials appear:

DK 160270 B

3

a. Ethyl cyanamide as EtNH-CIN 2 == in EtN = C = NH

b. 3-Aminocrotonic acid amide as. h2n nh2 hn nh2 hn nh2

I I Il I _ i! IN

^ 0 '^ 0 5 H3c / ΧΟΗ

H HH H

Likewise, the pyrimidine appears in various 10 tautomeric forms: R3 R3 R3

2 I 2 I 2 I

R ^ C ^ C \ / ° H R NC ^ C \ C ^ ° R · ^ C \ * ° I I f = * i i * = * i i 15 "ν '"% / ra R1 R1 R1

Various convenient embodiments of the method according to the invention can be used as set forth in claims 2-10.

The reaction proceeds in the presence of base which may be a free alkali metal or alkaline earth metal, or an alkali metal hydride, alkali metal amide, alkali metal alkoxide, alkali metal phenolate, alkali metal hydroxide, alkali metal carbonate or alkali metal carboxylate or a corresponding alkaline earth metal compound.

In the reaction, a salt, e.g. an alkali metal salt of the pyrimidine. The free pyrimidine can be released from it by treatment with an acid such as a mineral acid or an organic acid.

The reaction proceeds in the presence of a solvent, which may be, for example, an alcohol, ether, ethylene glycol ether, ketone or carbonic acid ester or an aliphatic or aromatic hydrocarbon.

The reaction usually proceeds at a temp.

DK 160270 B

In a range of between 20 ° C and 180 ° C, preferably between 80 ° C and 140 ° C.

A number of methods are known for preparing industrially interesting pyrimidines as described below: A. 2-Isopropyl-4-methyl-6-hydroxypyrimidine U.S. Patent No. 4,014,879, U.S. Patent No. 4,496,728, and GB patent 2,083,814 discloses the preparation of 2-isopropyl-4-methyl-6-hydroxypyrimidine from isobutyric acid nitrile.

Isobutyric acid nitrile is converted to isopropylimino ether by reaction with alcohol and dry hydrogen chloride.

15 isopropylimino ether is converted to isopropylamidine by reaction with ammonia. Isopropylamidine is reacted with methyl acetoacetate to 2-isopropyl-4-methyl-6-hydroxypyrimidine.

JP Patent Abstract No. 48/39943 discloses a similar reaction from isopropylamidine and the diket, whereas GB Patent No. 2,027,710 describes the reaction between isopropylimino ether and the diket followed by reaction with ammonia.

U.S. Patent No. 4,052,397, DE Publication No. 2,065,698 and No. 3,344,429 and JP Patent Abstracts No. 48/26020 and No. 48/39942 disclose the preparation of 2-isopropyl-4-methyl -6-hydroxypyrimidine by reaction of 3-aminocrotonic acid amide with isobutyric acid salt, isobutyric acid ester or isobutyric anhydride.

DK 160270 B

B. 2-Dimethylamino-4-methyl-6-hydroxypyrimidine GB Patent No. 1,182,584 discloses the preparation of 2-dimethylamino-4-methyl-6-hydroxypyrimidine from dimethylguanidine and ethylacetoacetate.

C. 2-Diethylamino-4-methyl-6-hydroxypyrimidine DE Publication No. 2,520,832 discloses the preparation of 2-diethylamino-4-methyl-6-hydroxy-pyrimidine from diethylguanidine and diketene.

D. 2-Ethylamino-4-methyl-5-butyl-6-hydroxypyrimide in DE Publication No. 2,109,880 and 2,308,858 discloses the preparation of 2-ethylamino-4-methyl-5-butyl-6-hydroxypyrimidine from ethyl guanidine and ethyl butyl acetoacetate.

U.S. Patent No. 2,008,875 discloses the preparation of 2-methoxy-4-methyl-5-butyl-6-hydroxypyrimidine from o-methylisourea and ethyl-butylacetoacetate. The 2-methoxy group is replaced by a 2-ethylamino group by reaction with ethylamine.

25 e. 2- (Di) alkylamino-4-methyl-5-substituted-6-hydroxy-pyrimidine DE Publication No. 2,239,213 and 2,533,710 discloses the preparation of 2- (di) alkyl-30-amino-4 -methyl-5-substituted-6-hydroxypyrimidine from nitroguanidine or thiourea and substituted acetoacetate. The nitroamino group is replaced by reaction with amine. The mercapto group is replaced by methylation and reaction with amine.

DK 160270 B

6

The process of the invention differs from the methods thus known in the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines by using already known starting materials, but in a combination not previously known, and surprisingly, nitriles react with the 3- or 2,3-substituted 3-aminoacrylic acid derivatives of formula II used in the invention. Compared to already known reactions employing nitriles, in the process of the invention, it is not necessary to convert the nitrile to the corresponding imino ether or amidine prior to the coupling reaction, and this results in fewer reaction steps than in the known methods.

The process of the invention also differs from the known processes in that the reaction is more general and the process of the invention can therefore be used to prepare a wide variety of substituted pyrimidines, the utility of which will be known or obvious to those skilled in the art.

The method according to the invention is further illustrated by the following examples with reference to the drawing which shows 13C NMR spectra of the products prepared according to the examples.

0.25

Example 1 In 300 ml of isobutanol, 23 g of sodium is dissolved under reflux. When all the sodium has dissolved, the mixture is cooled slightly and 157 g of 3-amino-crotonic acid isobutyl ester and 69 g of isobutyric acid nitrile are added. Then the mixture is heated to reflux for 3 hours. The reaction mixture is worked up as described in Example 7. The resulting 2-isopropyl-4-methyl-6-hydroxypyrimidine is obtained as a white to pale yellow product which after drying has a

DK 160270 B

7 purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 1].

Example 2

To a mixture of 100 g of 3-aminocrotonic acid amide dissolved in ca. Add 100 ml of liquid ammonia while cooling in small portions 23 g of sodium. When all of the sodium 10 has dissolved, the reaction mixture is heated slowly while distilling off ammonia. When the temperature reaches 20 ° C, 200 ml of toluene is added and heated to reflux.

At reflux temperature, 69 g of isobutyric acid nitrile is dropped over 1 to 2 hours. Upon completion of drip, the temperature is kept at reflux for an additional 3 hours. The reaction mixture is worked up as described in Example 7. The resulting 2-isopropyl-4-methyl-6-hydroxypyrimidine is obtained as a white to pale yellow product which, after drying, has a purity> 95% as determined by HPLC.

20 The drawing shows the 3 C NMR spectrum of the product in deuterated DMSO [Product 1].

Example 3 To a mixture of 143 g of 2-methyl-3-amino-carboxylic acid ethyl ester and 70 g of dimethyl cyanamide and ca. 200 ml of tetrahydrofuran heated to reflux are added in small portions totaling 23 g of sodium. The reaction mixture is kept at reflux for 3 hours. The reaction mixture is worked up as described in Example 7. The resulting 2-dimethylamino-4,5-dimethyl-6-hydroxypyrimidine is obtained as a white to pale yellow product which after drying has a purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 2].

DK 160270 B

8

Example 4

To a slurry of 24 g of sodium hydride in 100 g of monoethylene glycol dimethyl ether heated to reflux is added dropwise a mixture of 98 g of diethyl cyanamide and 100 g of 3-amino-crotonic acid amide dissolved in 100 g of monoethylene glycol dimethyl ether. The reaction mixture is kept at reflux for 3 hours. The reaction mixture is worked up as described in Example 7. The resulting 2-diethyl-10-amino-4-methyl-6-hydroxypyrimidine is obtained as a white to pale yellow product which, after drying, has a purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 3].

15

Example 5

A mixture of 157 g of 3-amino-crotonic acid isobutyl ester and 112 g of potassium tert-butoxide in ca. 200 ml of dioxane is heated to reflux and drops 98 g of diethyl cyanamide over 1-2 hours. Upon completion of the drip, the temperature is kept at reflux for an additional 3 hours. The reaction mixture is worked up as described in Example 7.

The resulting 2-diethylamino-4-methyl-6-hydroxypyrimidine 25 appears as a white to pale yellow product which, after drying, has a purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 3].

Example 6

A mixture of 100 g of 3-amino-crotonic acid amide, 98 g of diethyl cyanamide and 56 g of potassium hydroxide in ca. 200 ml of tetrahydrofuran is heated to reflux for 3 hours. The reaction mixture is worked up as described below

DK 160270 B

9 7. The resulting 2-diethylamino-4-methyl-6-hydroxypyrimidine appears as a white to pale yellow product which, after drying, has a purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 3].

Example 7

A mixture of 143 g of 2-methyl-3-amino-crotonic acid ethyl ester, 70 g of ethyl cyanamide and 138 g of potassium carbonate in 300 ml of diethyl carbonate is heated to reflux for 6 hours. The reaction mixture is worked up by one of the following methods: 15 a. The reaction mixture is neutralized with a mineral acid (e.g., dry hydrogen chloride or wife. to which 200 ml of water is added.

The product precipitates in the aqueous phase and can be filtered off.

b. The reaction mixture is evaporated on a rotary evaporator to dryness and 200 ml of water are added. The aqueous phase is neutralized with mineral acid, whereby the product precipitates and can be filtered off.

The resulting 2-ethylamino-4,5-dimethyl-6-hydroxy-pyrimidine appears as a white to pale yellow product which, after drying, has a purity> 95% as determined by HPLC.

In the drawing, the 13 C NMR spectrum of the product is shown in deuterated DMSO [Product 4].

By a similar method, 2-ethylamino-4-methyl-5-n-butyl-6-hydroxypyrimidine can be prepared by using

DK 160270 B

Using 2-n-butyl-3-amino-crotonic acid ethyl ester instead of 2-methyl-3-amino-crotonic acid ethyl ester.

Claims (10)

A process for the preparation of 2,4- or 2,4,5-substituted 6-hydroxypyrimidines of general formula I Process according to claim 1, characterized in that the base used is an alkali metal or alkaline earth metal, or an alkali metal hydride, alkali metal amide or alkali metal alkoxide or a corresponding alkaline earth metal compound. 2 I R v »® v» ° 30. In II h 2n X wherein R 2 and R 3 have the above meanings and X represents OR 4 or R 5 n / R 6 wherein R 4 represents alkyl, aryl or aralkyl [preferably CH 3, C 2 H 5, n-C 3 H 7, CH (CH3) 2, n-C4H9, C (CH3) 3, CgHg or CH2CgHg], and R5 and R6 each represent hydrogen, alkyl or aralkyl [preferably H, CH3, C2H5, n-C3H7, CH (CH3) 2 , n-C4Hg, C (CH3) 3, CH2C6H5 or CH2CH2CgH5], with a nitrile of general formula III R 1 -C = N III 15 wherein R 1 has the above meaning, in the presence of a base and a solvent, desirably, the salt formed converts to the free pyrimidine of formula I by the addition of an acid. Process according to claim 1, characterized in that the base used is an alkali metal phenolate, alkali metal hydroxide, alkali metal carbonate or alkali metal carboxylate or a corresponding alkaline earth metal compound. Process according to any one of the preceding claims, characterized in that the solvent used is an alcohol, ether, ethylene-glycol ether, ketone or carbonic acid ester or an aliphatic or aromatic hydrocarbon. Process according to any of the preceding claims, characterized in that the reaction temperature is between 20 ° C and 180 ° C, preferably between 80 ° C and 140 ° C. Wherein R 1 represents alkyl [preferably CH 3, C 2 H 5, n-C 3 H 7, CH (CH 3) 2 or n-C 4 H 9] or R 7 n / \ r 8 R 2 represents alkyl, aryl or aralkyl [preferably CH 3, C 2 H 5, n-C 3 H 7, CH (CH 3) 2, n-C 4 H 9, C (CH 3) 3, C 9 H 5 or CH 2 CH 2 C 6 H 5], and R3, R7 and R8 each represent hydrogen, alkyl or aralkyl [preferably H, CH3, C2H5, n-C3H7, CH (CH3) 2, n-C4H9, C (CH3) 3, CH2C6H5 or CH2CH2C6H5], or salts thereof with a salt-forming cation, characterized by reacting a 3- or 2,3-substituted 3-aminoacrylic acid derivative of the general formula I R3 Process according to any one of the preceding claims, characterized in that the reaction mixture is treated with a mineral acid or an organic acid. Process according to any one of the preceding claims, characterized in that the nitrile of formula III used is isobutyric acid nitrile, ethyl cyanamide, dimethyl cyanamide or diethyl cyanamide. Process according to any one of claims 1-7, characterized in that the acrylic acid derivative of formula II used is 3-amino-crotonic acid amide or a 3-amino-crotonic acid ester. Process according to any one of claims 1-7, characterized in that the acrylic acid derivative of formula II used is 2-methyl-3-amino-crotonic acid amide or a 2-methyl-3-amino-crotonic acid ester. Process according to any one of claims 1-7, characterized in that the acrylic acid derivative of formula II used is 2-n-butyl-3-aminocrotonic acid amide or a 2-n-butyl-3-amino-crotonic acid ester.