DE1271116B - Process for the preparation of 4-hydroxypyrimidines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

German KL:

Number:
File number:
Registration date:
Display day:

C07d

A61k

12 ρ -7/01
30 h-2/36

1271116
P 12 71 116.9-44
May 4, 1965
June 27, 1968

The invention relates to a process for the preparation of 4-hydroxypyrimidines; the procedure consists in that one acetic acid ester of the general formula

R ¹ - CH ₂ - COOR ² I.

in which R ^{1 is} optionally by halogen atoms or alkyl groups with 1 to 6 carbon atoms or by alkoxy or alkyl mercapto groups with 1 to 4 carbon atoms or by hydroxy or amino groups or by alkylamino or dialkylamino groups with 1 to 4 carbon atoms, two of these alkyl radicals together with the nitrogen atom can form a heterocyclic ring, substituted phenyl or naphthyl radical, or a 5- or 6-membered ring optionally substituted by alkyl groups with 1 to 6 carbon atoms, containing 1 to 3 identical or different heteroatoms N, S or O, on which also a Benzene ring can be fused, and in which R ^{2 is} an alkyl radical having 1 to 6 carbon atoms, with nitriles of the general formula Process for the preparation of
4-hydroxypyrimidines

R ³

CN

in which R ³ denotes a 5- or 6-membered ring containing 1 to 3 identical or different heteroatoms N, S or O, to which a benzene ring can also be fused, in the presence of an amount of an alkali metal alcoholate of a lower alcohol which is at least equimolar to the amount of the acetic acid ester , an alkali amide or high-boiling tertiary amine, optionally in the presence of an inert organic solvent at temperatures between 60 and 160 ^° C. to give 4-hydroxypyrimidine derivatives of the general formula

OH

in which R ¹ and R ^{3 have} the meanings given above.

For carrying out the process according to the invention, suitable acetic acid esters of the general Formula I are e.g. B. Phenylacetic acid methyl ester, ethyl ester, isopropyl ester and butyl ester, «- and / y-naphthylacetic acid ethyl ester, o-, m- and p-methylphenylacetic acid ethyl ester, o-, m- and p-methoxyphenylacetic acid ethyl ester, o-, m- and p-methyl mercaptophenylacetic acid ethyl ester, o-, m- and p-hydroxy

Applicant:

Paint factories Bayer Aktiengesellschaft,

5090 Leverkusen

Named as inventor:

Dr. Hans-Joachim Kabbe, 5090 Leverkusen;

Dr. Karl Eiter, 5000 Cologne-Stammheim

phenylacetic acid ethyl ester, o- and p-chlorophenylacetic acid ethyl ester, 3 - chloro - 4 - methoxyphenylacetic acid ethyl ester, 3,4 - dichlorophenylacetic acid ethyl ester, 3,5 - dichloro - 4-methoxyphenylacetic acid ethyl ester, 2-methoxy-4-methyl-5-chlorophenylacetic acid ethyl ester, p-ethyl aminophenylacetate, p- -Methylaminophenylacetic acid ethyl ester, ρ - dimethylaminophenylacetic acid ethyl ester, p-pyrrolidinophenylacetic acid ethyl ester, α - furyl acetic acid ethyl ester, α-, β- and γ-pyridyl acetic acid ethyl ester, 5-thiazolylacetic acid ethyl ester, 5-oxazolylacetic acid ethyl ester, 2 acetylacetate, 5-oxazolylacetyl acetic acid ethyl ester, benzoliacetyl acetate, benzyl acetate, 5-oxazolylacetyl acetate, benzyl acetate, ethyl acetate.

Suitable nitriles of the general formula II are, for example, 2-cyanopyrrole, 2-cyanofuran, 2-cyanothiophene, α-, β- and γ-cyanopyridine, 4- and 5-cyanothiazole, 4- and 5-cyanooxazole, 4-cyanopyrimidine and 3- Cyanoquinoline.

The molar ratio between acetic acid esters and nitriles is generally 1: 1.5 to 1: 3, expedient 1: 2.

Suitable alkali metal alcoholates are, for. B. potassium and sodium methylate, ethylate, tert-butylate, as alkali amides ζ. B. potassium and sodium amides, as high-boiling tertiary amines ζ. B. dimethylaniline, collidine and quinoline.

Implementation, the duration of which is 15 minutes up 10 hours is preferably carried out between 100 and 130 ° C. If solvent is used they must be compared to the acetic acid esters and nitriles used as well be inert towards the basic compounds given above and, if the reaction is below

809 567/566

normal pressure is carried out, at least one corresponding to the reaction temperature Have boiling point. Examples are hydrocarbons such as benzene, toluene and xylene, Ethers such as dibutyl ether and glycol diethyl ether, alcohols such as butanol and pentanol, and chlorinated ones Hydrocarbons such as carbon tetrachloride, di-1 chloroethane and chlorobenzene.

Surprisingly, by the process according to the invention obtained new 4-hydroxypyrimidines of the general formula III have a remarkable Effect on bacteria such as streptococci, staphylococci, coli bacteria, proteus bacteria and tubercle bacteria, as well as against fungi such as Trichophyton mentagrophytes and Candida albicans.

The parts given in the following examples are parts by weight.

example 1

33 parts of ethyl phenylacetate (0.2 mol) and 42 parts of α-cyanopyridine (0.4 mol) were stirred with 12 parts of sodium methylate (0.22 mol) at room temperature and then heated. At 60 ° C, a strongly exothermic reaction occurred, and the temperature then rose to 115 ° C. The reaction mixture was then another 20 minutes to 110 ⁰ C held, then cooled and dissolved in 250 parts of water. The 2,6-di-a-pyridyl-4-hydroxy-5-phenylpyrimidine formed was precipitated from the solution obtained by adding 100 parts of saturated aqueous ammonium chloride solution. The yield was 40 parts (= 62%), melting point 227 to 228.5 ° C. (after recrystallization from glacial acetic acid-water).

Analysis: C ₂₀ H ₁₄ N ₄ O (326.35).

Calculated ... C 73.61, H 4.33, N 17.17%;
found .... C 73.73, H 4.66, N 16.95%.

Example 2

A mixture of 33 parts of phenylacetic acid ethyl ester (0.2 mol), 42 parts of γ- cyanopyridine (0.4 mol) and 80 parts of butanol was mixed with 12 parts of sodium methylate (0.22 mol) and stirred at HO ⁰ C for IV2 hours. Then the reaction mixture was dissolved in 250 parts of water. The 2,6-di-y-pyridyl-4-hydroxy-5-phenylpyrimidine formed was precipitated by adding 100 parts of saturated aqueous ammonium chloride solution. The yield was 61 parts (= 80 ⁰ / o), m.p. 300-305 ⁰ C (after recrystallization from glacial acetic acid water).

Analysis: C ₂₀ H ₁₄ N ₄ O • CH ₃ COOH (386.39).
Calculated ... N 14.50%;
found .... N 14.67%.

If the equivalent amount of potassium tert-butoxide was used instead of sodium methylate, see above the 2,6-di-y-pyridyl-4-hydroxy-5-phenylpyrimidine was obtained in 78% yield.

In an analogous manner, the ethyl acetate shown in the following table were the general Formula I in the presence of sodium methylate with nitriles of the general formula II converted to the corresponding 4-hydroxypyrimidines of the general formula III.

The implementation of the 3,4-dichlorophenyl acetic acid ethyl ester listed in the table under n) with 2-cyanofuran was carried out without the use of a solvent; the implementation of the under a) listed phenylacetic acid ethyl ester with ^ -Cyanopyridin took place with the use of Pentanol as the solvent, and the remaining reactions were carried out with the use of butanol carried out as a solvent.

R ¹ R ³ Response time /
Reaction
temperature the end
prey Melting point
in ⁰ C Molecular formula of III a) 3 hours
110 ⁰ C 39 308 to 313 C ₂₀ H ₁₄ N ₄ O
calculated: N 17.17;
found: N 16.98. OH
I. b) OH νV-
\ / 2 hours
110 ⁰ C 30th 320
(Decomposition) C ₂₀ H ₁₄ N ₄ O ₃
calculated: N 15.63;
found: N 15.28. Cl c) // —N 4 hours
110 ° C 51 > 300 C ₂₀ H ₁₃ ClN ₄ O
Calculated: N 15.55, Cl 9.83;
found: N 15.55, Cl 9.90. Cl d) <^ 3 hours
110 ° C 35 232 to 238 C ₂₀ H ₁₃ ClN ₄ O
calculated: Cl 9.83;
found: Cl 9.85.

continuation

R ¹

R ³

Reaction time / reaction temperature

yield

Melting point
in ° C

Molecular formula of HI

Cl

CH ₃ O

3 hours 110 ^° C

3 hours 110 ^° C

4 hours 110 ^° C

5 hours 105 ^° C

I ¹ I ₂ hours HO ⁰ C

3 hours 115 ^° C

3 hours 105 ° C

2 hours 110 ^° C

1 hour 110 ^° C

4 hours 105 ^° C

6 hours 108 ⁰ C

IV2 hours 105 ° C

to 295

to 222

to 285

> 330

to 252

212 to 213

to 286

to 303

to 266

320

to 252

to 221

C ₂₀ H ₁₃ ClN ₄ O

Calculated: N 15.53, Cl 9.83; found: N 15.48, Cl 9.85.

C ₂₀ H ₁₃ ClN ₄ O

calculated: Cl 9.83; found: Cl 9.95.

C ₂₀ H ₁₃ ClN ₄ O

calculated: N 15.53; found: N 15.33.

C ₂₀ H ₁₃ ClN ₄ O

Calculated: N 15.53, Cl 9.83; found: N 15.15, Cl 9.80.

C ₂₁ H ₁₅ ClN ₄ O ₂

Calculated: N 14.34, Cl 9.07; found: N 14.36, Cl 8.75.

C ₂₀ H ₁₂ Cl ₂ N ₄ O

Calculated: N 14.18, Cl 17.94; found: N 14.19, Cl 17.55.

C ₂₀ N ₁₂ Cl ₂ N ₄ O

calculated: Cl 17.94; found: Cl 18.15.

C ₂₀ H ₁₂ Cl ₂ N ₄ O.1.5 CH ₃ COOH

calculated: N 11.54; found: N 11.40.

C ₁₈ H ₁₀ Cl ₂ N ₂ O ₃

Calculated: N 7.51, O 12.88; found: N 7.53, 0 13.13.

C ₂₀ H ₁₂ ClN ₄ O

calculated:

C 60.77, H 3.06, N 14.17; found:

C 60.44, H 3.25, N 14.37.

C ₂₄ H ₁₆ N ₄ O

calculated: N 14.88; found: N 14.70.

C ₁₉ H ₁₃ N ₅ O

calculated:

C 69.71, H 4.01, N 21.40; found:

C 69.37, H 4.27, N 20.97.

continuation

R ¹

R ³

Reaction time / reaction temperature

Yield melting point
in ⁰ C

Molecular formula of III

Q-

4 hours 115 ° C

2 hours 108 ⁰ C

IV2 hours 115 ⁰ C

Claims (1)

Claim: Process for the preparation of 4-hydroxypyrimidines, characterized in that that one acetic acid ester of the general formula R ^ CH ₂ -COOR ² in which R ^{1 is} optionally by halogen atoms or alkyl groups with 1 to 6 carbon atoms or by alkoxy or alkyl mercapto groups with 1 to 4 carbon atoms or by hydroxy or amino groups or by alkylamino or dialkylamino groups with 1 to 4 carbon atoms, two of these alkyl radicals together with the nitrogen can form a heterocyclic ring, substituted phenyl or naphthyl radical, or a 5- or 6-membered ring optionally substituted by alkyl groups with 1 to 6 carbon atoms, containing 1 to 3 identical or different heteroatoms N, S or O, on which also a Benzene ring can be fused, means, and in which R ^{2 is} an alkyl radical with 1 to 6 carbon 266 to 267 230
(Decomposition) 196 to 199 C ₂₂ H ₁₅ N ₅ O calculated: N 19.17; found: N 19.10. C ₁₆ H ₁₁ N ₇ O.2V ₂ H ₂ O calculated: C 53.02, H 4.45, N 27.06; found: C 53.22, H 4.26, N 27.22. C ₁₈ H ₁₂ N ₄ O ₂ Calculated: C 68.34, H 3.83; found: C 68.49, H 4.20. atoms, with nitriles of the general formula R ³ —CN in which R ³ denotes a 5- or 6-membered ring containing 1 to 3 identical or different heteroatoms N, S or O, to which a benzene ring can also be fused, in the presence of an amount of an alkali metal alcoholate of a lower alcohol which is at least equimolar to the amount of the acetic acid ester , an alkali amide or high-boiling tertiary amine, optionally in the presence of an inert organic solvent at temperatures between 60 and 160 ^° C. to give 4-hydroxypyrimidine derivatives of the general formula OH R ¹ R ³ OjO R ³ in which R ¹ and R ^{3 have} the meanings given above. 809 567/566 6.68 © Bundesdruckerei Berlin