HU187355B - Process for preparing 2-amino-4-hydroxy-5-halo-substituted pyrimidine derivatives - Google Patents

Abstract

2-Amino-4-hydroxy-5-halo- substituted pyrimidine derivatives of the formula (I), <IMAGE> wherein R is a C1-4 alkyl or a phenyl group, and X is bromine or iodine, are prepared from the corresponding 2-amino-4-hydroxypyrimidine derivatives by halogenation carried out with an acidic solution of a haloid complex of an interhalogen. The new method of the invention is economic and advantageous also on an industrial scale.

Description

The present invention relates to a novel process for the preparation of 2-amino-4-hydroxy-5-halopyrimidine derivatives of the general formula (I) in which R is C 1 -C 4 alkyl or phenyl, X is bromine or iodine. The compounds of the present invention have antiviral and interferon inducing activity.

J. Chem. Soc. Perkin Trans. I 1975 (II) 1023-8 discloses the preparation of 2,4-diaminopyrimidines and 2-aminopyrimidin-4 (3H) -one substituted 1,2,3-benzotriazinyl groups. The ring bromination of the substituted pyrimidine is carried out with elemental bromine in a yield of about 70%.

No. 2,522,047, which is cited by C. A. 84,111,652. U.S. Patent No. 4,600,125 discloses the preparation of 2-amino-4-hydroxy-5-halo-6-alkyl or benzylpyrimidine derivatives wherein halogen is bromo or iodine and halogenation is accomplished by halosuccinimide. The process can be carried out in a yield of 45-55%.

No. 2,522,090, cited by C. A. 121,890. U.S. Pat. No. 4,800,198 to Halogenated Halogen Succinimide

2-amino-4-hydroxy-5-halo-6-alkyl or benzylpyrimidines. Yields are between 42% and 55%.

No. 3,008,693, which is cited by C.A. 94 84,159. German Federal Patent Specification

He reported, among other things, on the preparation of 2-amino-4-hydroxy-5-halo-6-phenylpyrimidines. Iodination with elemental iodine in the same manner as described herein gives 78% yield of 2-amino-4-hydroxy-5-iodo-6-phenylpyrimidine. 2-Amino-4-hydroxy-5-bromo-6-phenylpyrimidine is mentioned in the specification, but it is not exemplified or exemplified by the preparation of the product.

No. 70,7905 to C.A. with reference to Pharmacie 1968, 23 (11) 614-18 a

It reports on pyrimidine derivatives without a hydroxyl group at position 4.

A disadvantage of the above processes is that the halogenation with an elemental halogen and / or halogen. in a non-aqueous medium with halogen succinimide, the halogenating agent is difficult to handle and store.

The halogenation of the present invention is carried out with an acidic aqueous solution of iodine chloride or bromine chloride, and the 2-amino-4-hydroxy-5-halo 6-alkyl / phenyl-pyrimidine. A further advantage of the halogenation process of the present invention is that the halogenating agent is readily available, handled, stored and the reaction is carried out in an aqueous medium instead of an organic solvent.

In accordance with the present invention, the halogenation is carried out in a so-called. acid halide complexes of interhalogens, in particular bromine chloride and, respectively, acid chloride. The preparation of interhaloidal complexes is described in Talanta 7: 1 (1960). For the halogenation of aromatic compounds, the reactants reacting rapidly and quantitatively as an analytical reagent are MTA Chem. Can. Share. Inter. 12 15 (1959).

In preparing the compounds of formula (I), the interhalide complexes are used for preparative purposes, the 2-amino-4-hydroxypyrimidine of the formula (II) wherein R is phenyl, (C 1 -C 4) derivatives are halogenated. The reaction is carried out in an aqueous medium containing acetic acid and hydrochloric acid to give compounds of formula (I) in high yield. The process according to the invention is surprising for those skilled in the art, as the use of the reagent in question as an industrial process is unprecedented. The halogen cation in the reagent that attacks the pyrimidine ring has a higher electrophilicity than any other reactant used for similar purposes. Therefore, the key reaction of the process according to the invention is rapid and quantitative conversion without any side processes.

According to the present invention, the compounds of formula I wherein R is C 1-4 alkyl or phenyl, X is bromine or iodine are prepared by reacting compounds of formula II wherein R is above - halogenated with an acidic solution of halide complexes of interhalogens.

The process of the invention is an economical industrial method. The main advantages, in addition to the high yields, that the halogenation takes place in aqueous media and in contrast to the reactions with the elemental halogen, the halogen utilization is more favorable and the halogenating agent is easy to handle and store.

The following examples illustrate the process of the invention.

Example 1

Preparation of 2-amino-4-hydroxy-5-bromo-6-phenylpyrimidine

Dissolve 3.74 g (0.02 mol) of 2-amino-4-hydroxy-6-phenylpyrimidine in 30 ml of acetic acid and 8 ml of 6N HCl and add dropwise at 70 ° C with stirring for half an hour. chloride reagent solution. The reagent was prepared as follows: Dissolve 1.66 g (0.011 mol) of sodium bromate in 13 ml of water and add 2.5 ml (0.022 mol) of 48% hydrobromic acid dropwise with stirring over 30 minutes at a maximum of 30 ° C. or a solution of potassium bromide (2.62 g) in HCl (30 mL).

After the addition, the mixture was stirred at this temperature for an additional hour. The still warm solution was neutralized with ammonium hydroxide (pH 7), the resulting crystalline material was cooled, filtered, washed with water and dried.

This gave 4.8 g (90%) of 2-amino-4-hydroxy-5-bromo-6-phenylpyrimidine. The material was recrystallized from 90% aqueous ethanol in 85% yield, m.p. 278-282 ° C.

Analysis: C ₁₀ H ₈ N ₃ OBr MS: 266.11. C, 45.40; H, 3.00;

N, 15.70; Br, 30.03; Found C, 45.85; H, 3.67;

N = 15.12%, Br = 29.79%,

187,355

Ultraviolet Spectrum 2 (EtOH): 310 nm Ig = 3.95; 233 nm Ig = 4.22.

IR (KBr) 3420, 3310, 1670, 1620, 1580, 1450, 1345, 1225 cm. ¹ .

Ή NMR <5 _(DMSO-d6): 6.55 (2H, s, ^5-NH _2), 7.02 (5H, s, phenyl-H), 11.5 (IH, s, OH).

Example 2

2-amino-4-hydroxy-5-bromo-6-methylpyrimidine ¹⁰

Dissolve 2.5 g (0.02 mol) of 2-amino-4-hydroxy-6-methylpyrimidine in 30 ml of acetic acid and 8 ml of 6N HCl and add dropwise at 70 ° C for half an hour with stirring. chloride reagent olda- tót ^15, prepared according to Example 1.

After the addition, the mixture was stirred at this temperature for an additional hour. The still warm solution was neutralized with aq. Ammonium hydroxide solution (pH = 7), and the resulting crystalline material was cooled, filtered, washed with water and dried.

This gave 3.87 g (95%) of 2-amino-4-hydroxy-5-bromo-6-methylpyrimidine. The material was recrystallized from 80% aqueous ethanol in 75% yield, mp 242-247 ° C. ²⁵

Analysis: C ₅ H ₆ N ₃ OBr, MS: 204.04. Calculated: C, 29.43; H, 2.96;

N, 20.60; Br, 39.17. Found: C, 29.54; H, 3.20;

N = 20.48%, Br = 39.33%. ³⁰

Ultraviolet Spectrum A (EtOH): 295 nm Ig = 3.90.

IR (KBr) 3480, 3330, 3160, 1670, 1640, 1600, 1465, 1390, 1215 cm -1.

1 H-NMR Spectrum J (DMSO-d ₆ ): 2.15 (3H, s, ³⁵ -CH 3); 6.45 (2H, s, -NH ₂ ) 11.5 (1H, s, -OH).

Example 3

2-amino-4-hydroxy-5-bromo-6-ethyl-pyrimidine

Dissolve 2.78 g (0.02 mol) of 2-amino-4-hydroxy-6-ethylpyrimidine in 30 ml of acetic acid and 8 ml of 6N HCl and add dropwise with stirring at 30 DEG C. for half an hour. , ⁴⁵ prepared according to Example 1.

After the addition, the mixture was stirred at this temperature for an additional hour and then neutralized with ammonium hydroxide (pH 7).

The resulting crystals were filtered off after cooling, washed ⁵ with water and dried.

4.14 g (95%) of 2-amino-4-hydroxy-5-bromo-6-ethylpyrimidine are obtained. The material was recrystallized from 50% aqueous acetic acid in a yield of 8% to 5%, m.p. 233-236 ° C. ⁵⁵

Analysis: C ₆ H ₈ N ₃ OBr, MS: 218.06. Calculated: C = 33.05%, H = 3.70%,

N = 19.27%, Br = 36.64% ² Found: C = 33.37%, H 3.56%,

N, 19.64%, Br = 36.45%.

Ultraviolet Spectrum x (EtOH): 297 nm Ig = 4.00.

IR u (KBr): 3390, 3330, 3140, 1660, 1640, 1610, 1460, 1395, 1210 ^cm-first

'H NMR O (DMSO-d _b). 1.1 (3H, t, -CH ₂ -CH ₃ ) 2.45 (2H, q, -CH ₂ -) 11.5 (1H, 5, -OH).

Example 4

2-amino-4-hydroxy-5-iodo-6-ethyl-pyrimidine

2.78 g (0.02 mol) of 2-amino-4-hydroxy-6-ethylpyrimidine are dissolved in a mixture of 30 ml of acetic acid and 8 ml of 6N HCl and the iodine chloride solution is added dropwise with stirring at room temperature. The reagent was prepared as follows: Dissolve 1.71 g (0.008 mol) of potassium iodate in 30 ml of water and 8 ml of HCl and add dropwise over a period of 30 minutes at a maximum temperature of 20 ° C. 0.016 mol) of potassium iodide in 25 ml water and 8 ml cc HCl.

The reaction mixture was stirred at room temperature for 24 hours and then neutralized with 20% ammonium hydroxide solution (pH = 7). The resulting crystalline material is filtered off, washed with water and dried.

2.15 g (81%) of 2-amino-4-hydroxy-5-iodo-6-ethylpyrimidine are obtained. The material was recrystallized from 95% ethanol in 75% yield, m.p. 232-234 ° C.

Analysis: C ₆ H ₈ N ₃ O ₁ , MS: 265.07. Calculated: C, 27.19; H, 3.04;

N = 15.85%, 1 = 47.88%.

Found: C, 27.38; H, 3.42;

N = 15.62%, 1 = 47.46%.

Ultraviolet Spectrum A (EtOH): 300 nm • g =

IR (KBr) 3450, 3400, 1640, 1605, 1455, 1310, 1210.

NMR. NMR: d _(DMSO-d6): 11.3 (IH, s, OH), 6.50 (2H, s, _NH2), 2.40 (2H, q, -CHJ 1.05 (3H, t , -CH,).

Claims (2)

Patent claims A process for the preparation of compounds of formula I wherein R is C 1-4 alkyl or phenyl, X is bromine or iodine by halogenation of compounds of formula II wherein R is as defined above, wherein halogenation is carried out with an acidic solution of halide complexes of ηη ^ halogens. The process according to claim 1, wherein the solvent is an aqueous medium containing organic and / or mineral acid.