CS226949B1 - Method of preparing substituted 4-hydroxy-5-formylamino-pyrimidines - Google Patents

Description

The invention relates to a process for the preparation of substituted 4-hydroxy-5-formylaminopyriniidines of the formula I

f) wherein R is hydrogen, amino, hydroxyl, C 1 -C 4 alkoxy, mercapto, C 1 -C 4 alkylthio or C 1 -C 6 alkyl. All tautomeric forms of substituted 4-hydroxy-5-formylaminopyrimidines are included in Formula I, for example when R is hydrogen, 3,4-dihydro-4-oxo-5-formylaminopyrimidine, and 4,5-dihydro-4- oxo-5-formylaminopyrimidine; when R represents a hydroxyl group or a mercapto group, the corresponding 2-oxo- and 2-thioxo compounds are also included in formula (I).

Most of the compounds of formula (I) are known, but their preparation is very complicated (see, for example, the procedure described by PV Boarland and JFW McOmi, J. Chem. Soc. 1942 (1952) using N-ethoxycarbonylglycirau ethyl ester as starting materials). Formula I are valuable intermediates for the preparation of substituted 4-hydroxy-5-aminopyrimitinines.

We have now found a simple process for preparing compounds of formula I using the readily accessible alkali metal salt of the N, C-diformylglycine ester of formula V below.

According to the prior art, C-formylation of glycine is performed after prior protection of the amino group of the glycine by acetylation by benzoylation or ethoxycarbonylation. In the process according to the invention, this two-step process is considerably simplified, since the protection of the amino group (in the form of the rimylamino derivative) and the C-formylation of the glycine ester are carried out simultaneously, in one step.

According to the invention, the substituted 4-hydroxy-5-formyl-aminopyrimidines of the formula I are prepared by the first step in the preparation of a glycine ester of the formula II

NH ² CH ² COOR ¹ (II) in which R ¹ represents an alkyl group having 1 to 3 carbon atoms is reacted with an alkyl formate of formula III

HCOOR ² (III), wherein R ² is methyl or ethyl, in the presence of an alkali metal alcoholate of formula IV

R ² OM (IV) in which R ² has the abovementioned meaning and M represents an alkali metal atom to form a salt of N, C-dif.ormylglycinu alkali metal of the formula V

Η H 7 ¹ 'and 4 OC = C-COOR 1 NHCOH + M <- -> (-J Vc = c ^{of H} nhcoh ^or »» »G— '

Wherein R ¹ and M are as defined above, and in a second step, the salt of formula (V) obtained is reacted with a compound of formula (VI)

NH2 /

R-C (VI),

NH ve. wherein R is as defined above to form a compound of formula I.

In the first step, the N, C-formylation of the glycine ester II is carried out by treatment with at least two equivalents of the formate III in the presence of one equivalent of the alcoholate IV, preferably sodium methylate, at a temperature of 0 ° to 80 ° C. at room temperature for 5 to 24 hours. The reaction is carried out either in an inert solvent such as ethanol, methanol, benzene, toluene or ether, or preferably without medium, and the precipitated solid salt of the general formula V is isolated by filtering, if necessary, after diluting the reaction mixture with ethyl ether.

In the second step, the condensation of a salt of formula V with a compound of formula VI is carried out in water or a lower alcohol medium, preferably methanol or ethanol, optionally in the presence of an alkaline condensing agent such as sodium or potassium hydroxide or alcoholate IV. ranging from room temperature to the boiling point of the reaction mixture. The product of formula (I) is isolated after distilling off the solvent by stirring the residue with water and adjusting the mixture to a value of about 4 to 7.

The details of the process according to the invention are explained in more detail in the following non-limiting examples.

Example 1

4-Hydroxy-5-formylaminopyrimidine

a) To a mixture of glycine ethyl ester (71.3 g; 0.69 mol) with ethyl formate (127.6 g; 1.72 mol) is added under stirring and cooling with water at a temperature of 15 to 20 ° C over a period of about 1 hour. h sodium methylate (87.2 g; 0.69 mol). The reaction mixture was stirred at room temperature for 5 h and then allowed to stand overnight. Anhydrous ethyl ether (500 mL) was added to the resulting suspension, and the precipitated sodium salt of N, C-diformylglycine ethyl ester was filtered off; t.

_149-155 ° C, UF spectrum (in methanol: _λmax 267 nm (log ε 3.61).

b) To a solution of sodium methylate prepared by dissolving sodium (9.0 g; 0.392 mol) in methanol (170 mL) was added formamidine acetate (40.8 g; 0.392 mol) and sodium N, C-diformylglycine ethyl ester (71.0 g). g (0.392 mol) and the suspension is stirred at room temperature for 15 h. The solvent was distilled off under reduced pressure, the residue was dissolved in hot water (300 ml), the solution was filtered with charcoal, the filtrate was adjusted to pH 6 with dilute hydrochloric acid (1: 1), and the mixture was placed in a refrigerator (+ 5 ° C) ^{and the} precipitated product is filtered off. Recrystallization of the crude material from water gave the title compound, mp 260-264 ° C; UV spectrum: λ max 284 nm (logs 3.97) and 254 nm (loge 3.91) in 0.1 M HCl; 285 nm (log ε 3.83) and 245 (log ε 3.95 in 0.1 M NaOH).

Example 2

2-Methyl-4-hydroxy-2-formylaininopyriniidine

To a suspension of N, C-diformylglycine ethyl ester sodium salt (13.22 g; 0.073 mol) [prepared according to Example 1a)] in methanol (30 mL) was added acetamidine (3.83 g; 0.066 mol) and the mixture was stirred for 12 hours. h at room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in water and the solution was filtered with charcoal. After cooling, it is separated from the filtrate

2.12 g (yield 21%) of the product which, after recrystallization from water, gives the title compound; m.p. above 300 ° C with decomposition. UV spectrum (λmax, log s): 291 (3.99), 285 (3.99), 256 nm (3.89) in 0.1 M HCl, 50% methanol; 292 (3.89) , 248.5 nm (3.98) in 0.1 M NaOH, 50% methanol Example 3

2-Amino-4-hydroxy-5-formylaminopyrimidine

To a solution of sodium methylate prepared by introducing sodium (0.7 g; 0.03 mol) into methanol (40 ml) was added with stirring guanidine hydrochloride (2.8 g; 0.03 mol) and after 10 min sodium was added. NC-di-methylglycine ethyl ester salt (5.44 g; 0.03 mol). The reaction mixture was stirred at room temperature for 24 h, then the solvent was distilled off under reduced pressure, the residue was dissolved in hot water and the solution was filtered with charcoal. The filtrate was acidified with dilute hydrochloric acid (1: 1) in H 2 O and the precipitated product (1.2 g; yield 26%) was recrystallized from water; m.p. above 350 ° C with decomposition. UV spectrum (λ max, log ε): 282 (3.92), 244nm (4.03) νΟ, ΙΜ HCl; 286 (3.84), 241 nm (3.91) in 0.1 M NaOH.

Example 4

2,4-Dihydroxy-5-formyl-aminopyrimidine

To a solution of sodium methylate prepared by dissolving sodium (0.9 g; 39.2 mmol) in methanol (20 mL) was added urea (2.36 g; 39.2 mmol) and N, C-diformylglycine ethyl ester sodium (7 mL). 1 g; 39.2 mmol] and the mixture was stirred at room temperature for 24 h, the solvent was distilled off under reduced pressure, the residue was dissolved in hot water (50 ml), adjusted to pH 6 with dilute hydrochloric acid (1: 1). and the precipitated product was filtered off upon cooling to give the title compound monohydrate at 1.1 above 300 ° C with decomposition UF spectrum (λ max, log ε): 291 (3.84), 235 nm (4.01) in 0.1 M HCl, 50% methanol; 282 (3.85), 235 nm 3.98) in 0.1 M NaOH,

50% NaOH.

Example 5

2-Eithylthio-4-hydroxy-5-formylaminopyrimidine

To a solution of N, C-diformylglycine ethyl ester sodium salt (18.1 g; 0.1 mol) in water (25 mL) was added a solution of ethylthiouronium bromide (18.5 g; 0.1 mol) and potassium hydroxide (5.61 g; 0.1 mol) in water (25 ml) and the mixture was allowed to stand at room temperature for 24 hours.After acidification with hydrochloric acid to pH 6, a colorless product precipitated which was filtered off after cooling, recrystallized from aqueous ethanol (1: 1). The title compound is obtained, mp 268-270 ° C, UF spectrum (λ max, log ε): 296 (4.04), 235.5 nm (4.01) in 0.1 M HG 1; 296 (3) , 95), 259 (3.93) in 0.1 M NaOH.

Example>

2-Mercapto-4-hydroxy-5-formylaminopyrimidine

To a suspension of N, C-diformylglycine ethyl ester sodium (13.2 g; 0.073 mol) in methanol (30 mL) was added thiourea (5.02 g; 0.066 mol) with stirring and the mixture was refluxed for 3 h. After working up the reaction mixture in the same manner as in Example 3 and purifying the crude product (2.36 g, 21% yield) by precipitating it from a solution in dilute ammonia, the title compound of m.p. &gt; 350 DEG C. is decomposed. UV spectrum (λ max, logs); 315 (4.17), 287 (4.14), 222 nm (4.10) in 0.1 M HCl, 50% methanol; 310 (4.00), 275 (4) Λ), 225 nm (4.14) in 0.1 M NaOH, 50% methanol.

Example 7

2-Methoxy-4-hydroxy-5-formylaminopyrimidine

To a 10 M sodium hydroxide solution (10 mL; 0.1 mol) was added, with stirring and cooling with water at 25-30 ° C, O-methylisourea hydrogen sulfate (8.61 g; 0.05 mol) was added and then the solution was added. The sodium salt of NC-diphenylglycine ethyl ester (9.6 g; 0.055 mol) in water (12 ml). The reaction mixture, from which the crystalline material gradually precipitates, is stirred for 8 h at room temperature and then allowed to stand overnight. The pH of 6 was filtered and the crude product (4.75 g; yield 56%) was recrystallized from water to give the title compound monohydrate, mp 1.185-187 ^° C. UF spectrum (λ max, log ε): 277 (3.85), 244 nm (3.96) in 0.1 M HCl, 50% methanol, 286 (3.88), 246 nm (3.94) in 0.1 M NaOH, 50% methanol.

Claims (1)

OBJECT OF Kynalezu A process for the preparation of substituted 4-hydroxy-5-formylaminopyrimidines of the formula I OH NHCOH (I) in which R represents a hydrogen atom, an amino group, a hydroxyl group, a (C1-C4) alkoxy group, a mercapto group, a (C1-C4) alkylthio group or a (C1-C6) alkyl group, characterized in that in the first step, a glycine ester of formula II NH ² CH ² COOR ¹ (II) in which R ¹ represents an alkyl group having 1 to 3 carbon atoms is reacted with an alkyl formate of formula III HCOOR ² (III), wherein, R ² is methyl or ethyl, in the presence of an alkali metal alcoholate of formula IV R ² OM (IV) in which R ² has the abovementioned meaning and M represents an alkali metal atom to form a salt of N, C-diformylglycinu alkali metal of the formula V _O -C≡C-COOR • I NHCOH 0. ^ C-C-C '' H ‘(-), 0 NHCOH OR wherein R ¹ and M are as defined above, and in a second step, the salt of formula (V) obtained is reacted with a compound of formula (VI). wherein R is as defined above to form a compound of formula I. R = C NH2 (VI) NH