HU177601B - New process for preparing 6-piperidino-2,4-diamino-pyrimidine-3-oxide - Google Patents

Abstract

A process for the preparation of 6-piperidino-2,4-diaminopyrimidine- 3-oxide of the formula (I> <IMAGE> comprises reacting 6-hydroxy- 2,4-diaminopyrimidine of the formula (II). <IMAGE> with either (a) a sulfonyl halide of the general formula (V> R-SO2-hal (V> wherein R stands for a C1-4 alkyl group or a phenyl group optionally having up to three C1-4 alkyl substituents and hal represents halogen, treating the resulting novel sulfonate of the general formula (III), <IMAGE> wherein R is as defined above, with an oxidizing agent in an aprotic solvent, reacting, the resulting novel N-oxide of the general formula (IV), <IMAGE> wherein R is as defined above, directly with piperidine, or first acylating it with a carbonyl halide of the general formula (XI), R'CO-hal (XI> wherein R' represents a C1-4 alkyl group or a phenyl group optionally substituted with a halogen substituent and hal stands for halogen, and reacting the resulting compound of the general formula (IX), <IMAGE> wherein R and R' are as defined above, with piperidine; or b) a sulfonyl halide of the general formula (V), wherein R and hal are as defined above, reacting the resulting sulfonate of the general formula (III), wherein R is as defined above, in an aprotic solvent with a peracid of the general formula (X), R'-COOOH (X> wherein R' is as defined above, and reacting the resulting compound of the general formula (IX), wherein and R' are as defined above, with R piperidine.

Description

The present invention relates to a novel process for the preparation of 6-piperidino-2,4-djaminopyrimidine-3-oxide of formula (I) from 6-hydroxy-2,4-diaminopyrimidine of formula (II). The compound has an outstanding antihypertensive effect.

Several processes for the preparation of the compound of formula (I) are known, but none can provide an economical industrial synthesis.

According to one known method, [Nos. 3,382,247 and 3,461,461]. U.S. Patents] convert 2,4-diamino-6-hydroxypyrimidine with phosphorus oxychloride in 60% yield to 2,4-diamino-6-chloropyrimidine which is reacted with phenol or 2,4-dichlorophenol. The 2,4-diamino-6-phenoxypyrimidine formed in a yield of 1% is oxidized to the corresponding N-oxide in a yield of 21% and finally treated with piperidine in 45% yield. In this known process, the total yield calculated for 2,4-diamino-6-hydroxypyrimidine is only 2 to 2.3%. 20

According to a further known method, U.S. Pat. US Patent Publication No. 2], 2,4-diamino-6-chloropyrimidine, prepared in 60% yield from 2,4-diamino-6-hydroxypyrimidine, is directly oxidized to the corresponding N-oxide in 45% yield and the 4-diamino-6-chloropyrimidine-3-oxide is converted to the final product in 89% yield with piperidine. Again, the total yield obtained does not exceed 24% (calculated on 2,4-diamino-6-hydroxypyrimidine). 30

A further disadvantage of both of these known processes is the use of 2,4 diamino-6-chloropyrimidine. This compound can be prepared by chlorination with phosphorus oxychloride and is difficult to isolate and purify as it is highly soluble in both water and pe5 dig organic solvents. A large excess of phosphorus oxychloride is required for chlorination, which further enhances the corrosive nature of the reaction mixture.

According to a further known method, U.S. Pat. No. 3,910,928. U.S. Pat. No. 5,197] converts N- (2-cyanoacetyl) piperidine to the methyl ether of formula (VI), treating it with cyanamide, reacting the dinitrile (VII) formed with hydroxylamine, and the compound of formula (VIII). by ring closure to the product of formula (I). Although the total yield of N- (2-cyanoacetyl) -piperidine is 35%, this known process is unsuitable for industrial use because it is difficult to obtain special reagents (e.g. trimethyloxonium fluoro-) for the preparation of the methyl ether of formula (VI). borate) is required. A further disadvantage is the relatively high number of reaction steps.

It is an object of the present invention to provide an economical, industrially simple, low-step process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide.

a) According to the invention, 6-hydroxy-2,4-diaminopyrimidine is substituted with a sulfonyl halide of the general formula (V) wherein R is phenyl, substituted with up to three C 1-4 alkyl groups. or C 1 -C 4 alkyl, halo is reacted with the resulting sulfonic acid ester of formula III, where R is as above, in a protic solvent at 0-15 ° C to form halogen perbenzoic acid and the resulting (IV) a) by reacting a N-oxide of the formula wherein R is as defined above or aa) directly with piperidine; or b) acylating a carboxylic acid halide of formula XI wherein R 'is a halogen substituted phenyl; Reacting a compound of formula (IX) wherein R and R 'are as defined above with piperidine; obsession

b) reacting the 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of formula V wherein R is as defined in variant a) to give the sulfonic acid ester of formula III where R is as defined above, in an aprotic solvent at 20-50 ° C with a percarboxylic acid of formula X wherein R 'is as defined in variant a) and reacting the resultant compound of formula IX wherein R and R' are as defined above with piperidine .

Preferred sulfonyl halides are phenylsulfonyl chloride, p-tolylsulfonyl chloride, 2,4,6-trimethylphenylsulfonyl chloride.

The reaction of 6-hydroxy-2,4-diaminopyrimidine with the sulfonyl halide of formula (V) is carried out in the presence of a base. The base is preferably an alkali metal hydroxide, preferably in aqueous solution.

Particularly preferred is the oxidation of the compound of formula (III) with m-chloroperbenzoic acid.

The reaction of the compound of formula (IV) with the piperidine is conveniently carried out in the presence of excess piperidine at a temperature of 0 to 100 ° C. The excess piperidine is optionally regenerated by distillation.

Preferably, the percarboxylic acid of formula (X) is m-chloroperbenzoic acid and the carboxylic acid halide of formula (XI) is preferably m-chlorobenzoyl chloride.

6-Hydroxy-2,4-diaminopyrimidine can be prepared in a manner known per se by reaction of cyanoacetate with guanidine [Org. Synth. Coll. Vol. 4, 245 (1963)].

In a preferred embodiment of the process of the invention, 6-hydroxy-2,4-diaminopyrimidine is reacted with the sulfonyl chloride of formula V without isolation from the reaction mixture to give the ester of formula III directly from the cyanoacetate and guanidine. which is a N-oxide of formula IV, a novel compound.

It is surprising to those skilled in the art that the 6-hydroxy-2,4-diaminopyrimidine can be converted into a reactive ester derivative in a simple and near quantitative manner. Indeed, hydroxypyrimidine compounds are generally difficult to acylate in the literature (The Pyrimidines, Interscience Publ. 1962, p. 252),

The process of the invention is an economical industrial method. The individual reaction steps are readily accomplished using readily available compounds. The overall yield for 6-hydroxy-2,4-diaminopyrimidine is 34-45% and, if isolated, the yield is further increased by 5%.

The following examples illustrate the invention.

Example 1 (1) 6- (p-Tolylsulfonyloxy) -2,4-diaminopyrimidine

Method A 6 g of 0.5-molar 6-hydroxy-2,4-diaminopyrimidine are dissolved in 250 ml of 2.5 N sodium hydroxide solution. This solution was added dropwise with a solution of 120 g (0.62 mole) of p-tolylsulfonyl chloride in 250 ml of acetone with stirring (about 0.5 to 1 hour) at room temperature in a round-bottomed flask equipped with 100 ml of stirrer. acetone. During the operation, the pH of the reaction mixture should be 7. After stirring at room temperature for 3 hours, water (1000 mL) was added to the reaction mixture and the precipitate was filtered. 134 g (95%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine are obtained, m.p. 179-181 ° C.

Analysis calculated for C ₁₁ H ₁₂ O ₃ S (M: 280.32): C, 47.13; H, 4.32; N, 19.99; S, 11.44 Found: C, 47.56; H 4.67%, N 19.51%, S 11.60%,

Ultraviolet spectrum: λ ^ ^Η = 275 mm; log Σ = 3.92. . IR (KBr): 3460, 1632, 1605, 1368, 1200 cm ^-1 .

Method B.

23 g of comminuted metal sodium are added to a round bottomed flask with stirring and 370 ml of absolute ethanol are prepared and a solution of sodium ethylate is prepared. 48.5 g (0.51 mol) of dried and powdered guanidine chlorohydrate are then added and the mixture is refluxed for 1.5 hours. After cooling at 25 ° C, 55 ml (0.52 mol) of ethyl cyanoacetate are added with stirring and the reaction mixture is refluxed for two hours. Then 100-150 ml of ethanol are evaporated off and 200 ml of water are added. The aqueous alcohol is evaporated until the vapor temperature reaches 100 ° C. The cooled residue was dissolved in water to a volume of 330 ml. This solution was added dropwise together with a solution of p-tolylsulfonyl chloride (99 g, 0.52 mol) in acetone (250 mL) into a round-bottomed flask, pre-charged with 100 mL of acetone. The pH of the mixture during the operation should be 7. After stirring at room temperature for 3 hours, water (1000 ml) was added and the precipitate was filtered to give 125 g (85%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine, m.p. 179-181 ° C. .

Method C

20 g (0.159 mol) of 6-hydroxy-2,4-dihydropyrimidine and 50 ml of absolute dimethylformamide were weighed into a round bottomed flask with stirring and reflux. Sodium hydride (6 g, 0.25 mol) was added at room temperature. The mixture is heated to 100 ° C and stirred at this temperature for two hours. It is then cooled to 0 ° C and a solution of 50 g (0.26 mol) of p-tolylsulfonyl chloride in 50 ml of dimethylformamide is added dropwise. The reaction mixture was stirred at this temperature for two hours and then at room temperature for two hours. It is then poured onto 400 g of ice and extracted with 3 x 200 ml of chloroform. The combined chloroform layer was shaken with 100 mL of water and the product precipitated. There was thus obtained 6- (p-tolylsulfonyloxy-2,4-diaminopyrimidine) (25 g, 57%), m.p. 179-181 ° C.

(2) 6-tosyloxy-2,4-diaminopyrimidine-3-oxide

5.6 g (0.02 mol) of 6 '(p-tolylsulfonyloxy) -2,4-diaminopyrimidine, 200 ml ethanol and 25 ml of a magnetic stirrer are placed in a 500 ml round bottom flask with an ice-water bath. ml of water. The slurry was cooled to 0-5 ° C and 4.0 g (0.02 mol) of 86% m-chloroperbenzoic acid dissolved in 50 ml of cold ethanol was added. The reaction mixture was stirred and allowed to warm to 25 ° C over 3.5 hours. The completion of the reaction is indicated by the fact that a small sample of the reaction mixture does not select iodine from the potassium iodide solution. The ethanol was then evaporated in vacuo from a water bath at 50 ° C and the residue was dissolved in ethyl acetate (250 ml). The solution was extracted with 2% aqueous sodium hydroxide in several portions until the final aqueous portion was slightly alkaline. The combined aqueous solutions were extracted with ethyl acetate (4 x 50 mL). The resulting m-chlorobenzoic acid can be recovered from the aqueous solution and reused after oxidation. The ethyl acetate extracts were combined, dried and concentrated to a small volume. During the operation, the product crystallizes. The crystals were filtered and washed with a little cold ethyl acetate to give pure 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine-3-oxide (3.9 g, 65%), mp 125-130 ° C. (dec).

Calc'd for C _n H ₁₂ N ₄ O ₄ S Calculated: C 44.32%, H 4.08%, N 18.91%, S 10.82% Found: C 44.32%, H: 4 , 47%, N 18.59%, S 10.42%.

Ultraviolet spectrum:> 3 ^ι .θ ^Η == 285 mm; hangs Σ = 3.75. Infrared spectrum: µ (ττ): 3420, 1650, 1620, 1400, 1380 cm @ ^-1 .

(3) 6-piperidino-2,4-diaminopyrimidine-3-oxide

In a 500 ml round-bottomed flask equipped with a stirrer and reflux condenser, add 140 ml of piperidine. (If piperidine contains more than 0.5% water, it is withdrawn by reaction with an equivalent amount of phosphorous pentoxide, aluminum isopropylate or butyllithium.) To anhydrous piperidine is added 20 g (0.067 mol) of 6- (p-tolylsulfonyloxy) - 2,4-diaminopyrimidine-3-oxide. After stirring at 100 ° C for 2 hours, the piperidine was evaporated in vacuo. The regenerated piperidine can be used for the following reaction. The residue was stirred with 50 ml of 5% aqueous sodium hydroxide solution at room temperature for half an hour, then filtered and washed with water. The resulting crystals were again stirred with 50 ml of benzene at room temperature for half an hour, then filtered and washed with benzene. 7.7 g (55%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide are obtained, m.p. 264-266 ° C.

Analysis for C ₉ H ₁₅ N ₅ O:

Found: C, 51.66; H, 7.22; N, 33.47; Found: C, 51.80; H, 7.00; N, 33.42.

Ultraviolet spectrum; Z® ^l ^ ^H 232N (Ig Σ 4 =>54);

286 nm (lfc & = 4.09};

IR: 3410. 3420, 3400, 3370,

3260, 1655, 1250, 1210, 1165, 1020 cm -1.

Example 2 (1) 6-Methylsulfonyloxy-2,4-diaminopyrimidine

12.6 g (0.1 mol) of 6-hydroxy-2,4-diaminopyrimidine and g (0.1 mol) of sodium hydroxide are dissolved in 35 ml of water. This solution was added dropwise to a solution of methyl sulfonyl chloride (9.3 mL, 0.12 mol) in acetone (50 mL) in a 250 mL round bottom flask (250 mL) with stirring at room temperature. After stirring for 3 hours, water (210 mL) was added to the reaction mixture, the pH was adjusted to 9 with 10% sodium hydroxide solution, and the precipitate was filtered. 11.1 g (54.4%) of 6-methylsulfonyloxy-2,4-diamino 15 -pyrimidine are obtained, m.p. 176-180 ° C.

In the following, the procedure of Example 1 (2) and (3) is followed.

Example 3 (1) 6-Phenylsulfonyloxy-2,4-diaminopyrimidine

12.6 g (0.1 mol) of 6-hydroxy-2,4-diaminopyrimidine;

2S 4 g (0.1 mol) of sodium hydroxide are dissolved in 35 ml of water. This solution was added dropwise with a mixture of phenyl sulfonyl chloride (15.4 mL, 0.12 mol) in acetone (50 mL) in acetone (20 mL), with stirring, in a 3-neck, 250 mL round bottom flask, at room temperature. After stirring for 3 hours, water (210 mL) was added to the reaction mixture, the pH was adjusted to 9 with 10% sodium hydroxide solution, and the precipitate was filtered. 20.25 g (75.6%) of 6-phenylsulfonyloxy-2,4-diaminopyrimidine are obtained, m.p. 189-193 ° C.

In the following, the procedure of Example 1 (2) and (3) is followed.

Example 4 (1) 6-Mesitylenesulfonyloxy-2,4-diaminopyrimidine

6.3 g (0.05 mol) of 6-hydroxy-2,4-diaminopyrimidine and 2 g (0.05 mol) of sodium hydroxide are dissolved in 17.5 ml of 45 water. This solution was added dropwise with a mixture of 12 g (0.055 mol) of mesitylene sulfonyl chloride (2,4,6-trimethylphenylsulfonyl chloride) in 25 ml of acetone in 10 ml of acetone with stirring at room temperature. After stirring for 3 hours, water (100 mL) was added to the reaction mixture and the pH was adjusted to 9 with 10% sodium hydroxide solution. The precipitated material was then filtered to give 11.35 g (73.6%) of 6-mesitylenesulfonyloxy-2,4-diaminopyrimidine, m.p. 183-186 ° C. Recrystallized from 25 times ethanol, m.p. 187-191 ° C.

In the following, the procedure of Example 1 (2) and (3) is followed.

Example 5 (1) 2-Imino-3- (3-chlorobenzoyloxy) -4-aminino-6- (4-tolylsulfonyloxy) pyrimidine

Resuspend at room temperature in 11.2 g of az

Prepared as described in Example 1, part 1.

(0.04 mol) of 6-tosyloxy-2,4-diaminopyrimidine and 8 g (0.04 mol) of 86% 3-chloroperbenzoic acid in 100 ml of dichloromethane were refluxed for 6 hours with stirring. Wash the dichloromethane solution with 35 mL of saturated sodium carbonate solution and 3 x 25 mL of water. After drying, it is concentrated until crystallization begins. After cooling, the crystals were filtered and washed with cold dichloromethane. 6.8 g (46.2%) of pure 2-imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-toluenesulfonyloxy) -pyrimidine are obtained, m.p. 159-164 ° C.

(The alkaline washing solution of the dichloromethane layer was worked up by extraction with ethyl acetate to give 2.64 g (22%) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide which was reacted with piperidine as described in Example 1 (3). .)

Analysis for C _Ig H ₁₅ N ₄ O ₅ SCL (Ms. 434.873) calculated: C 49.71, H 3.48, N 12.88, S 7.38, Cl 8.15%. Found: C, 49.54; H, 3.88; N, 12.80; S, 7.23; Cl, 8.12.

Ultraviolet Spectrum: λ ^ ® ^Η = 325 nm (Ig Σ = 3.73). Infrared spectrum (KBr): λmax = 3430, 1695, 1640 1575, 1385 cm -1.

(2) 6-piperidino-2,4-diaminopyrimidine-3-oxide

Into a 500 ml round-bottomed flask equipped with a stirrer and a reflux condenser, weigh 130 ml of piperidine and cool to 0-5 ° C. To the anhydrous piperidine was added 21.7 g (0.05 mol) of 2-imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-tolylsulfonyloxy) pyrimidine. After stirring for 3 hours at 0-5 ° C and for 3 hours at 100 ° C, the piperidine is evaporated in vacuo. The regenerated piperidine can be used for the next reaction. The residue was stirred with 80 ml of 5% aqueous sodium hydroxide solution at room temperature for half an hour, then filtered and washed with water. The resulting crystals were again stirred with 50 ml of benzene at room temperature for half an hour, then filtered and washed with benzene. 6.7 g (65%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide are obtained, m.p. 264-266 ° C.

Example 6

Claims (9)

A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of formula (I): 6-hydroxy-2,4-diamine of formula (II): Of 5-N-pyrimidine, characterized in that (a) 6-hydroxy-2,4-diaminopyrimidine optionally prepared in situ from cyanoacetate ester and guanidine with a sulfonyl halide of formula (V) wherein R 10 is phenyl, substituted with up to three C 1-4 -alkyl or C 1-4 -alkyl, hal is halogen to give the resulting sulfonic acid ester of formula III where R is in the above protic solvent 15 to 0 ° C to 25 ° C with halogen perbenzoic acid and reacting the resulting N-oxide of formula IV, wherein R is as defined above, or aa) directly with piperidine, or b) with a carboxylic acid halide of formula XI, wherein R ' halogen substituted phenyl; halogen is acylated and the resulting compound of formula IX, wherein R and R 'are as defined above, is reacted with piperidine; obsession b) 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of general formula (V) wherein R is a) reacting the resulting sulfonic acid ester of formula III wherein R is in the above aprotic solvent with a percarboxylic acid of formula X where R 'is as defined in variant a) at 20-50 ° C and reacting the resultant compound of formula IX, wherein R and R 'are as defined above, with piperidine. (Priority: 4th December 1979) 2. A process for preparing 6-piperidino-2,4-diaminopyrimidine-3-oxide of formula (I): 6-hydroxy-2,4-dia- 35 minopyrimidine, characterized in that 6-hydroxy-2,4-diaminopyrimidine, prepared in situ from cyanoacetate ester and guanidine, with a sulfonyl halide of formula (V) wherein R is phenyl has from 1 to 4 carbon atoms. ⁴⁰ alkyl-substituted phenyl group or a C1-4 alkyl group, hal is a halogen, is reacted to give (III), sulfonic acid ester of the formula wherein R is as defined above, is treated with a protic solvent 0-25 ^r C halogénperbenzolsavval, and reacting the resulting ve45 of formula IV, wherein R is as defined above, with piperidine. (Priority: 27.7.1978) (1) 2-Imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-tolylsulfonyloxy) pyrimidine 15 g (0.05 mol) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide obtained in the same manner as in Example 1 (2) are dissolved in 1000 ml of acetone at room temperature and 9.0 g (0 (05 moles) of a solution of 3-chlorobenzoyl chloride in 50 ml of acetone. After stirring for 1.5 hours, a solution of triethylamine (5.25 g, 0.052 mol) in acetone (50 ml) was added dropwise. The approx. To the mixture warmed to 30 ° C, add water at 30 ° C until slightly cloudy (about 1300 ml of water is required) and cool to 0-3 ° C. The precipitated crystalline product is filtered off, washed with 1: 1 acetone-water and dried. 18.4 g (84.6%) of the acylated product are obtained, m.p. 155-158 ° C. In the following, the procedure of Example 5 (2) is followed. 3. The process of claim 2, wherein the 6-hydroxy-2,4-diaminopyrimidine is used for the sulfonylation reaction without isolation from the reaction mixture prepared from the cyano ester and guanidine. (Priority: June 27, 1978) 4. The process of claim 2 wherein the sulfonyl halide of formula V is p-tolylsulfonyl chloride. (Priority: June 27, 1978) 5. A process according to claim 2 wherein the sulfonyl halide of formula V is phenyl sulfonyl chloride. (Priority: June 27, 1978) 6. A process according to claim 2 wherein the compound of formula V is methylsulfonyl chloride. (Priority: June 27, 1978) 7. The process of claim 2 wherein the halogen perbenzoic acid is m-chloroperbenzoic acid. (Priority: 27.X.1978) 8. A process according to claim 1, variant b), wherein the percarboxylic acid of formula (X) is m-chloroperbenzoic acid. (Priority: 4th December 1979) 9. A process according to claim 1, variant b), wherein the carboxylic acid halide of formula XI is m-chlorobenzoyl chloride. (Priority: 4/9/1979)