CH642365A5 - METHOD FOR PRODUCING 6-PIPERIDINO-2,4-DIAMINOPYRIMIDIN-3-OXIDE. - Google Patents

Description

The invention relates to a new process for producing 0CHo of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula is

(VI)

20th

r

N

(I)

implemented, the latter product treated with cyanamide, the dinitryl formed from the formula 6-hydroxy-2,4-diaminopyrimidine of the formula NH "

(II).

(VII)

reacts with hydroxylamine and the end product of formula (I) by ring closure of the compound of formula

40

The compound of formula (I) has an excellent hypotensive effect.

Although several processes are known for the preparation of the compound of formula (I), no process ensures their economical industrial synthesis.

According to a known process (US Pat. Nos. 3,382,247 and 3,461,461), 2,4-diamino-6-hydroxypyrimidine is reacted with phosphorus oxychloride in a 60% yield in 2,4-diamino-6-chloropyrimidine, then this product is mixed with phenol or 2,4-dichlorophenol and the 2,4-diamino-6-phenoxypy-rimidine which forms with a 40% yield is oxidized to the corresponding N-oxide (with a 21% yield), then finally the product of formula (I) is obtained in a 45% yield by treatment with piperidine. In this known method, however, the total yield calculated on 2,4-diamino-6-hydroxypyrimidine is only 2-2.3%.

According to a further known method (DT-OS No. 2 114 887), the 2,4-diamino-6-chloropyrimidine prepared from the 2,4-diamino-6-hydroxypyrimidine in a 60% yield is immediately converted to the corresponding N-oxide oxidized (yield 45%), then the 2,4-diamino-6-chloropyrimidine-3-oxide obtained is converted into the end product using piperidine in an 89% yield. However, the overall yield that can be achieved in this case is not more than 24% (calculated on 2,4-diamino-6-hydroxypyrimidine).

Another disadvantage of both known methods is the use of 2,4-diamino-6-chloropyrimidine. This

45

50

> 111)

receive. Although the overall yield calculated for N- (2-cyanoacetyl) piperidine 55 is 35%, this known process is unsuitable for industrial implementation because special reagents (eg trimethyloxonium fluoroborate) which are difficult to access are necessary for the preparation of the methyl ether of the formula (VI) . Another disadvantage is the 60 relatively large number of reaction steps.

The aim of the invention is to ensure an economical, industrially simple to carry out process consisting of a few reaction steps for the production of 6-piperidino-2,4-diaminopyrimidine-3-oxide.

65 According to the invention, the procedure is such that a) 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula

642365

4th

R-SCh-Hal

(V), tung has, with a percarboxylic acid of the general formula in which R represents a phenyl group, a phenyl group substituted by at most three Ci-4-alkyl groups or a Ci-4-alkyl group and Hai represents a halogen atom, the sulfonic acid ester obtained general formula

R'-COOOH

(X),

H2N

YY

0S02R

NH,

(III)

OSOgR

wherein R has the meaning given above, either directly with piperidine to give the compound of the formula I, or with a carboxylic acid halide of the general formula

R'-CO-Hal

10th

15

wherein R has the meaning given above, treated with an oxidizing agent in a protic solvent, 20 and the N-oxide of the general formula formed

(IV),

25th

30th

35

(XI), 40

wherein R 'represents a Ci-4-alkyl group or optionally a phenyl group substituted by a halogen atom and Hai represents a halogen atom, then acylated, then the compound of general formula 45 obtained

50

(IX),

0S02R

in which R and R 'have the meaning given above, react with piperidine, or in which R' has the meaning given for variant a), in an aprotic solvent and finally the compound of general formula (IX) obtained,

wherein R and R 'have the meaning given above, with piperidine.

Phenylsulfonylchloride, p-tolylsulfonyl chloride or 2,4,6-trimethylphenylsulfonyl chloride is advantageously used as the sulfonyl halide.

The reaction of 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula (V) is carried out in the presence of a base. An alkylimetal hydroxide, advantageously in the form of an aqueous solution, is advantageously used as the base.

A percarboxylic acid, such as peracetic acid, perbenzoic acid, etc., is advantageously used as the oxidizing agent. It is particularly advantageous to carry out the oxidation of a compound of the general formula (III) with m-chloroperbenzoic acid.

The reaction of the compounds of general formula (IV) with piperidine is expediently carried out with excess piperidine at a temperature between 0 and 100.degree. The excess piperidine is optionally regenerated by distillation.

M-Chloroperbenzoic acid is advantageously used as the percarboxylic acid of the general formula (X) or m-chlorobenzoyl chloride as the carboxylic acid halide of the general formula (XI).

The 6-hydroxy-2,4-diaminopyrimidine can be prepared in a manner known per se by the reaction of cyanoacetic ester and guanidine [Org. Synth. Coli. Vol. 4, 245 (1963)].

According to an advantageous variant of the process according to the invention, the 6-hydroxy-2,4-diaminopyrimidine is allowed to react directly with a sulfonyl chloride of the general formula (V) without being separated from the reaction mixture used for its preparation, starting from cyanoacetic ester and guanidine, immediately receives an ester of the general formula (III). The compounds of the general formula (III) and (IV) are new compounds.

In the case of the process according to the invention, it is surprising for the person skilled in the art that the 6-hydroxy-2,4-diaminopyrimidine can be converted into a reactive ester derivative in a simple manner and with an almost quantitative yield. According to the specialist literature, the hydroxypyrimidine compounds are generally difficult to acylate (The Pyrimidines, Interscience Pubi., 1962, p. 252).

The method according to the invention is an economical industrial method. The individual reaction steps can be carried out simply by using easily accessible compounds. The total yield calculated for 6-hydroxy-2,4-diaminopyrimidine is 34-35% or, if its removal is eliminated, the yield of the product is increased by a further 5%.

The method according to the invention is explained in more detail by the following examples, which do not limit the scope of protection of the application.

b) 6-hydroxy-2,4-diaminopyrimidine is allowed to react with a sulfonyl halide of the general formula (V), in which R has the meaning given in variant a), after which the sulfonic acid ester of the general formula (III) obtained, in which R the meaning given above

example 1

(1) 6- (p-Tolylsulfonyloxy) -2,4-diaminopyrimidine Method A

63 g (0.5 mol) of 6-hydroxy-2,4-diaminopyrimidine are in

5

642 365

Dissolved 250 ml of 2.5N sodium hydroxide solution. This solution, together with a solution of 120 g (0.62 mol) of p-tolylsulfonyl chloride in 250 ml of acetone, is introduced dropwise into a round-bottomed flask of 2000 ml in volume, with stirring, over the course of about 0.5-1.0 hours at room temperature with constant stirring , which already contains 100 ml acetone. During this operation, the pH of the reaction mixture should be 7. After stirring for three hours at room temperature, 1000 ml of water are added to the reaction mixture and the material which has separated out is then filtered off, as a result of which 134 g (95%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine, mp: 179-181 ° C. , result.

Analysis based on the formula C11H12O3S (Molecular Weight: 280.32):

Calc .: C 47.13%; Found: C 47.56%;

H 4.32%; H 4.67%;

N 19.99%; N 19.51%;

S 11.44%; S 11.60%.

Ultraviolet spectrum: X

ElOH _

275 nm; log Z = 3.92

Infrared spectrum: ji (KBr): 3460.1632.1605.1368.1200 cm-1.

Method B

23 g of crushed metallic sodium and 370 ml of a sodium ethylate solution prepared with absolute ethanol are introduced into a round-bottomed flask equipped with a stirrer and reflux condenser. Then 48.5 g (0.51 mol) of dried and powdered guanidine chlorohydrate are added and the mixture is refluxed for 1.5 hours. After cooling, 55 ml (0.52 mol) of ethyl cyanoacetate are added with stirring at 25 ° C., and the reaction mixture is boiled for a further two hours. Soon 100-150 ml of ethanol will be distilled off and 200 ml of water will be added to the mixture. Then aqueous ethanol is distilled off until the steam temperature reaches 100 ° C. The cooled residue is dissolved in the water in such a way that the total volume is 330 ml. This solution, together with a solution of 99 g (0.52 mol) of p-tolylsulfonyl chloride in 250 ml of acetone, is introduced dropwise into a round-bottomed flask equipped with a stirrer, which already contains 100 ml of acetone. During this operation, the pH of the mixture should be 7. After stirring for three hours at room temperature, 1000 ml of water are added and the separated material is filtered off, resulting in 125 g (85%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine, mp: 179-181 ° C.

Method C

20 g (0.159 mol) of 6-hydroxy-2,4-diaminopyrimidine and 50 ml of absolute dimethylformamide are introduced into a round-bottom flask equipped with a stirrer and reflux condenser. At room temperature, 6 g (0.25 mol) of sodium hydride are added to the mixture, then it is heated to 100 ° C. and stirred at this temperature for two hours. It is soon 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 is stirred at this temperature for two hours, then at room temperature for a further two hours, then it is poured onto 400 g of ice and extracted with 3 × 200 ml of chloroform. The combined chloroform phases are shaken with 100 ml of water, the product separating out. This gives 25 g (57%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine, mp. 179-181 ° C.

(2) 6-tosyloxy-2,4-diaminopyrimidine-3-oxide 5.6 g (0.02 mol) of 6- (p-tolylsulfonyloxy) -2, are placed in a round-bottom flask provided with a magnetic stirrer and an ice water bath. Weighed in 4-diaminopyrimidine, 200 ml of 5 ethanol and 25 ml of water. The suspension is cooled to 0-5 ° C., then a solution of 4.0 g (0.02 mol) of 86% m-chloroperbenzoic acid in 50 ml of cold ethanol is added. Then the reaction mixture is stirred and allowed to warm to 28 ° C. in 3.5 hours. The end of reaction 10 is indicated by the fact that a small sample of the reaction mixture does not separate iodine from a potassium iodide solution. The ethanol is then evaporated in vacuo on a water bath at a maximum of 50 ° C and the residue is dissolved in 250 ml of ethyl acetate. The solution is extracted with several portions of a 2% aqueous sodium hydroxide solution until the last aqueous portion shows a weak alkaline reaction. The combined aqueous solutions are extracted with 4x50 ml of ethyl acetate. The m-chlorobenzoic acid formed can be separated from the aqueous solution and can be reused after oxidation. The extracts obtained with ethyl acetate are combined, dried and concentrated to a small volume. The product crystallizes during this operation. The crystals are filtered off and washed with a little cold ethyl acetate for 2 s, 3.9 g (65%) of pure 6- (p-tolylsulfonyl-oxy) -2,4-diaminopyrimidine-3-oxide, mp. 125-130 ° C. (Dec.) Result.

30th

Analysis based on the formula CnHi2N404S:

Calc .: 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: = 285 nm; log E = 3.75. 35 Infrared spectrum: jj- (KBr): 3420.1650.1620.1400, 1380 cm-1.

(3) 6-Piperidino-2,4-diaminopyrimidine-3-oxide 140 ml of piperidine are weighed into a 40 500 ml round-bottom flask equipped with a stirrer and reflux condenser. (If the piperidine contains more than 0.5% water, the latter is decomposed by reaction with an equivalent amount of phosphorus pentoxide, aluminum isopropylate or butyllithium.) 20 g (0.067 mol) of 6- (p-45 tolylsulfonyloxy) are added to the anhydrous piperidine ) -2,4-diaminopyrimidine-3-oxide added. The mixture is stirred at 100 ° C for two hours and then the piperidine is distilled off in vacuo. The regenerated piperidine can be used in the next reaction. The residue is stirred with 50 ml of 5% aqueous sodium hydrosoxide solution at room temperature for half an hour, filtered off and washed with water. The crystals obtained are again stirred with 50 ml of benzene at room temperature for half an hour, filtered off and washed with benzene. In this way, 7.7 g (55%) of 55 pure 6-piperidino-2,4-diaminopyrimidine-3-oxide of mp. 264-266 ° C. are obtained.

Analysis based on the formula C9H15N5O:

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

65 Ultraviolet spectrum: A.® ™ - 232 nm (log S = 4.54), 286 nm (log X = 4.09).

Infrared spectrum: fi1 = 3410.3420.3400.3370.3260.1655, 1250.1210.1165.1020 cm- '.

642365

6

Example 2

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

12.6 g (0.1 mol) of 6-hydroxy-2,4-diaminopyrimidine and 4 g (0.1 mol) of sodium hydroxide are dissolved in 36 ml of water. This solution is introduced dropwise together with a solution of 9.3 ml (0.12 mol) of methylsulfonyl chloride in 50 ml of acetone with stirring at room temperature into a three-necked round-bottomed flask of 250 ml volume containing 20 ml of acetone and equipped with a stirrer. After stirring for three hours, 210 ml of water are added to the reaction mixture and the pH is adjusted to 9 with a 10% sodium hydroxide solution. After filtering off the separated material, 11.1 g (54.4%) of 6-methylsulfonyloxy-2,4-diaminopyrimidine, mp. 176-180 ° C., are obtained.

The procedure described in points (2) and (3) of Example 1 is followed.

Example 3

(1) 6-phenylsulfonyloxy-2,4-diaminopyrimidine

12.6 g (0.1 mol) of 6-hydroxy-2,4-diaminopyrimidine and 4 g (0.1 mol) of sodium hydroxide are dissolved in 35 ml of water. This solution, together with a mixture of 15.4 ml (0.12 mol) of phenylsulfonyl chloride and 50 ml of acetone, is added dropwise with stirring at room temperature to a three-necked round-bottomed flask of 250 ml volume containing 20 ml of acetone and equipped with a stirrer. After stirring for three hours, 210 ml of water are added to the reaction mixture, the pH of the reaction mixture is adjusted to 9 with a 10% strength sodium hydroxide solution and the material which has separated out is then filtered off. This gives 20.25 g (75.6%) of 6-phenylsulfonyloxy-2,4-diaminopyrimidine, mp. 189-193 ° C.

The procedure described in points (2) and (3) of Example 1 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 water. This solution is added dropwise to 10 ml of acetone together with a mixture of 12 g (0.055 mol) of mesitylenesulfonyl chloride (2,4,6-trimethylphenylsulfonyl chloride) and 25 ml of acetone with stirring at room temperature. After stirring for three hours, 100 ml of water are added to the reaction mixture, the pH of the reaction mixture is adjusted to 9 with a 10% strength sodium hydroxide solution and the material which has separated out is then filtered off. This gives 11.35 g (73.6%) of 6-mesitylenesulfonyl-oxy-2,4-diaminopyrimidine, mp. 183-186 ° C.

After recrystallization from a 25-fold amount of ethanol, the melting point rises to 187-191 ° C.

The procedure described in points (2) and (3) of Example 1 is followed.

Example 5

(1) 2-Imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-tolylsulfonyloxy) pyrimidine

11.2 g (0.04 mol) of 6-tosyloxy-2,4-diaminopyrimidine [prepared in the manner described in part (1) of Example 1] and 8 g (0.04 mol) of 86% 3-chloroperbenzoic acid suspended in room temperature in 1000 ml dichloromethane and then boiled for 6 hours with stirring and a reflux condenser. The chloroform solution is then washed successively with 35 ml of saturated sodium carbonate solution and 3x35 ml of water. After drying, the solution is concentrated until crystallization begins. After cooling, the crystals are filtered off and washed with cold dichloromethane. This gives 6.8 g (46.2%) pure

2-Imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-toluenesulfonyloxy) pyrimidine, mp. 159-164 ° C.

[The alkaline washing liquid of chloroform can be processed. Extraction with ethyl acetate gives 2.64 g (22%) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide, which can be reacted with piperidine according to part (3) of Example 1],

Analysis based on the formula C18H15N4O5SCI (molecular weight 434.873):

Calc .: C 49.71%; H 3.48%; N 12.88%; S 7.38%; Cl Found: C 49.54%; H 3.88%; N 12.80%; S 7.23%; Cl

Ultraviolet spectrum: X® ™ = 325 nm (log E = 3.73). Infrared spectrum: (KBr): jimax = 3430.1695.1640, 1575.1385 cm-1.

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

130 ml of piperidine are weighed into a round-bottomed flask of 500 ml volume provided with a stirrer and a reflux condenser and cooled to 0-5 ° C. 21.7 g (0.05 mol) of 2-imino-3- (3-chloro-benzoyloxy) -4-amino-6- (4-tolylsulfonyloxy) pyrimidine are added to the anhydrous piperidine. The mixture is stirred for 3 hours at a temperature between 0 and 5 ° C, then for 3 hours at 100 ° C and then the piperidine is evaporated in vacuo. The regenerated piperidine can be used in a subsequent reaction. The residue is stirred with 80 ml of 5% aqueous sodium hydroxide solution at room temperature for half an hour, then filtered off and washed with water. The crystals obtained are stirred with 50 ml of benzene at room temperature for half an hour again, then filtered and washed with benzene. This gives 6.7 g (65%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide with a melting point of 264-266 ° C.

Example 6

(1) 2-Imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-tolylsulfonyloxy) pyrimidine

15 g (0.05 mol) of 6-tosyloxy-2,4-diaminopyrimidine prepared in the manner described in part (2) of Example 1

3-oxide are dissolved in 1000 ml of acetone at room temperature and then a solution of 9.0 g (0.05 mol) of 3-chlorobenzoyl chloride in 50 ml of acetone is added with stirring. The mixture is stirred for one and a half hours, then a solution of 5.25 g (0.052 mol) of triethylamine in 50 ml of acetone is added dropwise. Water at 30 ° C. is added to the mixture, which is heated to about 30 ° C., until it becomes slightly cloudy (about 1300 ml of water are required for this) and then cooled to 0-3 ° C. The crystalline product which has separated out is filtered off, washed with a 1: 1 mixture of acetone and water and dried. This gives 18.4 g (84.6%) of the acylated product, mp. 155-158 ° C.

In addition, one proceeds to that in part (2) of Example 5.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

B

Claims (10)

642365 2. The method according to claim 1, characterized in that 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula (V), wherein R is a 45 phenyl group, a substituted with a Ci-4-alkyl group or a Ci-4-alkyl group and Hai for a halogen atom, can react, the resulting sulfonic acid ester of the general formula (III), wherein R has the meaning given above, with a Treated the oxidizing agent and reacted the compound of the general formula (IV), in which R has the meaning given above, with piperidine. 2nd PATENT CLAIMS 1. Process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula from 6-hydroxy-2,4-diaminopyrimidine of the formula H2N N Y Ì "VN NH, OH characterized, a) that 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula R-SCh-Hal (IV) 0S02R wherein R has the meaning given above, either directly with piperidine to the compound of formula I. reacted, or with a carboxylic acid halide of the general formula R'-CO-Hal (XI), (I) wherein R 'represents a Ci-4-alkyl group or optionally a phenyl group substituted by a halogen atom and Hai represents a halogen atom, then acylated, the compound of the general formula obtained 10th » H2N 0 - C - R ' (IX) (II) 25th 0S02R wherein R and R 'have the meanings given above, react with piperidine, or b) that 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula R-SOz-Hal (V), 30th (V), 3S wherein R has the meaning given in variant a), then react the sulfonic acid ester of the general formula (III) obtained, where R has the meaning given above, with a percarboxylic acid of the general formula R'-COOOH wherein R represents a phenyl group, a phenyl group substituted by at most three Ci-4-alkyl groups or a Ci-4-alkyl group and Hai represents a halogen atom, the resulting sulfonic acid ester of the general formula (HD, 0S02R wherein R has the meaning given above, treated with an oxidizing agent and the N-oxide of the general formula formed (X), in which R 'has the meaning given for variant a), and finally the compound obtained of the general 40 my formula (IX), wherein R and R 'have the meaning given above, can react with piperidine. 3rd 642365 characterized in that m-chloroperbenzoic acid is used as the percarboxylic acid of the formula (X). 3. The method according to claim 2, characterized in that p-tolylsulfonyl chloride as sulfonyl halo- 55 genid of formula (V) applies. 4. The method according to claim 2, characterized in that phenylsunfonyl chloride is used as the sulfonyl halide of the formula (V). 5. The method according to claim 2, characterized 60 shows that methylsulfonyl chloride is used as the compound of the formula (V). 6. The method according to claim 2, characterized in that a percarboxylic acid is used as the oxidizing agent. 65 7. The method according to claim 6, characterized in that one uses m-chloroperbenzoic acid as percarboxylic acid. 8. The method according to variant b) of claim 1, 9. The method according to variant a) of claim 1, characterized in that m-chlorobenzoyl chloride is used as the carboxylic acid halide of the formula (XI). 10. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide, characterized in that cyanoacetic acid esters and guanidine are converted to 6-hydroxy-2,4-diamino-nopyrimidine and the latter in the form of the crude reaction mixture used in the process according to claim 2. Binding can be produced by chlorination with phosphorus oxychloride, but their separation and purification is difficult due to their good solubility both in water and in organic solvents. A large excess of phosphorus oxychloride is required for chlorination, which further increases the corrosive character of the reaction mixture. According to a further known method (US Pat. No. 3,910,928), the N- (2-cyanoacetyl) piperidine is in the methyl ether of the formula CN i