SE432596B - PROCEDURE FOR PREPARING 6-PIPERIDINO-2,4-DIAMINOPYRIMIDINE-3-OXIDE - Google Patents

Description

Many methods have been developed for the preparation of the compound I, but none of these can be used economically for the preparation of the compound on a large scale.

According to one of the known methods (U.S. Pat. Nos. 3,382,247 and 3,461,461), 2,4-diamino-6-hydroxypyrimidine is reacted with phosphorus oxychloride to 2,4-diamino-6-chloropyrimidine in a yield of 60%. The latter compound is reacted with phenol or 2,4-dichlorophenol to 2,4-diamino-6-phenoxypyrimidine, which is obtained in a yield of 40%. This latter compound is oxidized to the respective N-oxide obtained in a yield of 21%. The N-oxide is then treated with piperidine to give the desired product. In this latter reaction step, a yield of 45% is obtained. For the whole process, a yield of only 2 - 2.3% is obtained, calculated on the starting material 2,4-diamino-6-hydroxypyrimidine.

In accordance with the process described in German Patent Application 2,144,887, 2,4-diamino-6-chloropyrimidine prepared from the respective 6-hydroxy compound is oxidized in a yield of 60%. The oxidation is carried out directly to the N-oxide and the 2,4-diamino-6-chloropyrimidine-3-oxide thus obtained, which is obtained in a yield of 45%, is reacted with piperidine to the resulting product which is obtained in a yield of 89%. In this process, a total yield of not more than 24% is obtained on the starting material 2,4-diamino-6-hydroxypyrimidine.

A further disadvantage of both of the methods discussed above is that 2,4-diamino-6-chloropyrimidine was used as the median product in the synthesis. This compound is prepared by reacting the 6-hydroxide derivative with phosphorus oxychloride which is a corrosive substance and which must be used in large excess. The resulting 6-chloro compound is soluble in water and organic solvents, and as a result it is quite difficult to repair and purify.

According to another known method (U.S. Pat. No. 3,910,928), N- (2-cyanoacetyl) -piperidine is converted to the respective methyl ether of the formula C1-4 / N-VI. This compound is treated with cyanamide to the dinitrile of the formula C10. The compound VIII is reacted with a hydroxyamine to form the compound of formula VIII, the compound VIII is subjected to ring solution to give the desired compound I. Although the total yield in this process based on the starting material N- (2-cyanoacetyl) -piperidine is 35%, the process can not be used on a large scale, because difficult-to-use specific reactants must be used in the preparation of methyl VI. The relatively large number of steps in this process is a further drawback.

According to the present invention, there is provided a simple and economical process consisting of a few reaction steps for the large scale production of 6-piperidino-2,4-diaminopyrimidine-3-oxide.

According to the present invention, there is carried out as follows: a) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide having the common form R - SO 2 - hai V wherein R represents a C 1-4 alkyl group or a phenyl group which is optionally substituted up to 11 C1-4 alkyl groups, and ha1 represents haiogen.

In this reaction, a sulfonate having the general formula HQN X N is obtained. NH 2 I II '111 "\\ If., Ozone 10 15 25 30 35 4D 790862 *" Li where R has the above meaning. This sulfonate is treated with an oxidizing agent1 in a protic solvent and the N-oxide thus obtained with the The monomeric form 0 in which R has the above meaning is reacted directly with piperidine or is first acylated with a carbonyl halide having the monomeric form 'R' - CO - hal XI where R * represents a C 1-4 alkyl group or a phenyl substituent which a halogen atom, and ha1 represents haiogen, thereby obtaining a compound with the aïmännaeformeïn O-CC> éR | I HN N 2 - / m / N fi a, Ix * \\ IT - where R and R 'have the meanings given above. compound is reacted with piperidine; or b) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the above-defined monomeric form V, whereupon the so-obtained sulfonate of the above-defined ammonium formine III is reacted in an apricot mede1 with a peracid with the aiïmänna formeïn R '- coooH I x where R 'has the above meaning. The compound thus obtained with the above-defined general form IX is reacted with piperidine.

Preferred sulphonyl halides for this process are phenylsulphonyl chloride, p-toisylsulphonyl chloride and 2,4,6-trimethylphenylsulphonyl chloride.

6-hydroxy4,4,4-diaminopyrimidine is reacted with the sulfonyl halide V in the presence of a base, preferably an alkali metal hydroxide, more preferably an aqueous solution thereof.

A percarboxylic acid, for example peracetic acid or perbenzoic acid, is suitably used as the oxidizing agent. According to a particularly preferred method, compound III is oxidized with m-chloro-perbenzoic acid.

Compound IV is preferably reacted with excess piperidine at 0-100 ° C. The excess piperidine can be distilled off and reused in the process.

According to a preferred method, m-chloro-perbenzoic acid is used as percarboxylic acid X and m-chlorobenzoic acid is used as carbonyl halide XI.

The compound 6-hydroxy-2,4-diaminopyrimidine used as starting material in the process according to the invention can be prepared in a manner known per se by reacting cyanoacetic acid ester with guanidine (Org. Synth. C01. V01. 4, 245/1963 / ).

According to another preferred embodiment of the process according to the invention, 6-hydroxy-2,4-diaminopyrimidine is reacted directly, i.e. without first being separated from the mixture in which it is formed, with sulfonyl halide V, whereby the ester III is obtained from the cyanoacetic acid ester and the guanoacetic acid ester process which could be described as a one-step process. Compounds III and IV are new substances.

It is very surprising to those skilled in the art that 6-hydroxy-2,4-diaminopyrimidine can be converted in a simple and almost quantitative manner to its reactive ester derivative, as indicated in the literature (The Pyrimidines; Interscience Pub1. 1962, p. 252) that hydroxypyrimidines are generally difficult to acylate.

The invention provides an economical process for the production of 6-piperidino-2,4-diaminopyrimidine-3-oxide in large scale. The individual reaction steps are easy to carry out and the starting materials and reactants are readily available. The total yield in the process based on 6-hydroxy-2,4-diaminopyrimidine amounts to 34-45% and if the starting material is not isolated from the reaction mixture, the yield can be further increased by 5%.

The invention is further described in detail in the following Articles: Preparation of 6-piperidino; 2QÅ-diaminopyrimidine-3-oxide a 2,5-Normal Aqueous Solution of Sodium Hydroxide Dissolved 63 g (0.5 mol) of 6-hydroxy-2,4-diaminopyrimidine. I 250 ml of acetone yields 120 g (0.62 mol) of p-toylisophonyicuride. In a 2-liter coif equipped with a stirrer, 100 ml of acetone were charged and the two solutions were added dropwise within about 0.5 and about 1 hour in the acetone at room temperature and with stirring at such a rate that pH 7 was maintained in the reaction mixture. The mixture was stirred at room temperature for three hours, then 1000 ml of water was added. The precipitated substance was filtered off to give 134 g (95%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopiperidine, m.p. 179-18100.

Analysis:% C 1% H% N% S calculated for ° 11H1z ° 35 47.13 4.32 19.99 11.44 (u = 280.32) found: 47.56 4.67 '19, s1 11, eo _ ston _ _ _ _ uv spectrum. _ 275 nn, ng X -s, 9z lllâX.

IR spectrum: 1.1 (KBr) = 3460, 1632, 1605, 1368, 1200 cmq Method B: Into a flask equipped with a stirrer and reflux condenser was introduced 23 g of cut metallic sodium and 370 ml of absolute ethanol was added. To the solution of sodium ethoxide thus obtained was added 48.5 g of 10.51 mol) of dry and powdered guanidine hydrochloride, and the mixture was refluxed for 1.5 hours. The mixture was allowed to cool to 25 ° C, 55 ml (0.52 mol) of ethyl cyanoacetate were added to the stirred mixture at 25 ° C and the resulting mixture was refluxed for a further two hours. Then 100-150 ml of ethanol were evaporated from the mixture and the residue was mixed with 200 ml of water. Aqueous ethanol was distilled off from the mixture until the vapor temperature reached 100 ° C. At this stage, the distillation was stopped, the residue was cooled and water was added to a final volume of 330 ml.

In a flask equipped with a stirrer, 100 ml of acetone were poured and the solution obtained above was dropped into the stirred acetone together with a solution of 99 g (0.52 mol) of p-tolylsulfonyl chloride in 250 ml of acetone. . The instillation rate was adjusted so that pH 7 was maintained in the reaction mixture. The mixture thus obtained was stirred at room temperature for three hours, after which 1000 ml of water were added. The precipitated substance was filtered off and 125 g (85%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine with a melting point of 179-18100 were obtained.

Preparation: A flask equipped with a stirrer and a reflux condenser was charged with 20 g (0.159 mol) of 6-hydroxy-2,4-diaminopyrimidine and 50 ml of absolute dimethylformamide, then 6 g of sodium hydride (0.25 mol) were added to the mixture at room temperature. The mixture thus obtained was heated to 100 ° C and stirred at this temperature for two hours. The mixture was cooled to 0 ° C and a solution of 50 g (0.26 mol) of p-tolylsulfonyl chloride in 50 ml of dimethylformamide was added dropwise to the mixture. It was stirred for two hours at 0 ° C and then for a further 10 hours. 7908629-4 two hours at room temperature, after which it was poured onto 400 g of ice. Extraction was performed with chloroform (3x200 ml), the chloroform solutions were combined and shaken with 100 ml of water, after which the product separated. There was thus obtained 25 (57%) 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine with a melting point of 179-181%.

Step 2: Preparation of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide A 5 ml flask equipped with a magnetic stirrer and external cooling bath (ice water) was charged with 5.6 g (0.02 mol) of 6- (p- tolylsulfonyloxy) -2,4-diaminopyrimidine, 200 ml of ethanol and 25 ml of water. The suspension was cooled to a temperature between 0 and 5 ° C, then a solution of 4.0 g (0.02 mol) of 86% m-chloro-perbenzoic acid in 50 ml of cold ethanol was added. The reaction mixture was stirred and its temperature was allowed to rise to 28 ° C within 3.5 hours. When the reaction ceased (which was indicated by a sample of the mixture not giving rise to iodine formation in a potassium iodide solution), ethanol was evaporated in vacuo on a water vapor bath with a temperature not exceeding 50 ° C and the residue was dissolved in 250 ml of ethyl acetate. The solution was extracted with several portions of a 2% aqueous solution of sodium hydroxide, until the aqueous phase after the extraction remained slightly alkaline, whereupon the aqueous solutions were combined and extracted with ethyl acetate (4x50 ml). The m-chlorobenzoic acid formed during the reaction can be recovered from the aqueous solution and reused in the process after oxidation. The ethyl acetate extracts were combined, dried and evaporated to a small volume, whereupon the product separated into crystalline form. The crystals were filtered off and washed with a small amount of ethyl acetate to obtain 3.9 g of (α) pure 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine-3-oxide having a melting point of 125 DEG-130 DEG C. (decomposition).

Analysis:% C% H% N% S calculated for C 11 H 12 N 4 O 4 S 44.32 4.08 18.91 10.82 Found: 44.32 4.47 18.59 10.42 UV spectrum: λmax = 285 nm, 109 2 : = 3.75 IR spectrum: ju (KBr) = 3420, 1650, 1620, 1400, 1380 cm -1 Step 1: Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide In a 500 ml flask equipped with a stirrer and a reflux condenser, 140 ml of piperidine were charged. (In cases where the piperidine contains more than 0.5% water, an equivalent amount of phosphorus pentoxide, aluminum isopropoxide or butyllithium is added to remove the water.) Then, to the dry piperidine 20 (0.067 mol) was added 6- (p-tolylsulfonyloxy). 2,4-Diaminopyrimidine-3-oxide and the reaction mixture was stirred at 10,000 for two hours, then the piperidine was distilled off in vacuo. The piperidine thus recovered can be reused in the process. The residue was diluted with 50 ml of a 5% aqueous solution of sodium hydroxide, the mixture was stirred at room temperature for 0.5 hours, then the precipitated crystals were filtered off and washed with water. The crystalline substance was suspended in 50 ml of benzene, the suspension was stirred at room temperature for 0.5 hours, after which the solid was filtered off and washed with benzene. 7.7 g (55%) of pure 6-piperidino-2,4,4-diaminopyrimidine-3-oxide with a melting point of 254-255 ° C were obtained in this way.

Anaïysz% C% H% N calculated for 51.55 7.22 33.47 09015050 Found: 51.30 7.00 33.42 "V'S '° ekt" "" "Ä 1151591' = 232 am (mg. 2 = 4.54) and zss mn (109 Z = 4.09) IR'SPekt '“” * / J :: i ° 1 = 3410, 3420, 3400, 3370, 3250, 1555, 1250, 1210, 1155, 1020 cm '1. ššë0E fl_ å = _ ._ _ ._ _ ..

Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide Step 1: Preparation of 6- (methylsulfonyloxy) -2,4-diaminopyrimidine I-35 in water Dissolve 12.6 g (0.1 mol) of 6-hydroxy -2,4-diaminopyrimidine and 4 g (0.1 mol) of sodium hydroxide. In 50 ml of acetone was dissolved 9.3 ml (0.12 mol) of methylsulfonic chloride. A 250 ml coil equipped with a stirrer was charged with 20 ml of acetone and both of the above solutions were dropped into the acetone at room temperature. After stirring the reaction mixture for three hours, it was diluted with 210 ml of water and the pH of the mixture was adjusted to 9 with a 10% aqueous solution of sodium hydroxide. The precipitated substance was filtered off to give 11.1 g (54.4%) of 6- (methylsulfonyloxy) -2,4-diaminopyrimidine, m.p. 176 DEG-150 DEG.

This intermediate was converted to the title compound of the present example in the manner set forth in Step 2 and Step 3 of Example 1.

Preparation of 5-oiperidino-2,1-diaminopyrimidine-3-oxide Step 1: Preparation of 6- (phenylsulfonyloxy) -2,4-diaminopyrimidine In 35 ml of water Dissolve 12.6 g (0.1 mol) of 6-hydroxy- 2,4-diaminopyrimidine and 4 g (0.1 mol) of sodium hydroxide. In 50 ml of acetone was dissolved 15.4 ml (0.12 mol) of phenylsulfonyl chloride. In a 250 ml coil with three husks and equipped with a stirrer, 20 ml of acetone were charged and both solutions were added dropwise to the acetone at room temperature. After stirring for three hours, the reaction mixture was diluted with 210 ml of water and the pH of the mixture was adjusted to 9 with a 10% aqueous solution of sodium hydroxide. The precipitated substance was filtered off and 20.25 g (75.6%) of 6- (phenylsulphonyoxy) -2,4-diaminopyrimidine having a melting point of 189 DEG-19300 were obtained.

Thereafter, the procedure is as described in steps 2 and 3 of Example 1 for the preparation of the title compound of the present invention. Example 4: Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide Step 1: Preparation of 6- (mesityenesulfonoxy) -2,4-diaminopyrimidine In 17.5 ml of water was dissolved 6.3 g (0.05 moi) of 6-hydroxy-2,4-diaminopyrimidine and 2 g (0.05 moi) of sodium hydroxide. In 25 ml of acetone was dissolved 12 g (0.055 mol) of mesityenesulfonic chloride (2,4,6-trimethylphenylsufonicuride). Both solutions were added dropwise and at room temperature to 10 ml with stirring in acetone. After stirring for three hours, the reaction mixture was diluted with 100 ml of water and the pH of the mixture was adjusted to 9 with a 10% aqueous solution of sodium hydroxide. The precipitated substance was filtered off to give 11.35 g (73.6%) of 6- (mesityenesulfonyloxy) -2,4-diaminopyrimidine, m.p. 183-18606. By recrystallization in a 25-fold amount of ethanol, the melting point t111 rose 187-191 ° C.

Thereafter, the procedure is as described in steps 2 and 3 of Example 1 for the preparation of the title compound of the present invention.

Example 5: Preparation of 6-pyridino-2,4-diaminopyrimidine-3-oxide Fig. 1: Preparation of 2-imino-3- (3-chlorobenzyloxy) -4-amino-6- (tolyl-sulphonyoxy) -pyrimidine.

In 1000 ml of dichloromethane were suspended at room temperature 11.2 g (0.04 mol) of 6-tosyloxy-2,4-diaminopyrimidine (prepared as indicated in step 1 of Example 1) and 8 g (0.04 mol) 86% 3-chloroperbenzoic acid. The suspension was stirred and refluxed for 6 hours. The reaction mixture was washed with 35 ml of a saturated aqueous solution of sodium carbonate and then with water (3 x 25 ml), after which it was evaporated to the initial crystallization. The crystalline suspension was cooled, the crystals were filtered off and washed with dichloromethane to give 6.8 g (46.2%) of pure 2-imino-3- (3-chlorobenzyloxy) -4-amino-6- (4-toluenesulphanyoxy) - pyrimiain with a melting point of 189-1s4 ° c.

M z ßi zc in% N is calculated for c18 H, 5N4o5sc1 49.71 3.48 12.88 7.38 8.15 (M = 434.873) found: 49.34 3.88 12.80 7.23 8.12 UV spectrum: 7 μg = 325 nm (109 Z: = 3.73) 1R'SPect * “” = 11 ga; = 3430, 1898, 1840, 1575, 1385 cm -1 The washing liquid (the aqueous aqueous solution) obtained in the above-mentioned washing of the reaction mixture was extracted with ethyl acetate to give 2.64 g (22%) of 6-tosyioxy-2.4. -diaminopyrimidine-3-oxide. This substance can be reacted with piperidine in the manner set forth in step 3 of Example 1 to prepare the title compound of the present example. §P§g_§: Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide In a 500 ml coif equipped with a stirrer and a reflux condenser, 130 ml of piperidine were charged. The dry piperidine was cooled to 0 DEG-5 DEG C. and 21.7 g (0.05 mol) of 2-imino-3- (3-chlorobenzyloxy) -4-amino-6- (4-toluysulfonyl) pyrimidine were added. The reaction mixture was stirred at a temperature between 0 and 5 ° C for three hours and then at 100 ° C for a further three hours, after which piperidine was distilled off in vacuo. The recovered piperidine can be reused in the process of the invention. To the residue was added 80 ml of a 5% aqueous solution of sodium hydroxide, the mixture was stirred at room temperature for 0.5 hours, the precipitated crystals were filtered off and washed with water. The crystals were suspended in 50 ml of benzene, the suspension was stirred at room temperature for 0.5 hours, then the crystals were filtered off and washed with benzene. 6.7 g (65%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide with a melting point of 264 DEG-6 DEG C. are obtained. Example 1 Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide Step 1: Preparation of 2-imino-3- (3-chlorobenzyloxy) -4-amino-6- (4-toluysonyloxy) -pyrimidine. In 1000 ml of acetone was dissolved at room temperature 15 g (0.05 mol) of 6-tosyioxy-2,4-diaminopyrimidine-3-oxide prepared as indicated in step 2 of Example 1.

To the solution was added with stirring a solution of 9.0 g (0.05 mol) of 3-chlorobenzoic chloride in 50 ml of acetone. The reaction mixture was stirred for 1.5 hours, then a solution of 5.25 g (0.052 mol) of triethylamine in 50 ml of acetone was added dropwise to the mixture, which, heated to about 3000, was mixed with hot (30 ° C) water. until a slight grumiing was applied (about 1300 ml of water was required for this purpose).

Then the mixture was cooled to a temperature between 0 and 3 ° C and the precipitated crystalline substance was filtered off, washed with a mixture of acetone and water 1: 1 and dried. 18.4 g (84.6%) of 2-imino-3- (3-chlorobenzoyioxy) -4-amino-6- (4-toluisophonyloxy) pyrimidine with a melting point of 155 DEG-140 DEG C. are obtained. Thereafter, the procedure is as described in step 2 of Example 5 to give the title compound of the present example.

Claims (10)

1. 9 15 20 25 30 35 79Û8629 * fi I2 Û T H2N ri N32 / '\ ï] “' - IV \\\ IW osogn dar R has the meaning given above, is directly reacted with piperidine, or is first acidified with a carbonyl halide with the common formula R '- CO - hai XI wherein R' represents a C1-4alkyl group or a phenyl group, which optionally contains a halogen substituent, and ha1 represents halogen, whereupon the compound thus obtained with the monoform RI taken ån / m: h 1x É]? OSOQR, where R and R 'have the meanings given above, are reacted with piperidine; or (b) reacting 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the above-defined ammonium form V, whereupon the so-prepared sulfonate of the above-defined ammonia formula III is reacted with a peracid of the ammonium COH formula X '- where R 'has the meaning given above, whereupon the compound thus obtained with the above-defined human formula IX is reacted with piperidine. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide having the formula I according to claim 1 from 6-hydroxy-2,4-diaminopyrimidine having the formula II according to claim 1, characterized in that 6-Hydroxy-2,4-diaminopyrimidine is reacted with a sulphonyl halide having the monomeric form V in claim 1, wherein R represents a C 1-4 alkyl group or a phenyl group optionally containing a C 1-4 alkyl halogen substituent , whereupon the compound thus obtained having the general formula III in claim 1, wherein R has the meaning given above, is treated with an oxidizing agent and the compound of the IV formula indicated in claim 1, wherein R has the meaning given above, is reacted. with piperidine. H 7908629-4 Claim 1. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula HZN m @ in, IHQ2 I-II / II from 6-hydroxy-2 4-Diaminopyrimidine of the formula N 3312 is characterized in that: (a) reacting 6-hydroxy-2,4-diaminopyrimidine with a sulfonyl halide of the general formula R - SO 2 - hai V where R represents a C 1-4 alkyl group or a phenyl group which is optionally substituted with up to three C 1-4 alkyl groups and hai represents haiogen, whereupon the so-formed sulfonate with the monomeric form N II / II II II \ 'N' III osoze where R has the meaning given above is treated with an oxidizing agent1 and the N-oxide thus obtained with the general formin | 15 | 3 3. A process according to claim 2, characterized in that the indicated starting compound 6-hydroxy-2,4-diaminopyrimidine is purified without first being isolated from the mixture in which the acetic acid with guanidine is prepared. 4. The method of claim 2, wherein the novel nucleic acid is used as sulfonyl halide V. 5. A method according to claim 2, wherein the chloride was used as sulphonylurea V. 6. The method of claim 2, wherein the chloride is used as the sulfonyl halide V. 7. A method according to claim 2, wherein no acid is used as the oxidizing agent. 8. The method of claim 7, wherein the acid used is percarboxylic acid. The method of claim 1 (b), benzoic acid being used as percarboxylic acid X. The method of claim 1 (a), soyl chloride was used as carbonyl halide XI. k ä nneteck ä nnetecknat by turnover of cyano- at of p-to1y1su1fo- at of fenyisutfonyi- at of metyisuifonyi- at of a perkarboxyi- at avaüim fl ommtmßæ- knat of that m-k1orper- of that m-k1orben-- The invention relates to a new process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide from 6-hydroxy-2,4-diaminopyrimidine, wherein (a) 6> hydroxy = 2 4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula R - SO 2 - hal V where R represents a C 1-4 alkyl group or a phenyl group which optionally contains up to three C 1-4 alkyl substituents and hal represents halogen, then the sulfonate formed is oxidized and the N-oxide thus obtained is directly reacted with piperidine, or first acylated with a carbonyl halide of the general formula R '- CO - hal XI where R' represents a C 1-4 alkyl group or a phenyl group, optionally containing a halogen substituent, and hal reprint halogen, then the compound thus obtained is reacted with piperidine, or (b) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide having the above-defined general formula V, Whereupon the compound thus formed is substituted with a peracid containing the general acid. the formula R '- COOOH - X where R' has the meaning given above, and the N-oxide thus obtained is reacted with piperidine. The process according to the invention is particularly suitable for the large-scale production of 6-piperidino-2,4-diaminopyrimidine-3-oxide, which compound has excellent hypotensive effects. R