GB2032434A - New Process for the Preparation of 6-piperidino-2,4- diaminopyrimidine-3-oxide - Google Patents
New Process for the Preparation of 6-piperidino-2,4- diaminopyrimidine-3-oxide Download PDFInfo
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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
SPECIFICATION
New Process for the Preparation of 6-piperidino-2,4-diamino-pyrimidine-3-oxide
The invention relates to a new process for the preparation of 6-piperidino-2,4-diaminopyrimidine3-oxide of the formula (I)
from 6-hydroxy-2,4-diaminopyrimidine of the formula (ill).
The compound of the formula (I) possesses excellent hypotensive effects.
Several methods have been elaborated for the preparation of the formula (I) compound, none of them provides, however, an economical way for the large-scale production of the aimed product.
According to one of these known methods (US patent specifications Nos. 3,382,247 and 3,461,461) 2,4-diamino-6-hydroxypyrimidine is reacted with phosphorus oxychloride to obtain 2,4diamino-6-chloropyrimidine with a yield of 60%, this latter compound is reacted with phenol or 2,4dichlorophenol; the resulting 2,4-diamino-6-phenoxypyrimidine, obtained with a yield of 40%, is oxidized into the respective N-oxide with a yield of 21%, and finally the N-oxide is treated with piperidine to obtain the required product. This latter reaction step runs with a yield of 45%; thus the total yield of the process, calculated for the starting 2,4-diamino-6-hydroxpyrimidine, is only 2 to 2.3%.
According to the process described in the published German patent application No.2,144,887 2,4-diamino-6-chloropyrimidine, obtained from the respective 6-hydroxy compound with a yield of 60%, is oxidized directly into the N-oxide, and the resulting 2,4-diamino-6-chloropyrimidine-3-oxide, obtained with a yield of 45%, is reacted with piperidine to obtain the end-product with a yield of 890iso.
The total yield of this process, calculated for the starting 2,4-diamino-6-hydroxpyrimidine, still does not exceed 24%.
Both methods have the further disadvantage of utilizing 2,4-diamino-6-chloropyrimidine as an intermediate in the synthesis. This compound is prepared by chlorinating the 6-hydroxy derivative with phosphorous oxychloride, a corrosive substance to be applied in large excess. The resulting 6-chloro compound is well soluble in water and organic solvents, therefore its separation and purification is rather difficult.
According to a further known method (US. Patent specification No. 3,910,928) N-(2cyanoacetyl)-piperidine is converted into the respective methyl ether of the formula (Vl),
this compound is treated with cyanamide, the resulting dinitrile of the formula (VII)
is reacted with hydroxylamine, and the resulting compound of the formula (VIII)
is subjected to ring closure to form the aimed compound of the formula (I). Although the total yield of this process, calculated for the starting N-(2-cyanoacetyl)-piperidine, is 35%, the method cannot be applied for large-scale production, since it requires hardly available specific reagents (such as trimethyl oxonium fluoroborate) in preparing the methyl ether of the formula (VI). The relatively large number of reaction steps is a further disadvantage of the process.
The invention aims at the elaboration of a simple and economical method, consisting of few reaction steps, for the large-scale production of 6-piperidino-2,4-diaminopyrimidine-3-oxide.
According to the invention one proceeds as follows:
a) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula (V), R-SO2-hal (V) wherein R stands for a C14 alkyl group or a phenyl group optionally having up to three C14 alkyl substituents and hal represents halogen, the resulting sulfonate of the general formula (III),
wherein R is as defined above, is treated with an oxidizing agent in a protic solvent and the resulting Noxide of the general formula (IV),
wherein R is as defined above, is reacted directly with piperidine, or it is acylated first with a carbonyl halide of the general formula (Xl).
R'-CO-ha I (Xl) wherein R' represents a C14 alkyl group or a phenyl group optionally with a halogen substituent and hal stands for halogen, and the resulting compound of the general formula (IX),
wherein R and R' are as defined above, is reacted with piperidine; or
b) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula (V), wherein R and hal are as defined above, the resulting sulfonate of the general formula (III), wherein R is as defined above, is reacted in an aprotic solvent with a peracid of the general formula (X), R'-COOOH (X) wherein R' is as defined above, the resulting compound of the general formula (IX), wherein R and R' are as defined above, is reacted with piperidine.
The preferred representatives of sulfonyl halides applied in the above process are phenylsulfonyi chloride, p-tolylsulfonyl chloride and 2,4,6-trimethylphenylsulfonyl chloride.
6-Hydroxy-2,4-diaminopyrimidine is reacted with the sulfonyl halide of the general formula (V) in the presence of a base, preferably an alkali metal hydroxide, particularly an aqueous solution thereof.
As oxidizing agent preferably a percarboxylic acid, such as peracetic or perbenzoic acid, can be applied. According to a particularly preferred method and compound of the general formula (III) is oxidized with m-chloro-perbenzoic acid.
The compound of the general formula (IV) is reacted preferably with an excess of piperidine at O to 1000C. The excess of piperidine can be removed by distillation, and the recovered piperidine can be used again in the process.
According to a prefered method m-chloro-perbenzoic acid is )applied as percarboxylic acid of the general formula (X), and m-chlorobenzoyl chloride is applied as carbonyl halide of the general formula (Xl).
6-Hydroxy-2,4-diaminopyrimine, utilized as starting substance according to the invention, can be prepared in a manner known per se by reacting cyanoacetic ester with guanidine (Org. Synth. Coll. Vol.
4, 245/1963/).
According to a preferred method of the invention 6-hydroxy-2,4-diaminopyrimidine is reacted directly, i.e. without separation from the mixture where it was formed, with a sulfonyl halide of the general formula (V), thereby preparing the ester of the general formula (III) from cyanoacetic ester and guanidine in a quasi single-step process. The compounds of the general formulae (III) and (1V) are new substances.
It is very surprising to one skilled in the art that 6-hydroxy-2,4-diaminopyridine can be converted simply and almost quantitatively into its reactive ester derivative, since, as stated in the literature (The -Pyrimidines; Interscience Publ., 1962, p. 252), hydroxypyrimidines are generally difficult to acylate.
The invention provides an economical method for the large-scale production of 6-piperidino-2,4diaminopyrimidine-3-oxide. The individual reaction steps are easy to perform and require easily available starting substances and reagents. The overall yield of the process, calculated for 6-hydroxy2,4-diaminopyrimidine, is 34 to 45%, and if the starting compound is not isolated from the reaction mixture the yield can be increased by further 5%.
The process of the invention is elucidated in detail with the aid of the following non-limiting
Examples.
Example 1
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide
Step 1:
Preparation of 6-(p-tolylsulfonyloxy)-2,4-diaminopyrimidine
Method A:
63 g (0.5 moles) of 6-hydroxy-2,4-diaminopyrimidine are dissolved in 250 ml of 2.5 n aqueous sodium hydroxide solution, and 120 g (0.62 moles) of p-tolylsulfonyl chloride are dissolved in 250 ml of acetone. Both solutions are introduced dropwise, within about 0.5 to 1 hour, into 100 ml of acetone filled with 2-litre flask equipped with a stirrer. The solutions are introduced at room temperature under stirring, and the rate of introduction is adjusted so that the pH of the reaction mixture remains equal to 7.The mixture is stirred at room temperature for 3 hours, thereafter 1000 ml of water are added, and the separated substance is filtered off. 134 g (95%) of 6-(p-tolylsulfonyloxy)-2,4-diaminopyrimidine are obtained; m.p.: 179-181 0C.
Analysis:
calculated for C"H,203S (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%
UV spectrum: Armt XH=275 nm; log F=3,92 IR spectrum: y (KBr)=3460, 1632, 1605, 1368, 1200 cm-'.
Method B:
23 g of cut metallic sodium are filled into a flask equipped with a stirrer and a reflux condenser,
and 370 ml of absolute ethanol are added. 48.5 g (0.51 moles) of dried and powdered guanidine
hydrochloride are added to the resulting solution of sodium ethoxide, and the mixture is refluxed for 1.5
hours. The mixture is allowed to cool to 250C, 55 ml (0.52 moles) of ethyl cyanoacetate are added to the stirred mixture at 250C, and the resulting mixture is refluxed again for two hours. Thereafter 100 to
1 50 ml of ethanol are evaporated from the mixture, and the residue is admixed with 200 ml of water.
Aqueous ethanol is distilled off from the mixture until the temperature of the vapours reaches 100 C.
At this stage distillation is stopped, the residue is cooled, and water is added to it to a final volume of 330 ml.
100 ml of acetone are filled into a flask equipped with a stirrer, and the above solution is dropped into the stirred acetone together with a solution of 99 g (0.52 moles) of p-tolylsulfonyl chloride in 250 ml of acetone. The rate of introduction is adjusted so that the pH of the reaction mixture remains equal to 7. The resulting mixture is stirred at room temperature for 3 hours, thereafter 1000 ml of water are added, and the separated substance is filtered off. 125 g (85%) of 6-(p-tolylsulfonyloxy)-2,4diaminopyrimidine are obtained; m.p.: 179-181 0C.
Method C:
20 g (0.159 moles) of 6-hydroxy-2,4-diaminopyrimidine and 50 ml of absolute dimethyl formamide are filled into a flask equipped with a stirrer and a reflux condenser. 6 g of sodium hydride (0.25 moles) are added to the mixture at room temperature. The resulting mixture is heated to 1 000C and stirred at this temperature for 2 hours. The mixture is cooled to OOC, and a solution of 50 g (0.26 moles) of p-tolylsulfonyl chloride in 50 ml of dimethyl formamide is added dropwise to the mixture. The mixture is stirred for 2 hours at OOC and then for additional 2 hours at room temperature. Thereafter the mixture is poured onto 400 g of ice and extracted thrice with 200 ml of chioroform, each.The chloroform solutions are combined and shaken with 100 ml of water, whereupon the product separates. 25 g (57%) of 6-(p-tolylsulfonyloxy)-2,4-diaminopyrimidine are obtained: m.p.: 179
1810C.
Step 2:
Preparation of 6-(p-tolylsulphonyloxy)-2,4-diaminopyrimidine-3-oxide
5.6 g (0.02 moles) of 6-(p-tolylsulfonyloxy)-2,4-diaminopyrimidine, 200 ml of ethanol and 25 ml of water are filled into a 500 ml flask equipped with a magnetic stirrer and an external cooiing bath (ice water). The suspension is cooled to O to 50C, and then a solution of 4.0 g (0.02 moles) of 86% mchloro-perbenzoic acid in 50 ml of cold ethanol is added. The reaction mixture is stirred and allowed to warm to 280C within 3.5 hours. When the reaction terminates (which is indicated by the fact that a sample of the mixture does not produce iodine from a potassium iodide solution), the ethanol is evaporated in vacuo on a steam bath of maximum 500C, and the residue is dissolved in 250 ml of ethyl acetate.The solution is extracted in several portions with 2% aqueous sodium hydroxide solution.
When the aqueous phase remains slightly alkaline after extraction, extraction is terminated, the aqueous solutions are combined, and extracted four times with 50 ml of ethyl acetate, each. The mchlorobenzoic acid formed in the reaction can be recovered from the aqueous solution and, after oxidation, can be used again in the process. The ethyl acetate extracts are combined, dried and evaporated to a small volume, whereupon the product separates in crystalline form. The crystals are filtered off and washed with a small amount of ethyl acetate. 3.9 g (65%) of pure 6-(p tolylsulfonyloxy)-2,4-diaminopyrimidine-3-oxide are obtained; m.p.: 125--1300C under decomposition.
Analysis:
calculated for C"H 2N404S: 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%
UV spectrum: 1 EtaOXH=285 nm, long S=3.75.
IR spectrum: u (KBr)=3420, 1650, 1620, 1400, 1380 cm-1.
Step 3:
Preparation of 6-piperidino-2,4-diamino-pyrimidine-3-oxide
140 ml of piperidine are introduced into a 500 ml flask equipped with a stirrer and a reflux condenser. If the piperidine contains more than 0.5% of water, an equivalent amount of phosphorous pentoxide, aluminium isopropoxide or butyl lithium is added to remove the water, and then 20 g (0.067 moles) of 6-(p-tolylsulfonyloxy)-2,4-diaminopyrimidine-3-oxide are added to the resulting dry piperidine. The reaction mixture is stirred at 1 000C for 2 hours, and then piperidine is distilled off in vacuo. This recovered piperidine can be used again in the process. The residue is diluted with 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred at room temperature for 0.5 hours, thereafter the separated crystals are filtered off and washed with water.The crystalline substance is suspended in 50 ml of benzene, the suspension is stirred at room temperature for 0.5 hours, thereafter the solid is filtered off and washed with benzene. 7.7 g (55%) of pure 6-piperidino-2,4diaminopyrimidine-3-oxide are obtained: m.p.: 264-2660C.
Analysis:
calculated for CgH,5N50: C: 51.66%, H: 7.22%, N: 33.47%
found:
C: 51.80%, H: 7.00%, N: 33.42%
UV spectrum: REt H=232 nm (log =4.54) and 286 nm (log =4.09) 1R spectrum:uq'=341 0, 3420, 3400, 3370, 3260, 1655, 1250, 1210, 1165, 1020 cm-l.
Example 2
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide
Step 1:
Preparation of 6-(methylsulfonyloxy)-2,4-diaminopyrimidine
12.6 g (0.1 moles) of 6-hydroxy-2,4-diaminopyrimidine and 4 g (0.1 moles) of sodium hydroxide are dissolved in 35 ml of water, and 9.3 ml (0.12 moles) of methylsulfonyl chloride are dissolved in 50 ml of acetone. Both solutions are added dropwise, at room temperature, to 20 ml of acetone filled into a 250 ml flask equipped with a stirrer. After 3 hours of stirring the reaction mixture is diluted with 210 ml of water, and the pH of the mixture is adjusted to 9 with 10% aqueous sodium hydroxide solution.
The separated substance is filtered off. 11.1 g (54.4%) of 6-(methylsulfonyloxy)-2,4-diaminopyrimidine are obtained; m.p.: 1 76-1 800C.
This intermediate is converted into the final compound by the reactions described in Steps 2 and 3 of Example 1.
Example 3
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide
Step 1:
Preparation of 6(-phenylsulfonyloxy)-2,4-diaminopyrimidine
12.6 g (0.1 moles) of 6-hydroxy-2,4-diaminopyridmidine and 4 g (0.1 moles) of sodium hydroxide are dissolved in 35 ml of water, and 1 5.4 ml (0.12 moles) of phenylsulfonyl chloride are dissolved in 50 ml of acetone. Both solutions are added dropwise, at room temperature, to 20 ml of acetone filled into a 250 ml three-necked flask equipped with a stirrer. After 3 hours of stirring the reaction mixture is diluted with 210 ml of water, and the pH of the mixture is adjusted to 9 with 10% aqueous sodium hydroxide solution; The separated substance is filtered off. 20.25 g (75.6%) of 6 (phenylsulfonyloxy)-2,4-diaminopyrimidine are obtained; m.p.: 189-1 930C.
Thereafer one proceeds as described in Steps 2 and 3 of Example 1 to obtain the final compound.
Example 4
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide
Step 1:
Preparation of 6-(mesitylenesulfonyloxy)-2,4-diaminopyrimidine
6.3 g (0.05 moles) of 6-hydroxy-2,4-diaminopyrimidine and 2 g (0.05 moles) of sodium hydroxide are dissolved in 1 7.5 ml of water, and 12 g (0.055 moles) of mesitylenesulfonyl chloride (2,4,6-trimethylphenylsulfonyl chloride) are dissolved in 25 ml of acetone. Both solutions are added dropwise, at room temperature, to 10 ml of stirred acetone. After 3 hours of stirring the reaction mixture is diluted with 100 ml of water, and the pH of the mixture is adjusted to 9 with 10% aqueous sodium hydroxide solution. The separated substance is filtered off. 11.35 g (73.6%) of 6 (mesitylenesulfonyloxy)-2,4-diaminopyrimidine are obtained; m.p.: 183186 C.When recrystallized from 25-fold amount of ethanol, the melting point raises to 187-191 OC.
Thereafter one proceeds as described in Steps 2 and 3 of Example 1 to obtain the final compound.
Example 5
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide Step 1:
Preparation of 2-imino-3-(3-chlorobenzoyloxy)-4-amino-6-(4-tolylsulfonyloxy)-pyrimidine 11.2 g (0.04 moles) of 6-tosyloxy-2,4-diaminopyridimine, prepared as described in Step 1 of
Example 1, and 8 g (0.04 moles) of 86% 3-chloroperbenzoic acid are suspended in 1000 ml of dichloromethane at room temperature, and the suspension is stirred and refluxed for 6 hours. The reaction mixture is washed with 35 ml of saturated aqueous sodium carbonate solution and then thrice with 25 ml of water, each, dried, and then evaporated until crystallization sets in.The crystal suspension is cooled, the crystals are filtered off and washed with cold dichloromethane. 6.8 g (46.2%) of pure 2-imino-3-(3-chlorobenzyloxy)-4-amino-6-(4-toluenesulfonyl-oxy)-pyrimidine are obtained: m.p.: 1 59-1 640 C.
Analysis:
calculated for C,8Ha5N405SCI (M=434.873):
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%
UV spectrum: Amt H=325 nm (log e=3.73) IR spectru mmKaBxr. =3430,1695, 1640, 1 575, 1385 cm~1.
The aqueous-alkaline wash obtained in processing the reaction mixture is extracted with ethyl acetate to obtain 2.64 g (22%) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide. This substance can be reacted with piperidine as described in Step 3 of Example 1 to obtain the final compound.
Step 2:
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide
130 ml of piperidine are introduced into a 500 ml flask equipped with a stirrer and a reflux condenser. The dry piperidine is cooled to O to 50C, and 21.7 g (0.05 moles) of 22imino-J-fJ- chlorobenzoyloxy)-4-amino-6-(4-tolylsulfonyloxy)-pyrimidine are added. The reaction mixture is stirred at O to 50C for 3 hours and then at 1 000C for additional 3 hours, thereafter piperidine is distilled off in vacuo. The recovered piperidine can be used again in the process of the invention. 80 ml of 5% aqueous sodium hydroxide solution are added to the residue, the mixture is stirred at room temperature for 0.5 hours, the separated crystals are filtered off and washed with water.The crystals are suspended in 50 ml of benzene, the suspension is stirred at room temperature for 0.5 hours, thereafter the crystals are filtered off and washed with benzene. 6.7 g (65%) of pure 6-piperidino-2,4-diaminopyrimidine-3oxide are obtained; m.p.: 264-2660C.
Example 6
Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide Step 1:
Preparation of 2-imino-3-(3-chlorobenzoyloxy)-4-amino-6-(4-tolylsulfonyloxy)-pyrimidine 15 g (0.05 moles) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide, prepared as described in Step 2 of Example 1, are dissolved in 1000 ml of acetone at room temperature, and a solution of 9.0 g (0.05 moles) of 3-chlorobenzoyl chloride in 50 ml of acetone are addled with stirring. The reaction mixture is stirred for 1.5 hours, and thereafter a solution of 5.25 g (0.052 moles) of triethylamine in 50 ml of acetone is added dropwise to the mixture. The mixture, warmed to about 300C is admixed with warm (300C) water until it gets slightly turbid (about 1300 ml of water are required), and then the mixture is cooled to 0--3 OC. The separated crystalline substance is filtered off, washed with a 1:1 mixture of acetone and water, and dried. 18.4 g (84.6%) of 2-imino-3-(3-chlorobenzoyloxy)-4-amino-6-(4tolylsulfonyloxy)-pyrimidine are obtained; m.p.: 1 55-1 580C.
Thereafter one proceeds as described in Step 2 of Exampe 5 to obtain the final compound.
Claims (14)
1. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula (I)
from 6-hydroxy-2,4-diaminopyrimidine of the formula (II),
wnerein
a) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula (V), R-S02-ha I (V) wherein R stands for a C14 alkyl group or a phenyl group optionally having up to three C14 alkyl substituents and hal represents halogen, the resulting sulfonate of the general formula (III),
wherein R is as defined above, is treated with an oxidizing agent in a protic solvent and the resulting Noxide of the general formula (IV),
wherein R is as defined above, is reacted directly with piperidine, or it is acylated first with a carbonyl halide of the general formula (Xl), R'-CO-ha I (Xl) wherein R' represents a C14 alkyl group or a phenyl group optionally with a halogen substituent and hal stands for halogen, and the resulting compound of the general formula (IX),
wherein R and R' are as defined above, is reacted with piperidine; or
b) 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula (V), wherein R and hal are as defined above, the resulting sulfonate of the general formula (III), wherein R is as defined above, is reacted in an aprotic solvent with a peracid of the general formula (X), R'-COOOH wherein R' is as defined above, and the resulting compound of the general formula (IX), wherein
R and R' are as defined above, is reacted with piperidine.
2. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula (I) from 6-hydroxy-2,4-diaminopyrimidine of the formula (II), wherein 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide of the general formula (V), wherein R stands for a C14 alkyl group or a phenyl group having optionally a C14 alkyl substituent, and hal represents halogen, the resulting compound of the general formula (III), wherein R is as defined above, is treated with an oxidizing agent, and the resulting compound of the general formula (IV), wherein R is as defined above, is reacted with piperidine.
3. A process as claimed in Claim 2, wherein 6-hydroxy-2,4-diaminopyridine is applied in the sulfonylation step without isolating it from the mixture obtained when reacting cyanoacetic ester with guanidine.
4. A process as claimed in claim 2, or claim 3, wherein p-tolylsulfonyl chloride is applied as sulfonyl halide of the general formula (V).
5. A process as claimed in claim 2, or claim 3 wherein that phenylsulfonyl chloride is applied as sulfonyl halide of the general formula (V).
6. A process as claimed in claim 2 or claim 3, wherein methylsulfonyl chloride is applied as sulfonyl halide of the general formula (V).
7. A process as claimed in any one of claims 1 to 6 wherein a percarboxylic acid is applied as oxidizing agent.
8. A process as claimed in Claim 7 wherein m-chioroperbenzoic acid is applied as percarboxylic acid.
9. A process as claimed in claim 1, wherein m-chloroperbenzoic acid is applied as percarboxylic acid of the general formula (X).
10. A process as claimed in claim 1, wherein m-chlorobenzoyl chloride is applied as carbonyl halide of the general formula (Xl).
11. A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide as claimed in claim 1 substantially as hereinbefore described in any one of the examples.
12. 6-piperidino-2,4-diaminopyrimidine-3-oxide when produced by a process as claimed in any one of the preceding claims.
13. A compound of the formula:
wherein R is a C14 alkyl group or a phenyl group optionally having up to three C14 alkyl substituents.
14. A compound of the formula:
wherein R is a C1--4 alkyl group or a phenyl group optionally having up to three C1--4 alkyl substituents.
New Claims or Amendments to Claims filed on 5 February 1 980.
New or Amended Claims: Claim 14 to be cancelled.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU78EE2594A HU177601B (en) | 1978-10-27 | 1978-10-27 | New process for preparing 6-piperidino-2,4-diamino-pyrimidine-3-oxide |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2032434A true GB2032434A (en) | 1980-05-08 |
GB2032434B GB2032434B (en) | 1982-11-17 |
Family
ID=10995794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7936681A Expired GB2032434B (en) | 1978-10-27 | 1979-10-23 | Process for the preparation of 6 - piperidino - 2,4 - diamino - pyrimidine - 3-oxide |
Country Status (14)
Country | Link |
---|---|
JP (1) | JPS5559172A (en) |
AT (1) | AT373246B (en) |
CH (1) | CH642365A5 (en) |
CS (1) | CS213398B2 (en) |
DE (1) | DE2943161A1 (en) |
DK (1) | DK454579A (en) |
ES (1) | ES485457A1 (en) |
FI (1) | FI793307A (en) |
GB (1) | GB2032434B (en) |
HU (1) | HU177601B (en) |
PL (1) | PL119712B1 (en) |
SE (1) | SE432596B (en) |
SU (1) | SU913942A3 (en) |
YU (1) | YU262579A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2518543A1 (en) * | 1981-07-15 | 1983-06-24 | Hoffmann La Roche | PROCESS FOR THE PREPARATION OF 6- (3,6-DIHYDRO-1 (2H) -PYRIDYL) -PYRIMIDINES 3-OXIDES |
EP0254158A2 (en) * | 1986-07-10 | 1988-01-27 | Richter Gedeon Vegyeszeti Gyar R.T. | Pyrimidin derivatives and process for their preparation |
FR2604707A1 (en) * | 1986-10-07 | 1988-04-08 | Farmos Oy | PROCESS FOR THE PREPARATION OF AN ACTIVE THERAPEUTIC COMPOUND |
EP0304649A1 (en) * | 1987-07-31 | 1989-03-01 | L'oreal | Salts of 6-piperidino-2,4-diaminopyrimidin-3-oxide and of derivatives of thiamorpholin-3-on-5-carboxylic acid, their cosmetical and medicinal use. |
EP0377437A1 (en) * | 1989-01-04 | 1990-07-11 | Lonza Ag | Process for the preparation of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide |
US4985563A (en) * | 1987-07-31 | 1991-01-15 | L'oreal | Process for the preparation of 6-piperidino-2,4-diamino pyrimidine-3-oxide |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH649291A5 (en) * | 1982-03-16 | 1985-05-15 | Hoffmann La Roche | DICARBAMATE. |
HU196067B (en) * | 1986-07-10 | 1988-09-28 | Richter Gedeon Vegyeszet | Process for production of 6-amin-1,2-dihydro-1-hydroxi-2-imino-4-piperidin-piramidin |
-
1978
- 1978-10-27 HU HU78EE2594A patent/HU177601B/en not_active IP Right Cessation
-
1979
- 1979-10-17 SE SE7908629A patent/SE432596B/en unknown
- 1979-10-23 GB GB7936681A patent/GB2032434B/en not_active Expired
- 1979-10-23 AT AT0689879A patent/AT373246B/en not_active IP Right Cessation
- 1979-10-24 FI FI793307A patent/FI793307A/en not_active Application Discontinuation
- 1979-10-25 CH CH958279A patent/CH642365A5/en not_active IP Right Cessation
- 1979-10-25 CS CS797272A patent/CS213398B2/en unknown
- 1979-10-25 DE DE19792943161 patent/DE2943161A1/en not_active Withdrawn
- 1979-10-25 SU SU792830754A patent/SU913942A3/en active
- 1979-10-26 ES ES485457A patent/ES485457A1/en not_active Expired
- 1979-10-26 PL PL1979219242A patent/PL119712B1/en unknown
- 1979-10-26 DK DK454579A patent/DK454579A/en not_active Application Discontinuation
- 1979-10-26 YU YU02625/79A patent/YU262579A/en unknown
- 1979-10-27 JP JP13829279A patent/JPS5559172A/en active Pending
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2518543A1 (en) * | 1981-07-15 | 1983-06-24 | Hoffmann La Roche | PROCESS FOR THE PREPARATION OF 6- (3,6-DIHYDRO-1 (2H) -PYRIDYL) -PYRIMIDINES 3-OXIDES |
US4549019A (en) * | 1981-07-15 | 1985-10-22 | Hoffmann-La Roche Inc. | Pyrimidinecarbamate derivatives as intermediates |
EP0254158A2 (en) * | 1986-07-10 | 1988-01-27 | Richter Gedeon Vegyeszeti Gyar R.T. | Pyrimidin derivatives and process for their preparation |
EP0254158A3 (en) * | 1986-07-10 | 1988-03-30 | Richter Gedeon Vegyeszeti Gyar R.T. | Pyrimidin derivatives and process for their preparation |
FR2604707A1 (en) * | 1986-10-07 | 1988-04-08 | Farmos Oy | PROCESS FOR THE PREPARATION OF AN ACTIVE THERAPEUTIC COMPOUND |
EP0270201A1 (en) * | 1986-10-07 | 1988-06-08 | Orion-Yhtymà Oy | A method for the preparation of a 2,4-diamino-3-oxy-pyrimidine derivative |
US4866174A (en) * | 1986-10-07 | 1989-09-12 | Farmos-Yhtyma Oy | Method for the preparation of a therapeutically active compound |
EP0304649A1 (en) * | 1987-07-31 | 1989-03-01 | L'oreal | Salts of 6-piperidino-2,4-diaminopyrimidin-3-oxide and of derivatives of thiamorpholin-3-on-5-carboxylic acid, their cosmetical and medicinal use. |
US4970063A (en) * | 1987-07-31 | 1990-11-13 | L'oreal | Salts of thiamorpholinone carboxylic acid with 2,4-diaminopyrimidine derivatives and their use in cosmetics and pharmaceuticals |
US4985563A (en) * | 1987-07-31 | 1991-01-15 | L'oreal | Process for the preparation of 6-piperidino-2,4-diamino pyrimidine-3-oxide |
EP0377437A1 (en) * | 1989-01-04 | 1990-07-11 | Lonza Ag | Process for the preparation of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide |
Also Published As
Publication number | Publication date |
---|---|
HU177601B (en) | 1981-11-28 |
CS213398B2 (en) | 1982-04-09 |
DE2943161A1 (en) | 1980-05-08 |
YU262579A (en) | 1983-01-21 |
SU913942A3 (en) | 1982-03-15 |
DK454579A (en) | 1980-04-28 |
SE432596B (en) | 1984-04-09 |
FI793307A (en) | 1980-04-28 |
CH642365A5 (en) | 1984-04-13 |
PL219242A1 (en) | 1980-06-16 |
PL119712B1 (en) | 1982-01-30 |
ATA689879A (en) | 1983-05-15 |
JPS5559172A (en) | 1980-05-02 |
SE7908629L (en) | 1980-04-28 |
GB2032434B (en) | 1982-11-17 |
ES485457A1 (en) | 1980-10-01 |
AT373246B (en) | 1983-12-27 |
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Legal Events
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PCNP | Patent ceased through non-payment of renewal fee |