CS213398B2 - Method of making the 6-piperidino-2,4-diaminopyrimidin-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 invention relates to a novel process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of the formula I

NH, tlí.

from 6-hydroxy-2,4-diaminopyrimidine of formula II.

OH. (II)

The compound of formula I exhibits excellent hypotensive effects.

Some procedures have been developed for the preparation of the compound of formula (i), but none of them provides economic; way; above; would be the desired product in an industrial change of the river.

According to one of these known methods (U.S. Pat. Nos. 3,382,247'and 3,461,461), 2,4-diamino-61-hydroxypyrintidine is reacted with phosphorus oxychloride to give 2,4-diamino-6-chloropyrimidine in 60% This compound is reacted with phenol or 2,4-dichlorophenol to form 2,4-diamino-phehoxypyrimidium. obtained at 40%. the yield is oxidized to the corresponding N-oxide with 21% yields and anakottecich; N-Oxide d-treated with piperidine, to give / yield; · For ^ duktr V-p & 31th. The reaction is carried out in a step (w) to obtain a yield. .45%. Total yield of the procedure, calculated? on. starting 2,4-diamino-6-hydroxy-roxypyr; ^: Nildin, is only 2 .When /; 2R3.%.

According to the method described in DOS No. 2144 887, the 2,4-α-α-6-chloro-6-chloro-pyrimidine, obtained from the corresponding 6-hydroxy compound in a yield of 63%, is oxidized directly to the N-oxide. -3 · -oxide ,; obtained in 45% yield, is reacted with piperidine to give the final product. Yield 89%: The total yield of this process, calculated on the starting 2,4-diamino-4-hydroxy-pyridine, still does not exceed 24%.

Both methods have the additional disadvantage of using 2,4-diamino-6-chloropyridinidine as an intermediate in the synthesis. This compound is prepared using chromium: 6-hydroxy ^; derivative, phosphorous oxy ciiloridem we .. i. кош- ⁵ nutrient substances, which must be used in large excess. The obtained 6-chloro compound is well soluble in water and organic solvents and therefore its separation and purification are quite difficult.

According to a further known method (U.S. Pat. No. 3,910,928), N- (2-cyanoacetyl) piperidine is converted to the corresponding methyl ether of formula VI,

this compound is treated with the cyanamide obtained from the dinitrile of formula VII

CN CN

is reacted with hydroxylamine and the resulting compound of formula VIII

The mixture is subjected to cyclization to give the desired compound of formula (I). žek ·. this. procedure; calculated: to the starting .K- (2-cyano.acetyl.) piperidine. .je ^; ; is not possible. for industrial scale production, since hardly available specific reactants (e.g., triethylethyloxonium fluoroborane) are required for the preparation of methyl ether of the formula VL A relatively large number of reaction steps is another disadvantage of the process.

The purpose of the invention is to provide a simple and economical process for the production of 6-piperidino-2,4-diaminopyrimidine-3-oxide in an industrial scale with few reaction steps.

The process of the invention is. is carried out by reacting the 6-hydroxy-2,4-diaminopyrimidine with the sulfonyl halide of the general formula V,

R = SO 2 - hal (V) wherein R represents a C 1-4 alkyl group or a phenyl group which optionally has up to three C 1-4 alkyl substituents and halo represents a halogen to the resulting sulfonate of the general formula III,

OSO2R (III) in which R is as defined above, is treated with an oxidizing agent in a protic solvent medium and the resulting N-oxide of formula (IV),

(IV). where. R. is as defined above, is reacted directly with piperidine, or is first acylated with a carbonyl halide of formula XI,

R‘ — CO — hal (XI) wherein R‘ represents a C 1-4 alkyl group or a phenyl group optionally having halogen as a substituent, and halo represents a halogen, and the resulting compound of the formula.

O-CHO-R ¹

OSO R (IX) wherein R and R R are as defined above is reacted with piperidine.

According to a preferred method, m-chloroperbenzoic acid is used as the percarboxylic acid of formula X and m-chlorobenzoyl chloride is the carbonyl halide of formula XI.

The 6-hydroxy-2,4-diaminopyrimidine used as the starting material for the process according to the invention can be prepared in a known manner by reacting a cyanacetic acid ester with guanidine [Org. Synth. Coll. Vol. 4, 245 (1963)].

In a preferred process of the invention, the 6-hydroxy-2,4-diaminopyrimidine is reacted directly, i.e. without isolating the compound of formula V with the sulfonyl halide of formula V to prepare the ester of formula III of formula III. from a cyanacetic acid ester and a guanidine as a one-step process. Compounds of formulas III and IV are novel compounds.

It is very surprising to the person skilled in the art that 6-hydroxy-2,4-diaminopyrimidine can be converted simply and almost quantitatively to its reactive ester derivative, since according to literature data (The Pyrimidines, Interscience Publ., 1962, p. 252) generally hydroxypyrimidines are difficult to acylate.

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

The process according to the invention is explained in detail in the examples, but these examples do not limit the scope of the invention.

Example 1

Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide

1st level:

preparation of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine

Method A:

g (0.5 mol) of 6-hydroxy-2,4-diaminopyrimidine are dissolved in 250 ml of 2.5 N aqueous sodium hydroxide solution and 120 g (0.62 mol) of p-tolylsulfonyl chloride are dissolved in 250 ml of acetone. they are added dropwise over 0.5 to 1 hour to 100 ml of acetone, which is filled with a two-liter flask equipped with a stirrer, and the solutions are added at room temperature with stirring and the dosing is adjusted to maintain the pH of the reaction mixture. 7. The mixture is stirred at room temperature for 3 hours, then 1000 ml of water are added and the precipitate is filtered off to give 134 g (95%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine. mp 179-181 ° C. Analysis for C 11 H 12 O 5 S (280.32):

calculated

% C, 47.13;% H, 4.312;% N, 19.99.

11.44% S;

found

% C, 47.56;% H, 4.617;% S 19.51;

11,60% S.

UV spectrum: A ™ ⁰ »= 275 nm = 3.92 logjj

IC spectrum: ν (KBr) = 3460, 1632, 1605, 1368, 1200 cm ^-1 .

Method B:

To a flask equipped with a stirrer and a reflux condenser was charged 23 g of sliced sodium metal and 370 ml of absolute ethanol was added. To the sodium ethoxide solution formed was added 48.5 g (0.51 mol) of dried guanidine hydrochloride powder and the mixture was refluxed for 1.5 hours, then allowed to cool to 25 ° C and 55 ml (25 ° C) was added to stir the mixture. 0.52 mol of ethyl cyanoacetate and the mixture is refluxed again for 2 hours, then 100 to 150 ml of ethanol are evaporated, the residue is mixed with 200 ml of water, and the aqueous ethanol is distilled off until the vapor temperature reaches 100 °. C. At this point, distillation is discontinued, the residue is cooled and water is added to a final volume of 330 ml.

The flask equipped with the stirrer was charged with 100 ml of acetone and the solution was added dropwise with stirring to acetone along with a solution of 99 g (0.52 mol) of p-tolylsulfonyl chloride in 250 ml of acetone. The dosing of the solutions is adjusted to maintain the pH of the reaction mixture at 7. The mixture is stirred at room temperature for 3 hours, then 1000 ml of water are added and the precipitate is filtered off. 125 g (85%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine of melting point 179-181 ° C are obtained.

Method C:

To a flask equipped with a stirrer and a reflux condenser was added 20 g (0.159 mol) of 6-hydroxy-2,4-diaminopyrimidine and 50 ml of absolute dimethylformamide, and 6 g (0.25 mol) of sodium hydride was added at room temperature. The mixture was heated to 100 ° C and stirred at this temperature for 2 hours, then cooled to 0 ° C and treated dropwise with a solution of 50 g (0.26 mol) of p-tolylsulfonyl chloride in 50 ml of dimethylformamide. The mixture is poured onto 400 g of ice and extracted 3 times with 200 ml of chloroform each. The chloroform solutions are combined and shaken with Ί00 ml of water, then precipitated. There was obtained 25 g (57%) of 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine, m.p. 179-181 ° C.

Step 2: Preparation of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide

To a 500 ml flask equipped with a magnetic stirrer and an external cooling bath (ice-water) was added 5.6 g (0.02 mol) of 6- (p-tolylsulfonyloxy) -2,4-diamino-pyrimidine, 200 ml. ethanol and 25 ml of water, cooled to 0-5 ° C, then a solution of 4.0 g (0.02 mol) of 86% m-chloroperbenzoic acid in 50 ml of cooled ethanol was added. When the reaction is complete (indicated by a sample that does not exclude iodine from the potassium iodide solution), the ethanol is evaporated under reduced pressure on a steam bath at a temperature of max. The solution is then extracted in several portions with 2% aqueous sodium hydroxide solution, and when the aqueous phase is slightly alkaline after extraction, the extraction is complete, the aqueous solutions are combined and extracted 4 times with 50 ml of ethyl acetate each time. m-chlorobenzoic acid can be regenerated from aqueous The ethyl acetate extracts are combined, dried and evaporated to a small volume, whereupon the product precipitates in crystalline form. The crystals were filtered off and washed with a small volume of ethyl acetate. 3.9 g (65%) of pure 6- (p-tolylsulfonyloxy) -2,4-diaminopyrimidine-3-oxide of melting point 125 DEG-130 DEG C. are decomposed.

Analysis for C11H12N4O4S:

calculated 4.08 O / o H, 18,91% 44,32% C, N, 10,8.2% WITH; found 44,32% C, 4.47% H, 18,59% N, 10.42% WITH.

UV spectrum: λ '° _χ ^Η = 285 nm, log log = 3.75,

IR (KBr) = 3420, 1650, 1620, 1400, 1380 cm @ -1.

Step 3: Preparation of 6-piperidino-2,4-diamino-pyrimidine-3-oxide

A 500 ml flask equipped with a stirrer and reflux condenser was charged with 140 ml plperidine. If the piperidine contains more than 0.5% water, an equivalent amount of phosphorus pentoxide, aluminum isopropoxide or butyllithium is added to remove the water, and 20 g (0.067 mol) of 6- (p-tolylsulfonyloxy) -2,4 -diamlnopyrimidine-3-oxide. The reaction mixture was stirred at 100 ° C for 2 hours and then the piperidine was distilled off under reduced pressure. The piperidine thus recovered can be used again in the process. The residue was diluted with 50 ml of 5% aqueous sodium hydroxide solution, stirred at room temperature for 0.5 hours, then the precipitated crystals were filtered off and washed with water. The crystalline solid is suspended in 50 ml of benzene, stirred at room temperature for 0.5 hours, then the solid is filtered off and washed with benzene. 7.7 g (55%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide of melting point 264 DEG-266 DEG C. are obtained.

Analysis for C 9 H 15 N 5 O: calculated

% C, 51.66;% H, 7.22;% N, 33.47;

ΠΗΐθΖθΩ O

% C, 51.80;% H, 7.00;% N, 33.42.

UV spectrum: Л ^ '° _а ^н = 232 nm [log £ = 4.54 • (A 286 nm) = 4.09 Loglo]

IC spectrum: ν = 3410, 3420, 3400, 3370, 3260, 1655, 1250, 1210, 1165, 1020 cm ^-1 .

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 mol) of 6-hydroxy-2,4-diaminopyrimidine, together with 4 g (0.1 mol) of sodium hydroxide, are dissolved in 35 ml of water and 9.3 ml (0.12 mol) of methylsulfonyl chloride are dissolved. Dissolve in 50 ml acetone. Both solutions are added dropwise at room temperature to 20 ml of acetone, which is filled with a 250 ml flask equipped with a stirrer. After stirring for 3 hours, the reaction mixture was diluted with 210 mL of water and the pH of the mixture was adjusted to 9 with 10% aqueous sodium hydroxide solution. The precipitate was filtered off to give 11.1 g (54.4%) of 6- (methylsulfonyloxy) -, 2,4-diaminopyrimidine, m.p. 176-180 ° C.

This intermediate was converted to the title compound by the reactions described in Steps 2 and 3 of Example 1.

Example 1 a d 3

Preparation of 6-Plperidino-2,4-diaminopyrimidine-3-oxide

Step 1: Preparation of 6- (phenylsulfonyloxy) -2,4-diaminopyrimidine

12.6 g (0.1 mol) of 6-hydroxy-2,4-diaminopyrimidine, together with 4 g (0.1 mol) of sodium hydroxide, are dissolved in 35 ml of water and 15.4 ml (0.12 mol) of phenylsulfonyl chloride are added. Dissolve in 50 ml acetone. Both solutions are added dropwise at room temperature to 20 ml of acetone, which is filled with a 250 ml three-necked flask equipped with a stirrer. After stirring for 3 hours, the reaction mixture was diluted with 210 mL of water and the pH of the mixture was adjusted to 9 with 10% aqueous sodium hydroxide solution. The precipitate was filtered off to give 20.25 g (75.6%) of 6- (phenylsulfonyloxy) -2,4-dlaminopyrimidine, m.p.

18 ° C.

Then proceed as described in

Of Steps 2 and 3 of Example 1 to give the title compound.

Example 4

Preparation of 6-piperidino-2,4-dlaminopyrimidine-3-oxide

Step 1: Preparation of 6- (lensulfonyloxy) -2,4-diaminopyrimidine mosque

6.3 g (0.05 mol) of 6-hydroxy-2,4-diaminopyrimidine, together with 2 g (0.05 mol) of sodium hydroxide, are dissolved in 17.5 ml of water and 12 g (0.055 mol) of mesitylenesulfonyl chloride (2, 4,6-trimethylphenylsulfonyl chloride) is dissolved in 25 ml of acetone. Both solutions were added dropwise at room temperature to 10 ml of acetone with stirring. After stirring for 3 hours, the reaction mixture was diluted with 100 mL of water and the pH of the mixture was adjusted to 9 with 10% aqueous sodium hydroxide solution. The precipitate was filtered off to give 11.35 g (73.6%) of 6- (mositylenesulfonyloxy) -2,4-diaminopyrimidine, m.p. 183-186 ° C. After recrystallization from a 25-fold amount of ethanol, the melting point was raised to 187-191 ° C.

Then proceed as described in

Of Steps 2 and 3 of Example 1 to give the title 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 mol) of 6-tosyloxy-2,4-diaminopyrimidine prepared as described in step 1 of Example 1 and 8 g (0.04 mol) of 86% 3-chloroperbenzoic acid are suspended in 1000 ml. of dichloromethane at room temperature and the suspension was stirred and refluxed for 6 hours. The reaction mixture is washed with 35 ml of saturated aqueous sodium carbonate solution and then with 3 times 25 ml of water each, dried and then evaporated until crystallization begins. The crystal suspension is cooled, the crystals are filtered off and washed with cooled dichloromethane. There was obtained 6.88 g (46.2%) of pure 2-imino-3- (3-chlorobenzoyloxy) -4-amino-6- (4-toluenesulfonyloxy) pyrimidine, m.p. 159-164 ° C.

Analysis calculated for C 13 H 15 N 4 O 5 SCl (434.873)

C 49.71, H 3.48, N 12.88, Cl 7.38, 8.15 Cl;

found

C 49.54, H 3.88, N 12.80, S 7.23, Cl 8.12.

UV spectrum: A ™ ¹¹ = 325 nm (= 3.73 Logs)

IR: 3430, 1695, 1640, 1575, 1385 cm @ ^-1 .

The aqueous-alkaline wash water obtained in working up the reaction mixture was extracted with ethyl acetate to give 2.64 g (22%) of 6-tosyloxy-2,4-diaminopyrimidine-3-oxide. This compound can be reacted with piperidine by the procedure described in Step 3 of Example 1 to give the title compound.

Step 2: Preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide

Into the flask volume. 500 ml equipped with a stirrer and a reflux condenser were poured into 130 ml of piperidine. The anhydrous piperidine was cooled to 0-5 ° C and 21.7 g (0.05 mol) of 2-immo-3- (3-chlorobenzoyloxy) -4-amino-6 '- (4-tolylsulfonyloxy) pyrimidine was added. The reaction mixture was stirred at 0-5 ° C for 3 hours and then at 100 ° C for an additional 3 hours, then the piperidine was distilled off under reduced pressure. The regenerated piperidine can be used again in the process of the invention. 80 ml of 5% aqueous sodium hydroxide are added to the residue, the mixture is stirred at room temperature for 0.5 hours, the precipitated crystals are filtered off and washed with water. Then, the crystals are suspended in 50 ml of benzene, the suspension is stirred at room temperature for 0.5 hours, then the crystals are filtered off and washed with benzene. 6.7 g (6.55%) of pure 6-piperidino-2,4-diaminopyrimidine-3-oxide having a melting point of 264 DEG-266 DEG C. are obtained.

Claims (9)

OBJECT OF THE INVENTION A process for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of formula I II) from 6-hydroxy-2,4-dimimopyrimidine of formula II, (II) characterized in that the 6-hydroxy-2,4-diaminopyrimidine of formula II is reacted with a sulfonyl halide of formula V, r-902-hal (Vj where R is a C _1-4 alkyl group or a phenyl group optionally having up to three C _1-4 alkyl substituents and hal denote halogen, the resulting sulfonate of formula III, wherein R (III) is as defined above, is treated with an oxidizing agent in a protic solvent medium and the resulting N-oxide of formula IV, O OSO.R (IV) wherein R is as defined above, is reacted directly with piperidine, or is first acylated with a carbonyl halide of formula XI, R '- CO - hal wherein R' represents a C _1-4 alkyl group or a phenyl group optionally having halogen as a substituent and hal represents a halogen, and the resulting compound of formula IX, CQ-O-R ¹ NH _Z OSO (IX) wherein R and R 'are as defined above is reacted with piperidine. 2. The method of item. 1 for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide of formula I from 6-hydroxy-2,4-diaminopyrimidine of formula II, characterized in that 6-hydroxy-2,4-diaminopyrimidine is reacted with a sulfonyl halide . wherein R is a C _1-4 alkyl group or a phenyl group optionally having a C _1-4 alkyl substituent and hal is a halogen, the resulting compound of formula III, wherein R is as defined above, is treated with an oxidizing agent and the compound of the formula of formula IV, wherein R is as defined above, is reacted with piperidine. 3. The process of claim 2, wherein 6-hydroxy-2,4-diaminopyrimidine is used in the sulfonylation step without isolation thereof from a mixture formed by reacting a cyanacetic acid ester with guanidine. 4. The process of claim 2 wherein the sulfonyl halide of formula (V) is p-tolylsulfonyl chloride. 5. The process of claim 2 wherein the sulfonyl halide of formula (V) is phenylsulfonyl chloride. , 6. The process of claim 2 wherein the sulfonyl halide of formula (V) is methylsulfonyl chloride. 7. The process of claim 2 wherein the oxidizing agent is a percarboxylic acid. 8. The process of claim 7, wherein the percarboxylic acid is m-chloroperbenzoic acid. 9. The process of claim 1 wherein the carbonyl halide of formula XI is m-chlorobenzoyl chloride.