JPS6044303B2 - Method for producing 2-cyclic amino-4-aminopyrimidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing bicyclic amino-4-aminopyrimidine derivatives.

More specifically, the present invention is directed to the general formula (1) [wherein R means a pyrrolidino group, a 3-hydroxypyrrolidino group, a 1-piperazinyl group, or a 4-acyl-1-piperazinyl group.

] and the general formula (■)
[In the formula, R1 and R2 are the same or different and mean a lower alkyl group.

] is reacted with a lower alkyl ester of alkoxymethylene cyanoacetic acid represented by the formula (■) in a lower alcohol in the presence of a base to form a compound of the general formula (■) [wherein R and R2 have the same meanings as defined above].

A bicyclic amino-4-amino-5-mono-alkoxycarbonylpyrimidine derivative represented by the above formula is prepared, and this is then hydrolyzed in the formula (■) [wherein R has the same meaning as defined above].

[In the formula (2), R has the same meaning as described above. This invention relates to a method for producing a bicyclic amino-4-aminopyrimidine derivative represented by . The object compound (■) of the present invention is useful as a synthetic intermediate for pharmaceuticals, veterinary drugs, etc.

For example, 8-monosubstituted-5,8-dihydro-2-'cyclic amino-5-oxopyride [2,3-
d] Pyrimidine-6-carboxylic acid derivative [Special Publication No. 42-2591, Special Publication No. 48-3727, Japanese Patent Publication No. 49-3
No. 6699]. First, as a method for producing 2-pyrrolidino-4-aminopyrimidine, the present inventors reacted N-amidinopyrrolidine sulfate with malic acid to produce 2-pyrrolidino-4-hydroxypyrimidine, and then converted this into 2-pyrrolidino-4-hydroxypyrimidine. - reported a method of amination after leading to chloropyrimidine [Che
n. Pharnl. Concave, 1426 (1971)].

However, this method not only requires the use of large amounts of concentrated sulfuric acid and phosphorus oxychloride, which are difficult to operate, but also requires high temperatures (1.
It is necessary to react at a temperature of 85 to 195° C. for a relatively long time (5 hours), and it cannot be said to be an excellent industrial production method for bicyclic amino-4-aminopyrimidine derivatives. On the other hand, there have been relatively many reports on the reaction between amidine derivatives (■) and ethoxymethylene cyanoacetic acid ethyl ester (hereinafter referred to as EMCA), and as shown in the reaction formula below, the product is an amino-ester type compound ( It is known that (2) or/and a cyano-hydroxy type compound (2) can be obtained.

[In the formula, R'' means a methyl group, mercapto group, alkylthio group, amino group or nitroamino group.

]To summarize the knowledge obtained from these reports, in the above reaction, depending on the type of substituent R'' of the amidine derivative (■) and the type of catalyst, the difference between the products (■) and (■)
It is suggested that the ratio of

In addition, the ratio of compound (■) and EMCA used has a significant effect on the yield of the product, and when 2 to 4 moles of compound (■) are used per mole of EMCA, the product (■) can be obtained with satisfactory yield. [Chen. P
harm. Bull. 1003 (1970)] However, to date, there has been no report on the reaction of EMCA with a guanidine derivative in which both hydrogen atoms of the amino group have been substituted.

Based on this state of the art, the present inventors have conducted various studies on the reaction between N-amidino cyclic amine (1) and alkoxymethylene cyanoacetic acid ester (■), and as a result, they have discovered two industrially advantageous compounds. A method for producing a cyclic amino-4-amino-5-alkoxycarbonylpyrimidine derivative (■) was discovered, and using this method, the reaction operation was simple,
Moreover, they discovered that the bicyclic amino-4-aminopyrimidine derivative (V) could be produced in good yield, and completed the present invention.

The reaction formula of the present invention is as follows.

[In the formula, R. R1 and R2 have the same meanings as defined above. ] In the first step, the lower alcohol compound (1) containing an appropriate amount of base is dissolved, and then the compound (■
) under mild conditions, and compound (■) can be obtained in good yield.

Note that the compound (■) obtained here has not been published in any literature. The ratio of compound (1) and compound (■) to be used is not particularly limited, but it is desirable to use the ratio of approximately 1:1.

Preferred examples of lower alcohols used as reaction solvents include methanol, ethanol, and isopropanol.

Examples of bases used as catalysts include sodium
Examples include sodium alkoxides such as methoxide, sodium ethoxide, and sodium isopropoxide, and inorganic bases such as sodium hydroxide and potassium hydroxide, but sodium alkoxides are particularly preferred.

The amount of base used is 0.2 to 1 per mole of compound (1).
You can choose within the mole range.

In order to prevent side reactions such as transesterification and obtain highly pure compound (■), a lower alcohol having an alkyl moiety equal to R2 of compound (■) is used as the reaction solvent, and the sodium salt of the alcohol is used as the reaction solvent. It is desirable to carry out the reaction as a catalyst. The reaction temperature is usually selected within the range of room temperature to 75°C, preferably room temperature to 45°C. It is preferable to add the compound (■) gradually in order to minimize the progress of side reactions, and the time required for addition is as follows:
Although it varies depending on the amount of preparation, for example, it takes 1 to 25 hours. The reaction time after the addition of compound (■) is usually 1 to 2 hours. Compound (1) can be used in the free state or in the form of an acid addition salt.

When used in the form of an acid addition salt, the compound (■) is neutralized in the reaction system with an equimolar amount of a base, preferably the same base used in the Wax catalyst, to form the free compound (1). It is better to react. Regarding the compound (■), it is convenient to use a lower alkyl ester of ethoxymethylene cyanoacetic acid, considering the ease of obtaining the raw material compound, the ease of synthesis, and the economy.

The hydrolysis reaction of compound (■) can be carried out in a conventional manner.

For example, after reacting with an aqueous solution of alkali hydroxide or alkali carbonate at 80 to 100 rpm for 1 to 5 hours,
When neutralized with acid, compound (■) will precipitate as crystals. When R in compound (■) is a 4-acyl-1-piperazinyl group, when the hydrolysis reaction is carried out under strong reaction conditions, the acyl group at the 4-position of the piperazine is also eliminated. The decarboxylation reaction of compound (■) is suitably carried out by heating compound (■) directly or in a high boiling point solvent such as diphenyl ether.

As the reaction temperature, a temperature around the melting point of the compound (■) is usually used. The reaction time is usually the time until foaming stops. The present invention will be explained in more detail with reference to Examples below.

Example 1 90 y of sodium ethoxide and 5 y of ethanol
00TrL1, and 180q of N-amidinopyrrolidine sulfate is added thereto at room temperature.

Next, 190 y of ethoxymethylene cyanoacetic acid ethyl ester was added in one drop while stirring at room temperature, and stirring was continued at the same temperature for 2 hours. After further reacting at 60 to 70°C for 1 hour, ethanol is distilled off. Add 1' of water to the residue, filter out the crystals, and recrystallize from ethanol to obtain 4-
Amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine 210y is obtained. Melting point 123-1250C Elemental analysis value Calculated value as CllHl6N4O2: C55.9lH6.83N23.72 Experimental value:
C56.2OH6.74N23.73 Example 2 200q of 4-amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine is added to 500ml of 5% aqueous sodium hydroxide solution and stirred at 100°C for 1 hour.

After cooling, the mixture is neutralized with dilute sulfuric acid, and the precipitated crystals are collected, washed with water, and dried to obtain 4-amino-5-carboxy-2-pyrrolidinopyrimidine 155y. Melting point 200-202℃ (decomposition)
Elemental analysis value C9Hl.

Calculated value as N4O2: C5l. 9lH5.8lN26
．． 9l experimental value: C5l. 75H6. O2N26.97 Example 3 10V of 4-amino-5-carboxy-2-pyrrolidinopyrimidine is suspended in 30f of diphenyl ether, and the mixture is heated and stirred at an internal temperature of 200 to 205°C for 5 minutes.

After cooling, n-hexane is added, the precipitated crystals are filtered out and dissolved in methanol, and after treatment with activated carbon, the methanol is distilled off.
When the residue is recrystallized from dilute ethanol, 4-amino-2-
Pyrrolidinopyrimidine 7.1y is obtained. Melting point 162~1
63°C Example 4 Sodium methoxide 82y was added to methanol 500ml
to which 100 y of 1-amidino-3-hydroxypyrrolidine sulfate is added.

Next, while keeping the internal temperature below 40°C, 1 part of ethoxymethylene cyanoacetic acid ethyl ester was added with stirring.
Add 05y in 3 parts. After heating under reflux for 4 minutes while stirring, methanol was distilled off under reduced pressure. Add 500TrL1 of 3% sodium hydroxide aqueous solution to the residue, and
1. While distilling off residual methanol over a boiling water bath. Heat and stir for an hour. Neutralize with acetic acid while cooling on ice, leave to stand overnight, and filter out the crystals. When washed with methanol and then ethanol, 4
-Amino-5-carboxy 2-(3-hydroxypyrrolidino)pyrimidine 100y is obtained. When recrystallized from dimethylformamide water, it exhibits a melting point of 202-204°C (decomposed). Calculated value as elemental analysis value C9Hl2O3・113H20: C46.95H5.56N24.34 Experimental value: C46.93H5.73N24. IO Example 54-
Amino-5-carboxy 2-(3-hydroxypyrrolidino)pyrimidine 60y was added on an oil bath (bath temperature 200-210
Heat at 5°C.

The reaction mixture is dissolved in methanol, treated with activated carbon, and then methanol is distilled off. Add 150ml of acetone to the residue,
When the precipitated crystals are collected, 4-amino-2-(3-hydroxypyrrolidino)pyrimidine 37y is obtained. Melting point 170~
171) Calculated value as C elemental analysis value C8Hl2N4O: C53.32H6.7lN3l. O9 experimental value:
C53. l4H6.65N3O. 93 Example 6 2 at room temperature
8% (Wlw) Methanolic Sodium Methoxide 5
Add 30.0q of N-amidinopiperazine sulfate to 0mt and stir for 3 times.

Then, ethoxymethylene cyanoacetic acid ethyl ester 2
After adding 9.8y at room temperature for 3 C@, the mixture was stirred at the same temperature for 1 hour, and the mixture was further heated to reflux for 3 minutes. After distilling off methanol, add 60 mL of water and 7 mL of sodium hydroxide to the residue.
．． Add Oy and heat to 80-100° C. for 1 hour while stirring.

After cooling, it is neutralized with dilute sulfuric acid, and the precipitated crystals are taken off, washed with water, and dried to obtain 4-amino-5-carboxy 2-(1-piperazinyl)pyrimidine 28.4f. Melting point 283~2
Calculated value as 84LiC (decomposition) elemental analysis value C9Hl3N5O2: C48.42H5.87N3l. 38 experimental value:
C48.65H5.97N3l. 27 Example 7 8.0 y of 4-amino-5-carboxy-2-(1-piperazinyl)pyrimidine is heated over direct heat (inner temperature 220-290°C) for 5 minutes.

After completion of the reaction, the reaction mixture is treated in the same manner as in Example 5 to obtain 6.0y of 4-amino-2-(1-piperazinyl)pyrimidine.
When recrystallized from ethanol, the melting point is 214-216°C. Calculated value as elemental analysis value C8Hl3N5: C53.
6lH7.3lN39. O8 experimental value: C53.8lH7
．． 27N38.89 Example 8 0.85y of sodium was dissolved in 70ml of ethanol, and 8.1y of 4-acetyl-1-amidinopiperazine sulfate was added to this at room temperature.
Stir for a minute.

Then ethoxymethylene cyanoacetic acid ethyl ester 4.
After adding 4 pieces of 8q at room temperature, stirring was continued at the same temperature for 3 hours. After further reaction at 70 to 80°C for 2.5 A, ethanol is distilled off. Add water to the residue and extract with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, and then chloroform is distilled off to obtain 2-(4-acetyl-1-piperazinyl)-4-amino-5-ethoxycarbonylpyrimidine 6.0f.
When recrystallized from ethanol, it shows a melting point of 142-144°C. Calculated value as elemental analysis value Cl3Hl9N5O3: C
53.23H6.53N23.88 Experimental value: C53. l
4H6.64N23.89 Example 9 2.0y of 2-(4-acetyl-1-piperazinyl)-4-amino-5-ethoxycarbonylpyrimidine was added to 50ml of a 3.2% aqueous sodium carbonate solution and stirred at 100°C for 5 hours.

After cooling, the mixture was neutralized with acetic acid, left overnight, and the precipitated crystals were collected overnight to obtain 1.2y of 2-(4-acetyl-1-piperazinyl)-4-amino-5-carboxypyrimidine. When recrystallized from dimethylformamide, the heat of fusion is 249-25 rC.
(decomposition). Calculated value as elemental analysis value CllHl5N5O3: C49.8OH5.7ON26.4O Experimental value:
C49.69H5.7ON26.2l Example 102-(
4-acetyl-1-piperazinyl)-4-amino-5-
Directly heat carboxypyrimidine 8.0V (inner temperature 210~2
Heat at 70°C for 5 minutes.

After the reaction is completed, the same procedure as in Example 5 is carried out to obtain 2-(4-acetyl-1-piperazyl)-4-aminopyrimidine6.
Obtain 0V. When recrystallized from ethanol, the melting point is 214 ~
It shows 216°C. As elemental analysis value ClOHl5N5O

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. do. ] N-amidinocyclic amine represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_
2 means the same or different lower alkyl group. General formula ▲Mathematical formula, chemical formula,
There are tables, etc. ▼ [In the formula, R and R_2 mean the same thing as above. ] A method for producing a 2-cyclic amino-4-amino-5-alkoxycarbonylpyrimidine derivative. 2 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R means a pyrrolidino group, 3-hydroxypyrrolidino group, 1-piperazinyl group, or 4-acyl-1-piperazinyl group. ] N-amidinocyclic amine represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_
2 means the same or different lower alkyl group. ] is reacted with a lower alkyl ester of alkoxymethylene cyanoacetic acid in a lower alcohol in the presence of a base to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R and R_2 are the same as above. mean something ] This is a 2-cyclic amino-4-amino-5-alkoxycarbonylpyrimidine derivative represented by the formula, which is then hydrolyzed to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is the same as above. means. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R means the same as above. ] A method for producing a 2-cyclic amino-4-aminopyrimidine derivative.