KR800001685B1 - Process for preparing pyrido (2,3-d)pyrimidine derivatives - Google Patents

Abstract

Title compd. (I; R = pyrrolidino, 3-hydroxypyrrolidino, l-piperazinyl) was prepd. by 7 steps. N-amidinocyclic amino (II) was reacted with alkoxymethylene cyanoacetate(III) and then hydrolyzed and decarboxylated to give 2-cyclic amino-4-amino pyrimidine(IV). IV was reacted with alkoxymethylene malonate(v; R3 = lower alkyl)and then heated to give cyclic compd., which the H on 8-position was substituted by C2H5-followed by hydrolysis to give I.

Description

Method for preparing pyrido [2,3-d] pyrimidine derivatives

The present invention is a pyrido [2,3-d] pyrimidine derivative useful as an antimicrobial agent, represented by the following general structural formula (I), in detail 2-cyclic amino-8-ethyl-5,8-dihydro-5- A novel industrial process for the preparation of oxopyrido [2,3-d] pyrimidine-6-carboxylic acid.

In the above formula,

R is a pyrrolidino group, 3-hydroxypyrrino group, or 1-piperazinyl group.

According to the present invention, the N-amidinocyclic amine represented by the following general formula (II) and the alkoxy methylenecyano acetate ester of the general formula (III) are reacted in the presence of a base in the lower alcohol at about the same molar ratio. It is set as the 2-cyclic amino-4-amino-5-alkoxycarbonyl pyrimidine represented by (IV),

In the above formula,

R ′ means a pyrrolidino group, 3-hydroxypyrrolidino group, 1-piperazinyl group or 4-acyl-1-piperazinyl group,

R ₁ and R ₂ are the same or different and represent a lower alkyl group. A 2-cyclic amino-4-amino-5-carboxypyrimidine represented by Structural Formula (V) by hydrolysis of the compound of formula (IV), followed by decarboxylation to give 2-cyclic form of general formula (IV) N- (2-cyclic amino-4-pyrimidinyl) represented by the general formula (VIII) by reacting with amino-4-aminopyrimidine and again reacting this with an alkoxymethylene martonate represented by the general formula (VII) It is set as aminomethylene maronic acid ester.

In the above structural formula,

R ¹ is as described above,

R ³ and R ⁴ are the same or different and represent a lower alkyl group.

2-cyclic amino-5,8-dihydro-5oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ester represented by the general formula (IX) by heating and closing the compound of formula (VIII) And then reacted with an ethylating agent to yield 2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6- represented by the general formula (X). The compound represented by general formula (I) is manufactured by making it into carboxylic acid ester and hydrolyzing it.

Wherein R ¹ and R ₄ are as described above.

The method of the present invention is represented by the following scheme.

Wherein R, R ', R ₁ , R ₂ , R ₃ and R ₄ are as described above.

Regarding compounds in which R in the general formula (I) is a pyrrolidino group or a 1-piperazinyl group, the steps below the fifth step in the above reaction scheme have already been established by the present inventors (Japanese Patent Publication No. 47-12351). , Japanese Patent Application Laid-Open No. 49-87699, Japanese Patent Application Laid-Open No. 49-85093, and Japanese Patent Application Laid-Open No. 49-86396) and provided tablets are disclosed in these specifications.

Regarding the production method of the 2-cyclic amino-4-aminopyrimidine (IV) as the starting compound, N-amidino cyclic amine and malic acid are reacted to obtain 2-cyclic amino-4-hydroxypyrimidine. A method of amination after induction with 2-cyclicamino-4-chloropyrimidine has been reported by the inventors. Pharm. Bull. 19, 1429 (1971)].

In this method, however, a large amount of concentrated sulfuric acid and phosphorus oxychloride having difficulty in the reaction operation must be used, and in the amination of the final process, it is allowed to react for a relatively long time (5 hours) at high temperature (185-195 ° C) under pressure. There is a need and it is difficult to say that it is an excellent industrial production method of 2-cyclic amino-4-aminopyrimidine.

On the other hand, in the reaction between amidine derivative (IX) and ethoxymethylene ethyl cyanoacetate (hereinafter referred to as EMCA), there are relatively more reports than before, and as shown in the following reaction formula, amino-ester compound (XII) as a product And / or cyano-hydroxy compound (XIII) is known.

In the formula, R ″ means a methyl group, a mercapto group, an alkylthio group, an amino group or a nitroamino group.

Taken together, the knowledge from these reports suggests that the ratio of product (XII) and (XIII) is significantly different depending on the type of the substituent R ″ and the catalyst of the amidine derivative (XI). It is reported that the use ratio of compound (IX) and EMCA significantly affects the ratio of the product, and using 2-4 moles of compound (XI) with respect to the molar amount of EMCA results in a satisfactory yield. . pharm. Bull, 18, 1003 (1970)]

However, there have been no reports on the reaction between the guanidine derivatives in which both hydrogen of the amino group is substituted with EMCA.

Under the technical level, the present inventors have conducted various studies in the reaction between N-amidino cyclic amine (II) and alkoxymethylenecyano acetate (III), and industrially advantageous 2-cyclic amino-4. A method for preparing -amino-5-alkoxycarbonyl pyrimidine (VI) (first step) was established, and the reaction procedure was simplified and yielded more favorably using 2-cyclic amino-4-aminopyrimidine ( VI) to prepare a method (second step) to produce 2-cyclic amino-3-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6 -Industrially advantageous method for producing carbonic acid (I) is completed.

Each process is explained in full detail below.

[Step 1]

After dissolving N-amidino cyclic amine (II) in a lower alcohol containing an appropriate amount of base, the compound (II) was reacted under approximately the same molar amount of alkoxymethylenecyanoacetic acid ester (III) under moderate conditions. Cyclic amino-4-amino-5-alkoxycarbonylpyrimidine (VI) can be obtained in good yield. Furthermore, the compound (VI) obtained here is not described in the literature.

Examples of lower alcohols used as reaction solvents include methanol, ethanol, isopropanol and t-butanol.

Examples of the base used as a catalyst include nathrium alcoholates such as sodium thorium methylate, natrium ethylate, natrium isobutylate, and sodium t-butylate, or inorganic bases such as caustic soda and caustic. One is natrium alcoholate. The use amount of base can be selected within the range of 0.2-1 mole amount with respect to 1 mole amount of compound (II).

The reaction temperature can usually be selected within the range of room temperature -75 ° C, but a good one is room temperature-45 ° C. The addition of compound (III) is preferably carried out slowly in order to minimize the progress of side reactions.

The time required for addition depends on the amount added, for example 15 minutes-2 hours. The reaction time after addition of compound (III) is usually 1-2 hours. Compound (II) can be used in free form or in the form of acid addition salts. In the reaction system used in the form of acid addition salt, it is preferable to neutralize with the same molar amount of base, preferably the same as the base to be used as a catalyst, to make free compound (II), and then react with compound (III).

Regarding compound (II), it is convenient to use a lower alkyl ester of ethoxymethylenecyano acetic acid in consideration of easy obtaining of a raw material compound or ease of synthesis and economical efficiency.

[Step 2]

The 2-cyclic amino-4-amino-5-alkoxycarbonylpyrimidine (VI) obtained in the previous step is hydrolyzed to obtain 2-cyclic amino-4-amino-5-carboxypyrimidine (V). The present invention is usually carried out in an embodiment.

For example, compound (VI) is reacted with an aqueous solution of caustic alkali, such as caustic soda and caustic, or alkali carbonate, such as sodium carbonate and caric carbonate, at 80-100 ° C. for 1-5 hours and then neutralized with acid. This crystal is precipitated as In the formula (VI), in the case of the compound wherein R 'is a 4-acyl-1 piperazinyl group, the hydrolysis reaction under strong reaction conditions also removes the acyl groups at the 4-position of piperazine. It is preferable. In the formula (V), in the case of a compound in which R 'is a 3-hydroxypiperidino group or a 1-piperazinyl group, this step or the following step yields 2-cyclic amino-4-aminopyrimidine (VI). After induction, it is preferable to acylate under milder conditions to protect the 3-position of hydroxyl or the 4-position of piperazine of piperidine.

[Step 3]

The 2-cyclic amino-4-amino-5-carboxypyrimidine (V) obtained in the previous step is decarbonized to obtain 2-cyclic amino-4-aminopyrimidine (VI). The reaction is easily carried out by solventless compound (V) or by heating in a high boiling point solvent of biphenyl, diphenyl ether, diphenylphenoxide or a mixture thereof. As the reaction temperature, the temperature near the melting point of the compound (V) is usually used. The reaction time is usually the time until foaming stops.

[Step 4]

Reaction of 2-cyclic amino-4-aminopyrimidine (VI) and alkoxy methylenemaronic acid ester (VII) obtained in the previous step to produce N- (2-cyclic amino-4-pyrimidinyl) aminomethylene mate ester ( VIII).

The present reaction is carried out by heating the compound (VI) with the compound (VII) under an aqueous medium or in an inert solvent. Examples of the inert solvent include toluene, xylene, dimethylformamide, biphenyl, diphenyl ether, 0-chlorobenzene, diphenyl oxide, or a mixture thereof. The reaction temperature is usually 80-200 ° C.

[Step 5]

2-cyclic amino-5,8-dihydro-5-oxopyrido [2,3] by heating and ring-closing N- (2-cyclic amino-4-pyriminyl) aminomethylenemaronic acid ester (VIII) obtained in the previous step. -d] pyrimidine-6-carboxylic acid ester (IX). This reaction heats compound (VIII) in the absence of a solvent or in a high boiling point inert solvent. Examples of the inert solvent include biphenyl, diphenyl ether, 0-dichlorobenzene, diphenyl oxide, butyl futalate or a mixture thereof. Suitable reaction temperatures are 140-260 ° C.

This reaction can also be made to react in presence of acidic condensing agents, such as polyphosphoric acid, polyphosphoric acid ester, concentrated sulfuric acid, and phosphorus pentaoxide. In the case of using polyphosphoric acid, polyphosphate ester or phosphorus pentaoxide, the reaction is carried out in a solvent such as benzene, dioxane, dimethylformamide, and in a solvent such as acetic anhydride and acetic acid when a solvent such as concentrated sulfuric acid is used. In general, when the condensing agent is a liquid, it may also serve as a reaction solvent. In the case of using a condensing agent, the reaction is performed at a relatively low temperature.

[Step 6]

2-cyclic amino-5,8-dihydro-5-oxopyrido [2, -d] pyrimidine-6-carboxylic acid ester (IX) obtained in the previous step was reacted with an ethylating agent to yield an 8-ethyl compound ( X). Ethyl iodide, diethyl sulfate, ethyl P toluene sulfonate, etc. are mentioned as an ethylating agent. This reaction is carried out in usual embodiments. For example, in an inert solvent, the reaction is preferably carried out by acting a deoxidizing agent on the compound of the basic condensing agent. The inert solvent may be either anhydrous or hydrous. Examples include mannol, etherol, isopropanol, dioxane, acetone, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide and water. Examples of the basic condensing agent include alkali carbonate, caustic alkali, alkali metal alcoholate, sodium hydride and triethylamine. This reaction is carried out without heating, but if it is carried out under heating, the reaction proceeds more smoothly. The suitable reaction temperature in the case of using ethyl iodide is 50-100 degreeC, and the suitable reaction temperature in the case of using diethyl sulfate and ethyl P-toluene sulfonate is room temperature-75 degreeC.

When the ethylating agent is reacted in the aqueous solvent, the acyl moiety present in the alkoxycarbonyl group at the 6-position and / or the cyclic amino group at the position may undergo hydrolysis depending on the reaction conditions.

In the formula (IX), when R 'is 4-acyl-1-piperazinyl, when the acyl group at the 4-position of piperazine is released, this part is also ethylated, so that the acyl group is protected. It is preferable to carry out under.

[Step 7]

2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ester (X) obtained in the previous step was hydrolyzed to give the desired compound ( I) This reaction is carried out under normal working conditions. For example, compound (X) is heated to 70-100 ° C. in water or hydrous lower alcohol in the presence of an acid such as hydrochloric acid, sulfuric acid or a base such as caustic alkali or alkali carbonate. After completion of the reaction, the target compound (I) can be obtained by neutralization with acid as necessary. Further, in the formula (X), in the case of a compound in which R 'is a 4-acyl-1-piperazinyl group, it is preferable to react in the presence of a strong acid or a strong base. As mentioned above, although each process was described about reaction operation, the product of each process may be isolated and refine | purified for each process, and may be used for the next process as it is.

An Example and a reference example are given to the following, and this invention is demonstrated to it further more concretely.

Example 1

(a) 90 g of nathium ethylate is dissolved in 500 ml of etherol, to which 180 g of N-amidinopyrrolidine sulfate is added. Next, 190 g of ethyl ethoxymethylene cyanoacetate is added over 15 minutes while stirring at room temperature, and stirring is continued for 2 hours at the same temperature. After reacting at 60-70 ° C. for 1 hour, etherol is organic. To the residue was added 1 liter of water, the crystals were filtered off and recrystallized with ethanol to give 210 g of 4-amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine. Melting point 123-125 ° C.

(b) 200 g of 4-amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine thus obtained is added to 500 ml of 10% aqueous sodium hydroxide solution and stirred at 10 ° C for 1 hour. After cooling, the mixture was neutralized with dilute sulfuric acid and the precipitated crystals were collected by filtration, washed with water and dried to obtain 160 g of 4-amino-5-carboxy-2-pyrrolidinopyrimidine. Melting Point 200-202 ° C (Decomposition)

(c) 20 g of 4-amino-5-carboxy-2-pyrrolidinopyrimidine thus obtained is heated and stirred for 8 minutes in a direct burn (internal temperature 200-205 ° C). The reaction mixture is dissolved in ethanol, treated with activated carbon, and the ethanol is distilled off. The residue is recrystallized from dilute ethanol to give 14.2 g of 4-amino-2-pyrrolidino pyrimidine. Melting point 162-163 ° C.

(d) The mixture of 10.0 g of 4-amino-2-pyrrolidino pyrimidine obtained in this manner and 14.0 g of ethyl ethoxymethylene matonate is heated and stirred at 135-40 ° C. for 70 minutes. After cooling, the crystals are filtered off and recrystallized in n-hexane to give 16.7 g of ethyl N- (2-pyrrolidino-4-pyrimidinyl) aminomethylene matonate. Melting point 93-94 ° C.

(e) 120 g of ethyl N- (2-pyrrolidino-4-pyrimidinyl) aminomethylene matonate thus obtained is added to 50 ml of diphenyl ether and heated to an internal temperature of 244-246 ° C. for 20 minutes.

After cooling, the crystals are filtered off and washed with 50 ml of etherol to give 9.8 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbonate.

Melting Point 295-299 ℃

(f) 5.0 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid obtained as described above was diluted with 3.8 g of ethyl iodide together. It is added to a mixture of 26 ml of formamide and 10 ml of 20% aqueous carbonate solution, and heated and stirred at 9-95 ° C. for 4 hours. After the reaction, the product was distilled under reduced pressure, the residue was extracted with chloroform, dehydrated with forget-me-not, the chloroform was distilled off, and the residue was recrystallized with dilute etherol. , 3-d] 5.0 g of pyrimidine-6-carboxylic acid is obtained.

(Melting point 197-198 ° C.).

(g) 7% hydroxylated 5.0 g of 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopydo [2,3-d] pyrimidine-6-ethyl carbonate obtained in this manner It is added to 45 ml of aqueous sodium solution and heated and stirred at 90-100 ° C. for 90 minutes. After cooling with acetic acid, acidified and precipitated crystals were filtered off and washed with 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbon Obtain 4.3 g of acid.

Recrystallization with dimethylformamide gives a melting point of 314-316 ° C.

Example 2

(a) 20.0 g of 4-amino-5-carboxy-2-pyrrolidino pyrimidine obtained by reaction treatment in the same manner as in (a) and (b) of Example (1) was suspended in 60 ml of diphenyl ether, After stirring for 10 minutes at -205 ° C, the internal temperature was lowered to 155-160 ° C and 20.6 g of ethyl ethoxymethylene matonate was added to the reaction solution and stirred at this temperature for 90 minutes. Next, the secondary reaction temperature is raised to 244-246 占 폚 and 20 minutes of heating and stirring are continued. After cooling, the crystals are filtered off and washed with 70 ml of etherol to give 20.0 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbonate. Melting Point 295-299 ℃

(b) 28.8 g of carbonic carbonate was dissolved in 160 ml of 50% isopropanol, and the above 5,8-dihydro-2-pyridino-5-oxopyrido [2,3-d] pyrimidine-6 20.0 g of ethyl carbonate is added. While keeping the internal temperature at 60-65 ° C., 32.4 g of diethylsulfuric acid was added every third minute by 1/3 amount under stirring. After the addition, the stirring is continued at the same temperature. The reaction mixture is concentrated under reduced pressure to about half, ice-cooled and poured into 100 ml of ice water. The crystals were filtered off, dissolved in 100 ml of chloroform, the insolubles were filtered off, and the chloroform was distilled off. The residue was recrystallized in dilute etherol to give 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxo. 20.4 g of pyrido [2,3-d] pyrimidine-6-ethyl carbonate is obtained. Melting Point 197-198 ℃

(c) 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido obtained in this manner was used in Example 1 using ethyl pyrimidine-6-carboxylate. The reaction was carried out as in (g) to obtain 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Melting point 314-316 ℃

Example 3

(a) 82 g of sodium methylate are dissolved in 500 ml of menol and 100 g of 1-amidino-3-hydroxypyrrolidine sulfate is added. Then, the mixture was stirred while maintaining the internal temperature below 40 ° C, and 105 g of ethoxymethylene cyano acetate was added in three portions over 15 minutes. While refluxing, the mixture was heated to reflux for 40 minutes and then the methanol was distilled off under reduced pressure.

500 ml of 3% sodium hydroxide aqueous solution is added to the residue, and the mixture is heated and stirred for 1.5 hours while distilling off the remaining methanol on the boiling water. The crystals which are neutralized with acetic acid and precipitated on ice cooling are collected by filtration.

100 g of 4-amino-5-carboxy-2-3-hydroxy pyrrolidino) pyrimidine is obtained by washing with ethanol followed by ethanol. Recrystallization from dimethylformamide-water has a melting point of 202-204 ° C. (decomposition).

(b) 60 g of 4-amino-5-carboxy-2- (3-hydroxypyrrolidino) -pyrimidine thus obtained is heated and stirred in an oil bath phase (bathing temperature 200-210 ° C.) for 50 minutes. The reaction mixture is dissolved in methanol, and methanol is distilled off after treatment with activated carbon. 50 ml of acetone is added to the residue, and the precipitated crystals are filtered to obtain 37 g of 4-amino-2- (3-hydroxypyridino) pyrimidine. Melting Point 170-171 ℃

(c) 10.0 g of 4-amino-2- (3-hydroxypyridino) pyrimidine and 13.0 g of ethyl ethoxymethylene mate were added to 20 ml of dimethylformamide, and heated and stirred for 13 hours on an oil bath at 110 ° C. do. When hot, chloroform is added to the reaction solution to dissolve it and extracted with dilute hydrochloric acid.

The acidic aqueous solution was washed with ethanol to make ammonia alkaline, and the precipitated crystals were filtered, washed with water and dried and then recrystallized from ether-n-pentane to give N-2- (3-hydroxypyrrolidino) -4-pyrimidinylaminomethylene. 14.5 g of ethyl matonate is obtained. Melting Point 54.5-56.0 ℃

(d) 10.0 g of N-2- (3-hydroxypyrrolidino) -4-pyrimidinyl aminomethylenematonate ethyl thus obtained is dissolved in 35 ml of diphenyl ether, refluxed and heated and stirred for 1 hour. After cooling, methanol was added to filter the crystals and washed with methanol to remove 5,8-dihydro-2- (3-hydroxypyrrolidino) -5-oxopyrido [2,3-d] pyrimidine-6- 7.5 g of ethyl carbonate are obtained.

(e) 6% of 6.1 g of 5,8-dihydro-2- (3-hydroxypyrrolidino) -5-oxopyrido [2,3-d] pyrimidine-6-ethyl carbonate obtained in this manner It is suspended in 100 ml of sodium hydroxide aqueous solution, 11.4 g of diethyl sulfate is added thereto, and the mixture is heated and stirred at an internal temperature of 70 ° C. for about 4 hours. Treated with activated charcoal, the filtrate was acetic acid, and the precipitated crystals were filtered off, washed with ethanol and then washed with ethanol and recrystallized with dimethylformamide-ethanol to give 8-ethyl-5,8-dihydro-2- (3- 3.7 g of hydroxypyridino) -5-oxopyrido (2,3-d] pyrimidine-6-carboxylic acid is obtained.

Melting point 281-282 ° C. (decomposition).

Example 4

(a) 30.3 g of N-amidino piperazine sulfate is added to 50 ml of 28% (w / w) methanolic sodium methylate at room temperature and stirred for 30 minutes. Next, 29.8 g of ethyl ethoxymethylene cyanoacetate is added at room temperature over 30 minutes, then stirred at the same temperature for 1 hour, and further heated to reflux for 30 minutes. After the methanol was distilled off, 60 ml of water and 7.0 g of sodium hydroxide were added to the residue, and the mixture was heated to 80-100 ° C. for 1 hour under stirring. After cooling, the crystals neutralized with dilute sulfuric acid and precipitated are filtered off, washed with water and dried to obtain 28.4 g of 4-amino-5-carboxy-2- (1-piperazinyl) pyrimidine. Melting Point 283-284 ℃ (Decomposition)

(b) 25.0 g of 4-amino-5-carboxy-2- (1-piperazinyl) pyrimidine obtained in this manner are heated and stirred for 5 minutes at direct fire (internal temperature 220-290 ° C). After the reaction was completed, 18.8 g of 4-amino-2- (1-piperazinyl) pyrimidine was obtained in the same manner as in (b) of Example (3).

Recrystallization with ethanol has a melting point of 214-216 ° C.

(c) 18.0 g of the above 4-amino-2- (1-piperazinyl) pyrimidine is added to 80 ml of acetic anhydride while stirring under ice cooling. After 20 minutes, return to room temperature and continue stirring for 30 minutes. 500 ml of water was added to the reaction mixture, followed by shaking with chloroform, followed by separation of the water layer and concentration under reduced pressure. Acetone is added to the residue and the crystals are filtered off to obtain 20.8 g of 2- (4acetyl-1-piperazinyl) -4-aminopyrimidine. Recrystallization with ethanol has a melting point of 214-216 占 폚.

(d) 20.0 g of 2- (4-acetyl-1-piperazinyl) -4-aminopyrimidine obtained in this manner and 23.1 g of ethyl ethoxymethylene matonate were heated and stirred at 150-160 ° C. for 4.5 hours. After cooling, the precipitated crystals were filtered off and washed with n-hexane to obtain 30.4 g of ethyl N- [2 (4-acetyl-1-piperazinyl) -4-pyrimidinyl] amino methylene martonate. recrystallized with n-hexane to give a melting point of 119-121 ° C.

(e) 20.0 g of N- [2- (4-acetyl-1-piperazinyl) -4-pyrimidinyl] amino methylene matonate obtained in this manner was suspended in 160 ml of phenyletel, and fired (internal temperature 240- It is heated and stirred for 20 minutes at 250 ℃). After each n-hexane was added, the precipitated crystals were filtered off and washed with ethanol to give 2- (4-acetyl-1-piperazinyl) -5-dihydro-5-oxopyrido [2,3-d] pyrimidine- 14.3 g of 6-ethyl carbonate are obtained. Recrystallized from ethanol and has a melting point of 300-302 ° C (decomposition).

(f) 12.0 g of potassium carbonate was dissolved in 100 ml of 50% ethanol, and 2- (4-acetyl-1-piperazinyl-5,8-dihydro-5-oxopyrido [2,3-] was added thereto. d] 8.0 g of pyrimidine-6-ethyl carboxylate is suspended, and 12.8 g of diethyl sulfuric acid is added dropwise for 10 minutes while stirring at room temperature, and stirring is continued for 3 hours at room temperature, and then the reaction solution is chloroform. After extraction, dehydration with anhydrous forget-me-not, chloroform is distilled off, n-hexane is added to the residue, and the crystals are filtered off and recrystallized with n-hexane-acetone to give 2- (4-acetyl-1-piperazinyl)-. 7.0 g of 8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid is obtained.

Melting Point 208-210 ° C (Decomposition)

(g) 2- (4-acetyl-1-piperazinyl) -8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carbon thus obtained 5.0 g of ethyl acid is added to 120 ml of 10% aqueous sodium hydroxide solution, and the resulting mixture is heated and stirred for 1 hour in a 90-95 ° C water bath. Treated with activated charcoal and added acetic acid to the filtrate to adjust pH to 7.0 and precipitate the precipitated crystals. Recrystallization from dimethylformamide gave 3.5 g of 8-ethyl-5,8-dihydro-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Get Melting point 252-255 ℃

Example 5

(a) 10.0 g of 4-amino-5-carboxy-2- (1piperazinyl) pyrimidine obtained by reaction treatment in the same manner as in (a) of Example (4) is added to 40 ml of acetic anhydride while stirring under ice-cooling. After 10 minutes, return to room temperature and stir for 3 more hours. After the completion of the reaction, 200 ml of water was injected, the crystals were filtered off, and washed sequentially with methanol and ether, to obtain 9.3 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine. Recrystallization with dimethylformamide has a melting point of 249-251 ° C. (decomposition).

(b) 8.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine thus obtained is heated by direct heating (internal temperature 210-270 ° C.) for 4 minutes. After the reaction was completed, the same procedure as in (b) of Example (3) was performed to obtain 6.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-pyrimidine.

Recrystallization with ethanol, melting point 214-216 ℃

(c) using 2- (4-acetyl-1-piperazinyl) -4-aminopyrimidine thus obtained and reacting as in Example 4 (d)-(g) to give 8-ethyl-5, Obtain 8-dihydro-2- (1-piperazinyl) -5-oxopyrido (2,3-d] pyrimidine-6-carboxylic acid, melting point 253-255 ° C.

Example 6

(a) 0.85 g of natrium is dissolved in 70 ml of ethanol, and 8.1 g of 4-acetyl-1-amidinopiperazine sulfate is added thereto at room temperature, followed by stirring for 30 minutes. Next, 4.8 g of ethyl ethoxymethylene cyanoacetate is added at room temperature over 40 minutes, and then stirring is continued at the same temperature for 3 hours. After 2.5 hours of reaction at 70-80 ° C, ethanol is distilled off. To the residue was added, extracted with chloroform, washed with water, dehydrated with anhydrous forage, and chloroform was distilled off to give 6.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-ethoxycarbonylpyrimidine. Get Recrystallization with ethanol has a melting point of 142-144 ° C.

(b) 2.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-ethoxycarbonylpyrimidine thus obtained was added to 50 ml of an aqueous 3.2% sodium carbonate solution and heated to 100 ° C. for 5 hours, Stir. After cooling, the mixture was neutralized with acetic acid and filtered out to obtain 1.2 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine.

Recrystallization from dimethylformamide has a melting point of 249-251 ° C. (decomposition).

(c) Reaction treatment was carried out as in Example 5 (b) using 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine thus obtained to obtain 2- (4-acetyl -1-piperazinyl) -4-aminopyrimidine was obtained and then used in the same manner as in (d)-(g) of Example (4) to give 8-ethyl-5,8-dihydro-2 Obtain-(1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Melting point 253-255 ℃

[Reference Example]

35 g of 50% aqueous sulfuric acid solution is added to 110 g of piperazine 6 whiskers, heating is continued at 48-53 ° C under stirring, and 30 g of 50% cyanamide aqueous solution is added dropwise over about 45 minutes. After completion of the dropwise addition, the mixture is reacted at 50-55 ° C for 2 hours. Water was distilled off under reduced pressure, 100 ml of methanol was added to the residue, and the crystals were collected by filtration, washed with methanol and dried before obtaining 52 g of N-amidinopiperazine sulfate. Melting point 305 ° C. (decomposition). The reaction is likewise carried out to obtain another N-amidinocyclic amine sulfate.

Claims (1)

The N-amidino cyclic amine of the following formula (II) is reacted with the alkoxymethylenecyano acetate ester of the following formula (III) in the presence of a base in the presence of a base in the ratio of the animal amount, respectively, to obtain 2 Obtain cyclic amino-4-amino-5-alkoxycarbonyl pyrimidine and hydrolyze the compound to obtain 2-cyclic amino-4-amino-5-carboxypyrimidine of the following structural formula (V) A 2-cyclic amino-4-aminopyrimidine of formula (VI) is prepared and is reacted with an alkoxymethylene malonic acid ester of formula (VII) by a known method to form N- (2) of formula (VIII) Cyclic amino-4-pyrimidinyl) aminomethylenemalonic acid ester is obtained, and then cyclized by heating to form a cyclic 2-aminoamino-5,8-dihydro-5-oxopyrido [2,3] -d] pyrimidine-6-carboxylic acid ester is obtained, and this compound is then ethylated Reacted with the agent to obtain 2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ester of the following structural formula (X) To prepare 2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2.3-d] pyrimidine-6-carboxylic acid of the following formula (I).

In the above structural formula R is a pyrrolidino group, 3-hydroxypyrrolidino group or 1-piperazinyl group R ′ is a pyrrolidino group, 3-hydroxypyrrolidino group, 1-piperazinyl group or 4-acyl-piperazinyl group R ₁ and R ₂ are the same or different lower alkyl groups R ₂ and R ₄ are the same or different lower alkyl groups.