JPS6053032B2 - 6-Carbalkoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydropyrido[2,3-d] Method for producing pyrimidine and its salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 8-Ethyl 5-oxo 2-piperazinyl-5.8-
Dihydro[2.3-d]pyrido 6-pyrimidine carboxylic acid [I] is an antibacterial substance that is particularly active against Gram-negative bacteria, and is a drug particularly suitable for treating diseases of the urinary tract caused by these microorganisms. Useful.

According to French Patent No. 2194420, this acid is
Obtained by saponifying ester [■].

To produce the ester of [■], 6-carbetoxy 2
-Chlor8-ethyl5-oxo5●8-dihydro [2
●3-d] Pyridopyrimidine is a suitable starting material.

However, since this halogenated derivative has extremely high reactivity, it cannot be directly condensed with basic piperazine. This is because under the conditions normally used for this type of reaction, a large amount of N-N''-disubstituted piperazine is formed. This can be overcome by using a piperazine derivative blocked with a protecting group and condensing it with 6-carbethoxy2-chloro8-ethyl5-oxo5●8-dihydro[2.3-d]pyridopyrimidine. Must be removed later.

According to the aforementioned French patent, 1-formylpiperazine can be used.

However, such known methods have two technical drawbacks compared to direct condensation with piperazine.

(a) There is a need to produce 1-formyl piperazine.

This compound is obtained by reacting excess piperazine with a lower alkyl ester of formic acid, but the yield is only about 50%, and separation from basic piperazine is extremely difficult even with careful distillation. Have difficulty.

(b) The need for an extra step to deformylate the intermediate compound.

Although the yield is not bad in this operation, the synthesis time is longer and the final product is more expensive.
6-carbalkoxy 8-ethyl-5 represented by the above formula
-Oxo2-piperazinyl-5●8-dihydropyrido [2●3-d] In producing pyrimidine and its salts, 6-carboalkoxy-8-ethyl-2-
Halogeno 5-oxo 5,8-dihydropyride [
2●3-d] pyrimidine and 1.5 to 4 moles of a neutral salt of piperazine per mole of the 2-halogeno-pyrimidine compound in a dilute alcoholic medium to a pH of 2.7 to 3.6.
A method is provided, which is characterized in that the ester of the above formula is obtained in the form of a salt by reacting in the presence of a base holding the ester, and optionally liberating the ester by alkaline treatment.

The neutral salt of piperazine can be a strong inorganic acid salt such as dihydrochloride [■] or a salt of an organic acid. The alkyl group R can be, for example, a methyl, ethyl, propyl or butyl group, most preferably an ethyl group.

The main part of the reaction should be carried out at a pH of 2.7 to 3.6, which can be adjusted by gradual addition of the base.

When the reaction rate between pH 3.4 and pH 3.6 becomes extremely low, add base in excess of the total amount of base determined by the following reaction formula (R is shown as an ethyl group). This completes the operation. In the formula, B represents 1 mol of a monovalent organic or inorganic base or an equivalent amount of a polyvalent base.

In this case, the product is 6-carbethoxy8-ethyl 5
-oxo2-piperazinyl 5,8-dihydro [2●3
-d] Pyrido pyrimidine hydrochloride [■a],
If this is treated with an alkali, a free ester is isolated.

This reaction is preferably carried out from the beginning of the operation in a reaction medium consisting of a lower water-soluble alcohol diluted with a sufficient amount of water to keep the salt [■] and the chlorinated derivative [■] dissolved.

By lower alcohol is meant an alcohol having 1 to 4 carbon atoms. For example, an aqueous ethanol solution with a concentration of 50 to 70% (by volume) can be used. In a medium that satisfies these conditions, reagents [■] and [■] can be used at a concentration of 10 to 20%.

Base B may be an aqueous solution of a weakly basic inorganic reagent such as an alkali metal carbonate or bicarbonate. However, it is preferred to use an aqueous or alcoholic solution of a tertiary aliphatic base, such as trimethylamine or triethylamine.

A detailed study of this reaction revealed the following. That is, (1) the maximum pH value should not exceed 3.6 over the main part of this reaction.

(2) Although the formation of N-N'' monosubstituted piperazine cannot be prevented under the quantitative conditions determined by the above reaction formula,
The presence of a sufficient excess of dihydrochloride [■] can prevent little or no formation of such di-substituted derivatives.

For this purpose, 1 mol of 6-carbethoxy2-chloro8-ethyl5-oxo5,8-dihydro[2,3-d]pyridopyrimidine[
(2) It is preferable to use 1.5 to 4 mol, more preferably 2 to 3 mol, of piperazine hydrochloride.

(3) Whatever excess amount of piperazine dihydrochloride is used, a total of 2 moles of tertiary amine (or slightly more, e.g. 2.1 to 2.2 moles) is
It is best to use per mole of chlorinated derivative [■].

(4) In order to obtain a sufficient reaction rate, the temperature should be 40 to 60°C.
It is preferable to operate between

When using a tertiary amine such as triethylamine,
An additional benefit is that excess piperazine dihydrochloride can be recovered in yields close to 80%, and the recovered dihydrochloride can be recycled.

In a preferred embodiment of the invention, the reaction can be carried out as follows.

Piperazine dihydrochloride solution in dilute alcoholic medium (2
to 3 mol) at 50°C and continuously measure its pH value.

When 6-carbethoxy 2-chloro 8-ethyl 5-oxo 5,8-dihydro [2,3-d] pyrido pyrimidine (1-1 mol) is added thereto, the pyrimidine dissolves, but at this time the pH value decreases to approximately 2.4. Addition of a base solution brings this pH value back to 3.3. The pH value drops to 2.7, but it will return to 3.3. By repeating these operations, the upper limit PH will be 3.6.
Then, the lower limit PH gradually rises to 3.4. PH3.4
Once the reaction rate between , for example, halogenated derivative [■] 1
Additional base is added to give 2.2 moles of tertiary amine per mole and the reaction is allowed to proceed overnight at ambient temperature. Since the solution is usually cloudy, it is filtered if necessary and then concentrated to dryness. The residue is dissolved in a sufficient amount of methanol to dissolve the hydrochloride (■a), but the excess piperazine dihydrochloride (monohydrate) is insoluble in this solvent. With cold filtration, piperazine dihydrochloride (monohydrate) can be recovered in 75% to 85% yield, which can be recycled to subsequent steps. The methanolic mother liquor is concentrated to dryness.

This residue, consisting mainly of hydrochloride [■a] and triethyleamine hydrochloride, is dissolved in water. The solution is made alkaline by adding a neutral carbonate of an alkali metal, and the ester [■] is extracted with a suitable solvent such as chloroform. Evaporation of the solvent leaves virtually pure ester [■] in amounts with a yield of 80 to 95%. formula〔
The old ester can be saponified to acid [1] by the above-mentioned known method.

The following examples are included to illustrate the invention. However, it is not intended to limit the technical scope of the present invention.
Example Double calomel glass electrode (tested) connected to a stirrer, reflux condenser, thermometer, and pH meter! 250cI equipped with a binder for the introduction of alkaline reagents and alkaline reagents.
In a four-necked glass flask, add ethanol 160C71.
1 water 7 4 and monohydrate piperazine dihydrochloride 19y (
0.108 mol) were added one after another.

The mixture was stirred and heated to a temperature of 50°C. The temperature was maintained at this value and stirring was performed throughout the entire operation.
19g (0.036 mol) of 6-carbethoxy2-chlor8-ethyl5-oxo5,8-dihydro [2●3-
d] Pyrido pyrimidine was added.

After the present invention was dissolved, the initial pH (3.9) began to decrease rapidly and stabilized at pH 2.4. A 1.08N triethylamine solution was added in a biuret until the pH returned to 3.3. (Amount added: 5.3a1) When the pH decreased to 2.7, this operation was repeated until the reaction rate between these two upper and lower pH limits decreased considerably. In this way, the pH ranges from 3.4 to 2. P for song
H3.5 to 3.3, final pH 3.5 to 3
．． I continued adding while keeping it at 4. When approximately 90% (57 d) of the calculated amount of alkaline reagent is used (reaction time 7
time), the reaction rate between these two limits became extremely slow. (In other words, it takes about 1 to bring the pH to the lower limit.)
It took 3 solutions for the pH to return to the upper limit. ) In this way, the amount of triethylamine solution is such that the total amount of triethylamine is 2.2 mol per mole of halogenated derivative used (i.e. a total of 72 c!).
l) was added. The mixture was stirred at 50° C. for 1 hour and then left at room temperature overnight.

The solution (filtered if necessary) was concentrated to dryness under vacuum.

150 cI1 to dehumidify the residue as completely as possible
It was dissolved in ethanol and concentrated again to dryness. 40% residue
After dissolving in 0c7j of methanol and refluxing, the mixture was
It was stored at ℃ for 3 hours. Insoluble materials were separated by filtration. In this way, 10f (or 79% of the excess used) of piperazine dihydrochloride (monohydrate) was recovered. The bottom liquid was concentrated to dryness and the residue was dissolved in 200ml of water.

This solution (slightly cloudy) was filtered over animal charcoal and
Add 70a of Na2cO3 to make alkaline, then 70a
Chloroform extraction of 1 was performed 5 times. The organic phase was concentrated to dryness under vacuum. 6-carbethoxy8-ethyl 5-oxo2-piperazinyl 5,8-dihydro [2,3-d]
Pyridopyrimidine, melting point 153-154℃, 11y(
(with a yield of 93% based on the halogenated derivative used).

This ester (11y) was mixed with ethanol (100c!l
) and Ayu were stirred for 3 hours in a mixture of NaOH.

The clear solution was acidified with 6cr1 of acetic acid. After standing for 2 hours, the precipitate was dried without heating, washed with water (20a1x3 times), washed with ethanol, and dried at 110°C.

In this way, 9.6f of 8-ethyl 5-oxo-2-piperazinyl 5●8-dihydro [2.3-d] pyrido 6-pyrimidine carboxylic acid was obtained.

Claims (1)

[Claims] 1 6-Carbalkoxy-8-ethyl-5-oxo-2 of the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼
-piperazinyl-5,8-dihydropyrido [2,3-d
] In producing pyrimidine and its salts, per mole of 6-carbalkoxy-8-ethyl-2-halogeno-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine and the 2-halogeno-pyrimidine compound. 1.5~
The ester of the above formula is obtained in salt form by reaction with 4 mol of the neutral salt of piperazine in dilute alcoholic medium in the presence of a base which maintains its pH between 2.7 and 3.6, optionally. The method is characterized by liberating the ester through alkali treatment.