JPS5929595B2 - Production method of pyrimidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug that exhibits remarkable antibacterial properties, and which is an 8-substituted 2-piperazine 5-oxo 5 represented by the following formula.
・8-dihydropyrido[2.3-d]pyrimidine 6-
This invention relates to a new method for producing carboxylic acid (■a).

In the formula, R2 is a lower alkyl group having 1 to 5 carbon atoms.

The method of this invention consists of the following two steps: (a) Formula (1)
8-substituted 2-alkylsulfonyl-6-carboalkoxy (wherein R2 is as defined above, and R and R3 are the same or different and each represents a lower alkyl group having 1 to 5 carbon atoms) -5-oxo-5
・8-dihydropyrido[2,3-d]pyrimidine is reacted with piperazine to produce 8-monosubstituted 2-piperazino-6-carbalkoxy-5-oxo-5,8-dihydropyrido[2,3-d] of formula (). ] A step of obtaining pyrimidine;
(b) and the corresponding acid () by saponifying the ester ()
It consists of the step of obtaining a).

The starting material, 8-monosubstituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydropyrido[2-3-d]pyrimidine of formula (1), is due to the nucleophilic effect of its alkylsulfonyl group. 8-monosubstituted 2-piperazino-6-carbalkoxy-5-oxo-5,8-dihydropyrido[2.3-d]pyrimidine () generate.

The reaction is expressed by the following formula.

In the formula, R1, R, and R3 correspond to the above definitions.

When the ester () is saponified, it becomes the corresponding acid (a)
becomes.

This acid (a) has high value as an antibacterial agent in the treatment of infectious diseases caused by Gram-negative bacteria. This has already been described in French Patent No. 2,194,420 of August 2, 1972. The reaction of piperazine with sulfone (1) is carried out using an excess of piperazine over the sulfone, for example 2 moles of piperazine per mole of sulfone.

Furthermore, at least 1 mole of a basic agent such as a tertiary aliphatic amine may be present and the two reaction components may be used in equimolar ratios. The amount of solvent used is such that the concentration of the reaction components is 10-25%.

The piperazine derivative () can be isolated depending on its solubility characteristics by the general procedure described in the Examples below.

A particularly interesting embodiment of this invention is 6-carbethoxy-8
-ethyl-2-methylsulfonyl-5-oxo-5
・6-Carbethoxy=8-ethyl-5-oxo-12 by a simple reaction of 8-dihydropyrido[2.3-d]pyrimidine (V) and piperazine hexahydrate
-piperazinyl-5/8-dihydropyrido [2
- Direct preparation of 3-d]pyrimidine ().

Esters () are important intermediates for the preparation of the corresponding acids with excellent antibacterial properties.

Ester () is 6-carbethoxy-2-chloro-8-
It is known that it cannot be obtained directly by reacting ethyl-5-oxo-5,8-dihydropyrid[2,3-d]pyrimidine with piperazine under normal conditions. There is. In fact, the halogen atom is highly reactive, so the reaction is not sufficiently selective.
The main reaction product will be the N-N'-disubstituted piperazine derivative (a). Therefore, French Patent No. 21944
No. 20 states that in order to produce the ester (), an N-formylated piperazine derivative must first be synthesized. However, according to the present invention, by allowing methylsulfone (V) to act on piperazine hexahydrate,
It was found that the ester () could be obtained directly with excellent yield.

Preferably, this operation involves the presence of an excess (2-5 moles) of a tertiary aliphatic base such as triethylamine and an excess (1.5-2 moles) of piperazine relative to the sulfone (1 mole). It is better to use

The piperazine and tertiary base are dissolved in a lower aliphatic alcohol such as ethanol (concentration of reactants in solution is 10-20%), stirred and heated to reflux. There, 1 mole of sulfone (V) was added to dimethylformamide (hereinafter referred to as D.
M. F. A solution dissolved in 3 to 5 volumes of a suitable solvent such as ) is added dropwise over a period of about 1 hour. After the addition is complete, reflux is continued for an additional 30 minutes to 1 hour to complete the reaction. Evaporate the solvent under vacuum. The residue is dissolved in a dilute solution of an inorganic or strong organic acid (eg methanesulfonic acid). Separate the insoluble substances.

The sap is made alkaline by adding an alkali metal carbonate, and the reaction product is extracted with a suitable solvent such as chloroform. Evaporation of this solvent leaves the ester () as a residue. If this is recrystallized in benzene and purified, it can be obtained with a yield of about 80%. Pyrid [2・3
-d] It is known that the amination reaction at this position of the pyrimidine derivative nucleus can be realized by reacting an amine with a 2-methylmercapto or 2-chloro derivative.

There are many technological advances in the use of alkylsulfonyl derivatives according to the present invention. In fact, the reactivity of this alkylsulfonyl group is intermediate between that of alkylmercapto groups (the least reactive) and halogens (the most reactive).
Compared to 2-alkylmercapto derivatives, bealkylsulfonyl derivatives allow the amination reaction to be carried out at much lower temperatures and do not require pressurization.

Furthermore, the reaction using the former generates toxic mercaptans and gives off an unpleasant odor, whereas the reaction using the latter is odorless and far more beneficial from a pollution standpoint. 2-...
Compared to rogogen compounds, sulfonyl groups are much less mobile and therefore can be operated in a wider range of solvents.

Particularly in the case of complex reactions, the selectivity is high. The starting material is a new compound corresponding to general formula (1).
(In the formula, R1, R2 and R3 may be the same or different and each may represent a lower alkyl group having 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms.

) These starting compounds, for example, the corresponding 8-substituted 2
It can be obtained by oxidizing -alkylmercapto-6-carboalkoxy-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine ().

The oxidation of alkylmercapto groups to alkylsulfonyl groups by means of weak oxidizing agents such as potassium permanganate, potassium dichromate or hydrogen peroxide, such as 2-alkylmercapto-6
-Carbethoxy8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine (a) may be oxidized.

However, preference is given to using rogens, especially chlorine, which operate in an aqueous medium.

The reaction according to this method is shown by the following formula. This reaction is 0~
This can be carried out by passing chlorine gas through a vigorously stirred suspension of the 2-alkylmercapto derivative (2) at a temperature of 25°C.

The introduction of chlorine gas is such that the weight of the reaction mixture corresponds to 90-105% of the theoretical weight of halogen calculated according to the above reaction, i.e. 2 moles of halogen for 1 mole of alkylmercapto derivative (). Do it until you get it. Once this weight increase is obtained, stop the flow of halogen, and
Continue stirring the starting materials at a temperature of 5°C.

Although it varies depending on the conditions, the reaction time is about 10 minutes to 1 hour. After optionally diluting with water, the solid reaction product is dried without heating, washed in a suitable solvent and recrystallized.

During this oxidation it is necessary to avoid using excess halogen.

If an excess of halogen is used, by-products are likely to be produced, and there is a risk of reducing the yield, which is usually 80 to 90%. The evolution of the reaction depends on the nature of the medium.

That is, the reaction is slow in water. This is probably due to the extremely low solubility of the alkylmercapto derivative (H). Therefore, water-soluble organic solvents such as lower alcohols (among which methanol is preferred)
Alternatively, it is preferable to use a dilute aqueous solution of acetic acid. These solubilization aids can be used in concentrations varying from 5 to 50%. When the concentration of the auxiliary agent is above 20%, it is observed that during the oxidation reaction the alkylmercapto derivative dissolves clearly or temporarily. Lower concentrations (5-1
The progress of the reaction at 0%) is manifested by a change in the appearance of the solid substance in the suspension, which can be seen by sampling this solid substance during the course of the reaction and measuring its appropriate physical constants, such as melting point. Certification can be achieved by Instead of chlorine gas, other methods of liberating halogens into the reaction medium can also be used. For example, hypochlorite salts of alkali metals or hydrogen peroxide can act on the compound ( ) suspended in hydrochloric acid in the presence of solubilization aids. Next, in order to explain the present invention, examples will be described without limiting the technical scope.

Reference Example 6-Carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d]
Pyrimidine (in formula (1), R1-CH3, R2-
6-carbetoxy-18ethyl-2-methylmercabut-5-oxo5,8-dihydropyride [2. 3-d]pyrimidine 29
．． 37 (0.1 mono(c)) was vigorously stirred into a solution containing acetic acid (15c?) in water (285c?).

Chlorine gas was passed through the solution while maintaining a temperature of 10-15°C.

The flask and contents were weighed before introducing the chlorine gas, and the weighing was repeated at regular time intervals thereafter. Approximately 1
After an hour, when the weight had increased by 137 (theoretically 14.27 for 2 moles of chlorine gas), the chlorine gas flow was stopped and the mixture was stirred at 10° C. for 30 minutes.

After adding 100 cd of water, the precipitate was filtered, washed with water, then washed with ethanol (35 cr 11 x 2 times), and dried under vacuum to obtain 26.67 (yield 81.8%) of 6-carbetoxy. 18-ethyl-2methylsulfonyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine (melting point 176°C) was obtained.

A sample recrystallized from isopropanol also had the same melting point. Analysis Cl3H[5N305S (molecular weight -325.
27) Example 1 50cr! i 3.97 piperazine hexahydrate (0.02 mol) and triethylamine 2.027 in ethanol
(0.02 mol) was heated to reflux.

Reference example 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyride [2.
3-d] Pyrimidine 3257 (0.002 mol) in DM
Fl5cr! The solution in solution was added dropwise over a period of about 1 hour. The solvent was evaporated under vacuum and the residue was dissolved in 15N hydrochloric acid 2
I combed it to 0cri.

Insoluble substances were extracted and removed with chloroform. N in aqueous solution
It was made alkaline by adding a2cO3, and the reaction product was extracted with chloroform (10 cd x 5). The organic extracts were combined, decolorized by stirring with animal charcoal, and filtered. When the liquid was evaporated, 2.657 (yield 80%)
6-carbethoxy-8-ethyl-2-piperazino-5
-oxo-5,8-dihydropyrido[2,3-d]pyrimidine (melting point 156°C) remained.

Analysis Cl6Hl2N5O3 (molecular weight -331.37)
If this ester is saponified, it becomes the corresponding acid.

2.65 t of this ester was suspended in 30 cd of 75% ethanol, treated with INMa2CO322c#f, and the mixture was stirred at room temperature for 2.5 hours.

The solution was acidified with 1.26 c111 glacial acetic acid. After storing it in the refrigerator, the precipitate was filtered, washed with alcohol, and dried under vacuum.
Ethyl-2-piperazino-5-oxo-5 ・8-
Dihydropyrido[2.3-d]pyrimidine 6-carboxylic acid was obtained. Decomposition melting point 260-262°C (Kofler Prok) analysis C.

Claims (1)

[Claims] 1 8-substituted-2-piperazino-5 of formula (IIIa) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_2 represents a lower alkyl group having 1 to 5 carbon atoms.) -Oxo-5,8-dihydropyride [2,3-d pyrimidine-6-carboxylic acid] When producing 2,3-d pyrimidine-6-carboxylic acid, formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_2 is defined above 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-, and R_1 and R_3 are the same or different and each represents a lower alkyl group having 1 to 5 carbon atoms
Oxo-5,8-dihydropyrido[2,3-d]pyrimidine is reacted with piperazine to give formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ 8-Substituted 2-piperazino-6-carbalkoxy-5
- A process characterized in that oxo-5,8-dihydropyrido[2,3-d]pyrimidine is obtained and its ester (III) is saponified to obtain the corresponding acid (IIIa).