KR800000737B1 - Process for preparing 2-oxo-1,2,3,4-tetrahydro-pyrido(2,3)pyrimidin derivatives - Google Patents

Abstract

Title compds. (I. R1 = pheny1, substituted pheny1; R2 = lower alky1, alkoxycarbony1, aralky1), useful as anaigesics and antiphlogistics, were prepd. by reaction of II and R2X1(X1 = halogen, = ulfonyloxy, ehter residus group), R2(OR2)2 (X2=carbony1,oxary1) or III(X3=diloweralkylamino, lower alkoxy; X4=H, lower alky1). Thus, 0.6 g sodium hydride was added to a mixt. of 3.0 g 1-(m-bromopheny1)- ! 2-oxo-1,2,3,4-tetrahydropyrido[2,3-d pyrimidine and 100 ml DMF and stirred for 30 min, following by addition of 3.5 g propagy1 bromide, and treated at room temp. for 1 hr to give I.

Description

Method for preparing 2-oxo-1,2,3,4-tetrahydropyrido [2,3-b] pyrimidine derivative

The present invention is represented by general formula [A]

2-oxo-1,2,3,4 represented by (wherein R represents a phenyl group and a substituted phenyl group, R 'represents a hydrogen atom, a lower alkyl group, a lower unsaturated alkyl group, a substituted lower alkyl group, a lower alkoxy carbonyl group and an aralkyl group) -Tetrahydro pyrido [2,3, -d] pyrimidine derivatives.

In the above general formula [A], when R and R 'are explained in more detail, R is a phenyl group, halogen atoms such as chlorine, cancellation, fluorine and oxo, lower alkyl groups such as methyl and ethyl, methoxy, ethoxy and the like. The lower alkoxy group, the nitro group, the trifluoromethyl group and the like represent a phenyl group substituted 1-2 at arbitrary positions.

R ′ is a lower alkyl group such as hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, halogen atom, hydroxyl group, lower alkoxy group, lower alkanoyl oxy group, lower cyclo Lower-unsaturated alkyl groups such as lower alkyl groups substituted by alkyl groups, carboxyl groups or amino groups, aryl, 3-methylaryl, 3,3-dimethylaryl and propalyl, aralkyl groups such as benzyl and phenethyl, and methoxycarbonyl And lower alkoxycarbonyl groups such as ethoxycarbonyl and propoxycarbonyl.

The compound obtained by the present invention is represented by the general formula [A].

These compounds are new compounds that have not yet been introduced in the literature, and have pharmacological effects such as anti-inflammatory, anti-ulcer, analgesic, antipyretic, anti-estamin and central nervous inhibitory effects. And it is a very useful compound industrially as medicines such as central nervous system inhibitors.

When the present invention is described in detail, the present invention is represented by the following reaction formulas [I] to [IV], and the target compound represented by the general formula [A] can be prepared by this reaction.

Wherein R ¹ is a phenyl group and a substituted phenyl group, R ² is a lower alkyl group, a lower unsaturated alkyl group, a substituted lower alkyl group, a lower alkoxy carbonyl group and an aralkyl group and X ¹ is a halogen atom, an organic sulfonyloxy group, an organic sulfonic acid ester residue, an inorganic acid ester Indicate residues.

As the compound represented by the general formula (2), for example, ethyl iodide, propargyl bromide, aryl bromide, 2,2,2-trifluoroethyl p-toluenesulfonate, dimethyl sulfide, dimethyl phosphate and the like Can be mentioned.

Here, R ¹ and R ² have the same meaning as electricity, and X ² represents a carbonyl group, oxaryl group, malonyl group, succinyl group, maleoyl group or fumaroyl group.

Moreover, as an example of the compound represented by General formula (4), diethyl carbonate, diethyl oxarate, diethyl malonate, dimethyl succinate, diethyl maleate, diethyl furalate, etc. are mentioned, for example.

Wherein R ¹ and R ² have the same meaning as electricity, X ³ represents a lower alkylamino group and a lower alkoxy group, and X ⁴ represents a hydrogen atom and a lower alkyl group.

Examples of the compound represented by the general formula (5) include, for example, N, N-dimethylformamide dimethylacetal, N, N-dimethylformamide diisopropylacetal, N, N-dimethylformamide ethylene acetal, and ethylol sorbent. Mate.

The reaction between the starting material represented by the general formula (1) and each reaction reagent is usually carried out in an organic solvent such as toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, diclime, chloroform or alcohol.

The reactions represented by the formulas [I] and [II] are preferably reacted in the presence of metal compounds such as potassium amide, sodium amide, sodium hydride and sodium etiratat, and inorganic bases such as alkali hydroxide and alkali carbonate. By using a metal compound, the target compound can be obtained in extremely good yield.

The reaction temperature is not particularly limited, either room temperature or heating. The reaction represented by Scheme [III] is completed by heating at reflux in an organic solvent such as chloroform, benzene, toluene, xylene or the like at 60 to 200 ° C. in a boron tube.

Where R ¹ and R ³ have the same meaning as electricity. In the reaction scheme [IV], however, the reaction is generally carried out by catalytic reduction with rani-nickel in an organic solvent such as tetrahydrofuran, alcohol or acetone. In the reaction schemes [I] to [IV], the reaction product can be obtained by distilling off the solvent under reduced pressure and recrystallization of the residue with an organic solvent such as ether, petroleum ether, chloroform, methanol, or by separating and purifying by column chromatography. have.

Next, the manufacturing method of the starting material represented by General formula (1) (9) is demonstrated.

The compound represented by the general formula (1) is obtained by reacting urea with 2-anilino-3-hydroxy methylpyrimidine derivative. The compound represented by the general formula (9) can be obtained by reacting phosphorus pentaemulsion with a pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione derivative.

By the above method, the electric starting material is obtained in good yield, but is not limited to this method alone. Moreover, the compound obtained by electroreaction formula [I]-[IV] can be made into addition salt with inorganic acid and organic acid again by a conventional technique. For example, hydrochloride, phosphate, sulfate, acetate, benzoate, lactate, succinate, citrate, tartarate, fumarate, malonate, maleate and the like.

The preparation of these salts, as well as being included in the present invention, can help to improve the solubility and stability of the compound obtained by using such salts.

2-oxo-1,2,3,4-tetra hydropyrido [2,3-d] pyrimidine derivatives, which are the target compounds of the present invention, are prepared, but their specific examples and melting points are shown in Table I below.

TABLE I

The compounds prepared according to the present invention were subjected to an acute toxicity test to confirm the stability, and the central nervous system inhibitory test, the anti-inflammatory test and the analgesic test were confirmed to have excellent effects in this test. .

Each test result is shown in Table II.

However, each test was performed by the following method.

(1) Acute toxicity test

The test compound was suspended in 0.5% tricant-physiological saline and administered to dd male mice (16-24 g) intraperitoneally or in case of lethal doses of animals that died after 72 hours.

(2) Anti-inflammatory effect

Five groups of wister male rats (100-150 g) were orally administered with a test compound suspended in 0.5% tragacanth-physiological saline and suspended in 0.5-1.0% carakenin-injected distilled water after 30 minutes. One was injected subcutaneously into 0.1 ml of the hindlimb vertebra and the edema after 3 hours was improved to obtain a inhibition rate for the comparative test.

Marked as.

(3) Analgesic effect

The test compound was suspended in 0.5% tragacanth-physiological saline solution and orally administered to dd male mice (18-20 g). After 1 hour, 0.1 ml / 10 g of 0.6% acetic acid-aqueous solution was administered intraperitoneally. After 30 minutes of administration, writhing syndrome was observed for 10 minutes and 50% analgesia and its 95% confidence limit were determined by the Litchfield-wilcoxon's method.

(4) Central nervous system depressive effect

The test compound was suspended in 0.5% tragacanth-physiological saline solution and administered to dd male mice (16-24 g) intraperitoneally, and the loss of cloves was observed in a quiet environment.

The dose at which cloves are lost is

Marked.

TABLE II

An example is as follows. This embodiment does not limit the method of the present invention.

Example 1

50% sodium hydride in a mixture of 3.0 g of 1- (m-bromophenyl) 2-oxo-1,2,3,4-tetrahydro pyrido [2,3-d] pyrimidine and 100 ml of dry dimethylformamide Add 0.6 g and stir for 30 minutes.

3.5 g of propargyl bromide was added thereto, the reaction was carried out at room temperature for 1 hour, the solvent was distilled off under reduced pressure, water was added to the residue, the mixture was diluted, and the free oil was extracted with ethyl ether. The ether layer was dehydrated with magnesium sulfate, adsorbed onto an alumina column, eluted with ether, and purified separately. 1- (m-bromophenyl) -3-propargyl-2-oxo-1,2,3,4 2.9 g of tetrahydropyrido [2,3-d] pyrimidine were obtained.

Melting point and elemental analysis of this material are as follows.

Melting point 118-119 ℃

Elemental Analysis C ₁₆ H ₁₂ ON ₃ Br

Theoretical C: 56.16 H: 3.54 N: 12.28

Found C: 56.01 H: 3.49 N: 12.24

Example 2

A mixture of 5 ml of 1- (m-profluoromethylphenyl) -2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine 0.7 with dimethylformamide was slowly added dropwise under ice-cooling. It was.

Immediately after dropping, the mixture was heated at 1,000 ° C. in jade for 1.5 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, and ice-water is added to the residue, followed by extraction with ether. The ether layer was washed with water, dehydrated, adsorbed onto a column packed with alumina, developed with ether, and concentrated in the solvent of the eluent. The colorless prism 1- (m-trifluoromethylphenyl) -3-methyl-2-oxo-1, 0.6 g of 2,3,4-tetrahydro pyrido [2,3-d] pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting point 122-124 ℃

Elemental Analysis C ₁₅ H ₁₂ F ₃ N ₃ O

Theoretical C: 58.63 H: 3.94 N: 13.68

Found C: 58.62 H: 3.89 N: 13.61

Example 3

1.2 g of 50% sodium hydride was added to a mixture of 50 ml of dry dimethylformamide of 4.5 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydro pyrido [2,3-d] pyrimidine, followed by room temperature The mixture was stirred for 30 minutes at, and the temperature was raised to 90-100 ° C. Then, 12.8 g of p-toluene sulfonic acid isopropyl ester was slowly added dropwise, and after 1 hour reaction, the solvent was distilled off under reduced pressure, and water was added to the residue to precipitate crystals. .

The filtrate was dissolved in ethyl ether, adsorbed onto a column packed with alumina, eluted with ethyl ether, and purified by separation. 1-phenyl-3-isopropyl-2-oxo-1,2,3,4-tetrahydro of colorless prism tablet 4.1 g of [2,3-d] pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting Point 164-165 ℃

Elemental Analysis C ₁₆ H ₁₇ N ₃ O

Theoretical C: 71.88 H: 6.41 N: 15.72

Found C: 71.75 H: 6.41 N: 15.72

Example 4

About 50% hydrogenation after dissolving 2.6 g of 1- (m-chlorophenyl) -2-oxo-1,2,3,4-tetrahydro pyrido [2,3-d] pyrimidine in 20 ml of dimethylformamide 0.6 g of sodium was added and stirred for 15 minutes.

Next, 3.4 g of methyl fluorosulfate was added thereto, followed by stirring at room temperature for 1.5 hours.

After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were extracted with ether, dehydrated, decanted into a column filled with alumina, developed into ether, and the solvent from the effluent was distilled off. Recrystallization with a mixed solvent afforded 2.1 g of scouring prism definition 1- (m-chlorophenyl) -3-methyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine. .

Melting point and elemental analysis of this material are as follows.

Melting point 139-140 ℃

Elemental Analysis C ₁₄ H ₁₂ CIN ₃ O

Theoretical C: 56.95 H: 4.10 N: 14.23

Found C: 56.89 H: 4.12 N: 14.25

Example 5

2.2 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine was dissolved in 20 ml of dimethylformamide, and 0.5 g of about 50% sodium hydride was added to room temperature. The mixture was allowed to stand for 30 minutes, and then 4.2 g of trimethyl phosphate was added dropwise and reacted at 170-180 ° C. for 7 hours in a tube. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was added with water to extract ether. After dehydration, the ether was distilled off and the residue was recrystallized from a mixed solvent of ether and petroleum ether to define colorless prism. 1.7 g of 1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting point 172-173 ℃

Elemental Analysis C ₁₄ H ₁₃ N ₃ O

Theoretical C: 70.27 H: 5.48 N: 17.56

Found C: 70.11 H: 5.38 N: 17.42

Example 6

A mixture of 10 g of 1- (m-trifluoromethylphenyl) -2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine 0.5 g dimethyl carbonate 0.8 g dimethylformamide Was heated at 160-170 ° C. for 20 hours in a tube.

After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with ether, dehydration, adsorption on a column packed with alumina, expansion with ether, and eluent concentrated and left to be 1- (m-trifluoro). 0.4 g of methylphenyl) -3-methyl-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting point 122-124 ℃

Elemental Analysis C ₁₅ H ₁₂ F ₃ N ₃ O

Theoretical C: 58.63 H: 3.93 N: 13.67

Found C: 58.52 H: 3.89 N: 13.62

Example 7

2.4 g of 1- (p-fluorophenyl) -2-oxo-1,2,3,4-tetrahydro pyrido [2,3-d] pyrimidine was dissolved in 15 g of dimethylformamide and dissolved in about 50% sodium hydride. When 0.5 g of hydrogen is stopped and hydrogen gas is stopped, 5.9 g of dimethyl hydroxide is added and reacted at 170 ° C. for 12 hours in a tube. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, ether extraction was carried out, and the solvent was concentrated after being left to dehydrate, leaving 1- (p-fluorophenyl) -3-methyl-2-oxo-1,2, 1.6 g of 3,4-tetrahydro pyrido [2,3-d] pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting Point 212-213 ° C

Elemental Analysis C ₁₄ H ₁₂ FN ₃ O

Theoretical C: 65.36 H: 4.70 N: 16.33

Found C: 65.21 H: 4.59 N: 16.24

Example 8

2.9 g of 1- (p-trifluoromethylphenyl) -2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine was diluted with 25 ml of dimethylformamide and dimethylformamide dimethyl acetal. 4.4g is reacted at 145-150 ° C for 5 hours. After completion of the reaction, the solvent is kept under pressure or water is added to the residue to extract it as ether, dehydrated and taken up in a packed column to develop ether, distill the solvent from the eluent and recrystallize the residue as ether as a mixed solvent of petroleum ether to define colorless prism 0.6 g of 1- (m-trifluoromethylphenyl) -3-ethyl-2-oxo-1,2,3,4-tetrahydro pyrido [2,3-d] pyrimidine was obtained.

Melting Point 155-157 ℃

Example 9

Activated rani-nickel (adjusted 10 g of Al-Ni) was added to 100 ml of methanol, and 1-phenyl-2-oxo-4-thio-1,2,3,4-tetrahydropyrido [2,3-d Pyrimidine 2.6 was added and reacted under reflux for 4 hours. After the reaction, Raani-Ni was filtered and the filtrate was distilled off under reduced pressure, and the residue was recrystallized as methanol, and 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d was obtained as a colorless needle. ]-1.6 g of pyrimidine was obtained.

Melting point and elemental analysis of this material are as follows.

Melting Point 269-271 ℃

Elemental Analysis C ₁₃ H ₁₁ N ₃ O

Theoretical C: 69.32 H: 4.92 N: 18.66

Found C: 69.18 H: 4.82 N: 18.71

Claims (1)

2-oxo-1,2,3,4-tetrahydropyrile represented by the following general formula (3) by reacting the following general formula (1) with the following general formula (2), (4) or (5) [2,3-d] method for preparing pyrimidine derivatives.

Wherein R ¹ is a phenyl group and a substituted phenyl group, R ² is a lower alkyl group, a lower unsaturated alkyl group, a substituted lower alkyl group, a lower alkoxy carbonyl group and an aralkyl group, X ¹ is a halogen atom organosulfonyl oxy group, an organic sulfonic acid ester residue and an inorganic acid Ester residue, X ² represents a carbonyl group, oxaryl group, malonyl group, succinyl group, maleoyl group and fumaroyl group, X ³ represents a lower alkylamino group and a lower alkoxy group, X ⁴ represents a hydrogen atom and a lower alkyl group .