JPS58429B2 - Synquina 2-oxo-1,2,3,4-tetrahydropyride (2,3-D) Pyrimidine - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (wherein R1 is substituted with (1) a phenyl group, (2) a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group or a trifluoromethyl group) The phenyl group, R2 is (
1) hydrogen atom, (2) lower alkyl group, (3) halogen atom, lower cycloalkyl group, hydroxyl group, alkoxy group,
A novel 2-oxo-1,2 represented by an acetoxy group, a phenyl group, a lower alkyl group substituted with an amino group, (4) alkenyl group, or (5) alkynyl group)
, 3,4-tetrahydropyrido[2<3-d]pyrimidine derivatives and acid addition salts thereof.

More specifically, a compound represented by the general formula (...) (wherein R1 and R2 have the same meanings as above) is added to a compound represented by the general formula (I[D (Y means a halogen atom, trihaloalkyl group, alkoxy group, aryloxy group, alkoxycarbonyloxy group, acyloxy group, or amino group) is reacted with a compound represented by the above general formula (1). The present invention relates to a method for producing a compound.

To explain R1 and R2 in the general formulas (I) and (II) in more detail, R1 is a phenyl group, a halogen atom such as chlorine, bromine, fluorine, or iodine, or a lower group such as methyl, ethyl, n-propyl, or isopropyl. alkyl group,
The lower alkyl group of R2 is a phenyl group substituted with one or two lower alkoxy groups such as methoxy, ethoxy, propoxy, nitro group, trifluoromethyl group, etc. at any position.The lower alkyl group of R2 is methyl, ethyl, n-propyl, isopropyl, n −
A lower alkyl group substituted with a lower alkyl group such as butyl isobutyl, n-pentyl, etc. is a lower alkyl group substituted with a halogen atom, a lower cycloalkyl group, a hydroxyl group, an alkoxy group, an acetoxy group, a phenyl group, or an amino group.
The alkenyl group represents allyl, 3-methylallyl, 3,3-dimethylallyl, etc., and the alkynyl group represents propargyl, etc.

Further, to explain X and Y in general formula (2) in more detail, the halogen atom of X is chlorine, bromine, etc., the alkoxy group is a lower alkoxy group such as methoxy or ethoxy, and the amino group is imidazolyl or triazolyl. represents a nitrogen-containing heterocyclic group such as

Further, the halogen atom and alkoxy group of Y have the same meaning as that of X, the trihaloalkyl group is a methyl group substituted with a halogen atom such as chlorine or bromine, and the alkoxycarbonyloxy group is methoxycarbonyloxy, ethoxycarbonyloxy, etc. The acyloxy group is an acyloxy group such as acetoxy or trihalogenoacetoxy, and the amino group is a secondary lower alkylamino group (e.g., dimethylamino, diethylamino, etc.) or a nitrogen-containing heterocyclic group (e.g., imidazole, 1°2,3-triazole, etc.).

The compound of general formula (II) which is the starting material of the present invention is 2-
It is obtained by reducing an aminonicotinamide derivative with lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, or the like.

The reaction formula of the present invention is as follows.

The present invention uses diglyme, tetrahydrofuran, dioxane,
In organic solvents that do not participate in the reaction, such as benzene, toluene, xylene, dimethylformamide, ethyl alcohol, etc.
Metal compounds such as sodium amide, sodium hydride, sodium ethylate, pyridine, trimethylamino,
General formula (It) in the presence of an organic base such as triethylamino, an alkali metal salt of an organic acid such as sodium acetate or potassium acetate, or an inorganic base such as alkali hydroxide or alkali carbonate.
This is carried out by reacting a compound represented by () with a compound represented by (general).

In particular, when the above metal compounds are used, the target compound can be obtained in good yield.

In addition, when R2 is a hydrogen atom and N as a reaction reagent,
When N'-carbonyldiimidazole is used, the reaction proceeds even in the absence of a catalyst.

The reaction temperature is not particularly limited, but the reaction time will be shortened if the reaction is carried out at or near the boiling point of the commonly used solvent.

A pure product can be obtained from the reaction product by distilling off the solvent under reduced pressure and recrystallizing the residue from an organic solvent such as ether or methanol, or by separating and purifying it by column chromatography.

In the present invention, the compound thus obtained can be further treated with an inorganic acid salt (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or an organic acid salt (e.g., acetic acid, maleic acid, etc.) by a conventional pharmaceutically acceptable technique.
succinic acid, fumaric acid, etc.).

The compound obtained by the present invention is a new compound that has not been described in any literature, and has pharmacological activities such as remarkable analgesic action, anti-inflammatory action, and central nervous system depressing action, and is an industrially useful compound as a pharmaceutical.

The present invention will be explained in more detail with reference to Examples below.
Of course, the present invention is not limited to these.

Example 1 2-(m-toluidino)-3-aminomethylpyridine 4
．． After heating 3g and urea 12.9 at 180℃ for 2 hours, 200
The reaction was carried out by heating at ℃ for 30 hours.

After cooling, the reaction product was thoroughly washed with warm water, and the residue was recrystallized from methanol to obtain colorless prismatic crystals of 1-(m-)lyl).
-2-oxo-1,2,3,4-tetrahydropyride (
2,3-d) 2.6 g of pyrimidine were obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 212-214°C Elemental analysis value C14H1°N30 Theoretical value C near 0.87 H: 4.67 N: 17.71
Actual value C near 0.63 H: 4.59 N: 17.6
6 Example 2 2.8 g of 2-(m-bromoanilino)-3-ethylamine methylpyridine was added to 30 ml of dry tetrahydrofuran.
After dissolving the mixture, N,N'-carbonyldiimidazole was added and the mixture was reacted under reflux for 10 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with ether, the ether layer was dehydrated, adsorbed on a column packed with alumina, developed with ether, the eluate was distilled off, and the residue was extracted with ether. Recrystallization from a mixed solvent of petroleum ether gave colorless prismatic crystals of 1-(m-bromophenyl)-3-
2.2 g of ethyl-2-,t+so-1,2.3.4-tetrahydropyrido(2,3-d)pyrimidine were obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 108-110°C Elemental analysis value C05H14Br N30 Theoretical value C: 54.23 H: 4.24 N: 12.64
Actual value C: 54.48 H: 4.28 N: 12.54
Example 3 2.3 g of 2-(m-fluoroanilino)-3-methylaminomethylpyridine was added to 30 ml of dry tetrahydrofuran.
About 50% sodium hydride (0.96 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes.

Next, under ice-cooling, about 30% carbon tetrachloride-phosgene solution 10
g was added dropwise and stirred for 1 hour.

Next, after decomposing excess phosgene with a 10% acetone-ammonia solution, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with ether, dehydrated, adsorbed on a column packed with alumina, developed with ether, and eluted. When the liquid was concentrated and allowed to stand, 1.3 g of 1-(m-fluorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidine was obtained as colorless prism crystals. I got it.

The melting point and elemental analysis values of this substance were as follows.

Melting point 189-192°C Elemental analysis value C14H1□FN30 Theoretical value C: 65.36 H: 4.70 N: 16.33
Actual value C: 63.44-H: 4.72 N: 16
．． 39 Example 4 2-(m-trifluoromethylanilino)-3-ethylamine methylpyridine 2.4 g of diethyl carbonate was added dropwise to a mixture of 1.0 g of 2.0F1 sodium ethylate and 30 ml of dioxane while stirring.

After the dropwise addition, the mixture was reacted under reflux for 5 hours.

After the reaction, dioxane was distilled off under reduced pressure and the residue was recrystallized from ether to give colorless prismatic crystals of 1-(m-trifluoromethylphenyl)-3-ethyl-2-oxo-1.
, 2.1 g of 2,3,4-tetrahydropyrido(2,3-d)pyrimidine was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 155-157°C Elemental analysis value C16H14F3N30 Theoretical value C: 59.81 H: 4.39 N: 13.07
Actual value C: 59.72 H: 4.29 N: 13.11
Example 5 After dissolving 2.1 g of 2-(m-toluidino)-3-aminomethylpyridine in 30 ml of tetrahydrofuran, 0.5 g of about 50% sodium hydride was added and stirred at room temperature for 30 minutes.

Next, 3.2 g of ethyl chlorocarbonate was added and reacted under reflux for 15 hours.

After the reaction, the solvent was distilled off under reduced pressure and the residue was recrystallized from methanol to obtain colorless prismatic crystals of 1-(m-tolyl)-
2-oxo-1,2,3,4-tetrahydropyride (2
, 3-d) 1.2 g of pyrimidine was obtained.

Melting point 212-214°C Example 6 A solution of 3.5 g of 2-(m-iodoanilino)-3-ethylamine methylpyridine and 15 ml of dry xylene was
, N-dimethylaminocarbamoyl chloride 1.6g
was added and reacted under reflux for 15 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure and water was added to the residue to form an oil.

This was extracted with chloroform, dehydrated, adsorbed on a column packed with silica gel, developed with chloroform, the solvent of the eluate was distilled off, and the residue was recrystallized from a mixed solvent of ether and petroleum ether to form colorless prism crystals. -(m-iodophenyl)-3-ethyl-2-oxo-1,2,3,4-
Tetrahydropyrido(2,3-d)pyrimidine 0.72
I got g.

The melting point and elemental analysis values of this substance were as follows.

Melting point 137-139°C Elemental analysis value C1, H14■N30 Theoretical value C: 47.51 H: 3.72 N: 11.08
Actual value C: 47.42 H: 3.68 N: 11.01
Example 7 After dissolving 3.3 g of 2-(m-iodoanilino)-3-aminomethylpyridine in 30 ml of dry tetrahydrofuran, 3.2 I of N,N'-carbonyldiimidazole was added and reacted under reflux for 12 hours.

After the reaction is complete, the solvent is distilled off under reduced pressure, the residue is dissolved in acetone, adsorbed on a column packed with alumina, developed with acetone, the eluate is concentrated, and when left to stand, colorless needle crystals of 1-(
m-iodophenyl)-2-oxo-1,2,3,4-
Tetrahydropyrido(2,3-d)pyrimidine 2.5g
I got it.

The melting point and elemental analysis values of this substance were as follows.

Melting point 175-177°C Elemental analysis value C13H1oIN30 Theoretical value C: 44.46 H: 2.87 N: 11.97
Actual measurement value C: 44.32 H: 2.78 N: 11
．． 88 Example 8 In place of 2-(m-trifluoromethylanilino)-3-ethylaminemethylpyridine in Example 4, 2-
(p-Fluoroanilino)-3-methylaminomethylpyridine was prepared in the same manner as in Example 4 using diethyl pyrocarbonate instead of diethyl carbonate to produce colorless needles of 1-(p-fluorophenyl pyridine). )-3-methyl-2
-oxo-1,2,3,4-tetrahydropyride (2,
3-d]pyrimidine was obtained.

Melting point 212-213°C Example 9 2-(3,4-dichloroanilino)-3-methylamine 2.5 g of methylpyridine was dissolved in 30 ml of dioxane, and 1.0 g of about 50% sodium hydride was added at room temperature. So 3
After stirring for 0 minutes, 2.4 g of diethyl carbonate was added, and the mixture was reacted under reflux for 4 hours.

After the reaction, the solvent was distilled off under reduced pressure and the residue was recrystallized from ether to give colorless needle-like crystals of 1-(3,4-dichlorophenyl)-3-methyl-2-oxo-1,2, 2.6 g of 3,4-tetrahydropyrido(2,3-d)pyrimidine was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 149-150°C Elemental analysis value C14H1□Cl2N30 Theoretical value C: 54.56 H: 3.59 N: 13.63
Actual measurement value C: 54.42 H: 3.51 N: 13
．． 58 Example 10 After dissolving 3.1 g of 102-(chloroanilino)-3-(2-ethoxyethyl)aminomethylpyridine in dioxane, approximately 50% sodium hydride Ig was added and the mixture was heated to 30% at room temperature.
Stir for a minute.

Next, 3.2 g of N,N'-carbonyldiimidazole was added and reacted for 1 hour at room temperature and for 5 hours under reflux.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with ether, dehydrated, adsorbed on a column packed with alumina, developed with ether, concentrated the eluate, and left to stand, resulting in colorless prism crystals. -(m-chlorophenyl)-3-(2
2.6 g of -ethoxyethyl)-2-oxo-1,2°3.4-tetrahydropyrido(2,3-d)pyrimidine was obtained.

The melting point and elemental analysis values of this substance were as follows.

Melting point 100-101°C Elemental analysis value C1□H18CIN30□ Theoretical value C: 61.54 H: 5.46 N: 12.66
Actual value C: 61.48 H: 5.43 N: 12.59
Examples 11-120 The compounds shown in the following table were synthesized according to the methods of Examples 1-10.

Claims (1)

Claims: (In the formula, R1 is (1) a phenyl group, (2) a phenyl group substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, or a trifluoromethyl group, and R2 is ( 1) hydrogen atom, (2) lower alkyl group, (3) lower alkyl group substituted with a halogen atom, lower cycloalkyl group, hydroxyl group, alkoxy group, acetoxy group, phenyl group or amino group, (4) alkenyl group, or (5) Means an alkynyl group) is a compound represented by the general formula (wherein, A novel 2-oxo compound represented by the general formula (wherein R1 and R2 have the same properties as above) is reacted with a compound represented by an oxy group, an acyloxy group, or an amino group. -1,2,3,4-tetrahydropyrido[2,3-d) A method for producing a pyrimidine derivative and an acid addition salt thereof.