JPH01125380A - Pyrido(1,2-a)pyrimidine ester compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A pyrido(1,2-a)pyrimidine ester compound shown by formula I (R<1> is H, halogen or methyl; R<2> is 1-4C straight-chain or branched alkyl; n is 0, 1 or 2). EXAMPLE:[9-(4-Acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2- a]pyrimidin-3-yl]acetic ethyl ester. USE:Useful as a synthetic intermediate for pyrido[1,2-a]pyrimidinecarboxylic acid compound having strong antagonism on slow-reacting substance of anaphylaxis and effective for treating allergic diseases. The titled compound itself is useful as an antiallergic agent. PREPARATION:A compound shown by formula II (X is Cl or Br) is condensed with 2,4-dihydroxy-3-n-propylacetophenone in the presence of an acid acceptor to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is directed to the following general formula The present invention relates to a pyrido1.2-a]pyrimidine ester compound (hereinafter simply referred to as "the compound of the present invention") represented by a branched alkyl group, and n represents Oll or 2, and a method for producing the same.

BACKGROUND OF THE INVENTION Compound [I] of the present invention was synthesized for the first time by the present inventors and is a novel compound not described in any known literature.

Problems to be Solved by the Invention The compound [I] of the present invention has a strong antagonistic effect against anaphylaxis-slow-reacting substances (hereinafter referred to as 5R3-A), and is useful for the treatment of type II allergic diseases caused by 5R3-A. It is a useful intermediate for producing a pit[1,2-a]pyrimidinecarboxylic acid compound represented by the following general formula [II] (wherein R1 and n have the same meanings as above), and is also a corresponding one itself. 5R3-A at almost the same level as carboxylic acid compounds
It has antagonistic effects and can be used as an antiallergic drug.

Means for Solving the Problems The compound of the present invention is a compound represented by the following general formula [I] (wherein R1, R2 and n have the same meanings as above, and X represents a chlorine atom or a bromine atom). and 1 to 6 times the molar amount of 2,4-dihydroxy-3-n-propylacetophenone in the presence of an acid acceptor.

Acid acceptors used include alkali metal carbonates such as sodium carbonate or potassium carbonate or alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. Note that potassium iodide may be present as a reaction accelerator.

Examples of the reaction solvent include acetone, methyl ethyl ketone, diethyl ketone, cyclohexanone, dimethyl formamide, dimethyl sulfoxide, or a mixture of two or more thereof. The reaction is 50~iio'
This is done by heating at c for 1 minute to 72 hours.

Note that the compound represented by the general formula [III] is a compound represented by the following general formula [IV] (the following is a blank space) (wherein R, R2, and n have the same meanings as above), by N-bromo Either by halogenating using succinimide or N-chlorosuccinimide, or by converting the compound represented by the following general formula [V] (wherein R, R2 and n have the same meanings as above) to thionyl chloride, phosphoryl chloride, Halogenation using a halogenating agent such as phosphoryl bromide, phosphorus trichloride or phosphorus tribromide, or ■ The following general formula rVI (hereinafter blank) (wherein R1, R2 and n have the same meanings as above) ) can be produced by halogenating the compound at the same time as ring closure using a mixture of phosphoryl chloride or phosphoryl bromide and polyphosphoric acid.

Action and Effect of the Invention The compound [I] of the present invention can be hydrolyzed with acid or alkali,
Then, by salt-forming treatment as necessary, a strong 5
It can be converted into pyrido[1,2-a]pyrimidinecarboxylic acid compound [II], which has R3-A antagonistic action and is useful for the treatment of type II allergic diseases caused by 5R3-A, and is also a good compound by itself. It was found in an in vitro (in VitrO) test that it exhibited 5R8-A antagonism.

The present invention will be further explained with examples.

Example 1 [9-bromomethyl-4-oxo-pyrido[1°2-a
]pyrimidin-3-yl]acetic acid ethyl ester 2.40
g (7.38 mmol), 2,4-dididroxy-3-
n-propylacetophenone 1.45 (j(7,47
mmol) and anhydrous potassium carbonate 1.507, methyl ethyl ketone 200m! ! The mixture was heated under reflux for 2 hours under stirring. Insoluble matter in the reaction solution was filtered off in cold water, the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. A fractionated solution containing the target product was collected and dried under reduced pressure. The obtained residue was recrystallized from monoethanol to give [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-
Pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester 2.309 (yield 70%) was obtained. The melting point was 134-135°C.

Infrared absorption spectrum <cm-', KBr): 1740
, 1685.1635 Elemental analysis value <C24H26N2 (as C6): Theoretical value (%:); C,65,74H,5,98N, 6.3
9 Actual value (%); C, 65, 63H, 6, 15N,
6.23[9-bromomethyl-4-oxo-pyrido[1
Almost the same as above except that 2.409 (7.38 mmol) of ゜2-a]pyrimidin-3-yl]acetic acid ethyl ester was changed to the corresponding compound [1] and the reaction molar ratio and reaction conditions were slightly changed. In the same manner, the following Examples 2 to 6
The compound was prepared.

Example 2 9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxorviride [1,2-
a] Pyrimidine-3-carboxylic acid ethyl ester.

White crystals; yield 2.38 g (yield 76%) melting point: 16
5-171°C (recrystallized with methyl ethyl ketone) Infrared absorption spectrum Ccm-1, KBI”): 17
35, 1680.1620 Elemental analysis value (as C23"24N2 C6): Theoretical value (%); C, 65,08F+, 5.70 N,
6.60 actual value (%); C, 65,34H, 5,98N
, 6.80 Example 3 [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-8-methyl-4-oxo-pyrido[1,2-a]pyrimidin-3-yl] Acetic acid ethyl ester.

White crystals; yield 1.37 g (yield 41%) melting point: 14
4-145℃ (recrystallized with ethanol) Infrared absorption spectrum <cm'', 8r): 1γ35.1685.163
5 Elemental analysis value (as C25H2BN2 C6): Theoretical value (%); C, 66,36H, 6,24N, 6.19
Actual value (%); C, 66, 53H, 6, 37N, 6
．． 39 Example 4 3-[9-(4-acedel-3-hydroxy-2-n
-propylphenoxymethyl)-4-oxo-pyrido [
1,2-a]pyrimidin-3-yl]pionic acid ethyl ester.

White crystals; yield 3.049. (Yield 91%) Melting point: 11
6-118°C (recrystallized with ethanol) Infrared absorption spectrum (cm”, KBr): 1730, 1680.163
0 Elemental analysis value (as C25H28N2 o6): Theoretical value (%); C, 66, 36H, 6, 24N, 6.19
Actual value (%); C, 66, 18H, 6, 13N, 6
．． 14 Example 5 3-[9-(4-acetyl-3-hydroxy-2-n
-propylphenoxymethyl)-7-bromo-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]propionic acid ethyl ester.

White crystals: yield 2.63 g (yield 67%) melting point: 15
3 to 155°C (recrystallized with methyl ethyl ketone) Infrared absorption spectrum Ccm-1, KBr): 174
0, 1680.1620 Elemental analysis value (as C25H27B r N206):
Theoretical value (%); C, 56, 51H, 5, 12N, 5
．． 27 Actual value (%); C, 56,69H, 5,24N,
5;32daishi■1 3- [7-(4-acetyl-3-hydroxy-2-n
-propylphenoxymethyl)-4-oxo-pyrido [
1,2-a]pyrimidin-3-yl]propionic acid ethyl ester.

White crystals: yield 2.109 (yield 63%) melting point: 15
7-159°C (recrystallized with ethanol) Infrared absorption spectrum (cm-1, KBr): 1720, 1670.
1620 Elemental analysis value (as C25H28N2 o6): Theoretical value (%); C, 66, 36H, 6, 24N, 6.19
Actual value (%); C, 66, 28H, 6, 33N, 6
．． 26 In addition, the following alternating compounds were also produced according to Example 1.

8-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,'2
-a] Pyrimidine-3-carboxylic acid ethyl ester.

9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-6-fluoro-4-oxo-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester; 9-(4- Acetyl-3-hydroxy-2-n-propylphenoxymethyl)-7-methyl-4-oxo-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester: [7-(4-acetyl-3- Hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2
-a]pyrimidin-3-yl]acetic acid ethyl ester; [7-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-8-chloro-4-oxo-pyrido[1,2-a] pyrimidin=3-yl]acetic acid ethyl ester.

Example 7 9-chloromethyl-4-oxo-pyrido [1°2-a]
Pyrimidine-3-carboxylic acid isopropyl ester2.
07 g (7,38 mmol>, 2,4-dihydroxy-3-n-propylacetophenone 1.45 (j (
7.47 mmol) and 1.50 g of anhydrous potassium carbonate
was heated to reflux with stirring in 200 d of methyl ethyl ketone for 2 hours. Cold welding, filtering out insoluble matter in this reaction solution,
The filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. A fractionated solution containing the target product was collected and dried under reduced pressure. The obtained residue was recrystallized from methyl ethyl ketone to give 9-(4-acetyl-3-
Hydroxy-2-n-propylphenoxymethyl)-4
-oxo-pyrido[1,2-a]pyrimidine-3-carboxylic acid isopropyl ester 1.81'j (yield 56
%) was obtained. The melting point was 130-140°C.

Infrared absorption spectrum <cm-1, KBr): 172
5, 1685.1620 Elemental analysis value (as C24H26N2 o6): Theoretical value (%); C, 65,74H, 5,98N, 6.39
Actual value (%); C, 65, 26H, 5, 79N, 6
．． 049-Chloromethyl-4-oxo-pyrido [1°2
2.07 g (7,38 mmol) of [9-bromomethyl-4-oxo-pyrido[1,2-a]pyrimidine-a]pyrimidine-3-carboxylic acid isopropyl ester
3-yl] acetic acid n-butyl ester 2.40'j (
The following compound of Example 8 was produced in substantially the same manner as described above, except that the reaction conditions were slightly changed.

Example 8 [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2
-a]pyrimidin-3-yl]acetic acid n-butyl ester.

White crystals; yield 2.79 g (yield 81%) melting point: 11
3-126°C (recrystallized with ethanol) Infrared absorption spectrum (cm”, KBr): 1730, 1680.162
0 Elemental analysis value (as C26H3ON2 o6): Theoretical value (%); C, 66,94H, 6,48N, 6.00
Actual value (%); C, 66, 50H, 6, 61N, 6
．． 23 Furthermore, the following compounds were also produced according to Example 7.

3-[9-(4-acetyl-3-hydroxy-2-n
-propylphenoxymethyl)-4-oxo-pyrido [
1,2-a]pyrimidin-3-yl]propionic acid methyl ester.

−1 et al. −

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom, a halogen atom, or a methyl group, and R^2 represents a linear or branched a pyrido[1,2-a]pyrimidine ester compound represented by (representing an alkyl group, n represents 0, 1 or 2). (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a hydrogen atom, a halogen atom, or a methyl group, and R^2 represents a linear or branched represents an alkyl group, X represents a chlorine atom or a bromine atom, and n represents 0, 1 or 2);
A general formula characterized by the condensation of 2,4-dihydroxy-3-n-propylacetophenone in the presence of an acid acceptor ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^ 2 and n have the same meanings as above.) A method for producing a pyrido[1,2-a]pyrimidine ester compound.