JPH04217646A - Phenoxy derivative - Google Patents

Abstract

PURPOSE:To provide a new phenoxy derivative which is a synthetic intermediate for a pyrimidone derivative useful as a treating agent for peptic ulcer having gastric acid secretion suppressing action as well as digestive tract mucosa protecting action. CONSTITUTION:A compound of formula I [Y is group of formula II (R<1> and R<2> are 1-6C lower alkyl) or formula III (n is 1-3)], e.g. 4-[3-(1,3-dioxolan-2-yl) phenoxy-cis-2-butenylamine. The compound can be produced by reacting a phthalimide derivative of formula IV with hydrazine hydrate in a solvent (e.g. ethanol) at room temperature. A treating agent for peptic ulcer can be prepared in high efficiency by reacting the compound of formula I with a pyrimidone compound and reacting the product with piperidine e.g. under reducing condition.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to phenoxy derivatives for producing pyrimidone derivatives having an inhibitory effect on gastric acid secretion.

0002

[Prior Art] For example, cimetidine, ranitidine, famotidine, and roxatidine have been clinically used as peptic ulcer agents that have excellent gastric acid secretion suppressing effects based on their antagonism of histamine H2 receptors. There was a problem that peptic ulcers would recur if the drug was discontinued. In order to reduce such side effects (rebound phenomenon), pyrimidone derivatives having the following structure are known as peptic ulcer therapeutic agents that have both gastric acid secretion suppressing action and gastrointestinal mucosal protective action (Japanese Patent Application Laid-Open No. 1-149774). (Japanese Patent Application No. 1-125067).

0003

[Case 2]

0004

SUMMARY OF THE INVENTION The present invention provides a novel intermediate for efficiently producing the above-mentioned pyrimidone derivatives.

[0005]

[Means for Solving the Problems] As a result of diligent efforts to solve the above problems, the present inventors have developed a compound represented by the following general formula (I) as a new production intermediate.

[0006]

[Chemical formula 3]

[0007] was selected and the present invention was completed. The compound represented by formula (I) of the present invention is represented by the following formula (II)
Compound represented by

[0008]

[C4]

(wherein, X represents a nitroamino group, a methylthio group, a methoxy group, or a halogen atom) to produce a compound represented by the following general formula (III)

00
10]

[C5]

(wherein Y is as defined above), which is then converted into the above-mentioned pyrimidone derivative useful as a therapeutic agent for peptic ulcers by reductive condensation with a secondary amine such as piperidine. can do. In the compound represented by the general formula (I) of the present invention, the lower alkyl group may be linear or branched, and examples of the alkyl group include methyl group, ethyl group, n-propyl group, and isopropyl group. , n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, etc., and preferably ethyl group. n is preferably 1.

The compound represented by formula (I) of the present invention can be produced from known substances according to the scheme shown below (in the scheme, Y is as defined above, and compounds 1 and 2 are (described in Japanese Patent Application Laid-open No. 165348/1983).

[0013]

[C6]

[0014]

EFFECT OF THE INVENTION The present invention provides a novel intermediate for the production of pyrimidone derivatives, which are excellent therapeutic agents for peptic ulcers. By this method, the pimidone derivative can be produced efficiently at low cost.

[0015]

EXAMPLES The manufacturing method of the present invention will be explained in more detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto. Example 1 4-[3-(1,3-dioxolan-2-yl)phenoxy]-cis-2-butenylamine A) N-[
4-[3-(1,3-dioxolan-2-yl)phenoxy]-cis-2-butenyl]phthalimide 3-(
1,3-dioxolan-2-yl)phenol (33.
2 g, 0.2 mol) was dissolved in DMSO (200 ml), and 60% oily sodium hydride (8.0 g, 0.2 mol) was dissolved in DMSO (200 ml) and cooled.
2 mol) was added little by little. After further stirring at 50° C. for 30 minutes, 4-chloro-cis-2-butenyl phthalimide (49.6 g, 0.21 mol) was added while cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the separated oil was poured into 1500 ml of water and dissolved in ethyl acetate (250 ml).
1) was poured out three times. The combined organic layers were washed with saturated brine, dried, and the solvent was distilled off to give the title compound 62.1 (85
%)g was obtained.

NMR (δ, CDCl3): 3.
95-4.2 (4H, m), 4.3-4.5 (2H
, d), 4.8-4.9 (2H, d), 5.5
~6.2 (3H, m), 6.8 ~ 7.3 (4H,
m), 7.6-7.9 (4H, m). B) 4-[3-(1,3-dioxolan-2-yl)phenoxy]-cis-2-butenylamine N-[4-[3-(1,3-dioxolane-) obtained in A) of Example 1 2-yl)phenoxy]-cis-2-butenyl]phthalimide (62 g, 0.17 mol) was dissolved in ethanol (1000 ml) and hydrazine hydrate (
32 ml) was added thereto and stirred at room temperature for 18 hours. After the reaction was completed, the precipitated crystals were filtered by suction, and the crystals were washed with ethanol. The filtrate and washing liquid were combined and concentrated under reduced pressure, and the residue was filtered with silica gel.
Purification was performed using column chromatography to obtain 35.1 g (88%) of the title compound as a pale yellow oil.

NMR (δ, CDCl3): 3.3
~3.5 (2H, d), 3.9~4.2 (4H,
m), 4.5-4.8 (2H, d), 5.6-5
．． 9 (3H, m), 6.8-7.4 (4H, m). Example 2 4-(3-diethoxymethylphenoxy)-cis-
2-Butenylamine A) N-[4-(3-diethoxyphenoxy)-cis-2-butenyl]phthalimide Example 1 A) 3-(1,3-dioxolane-2-
The title compound was obtained as a pale yellow oil by the same procedure except that 3-diethoxymethylphenol was used instead of phenol.

NMR (δ, CDCl3): 1.
05-1.3 (6H, t), 3.35-3.7 (4H
, q), 4.3-4.5 (2H, d), 4.7
~4.9 (2H, d), 5.4 (1H, s),
5.5-6.0 (2H, m), 6.8-7.4 (
4H, m), 7.5 to 7.9 (4H, m). B) 4-(3-diethoxymethyl)phenoxy-c
is -2-butenylamine Using the raw material A) of Example 2, the same procedure as B) of Reference Example 1 was carried out to obtain the title compound.

NMR (δ, CDCl3): 1.
05-1.4 (6H, t), 1.5 (2H, s),
3.3-3.8 (6H, m), 4.5-4.7 (
2H, s), 5.4 (1H, s), 5.6~
5.8 (2H, t), 6.7-7.4 (4H, m
). Reference Example 1 5,6-dimethyl-2-[[4-(3-diethoxymethyl)phenoxy]-cis-2-butenylamino]-
4-(1H)-Pyrimidone Example 2 B) 4-(3-diethoxymethyl)phenoxy-cis-2-butenylamine (3.5 g, 0.5 g)
0132 mol) and 5,6-dimethyl-2-methylthio-4-(1H)-pyrimidone (Pharmaceutical Journal 1976, 9
Volume 6, No. 3, p. 384. ) (2.5 g, 0.0147 mol) in toluene (100
ml) and refluxed for 48 hours with stirring.

After the reaction was completed, the solvent was distilled off under reduced pressure, and the residual oil was purified by column chromatography to obtain 1.38 g (27.0%) of the title compound as a pale yellow oil. NMR (δ, CDCl3): 1.1-1
．． 4 (6H, t), 1.9 (3H, s), 2.
15 (3H, s), 3.3-3.8 (4H, m
), 3.9-4.2 (2H, m), 4.6-4.
8 (2H, d), 5.5-6.0 (3H, m),
6.4-6.8 (1H, b), 6.7-7.4 (
4H, m). Reference Example 2 5,6-dimethyl-2-[4-[3-(1-piperidinomethyl)phenoxy]-cis-2-butenylamino]-4-(1H)-pyrimidone 5,6-dimethyl produced in Reference Example 1 -2- [[4-(
3-diethoxymethyl)phenoxy]-cis-2-
butenylamino]-4-(1H)-pyrimidone (2.0
g) in toluene (80 ml), piperidine (1
．． 5 g) and formic acid (8 ml) were added and refluxed with stirring for 12 hours, during which time the water that separated was removed from the reaction vessel. After the reaction was completed, a 10% aqueous potassium carbonate solution was added to make the mixture alkaline, and the organic layer was washed with water, dried, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 1.51 g (76.5%) of the title compound as a pale yellow oil.

NMR (δ, CDCl3): 1.2
~1.7 (6H, m), 1.85 (3H, s),
2.1 (3H, s), 2.2-2.5 (4H, m
), 3.4 (2H, s), 3.9-4.2 (2
H, m), 4.5-4.8 (2H, d), 5.
5-6.0 (2H, m), 4.6-7.3 (4H,
m). Reference Example 3 5,6-dimethyl-2-[4-[3-(1,3-dioxolan-2-yl)phenoxy]-cis-2-butenylamino]-4-(1H)-pyrimidone B of Example 1 4-[3-(1,3-
dioxolan-2-yl)phenoxy]-cis-2
-butenylamine (2.35 g, 0.01 mol) and 5
, 6-dimethyl-2-nitroamine-4-(1H)-pyrimidone (produced using the method described in the reference example of JP-A-60-228465) (1.84 g, 0.01
mol) in pyridine (50 ml) and stirred
Refluxed for an hour. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The title compound was obtained as a brown oil. Yield 2.21g (62%).

NMR (δ, CDCl3): 1.9
(3H, s), 2.2 (3H, s), 3.
2-3.8 (4H, m), 3.8-4.1 (2H,
m), 4.4-4.6 (2H, d), 5.6-5
．． 8 (3H, m), 6.4-6.7 (1H, b)
, 6.7-7.4 (4H, m). Reference Example 4 5,6-dimethyl-2-[4-[3-(1-piperidinomethyl)phenoxy]-cis-2-butenylamino]-4-(1H)-pyrimidone hydrochloride 5, obtained in Reference Example 3 6-dimethyl-2-[4-[3-(
1,3-dioxolan-2-yl)phenoxy]-ci
Using s-2-butenylamine]-4-(1H)-pyrimidone (3.6 g, 0.01 mol), a pale yellow oil obtained by the same procedure as in Reference Example 2 was added to a pale yellow oil in n-butanol solvent. The reaction was carried out with equimolar amount of hydrochloric acid to obtain 1.0 g of the title compound as colorless crystals.

Melting point: 101-2°C (d) NMR (δ,
DMSO-d6): 0.9-1.15 (3H, d
), 1.4-2.0 (6H, m), 2.1 (3
H, s), 2.6-3.4 (4H, m), 3.
85-4.2 (2H, m), 4.25 (2H, s
), 4.1-4.9 (2H, m), 5.5-5.
9 (2H, m), 6.7-7.5 (4H, m). The pyrimidone derivative obtained in Reference Example 4 is known to be useful as a therapeutic agent for peptic ulcers (Japanese Patent Application Laid-open No. 1-1497).
No. 74), the usefulness of the production intermediate of the present invention is clear.

Claims (1)

[Claims] [Claim 1] A compound represented by the following general formula (I) [Formula 1]