JP2590749B2 - Pyridyloxy derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula

Embedded image (In the formula, R ¹ is an N, N-dimethylamino group, an N, N-diethylamino group, a piperidino group, a pyrrolidino group, a 4-hydroxypiperidino group, a 3-methylpiperidino group,
2,3,6-tetrahydro-1-pyridyl group, 1-perhydroazepinyl group, morpholino group, thiomorpholino group or 4-methyl-1-piperazinyl group, R ² is a hydroxyl group,
It is a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and Y is an ethylene group or a vinylene group. )).

The pyridyloxy derivative represented by the general formula (I) of the present invention is a compound which becomes an intermediate for producing an anti-peptic ulcer agent based on, for example, histamine H ₂ receptor antagonism.

[0003]

_2. Description of the Related Art Conventionally, as an anti-peptic ulcer based on histamine H ₂ receptor antagonism, for example,

Embedded image The compound represented by the following formula is known (JP-A-61-853).
No. 65). As a result of studying to find a more active compound, the general formula

Embedded image (Wherein Y is as defined above) has been found (JP-A-63-225371).

[0004] The compound A and the compound B can be prepared by the general formula

Embedded image (Wherein R ⁵ is a disubstituted amino group) and a general formula

Embedded image (Wherein, Y is the same as described above), and reacted with an amino alcohol compound represented by the following general formula:

Embedded image (Wherein, R ⁵ and Y are the same as described above).

[0005]

However, in the conventional production method using the amine compound represented by the general formula (IV), the derivation to the amine compound represented by the general formula (IV) is extremely complicated. Thus, it cannot be said that the compound A and the compound B are simple methods, and a new production method has been required.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the conventional problems, and as a result, as an intermediate for producing the compounds A and B, the compound represented by the general formula (I) was used. The present inventors have found the pyridyloxy derivative represented and completed the present invention.

The pyridyloxy derivative represented by the general formula (I) of the present invention can be produced, for example, according to the following reaction formula 1.

[0008]

Embedded image (In the formula, R ¹ is the same as defined above, Y is vinylene group ethylene group or cis or trans, R ⁴
Represents a halogen atom of a chlorine atom or a bromine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group. )

(First Step) In this step, the above-mentioned general formula (V)
The pyridyloxy derivative represented by the general formula (Ia) is produced by reacting an aldehyde compound represented by the following with a secondary amine. The aldehyde compound represented by the general formula (V) used in this step is a compound that can be easily produced from 2-amino-4-methylpyridine or isonicotinic oxide according to the following reaction formula, for example.

[0010]

Embedded image (In the formula, X ² is a chlorine atom or a bromine atom, R ⁶ is a protected formyl group, and R ⁷ is a hydroxyl-protecting group.)

In this step, the aldehyde compound represented by the above general formula (V) is reacted with a secondary amine, and then reduced, whereby the pyridyloxy group represented by the above general formula (Ia) is obtained. Derivatives can be produced. As the secondary amine used in this step, for example, N, N-dimethylamine, N, N-diethylamine, piperidine, pyrrolidine, 4-hydroxypiperidine, 3-methylpiperidine, 1,2,3,6-tetrahydro-1 -Pyridine, 1
-Perhydroazepine, morpholine, thiomorpholine,
4-methyl-1-piperazine and the like can be mentioned.

The reaction is carried out by mixing and reacting the aldehyde compound represented by the above general formula (V) with a secondary amine in a solvent, and then using a reducing agent such as sodium borohydride. The pyridyloxy derivative represented by the general formula (Ia) can be produced. The reaction is preferably performed in an inert solvent, and chloroform or the like can be used as a solvent.

(Second step) In this step, the pyridyloxy derivative represented by the general formula (Ia) produced in the first step is converted to thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus pentabromide. Pyridyl represented by the above formula (Ib) by halogenating with a halogenating reagent of Oxy derivatives can be produced.

This step is preferably carried out in a solvent, for example, ethers such as ethyl ether, tetrahydrofuran (THF), dimethoxyethane (DME) and dioxane; and halogenated hydrocarbons such as chloroform and methylene chloride. , Aromatic hydrocarbons such as benzene and toluene, and amides such as dimethylformamide (DMF) can be used. This step is preferably performed in the presence of an organic base, and pyridine, triethylamine, or the like can be used. The reaction proceeds smoothly by selecting a temperature range of 0 to 30 ° C.

Further, the pyridyloxy derivative represented by the above general formula (Ib) produced in the second step is reacted with a metal azide such as sodium azide, potassium azide, etc.

Embedded image (Wherein R ¹ and Y are the same as described above), and then subjected to a reduction reaction to produce the amine compound represented by the general formula (IV). Yes (see Reference Example below).

[0016]

The present invention will be described in more detail with reference to the following Reference Examples and Examples.

Reference Example 1 4- [4- (formyl) pyridyl-2-oxy] -ci
s-2-buten-1-ol

Embedded image 4- [4- (Diethoxymethyl) pyridyl-2-oxy] -cis-2-buten-1-ol (2.0 g) was dissolved in an acetone-water (4: 1) mixture (50 ml), and p
-Toluenesulfonic acid-hydrate (143 mg) was added. After refluxing for 2 hours, the reaction solution was concentrated, the residue was taken up in ethyl acetate, added to cold saturated aqueous sodium hydrogen carbonate, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate, combined with the previous organic layer,
After washing with saturated saline and drying, the solvent was distilled off and 4- [4-
(Formyl) pyridyl-2-oxy] -cis-2-buten-1-ol (1.54 g, quantitative) was obtained.

¹ H-NMR (δ, CDCl ₃ ): 2.8
5 (1H, t, J = 5.6 Hz), 4.35 (2H,
d, J = 5.6 Hz), 5.05 (2H, d, J = 6.
9 Hz), 5.75 to 5.85 (1H, m), 5.85
-5.95 (1H, m), 7.16 (1H, s), 7.
31 (1H, d, J = 5.4 Hz), 8.32 (1H,
d, J = 5.4 Hz), 10,000 (1H, s) IR (cm ⁻¹ , film): 3352, 2880, 17
14,1616,1566 C ₁₀ H ₁₁ NO _3: Found 193.0728 Calculated 193.0738

Example 1 4- [4- (piperidinomethyl) pyridyl-2-oxy] -cis-2-buten-1-ol

Embedded image 4- [4- (formyl) pyridyl-2-oxy] -ci
s-2-Buten-1-ol (1.43 g) was dissolved in chloroform (15 ml), and piperidine (1.
After stirring at room temperature for 8 hours, the solvent and piperidine were distilled off. The residue was again chloroform (15 m
l), piperidine (1.26 g) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hours and concentrated. The residue was dissolved in chloroform (20 ml), and under ice-cooling, an ethanol solution (3) of sodium borohydride (0.74 g) suspended therein.
0 ml). After stirring for 1 hour, the excess sodium borohydride is decomposed with 10% acetic acid under ice cooling,
After making it weakly acidic, it was concentrated, and the residue was taken up in ethyl acetate.
Washed with 10% acetic acid. The aqueous layer (acetic acid layer) was basified with potassium carbonate under ice-cooling, extracted with chloroform, washed with water and dried, and the solvent was distilled off to give 4- [4- (piperidinomethyl).
Pyridyl-2-oxy] -cis-2-buten-1-ol (1.64 g, 85%) was obtained.

¹ H-NMR (δ, CDCl ₃ ): 1.3
5 to 1.50 (2H, m), 1.50 to 1.65 (4
H, m), 2.25 to 2.45 (4H, m), 3.40.
(2H, s), 4.33 (2H, d, J = 6.6H)
z), 5.00 (2H, d, J = 7.8 Hz), 5.7
0 to 5.80 (1H, m), 5.85 to 5.95 (1
H, m), 6.73 (1H, s), 6.88 (1H,
d, J = 4.5 Hz), 8.00 (1H, d, J = 4.
5 Hz) IR (cm ^-1 , film): 3396, 1656, 16
_{16,1562 C 15 H 22 N 2 O} 2: Found 262.1683 Calculated 262.1684

Example 2 4- [4- (piperidinomethyl) pyridyl-2-oxy] -cis-2-butene-1-azide

Embedded image 4- [4- (piperidinomethyl) pyridyl-2-oxy] -cis-2-buten-1-ol (500 m
g) and triethylamine (232 mg) in benzene (3
0 ml) and methanesulfonyl chloride (2 mL) at room temperature.
A solution (40 mg) of benzene (5 ml) was added dropwise. 30
After stirring for 2 minutes, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with benzene under alkaline conditions, and the organic layer was dried. In this solution,
Sodium azide (136 mg) and tetra-n-butylammonium bromide (62 mg) were added, and after stirring for 2 hours,
After diluting with ethyl acetate, washing with water and drying, the solvent was distilled off.
[4- (piperidinomethyl) pyridyl-2-oxy]-
cis-2-butene-1-azide (576 mg, quantitative) was obtained.

¹ H-NMR (δ, CDCl ₃ ): 1.3
5 to 1.50 (2H, m), 1.50 to 1.70 (4
H, m), 2.15 to 2.45 (4H, m), 3.41
(2H, s), 3.99 (2H, d, J = 6.6H)
z), 4.91 (2H, d, J = 7.8 Hz), 5.7
0 to 5.80 (1H, m), 6.00 to 6.20 (1
H, m), 6.73 (1H, s), 6.89 (1H,
d, J = 4.5 Hz), 8.05 (1H, d, J = 4.
5 Hz) IR (cm ^-1 , film): 2104, 1616, 15
_{64 C 15 H 21 N 5 O} : Found 287.1749 Calculated 287.1752

Reference Example 2 4- [4- (piperidinomethyl) pyridyl-2-oxy] -cis-2-buten-1-amine

Embedded image 4- [4- (piperidinomethyl) pyridyl-2-oxy] -cis-2-butene-1-azide (225 mg)
Was dissolved in anhydrous tetrahydrofuran (20 ml), and triphenylphosphine (226 mg) was added thereto at room temperature.
After stirring for 8 hours, water (0.02 ml) was added. After stirring for 3 hours, the reaction solution was concentrated, and the residue was taken up in ethyl acetate and extracted with 10% acetic acid. The aqueous layer (acetic acid layer) was washed with ethyl acetate, made basic with potassium carbonate, extracted with methylene chloride, washed with water and dried, and the solvent was distilled off.
[4- (piperidinomethyl) pyridyl-2-oxy]-
cis-2-buten-1-amine (180 mg, 88
%).

¹ H-NMR (δ, CDCl ₃ ): 1.3
5 to 1.50 (2H, m), 1.50 to 1.65 (4
H, m), 2.25 to 2.45 (4H, m), 3.40.
(2H, s), 3.46 (2H, d, J = 4.8H)
z), 4.88 (2H, d, J = 4.8 Hz), 5.7
0 to 5.82 (2H, m), 6.73 (1H, s),
6.87 (1H, d, J = 5.4 Hz), 8.06 (1
H, d, J = 5.4 Hz) IR (cm ⁻¹ , film): 3384, 1616, 15
_{64 C 15 H 23 N 3 O} : Found 261.1821 Calculated 261.1840

[0025]

The pyridyloxy derivative represented by the above general formula (I) of the present invention is a useful compound which becomes a raw material for producing, for example, various anti-peptic ulcer agents.

Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display A61K 31/535 A61K 31/535 31/54 31/54

Claims (4)

(57) [Claims] 1. A compound of the general formula (Wherein R ¹ is N, N
-Dimethylamino group, N, N-diethylamino group, piperidino group, pyrrolidino group, 4-hydroxypiperidino group, 3-methylpiperidino group, 1,2,3,6-tetrahydro-1-pyridyl group, 1-perhydro Azepinyl group, morpholino group, thiomorpholino group or 4-methyl-
1-piperazinyl group, R ² is a hydroxyl group, a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and Y is an ethylene group or a vinylene group. ). 2. The pyridyloxy derivative according to claim 1, wherein R ¹ is a piperidino group and R ² is a hydroxyl group. 3. The pyridyloxy derivative according to claim 1, wherein R ¹ is a piperidino group and R ² is a methanesulfonyloxy group. 4. A compound of the general formula And a sulfonyl derivative represented by the formula R ³ —SO ₂ X ¹ or a halogen reagent obtained by reacting an alcohol derivative represented by the formula: Wherein R ¹ and Y are the same as above, R ³ is a methyl group or a p-toluyl group, X ¹ is a halogen atom, R ⁴ is a halogen atom,
It is a methanesulfonyloxy group or a p-toluenesulfonyloxy group. ).