JPH075553B2 - Pyridyloxy derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) (In the formula, A is a formyl group dimethoxymethyl group, diethoxymethyl group, dipropoxymethyl group, 1,3-dioxolan-2-yl group or 1,3-dioxan-2-yl group, and Y is -CH. _2- CH ₂ -or a group represented by -CH = CH-, Z is a halogen atom, an amino group or a phthalimido group, a hydroxyl group 2-tetrahydropyranyloxy group,
It is a triphenylmethyloxy group, a benzyloxy group or a 2-tetrahydrofuryloxy group. ) Relating to a pyridyloxy derivative. The pyridyloxy derivative represented by the general formula (I) is a compound that can be an intermediate to a compound useful as an anti-peptic ulcer agent based on histamine H ₂ receptor antagonistic action (see Reference Example below).

(Prior Art) Conventionally, as an anti-peptic ulcer agent based on histamine H ₂ receptor antagonistic action, for example, A compound represented by the following formula is known (see JP-A-61-85365). As a result of investigations to find compounds with higher activity, general formula A compound represented by the formula (Y is the same as above) has been found (JP-A-63-32537). To prepare the compound A and the compound B, the general formula (In the formula, W is a disubstituted amino group.) And a general formula (In the formula, Y is the same as the above.) The compound represented by the general formula (In the formula, W and Y are the same as the above.) The common raw material was used.

(Problems to be Solved by the Invention) However, the conventional production method using the intermediate A is
The induction to the intermediate A is extremely complicated, and it is hard to say that it is a simple method for the compound A and the compound B, and a new production method has been demanded.

(Means for Solving Problems) As a result of the studies conducted by the present inventors to overcome the conventional drawbacks,
The present invention has been completed by finding that the pyridyloxy derivative represented by the general formula (I) is an extremely useful compound for producing the compounds A and B as described above.

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

(In the formula, A'is a dimethoxymethyl group, a diethoxymethyl group, a dipropoxymethyl group, a 1,3-dioxolane-2
-Yl group or 1,3-dioxan-2-yl group, Y is
A group represented by —CH ₂ —CH ₂ — or —CH═CH—, R ′ is
2-tetrahydropyranyl group, triphenylmethyl group,
A benzyl group or a 2-tetrahydrofuryl group, X
And X ′ are halogen atoms. ) [First step] In this step, the halogen pyridine derivative represented by the general formula (II) is reacted with the alcohol derivative represented by the general formula (III) to give the pyridine represented by the general formula (Ia). It produces an ether derivative.

As the halogen atom of the halogen pyridine derivative represented by the general formula (II), which is a raw material in this step, chlorine, bromine, or the like can be used, and is a compound which can be produced according to the reaction formula described below. .

(In the formula, A ′ is the same as the above.) That is, it can be produced by reacting 2-amino-4-methylpyridine which is industrially easily available under the conditions described in the above reaction formula ( See the reference example below).

(In the formula, A ′ is the same as the above.) That is, it can be produced by reacting industrially easily available isonicotinic acid N-oxide under the conditions described in the above reaction formula (see the following). See reference example). The alcohol that can be used to protect the formyl group is
For example, methanol (MeOH), ethanol (EtOH), propanol (PrOH), 1,2-ethylene glycol, 1,3-propylene glycol, etc. As the orthoformate ester, methyl orthoformate, ethyl orthoformate and the like can be mentioned. .

Examples of the alcohol derivative represented by the general formula (III) include 4- (2-tetrahydropyranyloxy) -2-buten-1-ol and 4- (toluphenylmethyloxy) -2-
Butene-1-ol, 4-benzyloxy-2-buten-1-ol, 4- (2-tetrahydrofuryloxy) -2-butene-
1-all etc. can be used.

[(B) method]

The reaction is carried out in the presence of an organic ammonium salt, crown ethers and an inorganic base. As the organic ammonium salt, for example, tetra-n-butylammonium iodide, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogen sulfate and the like can be used. As the inorganic base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like can be used. Furthermore, as crown ethers,
12-crown-4, 18-crown-6 and the like can be used.

The amount of organic ammonium salt and inorganic base used is 1/100 of the substrate.
Use 10 to 2 equivalents.

It is desirable to carry out the reaction in a solvent, such as aromatic hydrocarbons such as benzene, toluene, xylene, dimethoxyethane (DME), tetrahydrofuran (THF), ethers such as dioxane, dimethylformamide (DMF), etc. Nitriles such as amide, acetonitrile and propionitrile can be preferably used.

The reaction temperature is preferably in the range of 80 to 200 ° C.

[(B) method]

In addition, this step can be performed in the presence of an alcal metal compound. As the alkali metal compound, sodium hydride, potassium hydride, sodium amide and the like can be used, and the amount thereof is 1 to 3 equivalents of the substrate.

The above solvents can be used to carry out the reaction.

The reaction temperature is 35 to 120 ° C.

[Second step]

In this step, the pyridyl ether derivative represented by the general formula (Ia) is hydrolyzed to give the general formula (I-
It is intended to produce a pyridyloxy alcohol derivative represented by b).

In this step, hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid,
It is preferable to carry out in the presence of acids such as camphorsulfonic acid and phenic acid, p-toluenesulfonic acid pyridine salt, and pyridinium chloride.

It is desirable to carry out the reaction in a solvent, for example,
Water, alcohols such as acetone, MeOH, EtOH, PrOH can be used.

The reaction proceeds smoothly at 25 to 70 ° C.

[Third step]

In this step, the pyridyloxy alcohol derivative represented by the general formula (Ib) is reacted with a halogenating agent to produce the pyridyloxy halogen derivative represented by the general formula (Ic).

Examples of the halogenating agent used in this step include phosphorus pentabromide, phosphorus oxybromide, methanesulfonyl bromide,
Thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and the like can be used.

This step is preferably performed in the presence of a base. As the base, organic bases such as triethylamine and pyridine, and inorganic bases such as anhydrous potassium carbonate and anhydrous sodium hydrogen carbonate can be used. The amount of the base used is preferably at least equivalent to the halogenating agent.

In carrying out the reaction, it is desirable to use a solvent, for example, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, THF and D
Ethers such as ME can be preferably used.

The reaction proceeds smoothly at 10 to 15 ° C.

[Fourth step]

In this step, the pyridyloxyhalogen derivative represented by the general formula (Ic) is reacted with phthalimide or an alkali metal salt thereof to produce the pyridyloxyphthalimide derivative represented by the general formula (Id). is there.

When phthalimide is used in this step, the conditions may be exactly the same as those in the method of the first step (a) above. It may be carried out except for the use of a base.

All other conditions can be exactly the same as the conditions of the method of the first step (a).

[Fifth step]

In this step, the pyridyloxyphthalimide derivative represented by the general formula (Id) is hydrolyzed to produce the pyridyloxyamine derivative represented by the general formula (Ie).

This step is preferably carried out in the presence of hydrazine or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, or an organic base such as methylamine or ethylamine. The amount of hydrazine or the like to be used is preferably an equivalent amount with respect to the pyridyloxyphthalimide derivative represented by the general formula (Id).

It is desirable to carry out the reaction in a solvent,
Alcohols such as MeOH, EtOH and PrOH, water, ethers such as ethyl ether, THF and DME can be used.

The reaction proceeds smoothly at 30 to 100 ° C.

As described above, the compound of the present invention can be produced. The general formulas (Ia), (Ib), (Ic) of the present invention,
The compounds of (Id) and (Ie) may be treated with an acid, if desired.
For example, the compound can be deprotected by treatment with a mineral acid such as hydrochloric acid or sulfuric acid, an acetic acid, an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or citric acid to obtain a corresponding compound having a formyl group. Hereinafter, it will be described in more detail with reference to Examples and Reference Examples.

Reference example 1 2-Amino-4-methylpyridine (108.1 g) was dissolved in 47% hydrobromic acid (500 ml), the temperature was adjusted to 0 ° C. with a freezing agent, and bromine (500 g) was added dropwise. A solution of sodium nitrite (17.25 g) in water (500 ml) was added dropwise while adjusting the reaction to 5 ° C or lower. After dropping everything, the mixture was stirred for 1 hour, and a solution of sodium hydroxide (300 g) in water (1) was added dropwise to make the solution basic. It was extracted with ethyl acetate, the organic layer was washed with water and dried, and then the solvent was distilled off. Purification by distillation yielded 126 g of 2-bromo-4-methylpyridine. Yield 73%.

Boiling point 79〜81 ℃ / 4〜5mmHg ¹ H-NMR (δ, CDCl ₃ ): 8.22 (1H, d, J = 4.9Hz), 7.33 (1
H, s), 7.70 (1H, d, J = 4.9Hz), 2.34 (3H, s).

Reference example 2 2-Bromo-4-methylpyridine (50g) in concentrated sulfuric acid (400ml)
Chromic anhydride (87.2 g) was added little by little under ice cooling. The mixture was stirred for 1 hour and placed in ice water. The precipitated crystals were collected by filtration and recrystallized from EtOH. 48.8 g of 2-bromo-4-pyridinecarboxylic acid was obtained. Yield 83%.

Melting point 213.9-214.4 ° C Reference Example 3 Sodium borohydride (17.4g) is suspended in THF (1.6l) and stirred with a mechanical stirrer. After cooling with ice-water, 2-bromo-4-pyridinecarboxylic acid (62.6 g) was added little by little. After the temperature was raised to room temperature, the mixture was stirred until the generation of hydrogen stopped. Boron trifluoride etherate (75.8ml)
A THF (500 ml) solution was added dropwise at room temperature for 3 hours. After completion of dropping, the mixture was stirred as it was for 20 hours. The reaction solution was cooled with ice-water, and 1.5N-hydrochloric acid was added to adjust the pH to 1-2. THF was distilled off under reduced pressure. Add 4N-sodium hydroxide solution to adjust pH to 10-11,
The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline.
The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. 51.3 g of 2-bromo-4-pyridinemethanol by concentrating under reduced pressure
Obtained. Yield 80%.

Melting point 63.3-64.4 ° C (diisopropyl ether) ¹ H-NMR (δ, CDCl ₃ ): 8.31 (1H, d, J = 4.5Hz), 7.38 (1
H, s), 7.22 (1H, d, J = 4.5Hz), 4.76 (2H, s), 2.40 to 2.7
0 (1H, m) IR (cm ^-1 ,, KBr): 3268,1598,1382,1070 C ₆ H ₆ BrO: Measured value 186.9638 Calculated value 186.9633 Reference Example 4 A mixture of 2-bromo-4-pyridinemethanol (21.0 g), N-bromosuccinimide (32.3 g) and anhydrous sodium carbonate (23.1 g) was suspended in benzene (600 ml) and heated under reflux for 4 hours (bath temperature 110 ~ 120 ℃). Cool in an ice bath and add saturated sodium bicarbonate solution to bring the pH to 9-10. The insoluble material is removed (washing with ethyl acetate).

The organic layer is separated, washed with 10% sodium thiosulfate solution, then saturated brine, and dried over sodium sulfate. 2-Bromo-4-pyridine aldehyde 1 by distilling off the solvent
Obtained 8.2 g. Yield 88%.

Melting point 52.6-53.5 ° C (n-hexane) ¹ H-NMR (δ, CDCl ₃ ): 10.03 (1H, s), 8.64 (1H, d, J =
4.9Hz), 7.90 (1H, s), 7.68 (1H, d, J = 4.9Hz) IR (cm ^-1 ,, KBr): 1704,1554,1204 C ₆ H ₄ BrO: Measured value 184.9485 Calculated value 184.9476 Reference example 5 2-Brom-4-pyridine aldehyde (60 g) was added to benzene (6
(00 ml), ethylene glycol (40 g) and p-toluenesulfonic acid (6 g) were added, and the mixture was heated under reflux for 18 hours while removing water using a Dean Stark trap. After completion of the reaction, ice and saturated aqueous sodium hydrogen carbonate solution were added to make the mixture basic. The organic layer was washed with water, dried and the solvent was distilled off. The obtained compound was distilled to obtain 60 g of 2-bromo-4- (1,3-dioxolan-2-yl) pyridine. Yield 82%.

Boiling point 121-122 ℃ / 3mmHg ¹ H-NMR (δ, CDCl ₃ ): 8.39 (1H, d, J = 5.5Hz), 7.60 (1
H, s), 7.34 (1H, d, J = 5.5Hz), 5.80 (1H, s), 4.07 (2H,
d, J = 12Hz), 4.05 (2H, d, J = 12Hz) IR (cm ^-1 , film): 2894,1594,1553,1367,1121,1097 C ₈ H ₈ BrNO: Measured value 228.9738 Calculated value 228.9738 Reference Example 6 Isonicotinic acid oxide (87 g), phosphorus oxychloride (350
ml) and phosphorus pentachloride (192 g) were mixed and refluxed for 3 hours.
The reaction mixture was poured onto ice and left overnight. The resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 65 g of 2-chloro-4-pyridinecarboxylic acid. Yield 66%.

Melting point 228.1-228.7 ° C IR (cm ^-1 , KBr): 1718,1604,1566,1458,1372.

C ₆ H ₄ NO ₂ Cl: Measured value 156.9940 Calculated value 156.9931 Reference example 7 Sodium borohydride (35.59g) was suspended in THF (3l) and stirred with a mechanical stirrer. After cooling with ice water, 2-chloro-4-pyridinecarboxylic acid (98.83 g) was added little by little. After warming to room temperature, stir until hydrogen generation stops, and add boron trifluoride etherate (158 ml) to THF.
The (1000 ml) solution was added dropwise at room temperature over 3 hours. After completion of dropping, the mixture was stirred for 20 hours as it was. The reaction solution was cooled with ice water, 1.5N-hydrochloric acid was added to adjust the pH to 1-2, and THF was distilled off under reduced pressure. Add 4N-sodium hydroxide solution to adjust pH to 10-11,
The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline.
The aqueous layer was further extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-chrom-4-
75.0 g of pyridinemethanol was obtained. Yield 83%. ¹ H-NMR (δ, CDCl ₃ ): 8.30 (1H, d, J = 4.6Hz), 7.37 (1
H, s), 7.22 (1H, d, J = 4.6Hz), 4.76 (2H, s), 2.70 to 2.8
5 (1H, br-s) IR (cm ^-1 , KBr): 3284,1600,1394 Reference example 8 2-Chloro-4-pyridinemethanol (69.0g), N-bromosuccinimide (128.3g), anhydrous sodium carbonate (10
1.9 g) was suspended in benzene (1.8 l) and refluxed for 4 hours.

After cooling, saturated aqueous sodium hydrogen carbonate was added little by little while stirring until foaming subsided.

The insoluble matter was filtered off, the organic layer was separated, washed once with a 10% sodium thiosulfate solution and twice with a saturated saline solution, dried and evaporated to obtain 64.3 g of 2-chloro-4-pyridinealdehyde. Yield 95%. ¹ H-NMR (δ, CDCl ₃ ): 10.06 (1H, s), 8.66 (1H, d, J =
4.7Hz), 7.76 (1H, s), 7.66 (1H, d, J = 4.7Hz) IR (cm ^-1 , film): 2860,1712,1592,1558 Reference Example 9 2-Chloro-4-pyridine aldehyde (60 g) and ethyl orthoformate (90 g) were dissolved in ethanol (600 ml), p-toluenesulfonic acid (7 g) was added, and the mixture was refluxed for 1 hour.

After cooling, the reaction solution was concentrated, the concentrate was taken up in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried and evaporated.

The residue was distilled under reduced pressure to obtain 75 g of 2-chloro-4-diethoxymethylpyridine. Yield 82%.

Boiling point 102〜103 ℃ / 2mmHg ¹ H-NMR (δ, CDCl ₃ ): 8.39 (1H, d, J = 5.4Hz), 7.46 (1
H, s), 7.32 (1H, d, J = 5.4Hz), 5.48 (1H, s), 3.50 to 3.6
5 (4H, m), 1.26 (6H, t, J = 7.2Hz) IR (cm ^-1 , film): 2984,1596,1556 Example 1 2-Bromo-4- (1,3-dioxolan-2-yl) pyridine (10g), 4- (2-oxytetrahydropyranyl) -cis-2
-Buten-1-ol (9.7g), powdered sodium hydroxide (7.0g), potassium carbonate (9.7g) and tetrahydrogen sulfate
n-Butyl ammonium (1.3 g) was suspended in toluene (150 ml) and refluxed for 18 hours.

After cooling, dilute with benzene, wash with water, dry and evaporate the solvent to give 2- {4- (2-oxytetrahydropyranyl) -cis-2-
Butene-1-oxy} -4- (1,3-dioxolan-2-yl)
12.1 g of pyridine was obtained. Yield 87%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.5Hz), 6.96 (1
H, d, J = 5.5Hz), 6.85 (1H, s), 5.79 (1H, s), 5.70 to 5.9
0 (2H, m), 4.93 (2H, d, J = 5.4Hz), 4.65 ~ 4.68 (1H,
m), 4.37 (1H, dd, J = 12.5,5.5Hz), 4.20 (1H, dd, J = 12.
5,5.4Hz), 4.04 (4H, d, J = 2Hz), 3.82-3.91 (1H, m), 3.
46-3.56 (1H, m), 1.46 to 1.92 (6H, m) IR (cm ^-1 , film): 2952,1618,1566,1316 C ₁₇ H ₂₃ NO ₅ : measured value 321.1591 calculated value 321.1577 Example 2 2- {4- (2-oxytetrahydropyranyl) -cis-2-buten-1-oxy} -4- (1,3-dioxolan-2-yl) pyridine (12.1g) dissolved in EtOH (250ml) Then, add p-toluenesulfonic acid pyridine salt (1.5g) at 55 ℃ (bath temperature).
It was stirred for 18 hours.

After the reaction was completed, a saturated sodium hydrogen carbonate solution was added to make the solution basic, and the solvent was concentrated.

The residue is taken up in ethyl acetate, washed with water and dried, then the solvent is distilled off and 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-
8.9 g of oxy} -cis-2-buten-1-ol was quantitatively obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.10 (1H, d, J = 4.5Hz), 6.98 (1
H, d, J = 4.5Hz), 6.86 (1H, s), 5..83-5.92 (1H, m), 5.7
8 (1H, s), 5.69-5.78 (1H, m), 5.01 (2H, d, J = 7.4Hz),
4.32 (2H, d, J = 6.4Hz), 4.01-4.08 (4H, m) IR (cm ^-1 , film): 3424,2896,1620,1566,1426,1316,1032 C ₁₂ H ₁₅ NO ₄ : Actual measurement Value 237.0998 Calculated value 237.1001 Example 3 4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-buten-1-ol (10 g) and triethylamine (6 g) were dissolved in chloroform (250 ml) and ice Thionyl chloride (6 g) was added dropwise under cooling.

After stirring for 1 hour under the same conditions, ice and then saturated sodium hydrogen carbonate solution were added to make the mixture basic, and the organic layer was washed with water,
It was dried and evaporated.

The residue was immediately purified without purification (250 m
l), potassium phthalimide (8 g) and n-tetrabutylammonium hydrogensulfate (1.4 g) were added, and the mixture was refluxed overnight.

After cooling, the insoluble material was removed and the liquid was concentrated.

The concentrated solution was taken in ethyl acetate, washed with a 1N-sodium hydroxide solution, washed with water and dried, and the solution was distilled off.

The residue was recrystallized from EtOH to obtain 8 g of N- [4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-butene] phthalimide. Yield 53%.

Melting point 96.9-97.9 ° C ¹ H-NMR (δ, CDCl ₃ ): 8.17 (1H, d, J = 5.3Hz), 7.85 (2
H, dd, J = 6.3,3.7Hz), 7.72 (2H, dd, J = 6.3,3.7Hz), 6.9
8 (1H, d, J = 5.3Hz), 6.86 (1H, s), 5.88-5.96 (1H, m),
5.80 (1H, s), 5.64-5.74 (1H, m), 5,12 (2H, d, J = 7.2H
z), 4.47 (2H, d, J = 7.2Hz), 4.00-4.09 (4H, m) IR (cm ^-1 , KBr) 2496,1770,1716,1614,1568,1120,1092 C ₂₀ H ₁₈ N ₂ O ₅ : measured value 366.1221 calculated value 366.1216 Example 4 N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-
Oxy} -cis-2-butene] phthalimide (8.5 g) in MeOH
Dissolve in (200 ml), add hydrazine hydrate (2.3 g),
Refluxed for 0 hours.

After cooling, the insoluble material was removed and the liquid was concentrated.

The residue was crystallized by leaving it to give 10.3 g of 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-buten-1-amine. Yield 78%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 4.8Hz), 6.97 (1
H, d, J = 4.8Hz), 6.85 (1H, s), 5.78 (1H, s), 5.68-5.76
(2H, m), 4,90 (2H, d, J = 4.8Hz), 4.01-4.07 (4H, m),
3.45 (2H, d, J = 4.8Hz) IR (cm ⁻¹ , KBr) 3068,1666,1082 Example 5 2-Chloro-4-diethoxymethylpyridine (20g) and 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (31.92g) were added to tetrahydrofuran (500m
l), add dimethylformamide (10 ml),
Oily sodium hydride (9.28 g) was suspended under ice cooling. The mixture was returned to room temperature, gradually heated to 80 ° C., and further refluxed for 18 hours. After cooling, water was added under ice cooling and the mixture was concentrated. The residue was diluted with benzene, and the insoluble material was removed by Celite filtration.

The organic layer of the filtrate is separated, the aqueous layer is extracted again with benzene,
Combine with the organic layer above, wash with saturated saline, dry, evaporate the solvent and wash with 2- {4- (2-oxytetrahydropyranyl) -ci.
49.62 g of s-2-butene-1-oxy} -4- (diethoxymethyl) pyridine was obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.13 (1H, d, J = 5.5Hz), 6.98 (1
H, d, J = 5.5Hz), 6.87 (1H, s), 5.75 to 5.95 (2H, m), 5,4
4 (1H, s), 4.92 (2H, d, J = 6.4Hz), 4.65 ~ 4.70 (1H,
m), 4.40 ~ 4.50 (1H, m), 4.20 ~ 4.30 (1H, m), 3.85 ~ 3.
95 (1H, m), 3.40 ~ 3.70 (5H, m), 1.40 ~ 1.90 (6H, m),
1.24 (6H, t, J = 7.2Hz) IR (cm ⁻¹ , film): 2948,1616,1566 Example 6 2- {4- (2-oxytetrahydropyranyl) -cis-2-butene-1-oxy} -4- (diethoxymethyl) pyridine (4
9.62 g) was dissolved in ethanol (500 ml), p-toluenesulfonic acid (2.64 g) was added, and the mixture was stirred at a bath temperature of 60 ° C. for 3 hours.

After cooling, saturated aqueous sodium hydrogen carbonate was added under ice cooling, and the mixture was made basic and concentrated. The residue was extracted twice with ethyl acetate, the extract was washed with saturated brine, dried and concentrated, and 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butene-1- Oars
I got 20g. ¹ H-NMR (δ, CDCl ₃ ): 8.07 (1H, d, J = 5.3Hz), 6.99 (1
H, d, J = 5.3Hz), 6.88 (1H, s), 5.90 to 6.00 (1H, m), 5.7
0 to 5.80 (1H, m), 5.43 (1H, s), 5.01 (2H, d, J = 6.8H
z), 4.33 (2H, dJ = 6.5Hz), 3.50 to 3.70 (4H, m), 1.24
(6H, t, J = 7,4Hz) IR (cm ⁻¹ , film): 3416,1616,1586 C ₁₄ H ₂₁ NO ₄ : measured value 267.1477 calculated value 267.1471 Example 7 4- {4-diethoxymethyl) pyridyl-2-oxy} -cis-
2-buten-1-ol (29 g) was dissolved in methylene chloride (500 ml), anhydrous potassium carbonate (12.2 g) was suspended, and under ice cooling,
A solution of thionyl chloride (13.2 g) in methylene chloride (100 ml) was added dropwise. After stirring for 1 hour, the solid was filtered and the filtrate was concentrated.

The residue was dissolved in toluene (800 ml), potassium phthalimide (26.5 g), anhydrous potassium carbonate (6.9 g) and tetra-n-butylammonium hydrogen sulfate (3.1 g) were suspended, and the mixture was refluxed for 20 hours with vigorous stirring. .

After cooling, the insoluble matter was filtered and washed well with ethyl acetate.
The filtrate and washings were combined, washed with water, and the aqueous layer was reextracted with ethyl acetate. The organic layers were combined, washed with cold-1N-sodium hydroxide solution three times and with saturated saline once, respectively,
After drying and evaporation, 41.06 g of N- [4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butene] phthalimide
Obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.2Hz), 7.80〜
7.90 (2H, m), 7.70 to 7.80 (2H, m), 6.98 (1H, d, J = 5.2H
z), 6.89 (1H, s), 5.90 ~ 6.00 (1H, m), 5.60 ~ 5.70 (1
H, m), 5.44 (1H, s), 5.12 (2H, d, J = 6.5Hz), 4.57 (2H,
dJ = 6.2Hz), 3.50 to 3.70 (4H, m), 1.24 (6H, t, J = 7.2H
z) IR (cm ⁻¹ , film): 1770,1716,1614 C ₂₂ H ₂₄ N ₂ O ₅ : measured value 396.1694 calculated value 396.1688 Example 8 N- [4- {4- (diethoxymethyl) pyridyl-2-oxy}
-Cis-2-butene] phthalimide (41.06g) dissolved in methanol (500ml), hydrazine monohydrate (13.93g)
Was added and the mixture was refluxed for 2 hours.

The reaction solution was concentrated, the residue was diluted with methylene chloride, the insoluble material was filtered, the solid was washed with methylene chloride, and the filtrate and the washing solution were combined and concentrated. After concentration, methylene chloride was added, and filtration, washing, and concentration were repeated until no solid was deposited. The concentrate was dissolved in ethyl acetate, washed twice with water, and the organic layer was extracted with cold 10% acetic acid. Anhydrous potassium carbonate (solid) was added to the extract (acetic acid solution) under ice cooling to make it basic,
Extract twice with ethyl acetate, wash with saturated brine, dry and evaporate the solvent to give 4- {4- (diethoxymethyl) pyridyl-2-.
12.4 g of oxy} -cis-2-buten-1-amine was obtained. 50% overall yield from Example 5. ¹ H-NMR (δ, CDCl ₃ ): 8.13 (1 H, d, J = 4.5 Hz), 6.97 (1
H, d, J = 4.5Hz), 6.87 (1H, s), 5.75 (2H, m), 5.43 (1H,
s), 4.89 (2H, d, J = 5.4Hz), 3.55 (4H, m) 3.45 (2H, d,
J = 4.8Hz), 1.55 (2H, br-s), 1.23 (6H, t, J = 9Hz) IR (cm ^-1 , film); 3400,3200,3000,2950,1680,1620,157
0,1410,1060 C ₁₄ H ₂₂ N ₂ O ₃ : Actual value 266.1642 Calculated value 266.1641 Reference example 10 Furfurylsulfinyl acetic acid p-nitrophenyl ester (13.5 g) was suspended in THF (300 ml), and 4- {4-
(1,3-dioxolan-2-yl) pyridyl-2-oxy} ci
A THF solution (100 ml) of s-2-buten-1-amine (10.3 g) was added dropwise.

After 1 hour, the mixture was returned to room temperature and stirred overnight.

The solution is concentrated, the residue is taken up in ethyl acetate, washed with 1N-sodium hydroxide solution, washed with water and dried, then the solvent is distilled off and N-
16.1 g of [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} cis-2-butenyl] -2- (furfurylsulfinyl) acetamide was obtained. Yield 91%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.5 Hz), 7.44 (1
H, d, J = 2.4Hz), 7.10-7.20 (1H, br-s), 6.98 (1H, d, J =
5.5Hz), 6.47 (1H, d, J = 2.8Hz), 6.39 (1H, dd, J = 2.4,
2.8Hz), 5.79-5.90 (1H, m), 5.78 (1H, s), 5.63-5.72
(1H, m), 4.95 (2H, d, J = 6.9Hz), 4.27 (1H, d, J = 14.2H
z), 4.18 (1H, d, J = 14.2Hz), 4.10 (2H, t, J = 6.6Hz),
4.01-4.07 (4H, m), 3.59 (1H, d, J = 14.2Hz), 3.34 (1H,
d, J = 14.2Hz) IR (cm ^-1 , film): 1660,1618,1566,1310,1034 C ₁₉ H ₂₂ N ₂ O ₆ S: Measured value 406.1208 Calculated value 406.1199 Reference example 11 N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-
Oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide (10.0g) in water-acetone (1: 4)
Dissolved in (200 ml), p-toluenesulfonic acid (5.6 g)
Was added and refluxed for 18 hours.

After cooling, saturated sodium hydrogen carbonate solution was added to make it basic and concentrated. The concentrate was taken up in ethyl acetate, washed with water and dried, and the solvent was distilled off. The obtained residue was subjected to column chromatography (1% MeOH-chloroform) to give N- {4- (4
-Formyl-2-pyridyloxy) -cis-2-butenyl} -2
4.6 g of-(furfurylsulfinyl) acetamide was obtained. Yield 52%.

Melting point 67.6-69.9 ° C ¹ H-NMR (δ, CDCl ₃ ): 10.00 (1H, s), 8.36 (1H, d, J =
4.6Hz), 7.45 (1H, d, J = 3Hz), 7.30 (1H, d, J = 4.6Hz),
7.16 (1H, s), 7.08 (1H, br-s), 6.47 (1H, d, J = 3.5H
z), 6.40 (1H, dd, J = 3.5,3.0Hz), 5.82-5.92 (1H, m),
5.66-5.76 (1H, m), 5.00 (2H, d, J = 6.4Hz), 4.27 (1H,
d, J = 14.3Hz), 4.18 (1H, d, J = 14.4Hz), 4.12 (2H, t, J
= 6.3Hz), 3.59 (1H, d, J = 14.1Hz), 3.34 (1H, d, J = 14.
1Hz) IR (cm ^-1 ,, KBr): 3236,1712,1624,1564,1036 C ₁₇ H ₁₈ N ₂ O ₅ S: Measured value 362.0934 Calculated value 362.0937 Reference example 12 4- {4- (diethoxymethyl) pyridyl-2-oxy} -ci
s-2-Buten-1-amine (12.4 g) was dissolved in tetrahydrofuran (300 ml), sulfurylfurfurinyl acetic acid p-nitrophenyl ester (17.3 g) was added, and the mixture was stirred at room temperature for 5 hours and then concentrated. Dissolve the residue in ethyl acetate, 10%-
It was washed twice with an aqueous potassium carbonate solution and once with water. The aqueous layer was re-extracted with ethyl acetate, combined with the previous organic layer, washed with saturated brine, dried and evaporated to remove the solvent, and N- [4- {4- (diethoxymethyl) pyridyl-2- Oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide 1
Obtained 9.83 g. Yield 97%. ¹ H-NMR (δ, CDCl ₃ ): 8.12 (1H, d, J = 5.1Hz), 7.43 (1
H, d, J = 1.8Hz), 7.11 (1H, br-s), 6.98 (1H, d, J = 5.4H)
z), 6.87 (1H, s), 6.47 (1H, d, J = 3.3Hz), 6.40 (1H,
m), 5.86 (1H, m), 5.67 (1H, m), 5.43 (1H, s), 4.94 (2
H, d, J = 5.7Hz), 4.27 (1H, d, J = 18.5Hz), 4.18 (1H, d, J
= 18.5Hz), 4.11 (2H, d, J = 6.6Hz), 3.58 (5H, m), 3.33
(1H, d, J = 14.4Hz), 1.23 (6H, t, J = 9.0Hz) IR (cm ^-1 , film): 3400,2950,1680,1620,1570,1400 C ₂₁ H ₂₈ N ₂ O ₆ S: Measured value 436.1676 Calculated value 436.1668 Reference example 13 N- [4- {4- (diethoxymethyl) pyridyl-2-oxy}
-Cis-2-butenyl] -2- (furfurylsulfinyl) acetamide (19.83 g) was dissolved in a mixed solvent of acetone-water (4: 1) (600 ml) to prepare p-toluenesulfonic acid monohydrate ( 1.72 g) was added and the mixture was refluxed for 3 hours. After cooling, the solution was concentrated, the residue was taken up in ethyl acetate, added to cold-saturated aqueous sodium hydrogen carbonate, the precipitated insoluble material was filtered, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate, combined with the previous organic layer, washed with saturated brine, dried and evaporated to remove the solvent, N- {4- [4-formyl-2-pyridyloxy) -cis. -2-butenyl} -2-
16.64 g of (furfurylsulfinyl) acetamide was obtained. Yield quantitative.

Reference example 14 N- {4- [4-formyl-2-pyridyloxy) -cis-2-butenyl} -2- (furfurylsulfinyl) acetamide (4.0 g) was dissolved in EtOH (100 ml), and piperidine (2.0 g) was added and stirred.

After 3 hours, sodium borohydride (0.5 g) was added under ice cooling, and the mixture was stirred for 6 hours.

After acetic acid was added to decompose hydride, it was concentrated.

The residue was taken up in ethyl acetate and extracted twice with 20% acetic acid.

The acetic acid layer was washed four times with ethyl acetate, made basic with potassium carbonate, and extracted with ethyl acetate.

The organic layer was washed with water, dried and evaporated.

The residue was recrystallized from ether-hexane to give N- [4- {4-
(Piperidinomethyl) pyridyl-2-oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide
Obtained 2.2 g. Yield 46%.

Melting point 92.7-94.9 ° C NMR (δ, CDCl ₃ ): 1.40-1.50 (2H, m), 1.50-1.65 (4H,
m), 2.30-2.45 (4H, m), 3.34 (1H, d, J = 14.2Hz), 3.40
(2H, s), 3.96 (1H, d, J = 14.2Hz), 4.15 (2H, dd, J = 6.1
Hz, 6.1Hz), 4.14 (1H, d, J = 14.2Hz), 4.38 (1H, d, J = 1)
4.2Hz), 4.93 (2H, t, J = 6.1Hz), 5.60-5.75 (1H, m), 5.
80-5.90 (1H, m), 6.40 (1H, dd, J = 3.1Hz, 1.6Hz), 6.47
(1H, d, J = 3.1Hz), 6.73 (1H, s), 6.87 (1H, d, J = 5.1H
z), 7.15-7.25 (1H, brs), 7.44 (1H, d, J = 1.6Hz), 8.04
(1H, d, J = 5.1Hz) IR (cm ^-1 , KBr): 1645 (C = O) 1041 (S → O) C ₂₂ H ₂₉ N ₃ O ₄ S: Measured value 431.1883 Calculated value 431.1879 (Invention Effect) The pyridyloxy derivative represented by the above general formula (I) of the present invention is a useful compound as a raw material for producing various anti-peptic ulcer agents, for example.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 405/14 213 // A61K 31/44 ACL 9454-4C

Claims (1)

[Claims] 1. A general formula A pyridyloxy derivative represented by the formula (wherein A represents a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a dipropoxymethyl group, a 1,3-dioxolan-2-yl group or a 1,3-dioxane-2- yl group, Y is -CH ₂ -CH ₂ - group represented or -CH = CH-, Z is a halogen atom, an amino group, a phthalimido group, a hydroxyl group, 2-tetrahydropyranyloxy group, triphenyl Methyloxy group, benzyloxy group or 2-
It is a tetrahydrofuryloxy group. ).