JPH0649698B2 - Pyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) (In the formula, A is a formyl group or a protected formyl group,
Y is, -CH ₂ -CH ₂ - is a group represented by or a group represented by -CH = CH-, n is 0, 1 or 2. ) Related to the pyridine derivative. The pyridine derivative represented by the general formula (I) of the present invention is a compound that can be an intermediate of a compound useful as an anti-peptic ulcer agent based on histamine H ₂ receptor antagonistic action (see Reference Example below).

(Prior Art) Conventionally, an anti-peptic ulcer agent based on histamine H ₂ receptor antagonistic action is disclosed in JP-A-61-85365. Compounds represented by are disclosed. Results of investigation to find compounds with higher activity (Wherein Y is the same as above) was developed by the present applicant (Japanese Patent Application No. 62-56434).
issue). Both compounds have basically the same synthetic method. (In the formula, W is a disubstituted amino group.) (In the formula, Y is the same as the above.) By reacting both of the compounds (In the formula, W and Y are the same as the above.).

(Problems to be Solved by the Invention) However, in the conventional synthesis method described above, the induction to the intermediate A is extremely complicated, and the compounds A and B are
However, it has been desired to develop a better synthesis method.

(Means for Solving Problems) Therefore, the present inventors have (In the formula, A and Y are the same as the above.) It was found that this compound can be easily induced to the compound B, and it was found that the compound B can be derived in good yield by synthesizing via the intermediate compound of the present invention. completed.

(In the formula, A ′ is a protected formyl group, and R ¹ is p-
A nitrophenyl, 2,4-dinitrophenyl or o-nitrophenyl group. Y and n are the same as above. ) [First step] In this step, the pyridyloxyamine represented by the general formula (II) is reacted with the furfurylthioacetic acid ester represented by the general formula (III) to give the compound represented by the general formula (Ia). It is intended to produce the represented acetal pyridyloxy derivative.

The pyridyloxyamine represented by the general formula (II) is a compound that can be produced according to the reaction formula described below.

(In the formula, A ′ is a protected formyl group. R ² is a hydroxyl group-protecting group, and Y is the same as above.)
It can be produced from 2-amino-4-methylpyridine, which is industrially easily available, according to the above reaction formula (see Reference Example below). In protecting the formyl group, usable alcohols are, for example, methanol, ethanol, propanol, 1,2-ethylene glycol, 1,3-propylene glycol and the like, and as orthoformate esters, methyl orthoformate, ethyl orthoformate and the like. Can be mentioned. The alcohol is reacted in the presence of an acid catalyst. As the acid, hydrochloric acid, sulfuric acid, a mineral acid such as p-toluenesulfonic acid, or an organic acid can be used.

The furfuryl thioester represented by the general formula (III), which is one of the starting materials in this step, is obtained by, for example, adding 2- (furfurylsulfinyl) acetic acid and nitrophenol in the presence of a dehydration condensing agent (for example, dicyclohexylcarbodiimide). It can be obtained by reacting.

It is desirable to carry out this step in a solvent, for example, ethyl ether, tetrahydrofuran (THF),
Ethers such as dimethoxyethane (DME) and dioxane,
Halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, and amides such as dimethylformamide can be used.

The reaction proceeds smoothly by selecting the temperature range of 0 to 50 ° C.

[Second step]

In this step, the acetal pyridyloxy derivative represented by the general formula (Ia) is deprotected to produce the pyridyloxy derivative represented by the general formula (Ib).

This step needs to be performed in the presence of an acid. As the acid, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and citric acid can be preferably used. The amount of the acid used is 1 to 5 equivalents.

It is desirable to use a solvent in carrying out this step,
Water, ketones such as acetone, ethers such as THF and DME, and nitriles such as acetonitrile can be used alone or as a mixture.

The reaction can be performed in the range of 30 to 100 ° C.

The pyridyloxy derivative represented by the general formula (Ib) obtained as described above can be converted to the compound B by a conventional method after reacting with an amine (see Reference Example below).

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

47% of 2-amino-4-methylpyridine (108.1 g)
It was dissolved in hydrobromic acid (500 m), adjusted to 0 ° C. with a freezing agent, and bromine (500 g) was added dropwise. A solution of sodium nitrite (172.5 g) in water (500 m) was added dropwise while adjusting the reaction to 5 ° C or lower. 1 after dropping all
Stir for a period of time and add sodium hydroxide (300 g) in water (1)
The solution 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 ° C / 4-5 mmHg. ¹ H-NMR (δ, CDCl ₃ ): 8.22 (1H, d, J = 4.9Hz), 7.33 (1H,
s), 7.70 (1H, d, J = 4.9Hz), 2.34 (3H, s) Reference example 2 2-Bromo-4-methylpyridine (50.0 g) was dissolved in concentrated sulfuric acid (400 m), and chromic anhydride (87.2) was added under ice cooling.
g) was added in small portions. The mixture was stirred for 1 hour and placed in ice water.
The precipitated crystals were collected by filtration and recrystallized from ethanol. Two
48.8 g of -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 (1.6) and stirred with a mechanical stirrer. After cooling with ice-water, 2-bromo-4-pyridinecarboxylic acid (62.2
g) was added in small portions. After the temperature was raised to room temperature, the mixture was stirred until the generation of hydrogen stopped. Boron trifluoride etherate (7.5
-8 m) in THF (500 m) was added dropwise at room temperature for 3 hours. After completion of dropping, the mixture was stirred for 20 hours as it was. 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. The pH was adjusted to 10 to 11 by adding a 4N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. 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. 2-by concentrating under reduced pressure
51.3 g of bromo-4-pyridinemethanol was obtained. Yield 88%.

Melting point 63.3-64.4 ° C (diisopropyl ether) ¹ H-NMR (δ, CDCl ₃ ): 8.31 (1H, d, J = 4.5Hz), 7.38 (1H,
s), 7.22 (1H, d, J = 4.5Hz), 4.76 (2H, s), 2.40 ~ 2.70 (1H, m) IR (cm ^-1 ,, KBr): 3268,1598,1382,1070 C ₆ H ₆ BrO: Measured value 186.9639 Calculated value 186.9633 Example 4 2-Bromo-4-pyridinemethanol (21.0 g), N
-A mixture of bromosuccinimide (32.3 g) and anhydrous sodium carbonate (23.1 g) was added to benzene (600 m).
) And heated under reflux for 4 hours (bath temperature 110-12)
0 ° C). It is cooled in an ice bath and saturated sodium hydrogen carbonate solution is added to adjust 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. The solvent was distilled off to obtain 18.2 g of 2-bromo-4-pyridine aldehyde. 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 = 4.9H)
z) 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-pyridinealdehyde (60 g) was dissolved in benzene (600 m), and ethylene glycol (4
0 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 ° C / 3 mmHg ¹ H-NMR (δ, CDCl ₃ ): 8.39 (1H, d, J = 5.5Hz), 7.60 (1H,
s), 7.34 (1H, d, J = 5.5Hz), 5.80 (1H, s), 4.07 (2H, d, J = 12H
z), 4.05 (2H, d, J = 12Hz) IR (cm ⁻¹ , film): 2894,1594,1553,1367,1121,1097 C ₈ H ₈ BrNO ₂ : measured value 228.9738 calculated value 228.9738 Reference example 6 Mix isonicotinic acid oxide (87 g), phosphorus oxychloride (350 m) and phosphorus pentachloride (192 g) and mix 3
Reflux for 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 to 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) in THF (3)
And was stirred with a mechanical stirrer. After cooling with ice water, 2-chloro-4-pyridinecarboxylic acid (98.
83 g) was added in small portions. After heating to room temperature, stir until hydrogen generation stops, and then boron trifluoride etherate (1
58m) in THF (1000m) was added dropwise at room temperature over 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 pH.
1 to 2, and THF was distilled off under reduced pressure. The pH was adjusted to 10 to 11 by adding a 4N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. 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 are combined and dried over anhydrous sodium sulfate,
By concentrating under reduced pressure, 75.0 g of 2-chloro-4-pyridinemethanol was obtained. Yield 83%.

Melting point: 65.7-66.4 ° C. ¹ H-NMR (δ, CDCl ₃ ): 8.30 (1H, d, J = 4.6 Hz), 7.37 (1H,
s), 7.22 (1H, d, J = 4.6Hz), 4.76 (2H, s), 2.70 to 2.85 (1H, br
-s) IR (cm ^-1 , KBr): 3284,1600,1394 Example 8 2-chloro-4-pyridinemethanol (69.0 g), N
-Bromosuccinimide (128.3 g) and anhydrous sodium carbonate (101.9 g) were suspended in benzene (1.8),
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 = 4.7H
z), 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 m), 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 subjected to vacuum distillation to obtain 75 g of 2-chloro-4-diethoxymethylpyridine. Yield 82%.

Boiling point 102-103 ° C / 2 mmHg ¹ H-NMR (δ, CDCl ₃ ): 8.39 (1H, d, J = 5.4Hz), 7.46 (1H,
s), 7.32 (1H, d, J = 5.4Hz), 5.48 (1H, s), 3.50-3.65 (4H,
m), 1,26 (6H, t, J = 7.2Hz) IR (cm ⁻¹ , film): 2984,1596,1556 Reference example 10 2-Bromo-4- (1,3-dioxolan-2-yl) pyridine (10 g), 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (9.7 g), powder Sodium hydroxide (7.0 g), potassium carbonate (9.7
g) and tetra-n-butylammonium hydrogen sulfate (1.
3 g) was suspended in toluene (150 m) and refluxed for 18 hours.

After cooling, it was diluted with benzene, washed with water and dried, and then the solvent was distilled off to give 2- {4- (2-oxytetrahydropyranyl)-
12.1 g of cis-2-butene-1-oxy} -4- (1,3-dioxolan-2-yl) pyridine was obtained. Yield 87
%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.5Hz), 6.96 (1H, d,
J = 5.5Hz), 6.85 (1H, s), 5.79 (1H, s), 5.70-5.90 (2H, m),
4.93 (2H, d, J = 5.4Hz), 4.65-4.68 (1H, m), 4.37 (1H, dd, J
= 12.5,5.4Hz), 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), 1.46-1.92
(6H, m) IR (cm ^-1 ): 2952,1618,1566,1316 C ₁₇ H ₂₃ NO ₅ : measured value 321.1591 calculated value 321.1577 reference example 11 2- {4- (2-oxytetrahydropyranyl) -cis
2-butene-1-oxy} -4- (1,3-dioxolan-2-yl) pyridine (12.1 g) was added to ethanol (2
50 m), p-toluenesulfonic acid pyridine salt (1.5 g) was added, and the mixture was stirred at 55 ° C (bath temperature) 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 to give 4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-buten-1-ol. 8.9 g was quantitatively obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.10 (1H, d, J = 4.5Hz), 6.98 (1H, d,
J = 4.5Hz), 6.86 (1H, s), 5.83-5.92 (1H, m), 5.78 (1H, s), 5.
69-5.78 (1H, m), 5.01 (2H, d, J = 7.4Hz), 4.32 (2H, d, J = 6.4
Hz), 4.01-4.08 (4H, m) IR (cm ^-1 , film): 3424,2896,1620,1566,1426,1316,1032 C ₁₂ H ₁₅ NO ₄ : Measured value 237.0998 Calculated value 237.1001 Reference example 12 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-buten-1-ol (10
g) and triethylamine (6 g) with chloroform (25
0m) and thionyl chloride (6g) under ice cooling.
Was dripped.

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 by acetonitrile (25
0 m), potassium phthalimide (8 g) and tetra-n-butylammonium 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 concentrate is taken up in ethyl acetate and washed with 1N-sodium hydroxide solution,
It was washed with water and dried, and the solvent was distilled off.

The residue was recrystallized from ethanol and N- [4- {4- (1.
3-dioxolan-2-yl) pyridyl-2-oxy}
8 g of -cis-2-butene] phthalimide was obtained. Yield 5
3%.

Melting point 96.9-97.9 ° C ¹ H-NMR (δ, CDCl ₃ ): 8.17 (1H, d, J = 5.3Hz), 7.82 (2H, d)
d, J = 6.3,3.7Hz), 7.72 (2H, dd, J = 6.3,3.7Hz), 6.98 (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 = 7.2Hz), 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 Reference example 13 N- [4- {4- (1,3-dioxolan-2-yl) pyridin-2-oxy} -cis-2-butene] phthalimide (8.5 g) was dissolved in methanol (200 m) to give hydrazine hydrate. (2.3 g) was added and the mixture was refluxed for 10 hours.

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

The residue crystallizes on standing and becomes 4- {4- (1,3-
Dioxolan-2-yl) pyridyl-2-oxy} -ci
10.3 g of s-2-buten-1-amine was obtained. Yield 78
%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 4.8Hz), 6.97 (1H, 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 = 4.8
Hz) IR (cm ^-1 , KBr): 3068,1666,1082 Reference Example 14 2-chloro-4-diethoxymethylpyridine (20
g) and 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (31.92 g) were dissolved in tetrahydrofuran (500 m), dimethylformamide (10 m) was added, and the mixture was cooled with ice. , Oily sodium hydride (9.28 g) was suspended. Return to room temperature,
The mixture was 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,
The organic layers were combined, washed with saturated saline, dried, and the solvent was distilled off to give 2- {4- (2-oxytetrahydropyranyl) -cis-2-butene-1-oxy} -4- (di 49.62 g of ethoxymethyl) pyridine was obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.13 (1H, d, J = 5.5Hz), 6.98 (1H, d,
J = 5.5Hz), 6.87 (1H, s), 5.75 ~ 5.95 (2H, m), 5.44 (1H, s),
4.92 (2H, d, J = 6.4Hz), 4.65 ~ 4.70 (1H, m), 4.40 ~ 4.50 (1
H, m), 4.20-4.30 (1H, m), 3.85-3.95 (1H, m), 3.40-3.70
(5H, m), 1.40 to 1.90 (6H, m), 1.24 (6H, t, J = 7.2Hz) IR (cm ⁻¹ , film): 2948,1616,1566 Reference Example 15 2- {4- (2-oxytetrahydropyranyl) -cis
2-butene-1-oxy} -4- (diethoxymethyl) pyridine (49.62 g) was added to ethanol (500 m).
), 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 to make the mixture basic and concentrated. The residue was extracted twice with ethyl acetate, the extract was washed with saturated brine, dried and concentrated to give 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butene-1.
-29 g of oar was obtained. ¹ H-NMR (δ, CDCl ₃ ): 8.7 (1H, d, J = 5.3Hz), 6.99 (1H, d, J
= 5.3Hz), 6.88 (1H, s), 5.90 ~ 6.00 (1H, m), 5.70 ~ 5.80 (1
H, m), 5.43 (1H, s), 5.01 (2H, d, J = 6.8Hz), 4.33 (2H, d, J =
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 Reference example 16 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-ol (29 g) was dissolved in methylene chloride (500 m), anhydrous potassium carbonate (1
2.2 g) was suspended and thionyl chloride (13.2 g) was added under ice cooling.
Methylene chloride (100 m) solution of was added dropwise. After stirring for 1 hour, the solid was filtered and the filtrate was concentrated.

The residue was dissolved in toluene (800 m), potassium phthalimide (26.5 g), anhydrous potassium carbonate (6.9 g),
Tetra-n-butylammonium hydrogen sulfate (3.1 g) was suspended and 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 3 times and saturated brine once, dried and evaporated to obtain N- [4- {4- (diethoxymethyl) pyridyl-2-. Oxy} -cis-2-butene] phthalimide was obtained in an amount of 41.06. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.2Hz), 7.80 to 7.90
(2H, m), 7.70 ~ 7.80 (2H, m), 6.98 (1H, d, J = 5.2Hz), 6.89 (1
H, s), 5.90 ~ 6.00 (1H, m), 5.60 ~ 5.70 (1H, m), 5.44 (1H, s),
5.12 (2H, d, J = 6.5Hz), 4.57 (2H, d, J = 6.2Hz), 3.50-3.70
(4H, m), 1.24 (6H, t, J = 7.2Hz) IR (cm ^-1 , film): 1770,1716,1614 C ₂₂ H ₂₄ N ₂ O ₅ : Actual value 396.1694 Calculated value 396.1688 Reference Example 17 N- [4- {4- (diethoxymethyl) pyridyl-2-
Oxy} -cis-2-butene] phthalimide (41.06
g) was dissolved in methanol (500 m), hydrazine monohydrate (13.93 g) 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 remove 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-amine. .
4 g was obtained. Total yield 50% from Reference Example 14. ¹ H-NMR (δ, CDCl ₃ ): 8.13 (1H, d, J = 4.5Hz), 6.97 (1H, d,
J = 4.5Hz), 6.87 (1H, s), 5.75 (2H, m), 5.43 (1H, s), 4.89 (2
H, 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): 3400,3200,3000,2950,1680,1620,1570,
1410,1060 C ₁₄ H ₂₂ N ₂ O ₃ : Actual value 266.1642 Calculated value 266.1641 Example 1 Furfurylsulfinyl acetic acid p-nitrophenyl ester (13.5 g) was suspended in THF (300 m), and 4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy}-under ice cooling. A THF solution (100 m) of cis-2-buten-1-amine (10.3 g) was added dropwise.

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

The solvent is concentrated, the residue is taken up in ethyl acetate, washed with 1N-sodium hydroxide solution, washed with water and dried, and then the solvent is distilled off,
N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-butenyl] -2-
16.1 g of (furfurylsulfinyl) acetamide was obtained. Yield 91%. ¹ H-NMR (δ, CDCl ₃ ): 8.15 (1H, d, J = 5.5Hz), 7.44 (1H, 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 = 14.2Hz), 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 = 1
4.2Hz) 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 Example Two N- [4- {4- (1,3-dioxolan-2-yl) pyridyl-2-oxy} -cis-2-butenyl] -2-
(Furfurylsulfinyl) acetamide (10.0 g)
Was dissolved in water-acetone (1: 4) (200 m) and p
-Toluenesulfonic acid (5.6 g) was added, and the mixture was 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% methanol-chloroform), N
-{4- (4-formyl-2-pyridyloxy) -cis
2-butenyl} -2- (furfurylsulfinyl) acetamide (4.6 g) 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 = 4.6H
z), 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 = 3.5Hz), 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 =
14.3Hz), 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 Example 3 4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-buten-1-amine (12.4 g) in THF
Dissolved in (300m), sulfuryl furfuryl acetate p
-Nitrophenyl ester (17.3 g) was added, and the mixture was stirred at room temperature for 5 hr and concentrated. Dissolve the residue in ethyl acetate,
It was washed twice with a 10% aqueous potassium carbonate solution and once with water. The aqueous layer was re-extracted with ethyl acetate, combined with the above organic layer, washed with saturated brine, dried, and the solvent was distilled off.
There was obtained 19.83 g of [4- {4- (diethoxymethyl) pyridyl-2-oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide. Yield 97%. ¹ H-NMR (δ, CDCl ₃ ): 8.12 (1H, d, J = 5.1Hz), 7.43 (1H, d,
J = 1.8Hz), 7.11 (1H, br-s), 6.98 (1H, d, J = 5.4Hz), 6.87 (1
H, s), 6.47 (1H, d, J = 3.3Hz), 6.40 (1H, m), 5.86 (1H, m), 5.6
7 (1H, m), 5.43 (1H, s), 4.94 (2H, d, J = 5.7Hz), 4.27 (1H, d, J
= 18.5Hz), 4.18 (1H, d, J = 18.5Hz), 4.11 (2H, d, J = 6.6H
z), 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 Example 4 N- [4- {4- (diethoxymethyl) pyridyl-2-
Oxy} -cis-2-butenyl] -2- (furfurylsulfinyl) acetamide (19.83 g) was added to acetone-
Dissolve in a mixed solvent (600 m) of water (4: 1), p-
Add toluenesulfonic acid monohydrate (1.72g) and add 3
Reflux for 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 above organic layer, washed with saturated brine, dried and evaporated to remove the solvent, and N- {4- (4-formyl-2-pyridyloxy) -cis was added. 16.64 g of 2-butenyl} -2- (furfurylsulfinyl) acetamide was obtained. Yield quantitative.

Reference cold 18 N- {4- (4-formyl-2-pyridyloxy) -ci
s-2-butenyl} -2- (furfurylsulfinyl)
Acetamide (4.0 g) was dissolved in ethanol (100 m), and piperidine (2.0 g) was added under ice cooling and the mixture was stirred.

After 3 hours, under cooling with ice, sodium borohydride (0.5 g)
Was added and 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 10% 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}-
2.2 g of cis-2-butenyl] -2- (furfurylsulfinyl) acetamide was obtained. 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.
69 (1H, d, J = 14.2Hz), 4.15 (2H, dd, J = 6.1Hz, 6.1Hz), 4.14
(1H, d, J = 14.2Hz), 4.38 (1H, d, J = 14.2Hz), 4.93 (2H, t, J
= 6.1Hz), 5.60-5.75 (1H, m), 5.80-5.90 (1H, m), 6.40 (1H, d)
d, J = 3.1Hz, 1.6Hz), 6.47 (1H, d, J = 3.1Hz), 6.73 (1H, s),
6.87 (1H, d, J = 5.1Hz), 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 (Effect of the invention) The pyridine derivative represented by the general formula (I) of the present invention can be easily produced. Further, the compound B and the like have an excellent histamine H ₂ receptor antagonistic action, which can be easily led to the compound B and the like by subjecting it to a reaction as shown in Reference Example.

Claims (1)

[Claims] 1. A general formula (In the formula, A is a formyl group or a protected formyl group obtained by reacting a formyl group with an alcohol or an orthoformate ester.)
The alcohol is methanol, ethanol, propanol, 1,2-ethylene glycol or 1,3-propylene glycol, and the orthoformate is methyl orthoformate or ethyl orthoformate. Y
Is, -CH ₂ -CH ₂ -, a group represented by or -CH = CH-
And n is 0, 1 or 2. ).