JPH01193247A - Pyridyloxy derivative - Google Patents

Abstract

NEW MATERIAL:The pyridyloxy derivative of formula I (A is hydroxyl group or protected hydroxyl group; Y is -CH2CH2- or -CH=CH-; Z is halogen, amino, phthalimido, hydroxyl group or protected hydroxyl group). EXAMPLE:4-[4-(Methoxymethoxymethyl)pyridyl-2-oxy]-eis-2-buten-1-ol. USE:Effective as an intermediate for a compound useful as an antiulcer agent by the antagonistic action against histamine H2 receptor. PREPARATION:A compound of formula IV which is one of the compound of formula I is produced by the reaction of a pyridyloxy derivative of formula II (A' is protected hydroxyl group; X'' is halogen) with a compound of formula III (R' is protecting group of hydroxyl group). Hydrolysis of the compound of formula IV gives a compound of formula V which is also one of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is based on the following invention:
A group represented by H2CH2-cross-○H=CH-, where z is a halogen atom, an amino group, a phthalimide group, a hydroxyl group or a protected hydroxyl group. ), and - formula (wherein A is a halogen atom, hydroxyl group or protected hydroxyl group, Y is -CH2
It relates to a pyrisoloxy derivative represented by CI (a group represented by 2- or -0H=CH-, with nt'io% l spanning 2). - The pyridyloxy derivative represented by the formula (1) and - the pyridyloxy derivative represented by the formula (I) can be used as an intermediate to a compound useful as an anti-ulcer agent based on histamine H2 receptor antagonism. It is a compound (see reference side below).

(Prior Art) Conventionally, as an anti-peptic ulcer agent based on histamine H2 receptor antagonism, a compound represented by JP-A-61-85365 has been disclosed. As a result of further studies to find a highly active compound (compound B), the present applicant developed it (Japanese Patent Application No. 62-56434).
issue). As a common synthesis method for solid compounds (in the formula, W,
It is a disubstituted amino group. ) and HO△YANH2 (wherein, Y is the same as above), an intermediate to the desired compound (wherein, W and Y are the same as above) can be produced by reacting both the compound (wherein, Y is the same as above). .) was obtained.

(Problems to be Solved by the Invention) However, in the conventional synthesis method described above, the derivation of the above-mentioned intermediate is extremely complicated and there is a problem in industrially employing it.

(Means for Solving the Problems) As a result of studies to overcome the conventional drawbacks, the inventors of the present invention found that
It has been discovered that the pyridyloxy derivatives represented by the above-mentioned formula (1) and the above-mentioned formula (ID) are extremely useful compounds for the production of compounds A and B as described above,
The invention has been completed.

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

[First step] ↓+HOAY△OR'
(■) [Second step] ↓ [Third step] ↓ [Fourth step] ↓ [Fifth step] ↓ (In the formula, A' is a protected hydroxyl group, Y-CH2CH2
It is a group represented by - or -CH=CH-, R' is a hydroxyl protecting group, and x' and x' are each independently a halogen atom. ) Furthermore, the pyridyloxy derivative represented by the above-mentioned formula (m) of the present invention can be produced, for example, according to the following reaction formula.

[Seventh step] ↓ (gb) [Eighth step] ↓ (II-e) (A'i protected hydroxyl group, X is...logon atom, Y is -CH2CH2- or -CH=C)I- It is a group represented by Rtfp-nitrophenyl group, 2,4-dinitrophenyl group and 0-nitrophenyl group, n is 0,14 and 2) [No. Step 1] In this step, the halogen pyridine rust conductor represented by the above-mentioned formula is reacted with the alcohol derivative represented by the general formula (IV) to form a pyridyloxy derivative represented by the above-mentioned formula (1-a). It manufactures.

A bromine atom, a chlorine atom, etc. can be used as XI of the above-mentioned formula pyridine, which is a raw material for this step, and the following (1) and (i)
It is a compound that can be produced according to the reaction formula described in i).

(In the formula, A' is a protected nonacid group.) In other words, it is possible to react 2-amino-4-methylpyridine, which is easily available industrially, under the conditions listed in the above reaction formula. can be manufactured.

(iD (In the formula, A' is a protected hydroxyl group.) That is, it can be produced by reacting industrially easily available isonicotinic acid N-oxide under the conditions listed in the above reaction formula. .

In addition, as a protecting group for a hydroxyl group, tetrahydropyranyl, methoxymethyl, methoxyethyl, triphenylmethyl, trimethylsilyl, etc. can be used.

Examples of the alcohol derivative represented by formula (■) include 4-(2-tetrahydropyranyloxy)-2
-buten-1-ol, 4-(triphenylmethyloxy)-2-buten-1-ol, 4-benzyloxy-
2-Buten-1-ol, 4-(2-tetrahydrofuryl)-2-buten-1-ol 4-(2-tetrahydropyranyloxy)-butan-1-ol, 4-(triphenylmethyloxy)- Butane-1-, t-k, 4-
Hensyloxy-butan-1-ol, 4-(2-tetrahydrofuryl)-but-7-1-ol, etc. can be used.

The pyridyloxy derivative represented by the formula (1-a) obtained by the reaction between the formula (2) and the formula (■) can be produced under the conditions of method (a) and method (b) shown below. can.

(a) The nature of the process is that it is carried out in the presence of a phase transfer catalyst and an inorganic base. As the phase transfer catalyst, organic ammonium salts and crown ethers are preferable. Examples of organic ammonium salts include tetra-n-butylammonium iodide,
Tetra-n-butylammonium bromide, tetra-n chloride
-butylammonium, tetra-n-butylammonium hydrogen sulfate, etc. can be used, and as the crown ether, 12-crown-4,18-crown-6 etc. can be used. Further, as the inorganic base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. can be used.

The amount of phase transfer catalyst and inorganic base used is 1/l of the substrate.
Use 2 equivalent m from O equivalent.

The reaction is preferably carried out in a solvent, and aromatic hydrocarbons such as benzene, toluene, xylene, dimethoxyethane (DME), tetrahydrofuran (THF), etc.
), ethers such as dioxane, amides such as dimethylformamide (DMF'), and nitriles such as acetonitrile and propionitrile can be suitably used.

The reaction temperature is preferably 80 to 200°C.

(b) This step can be carried out in the presence of an alkali metal compound. As the alkali metal compound, sodium hydride, potassium hydride, sodium amide, etc. can be used, and the amount used is 1 to 3 violet of the substrate.

The reaction is preferably carried out in a solvent, and aromatic hydrocarbons such as benzene, toluene, xylene, DME
Ethers such as , THF and dioxane, amides such as DMF, and nitriles such as acetonitrile and propionitrile can be suitably used.

The reaction temperature is preferably in the range of 35 to 120°C.

[Second Step] In this step, the pyridyloxy derivative represented by the above-mentioned formula (1-a) is hydrolyzed to obtain the above-mentioned formula (1-a).
A pyridyloxy derivative represented by -b) is produced.

This step is preferably carried out in the presence of acids such as hydrochloric acid, sulfuric acid, acetic acid, p-)luenesulfonic acid, camphorsulfonic acid, citric acid, pyridinium p-toluenesulfonate, pyridinium chloride, and the like.

The reaction is preferably carried out in a solvent, such as methanol (MeOH), ethanol (Etoa), or
Alcohols such as alcohol (PrOH), water, and acetone can be used.

The reaction proceeds smoothly at 25-70°C.

[Third Step] In this step, the pyridyloxy derivative represented by the above-mentioned formula (1-b) and a halogenating agent are reacted to form the above-mentioned formula (1-b).
A pyridyloxy derivative represented by I-c) is produced.

Examples of the halogenating agent used in this step include f-onyl ifu, p-)luenesulfonyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonic anhydride, and phosphorus tribromide. , methanesulfonyl bromide, etc. can be used.

It is preferable to use a base in this step. As the base, organic bases such as triethylamine and pyridine, and inorganic bases such as potassium carbonate, sodium carbonate, hydrogen carbonate, etc. can be used. The amount of base used is preferably at least equal to the amount of the halogenating agent.

The reaction is preferably carried out in a solvent, for example, fluorinated hydrocarbons such as chloroform and sochloromethane, aromatic hydrocarbons such as benzene and toluene, THF, D
Ethers such as ME can be suitably used.

The reaction proceeds smoothly at -10 to 15°C.

[Fourth step]

In this step, the pyridyloxy derivative represented by the general formula (1-d') is reacted with the pyridyloxy derivative represented by the formula (1-c) and phthalimide or an alkali metal salt thereof. It is used to produce derivatives.

When using phthalimide in this step, the first step (
The process may be carried out under exactly the same conditions as in method (a), and when an alkali metal salt of phthalimide is used, the method may be carried out in accordance with method No. 1 (a) except that the inorganic metal is used.

All other conditions can be carried out in exactly the same manner as in the first step ((a)).

[Fifth step]

In this step, the pyridyloxy derivative represented by the formula (1-d) is hydrolyzed.
A pyridyloxy derivative represented by e) is produced.

In this process, inorganic bases such as hydrazine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
It is preferable to carry out the reaction in the presence of an organic base such as methylamine or ethylamine. It is desirable that the amount of the reagents used is equal to the amount of the pyridyloxy derivative represented by the formula (1-d).

The reaction is preferably carried out in a solvent, M@OH,
Alcohols such as EtOH and PrOH, water, ether,
THF, Dllll! Ethers such as E can be used.

The reaction proceeds smoothly at 30-100°C.

[Sixth step]

This step consists of reacting the pyridyloxy derivative represented by the formula (I-) with the furfuryl thioester represented by the formula (■).
A pyridyloxy derivative represented by a) is produced.

Furfuryl thioester, which is one of the raw materials in this step and is represented by the formula
Nitrophenol, 2,4-dinitrophenol, 0-
nitrophenol, etc.) in the presence of a total dehydration condensation agent (for example, dicyclohexyl rugedimide, etc.).

It is desirable to carry out this step in a solvent, for example, ethyl ether, 'l'l(P, DME,
Ethers such as dioxane, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, and amides such as DMF can be used.

The reaction proceeds smoothly at 0 to 50°C.

[Seventh step]

In this step, the pyridyloxy derivative represented by the above-mentioned formula (1) is deprotected to produce the pyridyloxy derivative represented by the above-mentioned formula (g).

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-)luenesulfonic acid, camphorsulfonic acid, and citric acid can be suitably used. The amount of acid to be used is determined according to the above-mentioned formula (I
It is 1 to 5 equivalents relative to the pyridyloxy derivative represented by f-a).

The reaction is preferably carried out in a solvent, MeOH,
Alcohols such as EtOH and PrOH, water, and acetone can be used.

The reaction proceeds smoothly at 70-120°C.

[Eighth process]

In this step, the pyridyloxy derivative represented by the above formula (II-b) is reacted with a halodanating agent to produce the pyridyloxy derivative represented by the above formula (II-e).

Examples of the halodanizing agent used in this step include thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonic anhydride, phosphorus tribromide, and methane bromide. Sulfonyl etc. can be used.

This step is preferably used in the presence of a base. Examples of bases include organic bases such as triethylamine and pyridine, potassium carbonate, sodium carbonate, and hydrogen carbonate) IJ
Inorganic bases such as aluminum can be used.

The amount of base used is preferably at least equal to the amount of the halodanizing agent.

The reaction is preferably carried out in a solvent, and suitable examples include halodanized hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, and ethers such as THF and DME.

The reaction proceeds smoothly at -10 to 15°C.

The pyridyloxy derivative represented by the general formula (If-e) produced in this step is usually not isolated and can be used in the next reaction.

The compound of the present invention can be produced in the manner described above. The present invention will be explained in more detail below using Examples and Reference Examples.

Reference Example 1 2-Amino-4-methylpyridine (108,1,9) was dissolved in 47 hydrobromic acid (500m), the temperature was brought to 0°C with a cryogen, and bromine (50ON) was added dropwise. Add sodium nitrite (172,5II) while adjusting the reaction temperature to below 5°C.
) in water (500 mj) was added dropwise. After dropping everything, stir for 1 hour to hydroxylate.

A solution of thorium (approximately 300 Ii) in water (11) was added dropwise to make the solution basic. After extraction with ethyl acetate, the organic layer was washed with water and dried, and then the solvent was distilled off. The residue was distilled to obtain 2-promo-4-methylpyridine (1261,73).

Boiling point 79-81'C/4-5 degrees Hg.

'H-NMR (d, CDC25): 8.22
(I H-d, J=4.9 Hz).

7.33 (IH, s), 7.70 (IH, d, J=4.
9Hz).

2.34 (3H, m).

Reference example 2 2-promo 4-methylpyridine (50,9) was dissolved in sulfuric acid (
chromic anhydride (87,2 mj) and cooled with water.
&) were added little by little. Stir for 1 hour and place in ice water.
The precipitated crystals were collected by filtration. The crude crystals were recrystallized from ethanol to give 2-promo-4-pyridinecarboxylic acid (48,
8F, 83%) was obtained.

Melting point: 213.9-214.4°C Reference Example 3 Sodium borohydride (17,4#) was dissolved in THF (1,
6)) and stirred with a mechanical stirrer.

The mixture was cooled with ice water, and 2-promo-4-pyridinecarboxylic acid (62,8,F) was added little by little. After heating up to room temperature,
The mixture was stirred until hydrogen generation stopped, and a THF (500 mJ) solution of boron trifluoride (Nieterer) (75,81I7) was added dropwise at room temperature over 3 hours. After the dropwise addition was completed, the mixture was stirred for 20 hours. The reaction solution was cooled with ice water, and 1.5
N-hydrochloric acid was added to give a concentration of -1 to 2, and THF was distilled off under reduced pressure.

The pH was adjusted to 10 to 11 by adding 4N sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The aqueous layer was further extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. Combine the organic layer with anhydrous sulfuric acid)
2-promo-4-pyridinemethanol (51,31,88) was obtained by drying with IJum and concentrating under reduced pressure.
I got it.

Melting point 63.3-64.4℃ (diisopropyl ether)
'H-NMR (δ, CDC23) = 8.31 (IHld
, J=4.5H1), 7°38(LH,s), 7.22
(IH, d, J=4.5Hz), 4.76 (2H+s)
+2.40~2.70 (IHlm) - IR (cm,
KBr): 3268, 1598, 1382.1070
-C6H6BrO: Actual value 186.9638 Calculated value
186.9633 Reference example 4 2-promo 4-pyridine methanol (21,36y)
, dimethoxymethane (71tA and p-)luenesulfonic acid-hydrate (2,1s I) tbenzene (3
00d) IC suspension L, 31 mol L'Kis-5'/-F (251) was passed through a Soxhlet extractor and refluxed for 20 hours. After cooling, the reaction solution was diluted with saturated hydrogen carbonate) IJ
After washing with a solution of aluminum, washing with water, drying, and concentrating under reduced pressure.

Distillation of the residue gave 2-promo-4-(methoxymethoxymethyl)pyridine (13.2 g, 5°).

Boiling point: 118~b'H-NMR (δ, CDCts): 8.33 (
I H, d, J = 4.8 Hz), 7.51 (
IH, s), 7.22 (IH, dd, J=4.8, 2.
1Hz).

4.73 (2H, m), 4.59 (2H, s)
, 3.41 (3H.

S)・IR(CIll-', fl1m): 2950,160
0,1550,1470°1390°C3H1°BrN0□: Actual value 232°9880 Calculated value 232.9876 Reference example 5 Isonicotinic acid oxide (87N), phosphorus oxychloride (
350m) and phosphorus pentachloride (192,9) were mixed and refluxed for 3 hours. The reaction mixture was poured into ice and incubated overnight. The resulting precipitate was collected by filtration and recrystallized from ethanol.
-Chloro-4-pyridinecal? acid (65y, 66y)
I got it.

Melting point: 228.1-228.7°C IR (cm, KBr): 1718.1604.15
66.1458.1372°C6H4N02CL: Actual value 156.9940 Calculated value 156.9931 Reference example 6 Sodium borohydride (35,59,P) was dissolved in THF (
31) and stirred with a mechanical stirrer.

The mixture was cooled with ice water, and 2-chloro-4-pyridinecargenic acid (98,83#) was added in small portions.

After raising the temperature to room temperature, the mixture was stirred until hydrogen generation stopped, and boron trifluoride etherate (158 m7) was dissolved in THF (10
00d) The solution was added dropwise at room temperature over 3 hours. After the dropwise addition was completed, the mixture was stirred for 20 hours. The reaction solution was cooled with ice water, 1.5N hydrochloric acid was added to make P) 11-2, and THF
was distilled off under reduced pressure. A 4N sodium hydroxide solution was added to bring the mixture to -10~11, extracted with ethyl acetate, and the organic layer was washed with saturated brine.

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-chloro-
4-pyridine methanol (75, OI, 83 section) was obtained.

Melting point: 65.7-66.4°C 'H-NMR (δ, CDC15): 8.30 (I
H, d, J = 4.6 Hz), 7.37 (IH
, s ), 7.22 (IH, d , J = 4.6
Hz), 4.76 (2H, m), 2.70~
2.85 (IH, br-s).

IR (cm-', KBr): 3284.1600.1
394° Reference Example 7 2-chloro-4-pyridinemethanol (4,3(1),
Dimethoxymethane (20rR1) and p-)luenesulfonic acid-hydrate (0,57g) Wobenzene (20
The suspension was suspended at a temperature of 0.00 mm, passed through a Soxhlet extractor containing 3X Moleculer sheep (25#), and refluxed for 20 hours.

After cooling, the reaction solution was washed with saturated sodium bicarbonate solution,
After washing with water and drying, it was concentrated under reduced pressure.

By distilling the residue, 2-chloro-4-(methoxymethoxymethyl)pyridine (4,0,9,71) was obtained.

Boiling point: 118-120°C/5 mHg.

'H-NFillR(δ, CDCL3): 8.35
(I H, d, 5.6 Hz) 17.36 (
IH, i), 7.20 (IH, d, J=5.6Hz),
4.74' (2H, s), 4.61 (2H, @), 3.
41 (3H, a).

Example 1 Sodium hydride (60% purity, 4.81) was suspended in tetrahydrofuran (50%) and dimethylformamide (5%), and under water cooling, 2-promo-4-(methoxymethoxymethyl)pyridine (13,91%) was suspended in tetrahydrofuran (50%) and dimethylformamide (5%). and 4-(
A solution of 2-oxytetrahydropyranyl)-cig-2-buten-1-ol (13,25II) in tetrahydrofuran (2o01!Lt) was added dropwise, and the mixture was refluxed for 18 hours. After cooling, water (10 ml) was added and the mixture was concentrated under reduced pressure. The residue was taken up in benzene, filtered through Celite, and the filtrate was washed with water.
After drying, the solvent was distilled off and 2-C4-<2-oxytetrahydropyranyl)-ci-2-butene-1-oxy)
-4-(methoxymethoxymethyl)pyridine (16,P
, 82%).

'H-NMR (δ, CDCAs): 8.10 (
IH,d, J=5.4Hz), 6.84(I
H, d, J = 5.4 Hz), 6.74 (IH, s), 5
．． 84 (2H, a), 4.92 (2H, d, J = 6H
z), 4.71 (2H.

a), 4.66 (IH, t, J=3.6Hz), 4.5
5 (2H, a).

4.37 (IH, dd, J=11.7, 6.3Hz),
4.19 (IH.

dd, J=11.7, 6.3Hz), 3.8
7 (IH, m), 3.55 (IH, m), 3.40
(3H, s), 1.49-1.80 (6H.

m)・IR((*-', fi1m):2950,1620,1
570,1450°1320°C17H25N05: Actual value 323.1745 Calculated value 323.1733 Example 2 2-(4-(2-oxytetrahydropyranyl)-ai
m -2-Buten-1-oxy)-4-(methoxymethoxymethyl)pyrinone (16,9) was dissolved in ethanol (30
0d), pyridinium p-)luenesulfonate (1,3#) was added, and the mixture was stirred at 60°C (bath temperature) for 18 hours. After the reaction was completed, the mixture was made alkaline by adding saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried, and the solvent was distilled off to give 4-(4-(methoxymethoxymethyl)pyridyl-2-oxy] -cig -
2-Buten-1-ol (11,28#, 95 units) was obtained.

'H-NMR (δ, CDCl2): 8.05 (I
H,d, J=5.4Hz), 6.85(IH,d
, J=5.4Hz), 6.76(IH,s), 5.89
(IH, m), 5.76 (IH, m), 5.01 (2H
, d, J=6.9Hz), 4.71 (2H, m), 4.
56 (2H, a), 4.32 (2H, d, J = 6.0H
z), 3.40(3H,s)-IR(cm, fil
m): 3400.2950, 1620, 1560° 1420.1320° Cl2H17NO4: Actual value 239.1161 Calculated value 239.1158 Example 3 Su4-(4-(methoxymethoxymethyl)pyridyl-2-
Oxy] -cis-2-buten-1ol (2I) was dissolved in dichloromethane (3 oml), anhydrous potassium carbonate (3 g) was suspended, and thionyl chloride (1,4
, 1 in dichloromethane (5id) was added dropwise. After stirring for 1 hour under the same conditions, insoluble matter was filtered off and concentrated under reduced pressure.

The residue was dissolved in toluene (100 d), potassium phthalimide (z, 3y) and tetra-n-butylammonium hydrogen sulfate (305 d) were suspended, and the mixture was refluxed for 18 hours. After cooling, insoluble matter was removed by filtration, diluted with benzene, and IN-hydroxylated). After washing with IJum solution, water, and drying, the solvent was distilled off to give N-(4-(4-(methoxymethoxymethyl)pyridyl). -2-oxy)-elm-2-butenyl]phthalimide (2,97,197%) was obtained.

Melting point: 69.2-70.1°C (ethanol ethyl ether).

"H-NMR (δ, CDCLs): 8.13 (
IH, d, J=5.4Hz), 7.84(2H
, m), 7.72 (2H, m), 6.85 (I
H, d, J=5.4Hz), 6.76(IH
, s ), 5.92 (IH, m), 5.68 (IH,
m), 5.11 (2H, d, J=6.6Hz), 4.7
1 (2H, s), 4.56 (2H, s), 4
．． 47 (2H, d, J=7.2Hz), 3.41(
3H,s).

IR (cm, , KBr): 2960, 1720.1
630,1570.1400,1320°C2oH2o
N205: Actual value 368.1360 Calculated value 368.
1372 Example 4 N-(4-(4-(methoxymethoxymethyl)pyridyl-2-oxy)-elm-2-butene]phthalimide (3,285,1id) was dissolved in methanol (100+ al
), hydrazine-hydrate (1.48 g) was added thereto, and the mixture was refluxed for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue (crystals) was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried, and the solvent was distilled off.
Amino-4-[4-methoxymethoxymethyl)pyridyl-2-oxy]-aim-2-butene (1,84F, 86
%) was obtained.

1H-NMR (δ, CDCl2): 8.10 (
IH, d, J=4.5Hz), 6.85 (IH,
d, J=4.5Hz), 6.75 (LH, m), 5.7
4 (2H, m), 4.89 (2H, m), 4.71 (2
H, s), 4.55 (2H, a), 3.45 (2H, m
), 3.40 (3H, s).

1.49 (2H, br-s).

IR (crIL-', fl1m): 3400,330
0.2950,1620°1570.1430,132
0°C1□H18N203: Actual value 238.1294 Calculated value 238.1317 Example 5 1-amino-4-[:4-(methoxymethoxymethyl)
pyridyl-2-oxy] cim -2-butene (1,
7,! i') in tetrahydrofuran (100TIL)
Furfurylthioacetic acid p-nitrophenyl ester (2.34 g) was dissolved in the solution and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, the residue was taken up in ethyl acetate, and IN-
After washing with an IJ solution, washing with water, and drying, the solvent was distilled off to give N-[4-(4-(methoxymethoxymethyl)).
pyridyl-2-oxy)-cis-2-butenyl]-2
-(Furfurylthio)acetamide (2,5II, 89
I was disappointed.

'H-NMR (δ, CDCt3): 8.12 (
I H, d 1J=4.2 Hz ), 7.36 (I
H, m), 6.86 (2H, d, J=4.2Hz), 6
．． 77 (LH, a).

6.29 (IH, dd, J=3.3.1.8Hz),
6.20 (IH, d, J=3.9Hz), 5.
85 (IH, m), 5.62 (IH, m), 4.93 (
2H, d, J = 6.3Hz), 4.72 (2H, s),
4.56 (2H, a ), 3.99 (2H, t, J=5
．． 4Hz), 3.74 (2H, s), 3.41 (3H,
s), 3.22 (2H, s).

IR (cm, film): 3350.2950.1
660.1620, 1560.1420-C4, H24
N205S: Actual value 392.1402 Calculated value 392.1
405 Example 6 N-(4-(4-(methoxymethoxymethyl)pyridyl-2-oxy-elm-2-butenyl:)-2-(furfurylthio)acetamide (200In9) was dissolved in methanol (15-) and p -) Luenesulfonic acid--hydrate (10 ml) was added and R-flowed. After the reaction was completed, the mixture was cooled, made alkaline by adding saturated sodium bicarbonate solution, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and dried.
The solvent was distilled off. The residue was separated by column chromatography (mobile phase: benzene/ethyl acetate) and N-(4-(4
-(hydroxymethyl)pyridyl-2-oxy)-el
m-2-Butenyl:)-2-(furfurylthio)acetamide (871n9), 50) was obtained.

'H-NMR (δ, CDC23): 8.11 (I
H,d, J=6Hz), 7.35(IH,d.

1.5Hz), 6J36 (2H, d, J-4, 2Hz)
, 6.79 (IH, s), 6.29 (IH, dd, J=
3.3, 1.5Hz), 5.84 (IH, m), 5.6
0(IH, m).

4.93 (2H, d, J-5, 7Hz), 4.68 (2
H,s), 3.98 (2H.

t, J=6.6Hz), 3.73(2)I, s)
, 3.22 (2H,s).

IR(m-', fi1m): 3400.2950.1
660.1620.1570°1420.1400°C17H2oN204S: Actual value 348.1140
Calculated value 348.1143 Example 7 N-[4-[4-(hydroxymethyl)pyridyl-2-
Oxy]-clm-2-butenyl]-2-(furfurylthio)acetamide (900 µ) and hydrethylamine (834 µ) were dissolved in chloroform (30d),
A solution of methanesulfonyl chloride (9461n9) in chloroform (5111) was added dropwise under water cooling. After stirring for 1 hour, the reaction solution was washed with saturated hydrogen carbonate solution, washed with water,
After drying, the solvent was distilled off. Dissolve the residue in ethanol,
Biiridine (1,17#) was added under water cooling, and the mixture was refluxed for 6 hours.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate for 10 minutes.
% acetic acid aqueous solution. Potassium carbonate (solid) in the aqueous layer
The mixture was made alkaline by adding and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off to give N-[4-[4-(
piperidinomethyl)pyridyl-2-oxy] -cim
-2-Butenyl]-2-(furfurylthio)acetamide (820In 9.79%) was obtained.

'H-NMR (δ1CDCLs): 8.06 (
I H, d, J = 4.2'Hz), 7.35 (I
H, d, J=1.8Hz), 6.88(2H
, d, J==4.2Hz).

6.74 (IH, @), 6.29 (IH, d d,
J=4.2.1.8Hz).

6.20 (IH, d, J = 1.8Hz), 5.86 (
LH, m).

5.64 (IH, m), 4.91 (2H, d, J
=7.2Hz).

3.99 (2H, t, J=6.0Hz), 3
．． 74 (2H,a).

3.41(2H,a), 3.22(2f(,a)
, 2.37 (4H, m).

1.58 (4H, m), 1.44 (2H, m).

rR (crIL-', film): 3350.295
0.1670.1620.1570°1430, 142
0.1310°C2□H2,N303S: Actual value 415.1927 Calculated value 415.1929 Reference example 8 N-[4-[:4-(piperidinomethyl)pyridyl-2
-oxy]-cig-2-butenyl]-2-(fur7lylthio)acetamide (8zOda) was dissolved in dichloromethane (30 ml), cooled with ice-salt, and dissolved in m-chloroperbenzoic acid (493). A dichloromethane (15m) solution was added dropwise. After stirring for 15 minutes under the same conditions, the reaction solution was washed with cold saturated hydrogen carbonate solution, washed with water, and dried.
The solvent was distilled off to give N-[4-[4-(piperidinomethyl)pyridyl-2-oxy] -cim -2-butenyl]-
2-(furfurylsulfinyl)acetamide (387
9.45%).

Melting point: 92.7-94.9°C') I-NMR (δ, CDCLs): 8.04
(IH, d, J==5.I Hz) 17.44(
IH, d, J = 1.6Hz), 7.15-7.25 (I
H, br-s).

6.73 (IH, s), 6.47 (IH, d, J=5.
1Hz).

6.40 (IH, dd, J=3.1, 1.6Hz),
5.80-5.90 (lH, m), 5.60-5.75
(LH, m), 4.93 (2H, t.

J=6.1Hz), 4.38(IH,d, J=14.2
Hz), 4.15 (2H, dd, J=6.1.6.1H
z), 4.14 (lH, d, J=14.2Hz), 3.
69 (IH, d, J = 14.2Hz), 3.40 (2H
, 5) = 3.34 (IH, d, J = 14.2 Hz), 2
．． 30-2.45 (4H, m), 1.50-1.65 (
4H, m), 1.40-1.50 (2H, m).

IR (crrL, KBr): 3350.2950,1
645,1620°1530.1410,1290,1
041°C2□H29N, 04S2 actual measurement value 431.1
883 Calculated value 431.1879 (Effect of the invention) The above-mentioned formula (1) of the present invention and the pyridyloxy derivative represented by (ID) can be easily produced. Compound B has excellent histamine H2 receptor antagonism.

Patent applicant: Fujirebio Co., Ltd.

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A is a hydroxyl group or a protected hydroxyl group, Y is -C
It is a group represented by H_2CH_2- or -CH=CH-, and Z is a halogen atom, an amino group, a phthalimide group, a hydroxyl group, or a protected hydroxyl group. ) Pyridyloxy derivatives. 2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A is a halogen atom, hydroxyl group or protected hydroxyl group, Y is -CH_2CH_2- or -CH=CH-
It is a group represented by, and n is 0, 1 or 2. )
A pyridyloxy derivative represented by