JP3202106B2 - Method for producing aminobutene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate for producing a therapeutic agent for anti-peptic ulcer and an aminobutene useful as a therapeutic agent for anti-peptic ulcer having an acid secretion inhibitory action based on histamine H ₂ receptor antagonism. The present invention relates to a method for producing a derivative.

[0002]

2. Description of the Related Art The general formula (I-1)

Embedded image And the general formula (I-2)

Embedded image (Wherein, R ¹ is a hydrogen atom, a hydroxyl-protecting group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and R ² is a hydrogen atom, an alkoxyl group, a substituted or unsubstituted group. Is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group.) Is known as an intermediate for producing an anti-peptic ulcer therapeutic agent. (See JP-A-63-2253715).

Further, the following general formula

Embedded image (Wherein, R ¹¹ represents a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, a piperidinomethyl A dimethylaminomethyl group, and n is 0,
1 or 2. The aminobutene derivative represented by
It is also known as a pyridyloxy derivative, and is known as an anti-peptic ulcer therapeutic agent having an acid secretion inhibitory action based on histamine H ₂ receptor antagonism and an intermediate for producing such a therapeutic agent (JP-A-63-1988). 2253715).

General formula

Embedded image The aminobutene derivative represented by is conventionally produced by a so-called Gabriel reaction in which a phthalimide compound is reacted with a halogen compound to introduce an amino group into the halogen compound.

As another method, a method is known in which the above aminobutene derivative of the formula (I-2) uses an azide compound instead of the phthalimide compound used in the above reaction (see JP-A-2-1219695). . Further, another method using a dioxapiene derivative (see JP-A-3-2093495) is also known.

However, the above method requires a large number of steps, expensive reagents, many by-products, a low yield of the aminobutene derivative, and a disadvantage in the production of the aminobutene derivative. The industrial production method has many problems, for example, because it is extremely difficult to separate the target aminobutene derivative from the product.

Further, the aminobutene derivative represented by the general formula (I-1) is conventionally obtained by acylating the aminobutene derivative represented by the general formula (I-2). It is difficult to obtain an aminobutene derivative represented by the general formula (I-1) using the aminobutene derivative of I-2) as a starting material.

Accordingly, an aminobutene derivative of the general formula (I-3) called a pyridyloxy derivative can be produced by reacting an amine compound with a carboxylic acid compound (JP-A-63-225371 and JP-A-63-225371). 1-19 Kaihei
However, the conventional method for producing an amine compound used as a starting material for producing the above-mentioned pyridyloxy derivative requires a large number of production steps and requires complicated treatment using expensive reagents. In addition, there are problems such as that many by-products are generated and the yield of the target amine compound is extremely low.

On the other hand, a carboxylic acid compound, which is another starting material for producing the aminobutene derivative of the general formula (I-3), is used as an activated ester derivative. Must use expensive reagents. Further, in the condensation reaction between the amine compound and the carboxylic acid compound, a large amount of by-products are generated, and the desired aminobutene derivative represented by the general formula (I-3) is separated from the by-products. Requires operation. Therefore, the above method is not suitable as an industrial production method of the aminobutene derivative (I-3).

Aminobutenol used as an intermediate for producing the aminobutene derivative

Embedded image A conventional method for (1) a method of catalytically reducing aminobutenol [Andree Marszak-Flenry et al., Bull. Soc. Chim.
rance, 6 , 1270 (1963)], (2) A method of reductively opening a dihydrooxazine [O. Wichterle et. al., Coll.
ect. Czech. Chem. Commun, 15 , 309 (1905)], and (3) a method of releasing aminobutenol by deprotection from phthalimide-protected aminobutenol (JP-A-3-209349). I have.

In the above method (1), it is difficult to stop the catalytic reduction reaction so as to selectively obtain aminobutenol, and it is also possible to control the geometrical isomerism of the double bond of the product. It has the disadvantage of being difficult. Furthermore, the method (2) has a disadvantage that it is difficult to industrially obtain dihydrooxazine, which is a raw material for synthesizing aminobutenol, and the method (3) is complicated in operation. It has the disadvantage that it is very difficult to isolate the desired aminobutenol.

[0012]

Accordingly, a first object of the present invention is to provide a compound of the following general formula (I) which does not have the drawbacks found in the above-mentioned conventional method.

Embedded image (Wherein, R ¹ is a hydrogen atom, a hydroxyl-protecting group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and R ² is a hydrogen atom, an alkoxyl group, a substituted or unsubstituted group. An alkyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and R ³ is a hydrogen atom, a substituted or unsubstituted acyl group, an alkoxycarbonyl group, a sulfonyl group or a substituted alkyl group. The present invention provides a method for producing an aminobutene derivative represented by the formula:

A second object of the present invention is to provide a compound represented by the following general formula (I-
1)

Embedded image (In the formula, R ¹ and R ² are the same as the groups defined in the general formula (I).) The present invention provides a method for producing an aminobutene derivative represented by the formula:

A third object of the present invention is to provide a compound represented by the following general formula (I-
2)

Embedded image (In the formula, R ¹ is the same as the group defined in the general formula (I).) A method for producing an aminobutene derivative represented by the formula:

A fourth object of the present invention is to provide a pyridyloxy derivative represented by the following general formula (I-3)

Embedded image (Wherein, R ¹¹ represents a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, a piperidinomethyl Or a dimethylaminomethyl group).

A fifth object of the present invention is to provide a compound represented by the following general formula (I-
3a)

Embedded image (Wherein, R ¹¹ is the same as the group defined in the formula (I-3), m is n + 1, where n is 0 or 1), and a method for producing an aminobutene derivative represented by the formula: That is.

Any or all of the above aminobutene derivatives may be used as an intermediate for producing an antipeptic ulcer remedy or an antipeptic ulcer treatment having an acid secretion inhibitory action based on histamine H ₂ receptor antagonism. Useful as an agent.

[0018]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the desired aminobutene derivative can be obtained easily and in large quantities by using the following reaction, and completed the present invention. That is, the general formula (I)
A first object of the present invention for producing an aminobutene derivative represented by the following formula is a reaction between a butene derivative represented by the general formula (II) and an amide derivative represented by the general formula (II) by the following reaction formula ( It can be achieved by reacting according to A).

Embedded image (R ¹ , R ² and R ³ are respectively the same as the groups defined in the formula (I), and X is a hydroxyl group, a halogen atom, a sulfonyloxy group, an acyloxy group or an alkoxycarbonyloxy group; (It is a group which forms a cyclic sulfite, sulfate or carbonate together with R ^1, and Y is an alkali metal atom, an alkaline earth metal atom or a hydrogen atom.)

A second object of the present invention for producing the aminobutene derivative represented by the general formula (I-1) is to provide an amide derivative represented by the general formula (III) wherein R ³ is hydrogen in the reaction formula (A). Or by deprotecting the aminobutene derivative represented by the general formula (Ia) according to the following reaction formula (B).

Embedded image (Wherein, R ¹ is a hydrogen atom, a hydroxyl-protecting group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and R ² is hydrogen, an alkoxyl group, a substituted or unsubstituted An alkyl group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and R ^3a is a substituted or unsubstituted acyl group, an alkoxycarbonyl group, a sulfonyl group or a substituted alkyl group.)

The third object of the present invention for producing the aminobutene derivative represented by the above general formula (I-2) is to convert the aminobutene derivative represented by the general formula (I) according to the following reaction formula (C). This can be achieved by performing deprotection on the aminobutene derivative represented by the general formula (I-1) according to the following general formula (D).

Embedded image

The fourth object of the present invention for producing the aminobutene derivative represented by the general formula (I-3) can be achieved by performing a condensation reaction according to the above-mentioned reaction formula (A).

Embedded image

More specifically, the butene derivative of the general formula (II) is a butene derivative wherein R ¹ is

Embedded image (Wherein, R ¹¹ is a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, a piperidinomethyl A dimethylamino group, and X is a halogen atom, a hydroxyl group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a benzenesulfonyloxy group), and the amine derivative represented by the general formula (III) Is that R ²

Embedded image (Wherein n is 0, 1 or 2), and by using an amide derivative of the general formula (III) wherein R ³ is a hydrogen atom, the following general formula (I-3)

Embedded image Can be produced.

The aminobutene derivative represented by the above formula (I-3) is also called a pyridyloxy derivative.

A fifth object of the present invention for producing the aminobutene represented by the general formula (I-3a) is to prepare the aminobutene represented by the general formula (I-3a)
It can be achieved by oxidizing the aminobutene derivative represented by 3).

Embedded image (Wherein, R ¹¹ is the same as defined in the general formula (I-3), m is n + 1, provided that n is 0,
1 or 2. )

According to the present invention, as described above, the butene derivative represented by the general formula (I-2) is reacted with the amide derivative represented by the general formula (III) according to the following reaction formula (A). Thus, a method for producing an amine derivative represented by the general formula (I) is provided.

Embedded image (Wherein, R ¹ is a hydrogen atom, a hydroxyl-protecting group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and X is a hydroxyl group, a halogen atom, a sulfonyloxy group, an acyloxy group. Or an alkoxycarbonyloxy group or a group which forms a cyclic sulfite, sulfate or carbonate together with R ¹ , Y is an alkali metal atom, an alkaline earth metal atom or a hydrogen atom; ² is a hydrogen atom, an alkoxyl group,
A substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, and R ³ represents a hydrogen atom, a substituted or unsubstituted acyl group, an alkoxycarbonyl group, a sulfonyl group; Or a substituted alkyl group. )

In the butene derivative of the general formula (II), examples of the hydroxyl-protecting group represented by R ¹ include tetrahydropyranyl, methoxymethyl, benzyloxymethyl, ethoxyethyl, 2-methoxy Ethyl group, t-butyl group, benzyl group, 4-methoxybenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, formyl group, acetyl group, n-propionyl group , Iso-propionyl group, n-butyryl group, i
so-butyryl group, valeryl group, iso-valeryl group,
Pivaloyl, benzoyl, naphthoyl, methoxycarbonyl, ethoxycarbonyl, iso-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phenyloxycarbonyl, etc. Can be.

In the butene derivative represented by the general formula (II), examples of the aromatic hydrocarbon group represented by R ¹ include:
Phenyl group, naphthyl group, anthranyl group, 3- (tetrahydropyranyl-2-oxymethyl) phenyl group, 3
-(Methoxymethoxymethyl) phenyl group, 3-formylphenyl group, 3- (diethoxymethyl) phenyl group,
A 3- (1,3-dioxolan-2-yl) phenyl group,
3- (piperidinomethyl) phenyl group, 3- (dimethylaminomethyl) phenyl group, 4- (tetrahydropyranyl-2-oxymethyl) phenyl group, 4- (methoxymethoxymethyl) phenyl group, 4-formylphenyl group,
4- (diethoxymethyl) phenyl group, 4- (1,3-
Dioxolan-2-yl) phenyl group, 4- (piperidinomethyl) phenyl group, 4- (dimethylaminomethyl)
Phenyl group, 2- (tetrahydropyranyl-2-oxymethyl) phenyl group, 2- (methoxymethoxymethyl)
Phenyl group, 2-formylphenyl group, 2- (diethoxymethyl) phenyl group, 2- (1,3-dioxolane-
Examples thereof include a 2-yl) phenyl group, a 2- (piperidinomethyl) phenyl group, and a 2- (dimethylaminomethyl) phenyl group.

In the aminobutene derivative represented by the general formula (II), examples of the heterocyclic group represented by R ¹ include pyridyl, quinolyl, iso-quinolyl, thienyl, furyl, and 3- ( A tetrahydropyranyl-2-oxymethyl) -2-pyridyl group, a 3- (methoxymethoxymethyl) -2-pyridyl group, a 3-formyl-2-pyridyl group, a 3- (diethoxymethyl) -2-pyridyl group, 3
-(1,3-dioxolan-2-yl) -2-pyridyl group, 3- (piperidinomethyl) -2-pyridyl group, 3-
(Dimethylaminomethyl) -2-pyridyl group, 4- (tetrahydropyranyl-2-oxymethyl) -2-pyridyl group, 4- (methoxymethoxymethyl) -2-pyridyl group, 4-formyl-2-pyridyl group , 4- (diethoxymethyl) -2-pyridyl, 4- (1,3-dioxolan-2-yl) -2-pyridyl, 4- (piperidinomethyl) -2-pyridyl, 4- (dimethylaminomethyl ) -2-pyridyl group, 5- (tetrahydropyranyl-
2-oxymethyl) -2-pyridyl group, 5- (methoxymethoxymethyl) -2-pyridyl group, 5-formyl-2
-Pyridyl group, 5- (diethoxymethyl) -2-pyridyl group, 5- (1,3-dioxolan-2-yl) -2-
Examples thereof include a pyridyl group, a 5- (piperidinomethyl) -2-pyridyl group, and a 5- (dimethylaminomethyl) -2-pyridyl group.

In the butene derivative represented by the general formula (II), examples of the halogen atom represented by X include a chlorine atom, a bromine atom and an iodine atom. Further, in the butene derivative represented by the general formula (II), examples of the sulfonyloxy group represented by X include a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-
Examples thereof include a toluenesulfonyloxy group and an imidazosulfonyloxy group. In the butene derivative represented by the general formula (II), examples of the acyloxy group represented by X include a formyloxy group, an acetyloxy group, an n-propionyloxy group, an iso-propionyloxy group, and an n-butyryloxy group. , Iso-butyryloxy group, valeryloxy group, iso-valeryloxy group, pivaloyloxy group, benzoyloxy group, naphthoyloxy group and the like.

In the butene derivative represented by the general formula (II), examples of the alkoxycarbonyloxy group represented by X include methoxycarbonyloxy, ethoxycarbonyloxy, iso-butoxycarbonyloxy, allyloxy Examples thereof include a carbonyloxy group, a benzyloxycarbonyloxy group, a 9-fluorenylmethoxycarbonyloxy group, and a phenyloxycarbonyloxy group.

Specific examples of the butene derivative represented by the general formula (II) include 4,7-dihydro-1,3,2-dioxathiepin-2-oxide and 4,7-dihydro-1,3,2-dioxathiepin-2. , 2-dioxide, 4,7-dihydro-1,3,2-dioxepin-2-oxide and the like.

In the amide derivative of the general formula (III), examples of the alkali metal atom represented by Y include a lithium atom, a sodium atom, a potassium atom, a rubidium atom, a cesium atom and the like. Examples of the alkaline earth metal atom include a magnesium atom and a calcium atom.

Further, in the amide derivative of the general formula (III), examples of the alkoxy group represented by R ² include a methoxy group, an ethoxy group, a propoxy group, an iso-butoxy group, a t-butoxy group and a benzyloxy group. And the like.

In the amide derivative of the general formula (III), examples of the alkyl group represented by R ² include a methyl group, an ethyl group, a propyl group, a butyl group, a chloromethyl group, a dichloromethyl group and a trichloromethyl group. , Trifluoromethyl group, benzyl group, furfurylthiomethyl group,
Furfurylsulfinylmethyl group, furfurylsulfonylmethyl group and the like can be mentioned.

In the amide derivative of the formula (III), examples of the aromatic hydrocarbon group represented by R ² include a phenyl group, a naphthyl group and an anthryl group. These aromatic carbon groups may have a substituent such as an alkyl group, an alkoxyl group, a halogen atom, a nitro group, and an amino group.

In the amide derivative of the formula (III), examples of the heterocyclic group represented by R ² include a pyridyl group, a quinolyl group, an iso-quinolyl group, a thienyl group, a furyl group and the like. These heterocyclic groups may further have a substituent such as an alkyl group, an alkoxyl group, a halogen atom, a nitro group, and an amino group.

In the amide derivative of the general formula (III), examples of the acyl group represented by R ³ include formyl, acetyl, propionyl, butyryl, valeryl, chloroacetyl, dichloroacetyl, Trichloroacetyl group, trifluoroacetyl group, phenylacetyl group, benzoyl group, naphthoyl group, furoyl group,
Examples thereof include a tenoyl group, a nicotiyl group, and an iso-nicotiyl group.

In the amide derivative represented by the general formula (III), examples of the alkoxycarbonyl group represented by R ³ include a methoxycarbonyl group, an ethoxycarbonyl group, and an i.
Examples thereof include a so-butoxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, and a phenyloxycarbonyl group.

In the amide derivative of the general formula (III), examples of the sulfonyl group represented by R ³ include methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, imidazosulfonyl and the like. Can be mentioned. In the amide derivative of the general formula (III), examples of the substituted alkyl group represented by R ³ include a benzyl group, a 4-methoxybenzyl group, and a 2,4-dimethoxybenzyl group.

According to the following reaction formula (A), a butene derivative of the general formula (II) is reacted with an amide derivative of the general formula (III) to produce an aminobutene derivative of the general formula (I). The butene derivative (II) is easily available 2
-Can be easily prepared from butene-1,4-diol.

Embedded image

In the butene derivative of the general formula (II), X
Represents one of the groups described above, which undergoes a condensation reaction with the amide derivative of the general formula (III).

The butene derivative of the general formula (II) and the general formula (II)
The reaction with the amide derivative of I) may be performed by mixing both.
Thereby, an aminobutene derivative of the general formula (I) can be obtained. In order to promote such a reaction smoothly, it is preferable to carry out the reaction in the presence of a base. Examples of a base that can be used include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, potassium p-butoxide,
Examples thereof include alkoxides such as sodium methoxide, alkali metal hydrides such as sodium hydride and lithium hydride, alkali metal atoms such as sodium and potassium, and organic amines such as triethylamine and pyridine. The amount of the base to be used is generally 0.1 to 2.0 equivalents to the butene derivative represented by the general formula (II).

The above reaction is preferably carried out in an inert solvent, for example, aromatic hydrocarbon groups such as benzene and toluene, THF, dioxane, and DME.
Etc., halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, etc., ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, DM
F, dimethylacetamide, DMSO, or the like can be used.

The above-mentioned reaction proceeds at -100 ° C to 200 ° C, but is preferably performed at 0 ° C to 100 ° C for efficient reaction.

Further, in order to carry out the reaction more efficiently,
Catalysts such as tetrabutylammonium sulfate, tetrabutylammonium chloride, triethylbenzylammonium chloride, crown ethers, and hexadecyltributylammonium bromide can be used. The amount used is based on the butene derivative represented by the general formula (II).
0.001 to 1 equivalent.

The aminobutene derivative represented by the following general formula (I-1) can be produced in the same manner as described above.

Embedded image (In the formula, R ¹ or R ² is the same as the group defined in the general formula (I).)

Specifically, by reacting a butene derivative of the general formula (II) with an amide derivative of the general formula (III-1) according to the following reaction formula, the aminobutene of the general formula (I-1) Derivatives can be produced.

Embedded image (In the formula, R ² is the same as the group defined in the general formula (III).)

Further, according to the present invention, the compound represented by the general formula (II-1):
By reacting the pyridylbutenyl derivative of formula (III) with the acetamide derivative of formula (III-2), an aminobutene derivative of formula (I-2) called a pyridyloxy derivative can be produced as follows.

Embedded image (Wherein, R ¹¹ is a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, X is a hydroxyl group, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-
A substituted sulfonyloxy group such as a toluenesulfonyloxy group or an imidazosulfonyloxy group;
Or 2. )

The pyridyloxybutenyl derivative represented by the general formula (II-1) can be obtained, for example, by reacting a 2-chloropyridine derivative having a substituent at the 4-position with a 2-butenol derivative. It can be easily manufactured.

The acetamide derivative represented by the general formula (II-2) can be obtained by reacting furfurylmercaptan with 2-chloroacetamide or by reacting 2-furfurylsulfnylacetic acid = p-nitrophenol ester with ammonia. It can be produced by reacting.

The reaction between the pyridyloxybutenyl derivative represented by the general formula (II-1) and the acetamide derivative represented by the general formula (III-2) may be performed by mixing both. In order to carry out the reaction smoothly, the reaction is preferably performed in the presence of a base. Examples of the base that can be used in this reaction include alkoxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and lithium hydride, and alkali metal atoms such as sodium and potassium. And organic amines such as triethylamine and pyridine. The amount of the base to be used is generally 0.1 to 2.0 equivalents to the pyridyloxybutenyl derivative represented by the general formula (II-1).

The above reaction is desirably carried out in an inert solvent. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as THF, dioxane and DME; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, methyl ethyl ketone, acetonitrile, DM
F, dimethylacetamide, DMSO, or the like can be used.

The above reaction proceeds at -100 ° C. to 200 ° C., but is preferably carried out at 0 ° C. to 100 ° C. for efficient reaction.

In order to carry out the above reaction more efficiently,
For example, catalysts such as tetrabutylammonium sulfate, tetrabutylammonium chloride, triethylbenzylammonium chloride, crown ether, and hexadecyltributylphosphonium bromide can be used. The amount of use is 0.001 to 1 equivalent to the pyridyloxybutenyl derivative represented by the general formula (II-1).

Further according to the present invention, according to the following reaction formula:
An aminobutene derivative of the general formula (I-3) can be produced by reacting the pyridyloxybutenyl derivative of the general formula (II-1) with an imide derivative of the general formula (III-3).

Embedded image (Wherein, R ¹¹ and X are the same as defined above, and R ¹² is a group having 1 to 6 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butenyl group, a pentyl group or a hexyl group. An alkyl group, an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, provided that the group may have a substituent,
Methoxy, ethoxy, propoxy, butoxy,
1-6 carbon atoms such as pentyloxy group and hexyloxy group
And an aryloxy group such as an alkoxyl group, a phenoxy group or a naphthyloxy, wherein n is 0, 1 or 2. )

The imide derivative of the general formula (III-3) is
After the reaction of furfuryl mercaptan with 2-chloroacetamide, acylation or the reaction of 2-furfurylsulfnylacetic acid = p-nitrophenyl with ammonia to thereby acylate the intermediate thus formed. Can be manufactured.

The reaction between the pyridyloxybutenyl derivative of the general formula (II-1) and the imide derivative of the general formula (III-3) can be carried out by mixing the two.
Although the aminobutene derivative of 3) can be obtained, it is preferable to carry out the reaction in the presence of a base in order to smoothly carry out the reaction.

Examples of the base that can be used in the above reaction include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as potassium carbonate and sodium carbonate, sodium methoxide and sodium ethoxide. Alkoxides such as potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metals such as sodium and potassium; organic amines such as triethylamine and pyridine. The amount of the base to be used is generally 0.1 to 2.0 equivalents to the pyridyloxybutenyl derivative represented by the general formula (II-1).

The reaction is preferably carried out in an inert solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene, THF, dioxane, DM
Ethers such as E, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate;
Methyl ethyl ketone, acetone, acetonitrile, DM
F, dimethylacetamide, DMSO, or the like can be used.

The above reaction proceeds at -100 ° C. to 200 ° C., but is preferably performed at 0 ° C. to 100 ° C. for efficient reaction.

In order to carry out the above reaction more efficiently, for example, tetrabutylammonium sulfate, tetrabutylammonium chloride, triethylbenzylammonium chloride,
A catalyst such as crown ether and hexadecyltributylphosphonium bromide can be used. The amount of use is 0.001 to 1 equivalent based on the pyridylbutenyl derivative represented by the general formula (II-1).

According to the present invention, the aminobutene derivative represented by the general formula (I-1) is deprotected from the aminobutene derivative represented by the general formula (Ia) according to the following reaction formula (B). Can be produced.

Embedded image

Further, according to the present invention, the following reaction formula (C)
Deprotection of the aminobutene derivative represented by the general formula (I) or the following reaction formula (D)
The aminobutene derivative represented by the general formula (I-1) is deprotected according to
The aminobutene derivative of 2) can be produced.

Embedded image

In the above reaction formulas (B), (C) and (D), R ¹ , R ² or R ³ are each represented by the general formula (I)
And R ^3a represents a substituted or unsubstituted acyl group, alkoxycarbonyl group, sulfonyl group or substituted alkyl group.

In the aminobutene derivative of the formula (Ia), examples of the acyl group represented by R ^3a include a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, a chloroacetyl group, a dichloroacetyl group and a trichloroacetyl group. Acetyl group, trifluoroacetyl group, phenylacetyl group, benzoyl group, naphthoyl group, furoyl group, tenoyl group, nicotinoyl group, and iso-nicotinoyl group.

In the aminobutene derivative of the formula (Ia), the alkoxycarbonyl group represented by R ^3a includes a methoxycarbonyl group, an ethoxycarbonyl group,
There are an iso-butoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, and a phenyloxycarbonyl group.

In the aminobutene derivative of the general formula (Ia), examples of the sulfonyl group represented by R ^3a include methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and imidazosulfonyl. is there.

In the amide derivative of the general formula (Ia), the substituted alkyl group represented by R ^3a includes, for example,
There are a benzyl group, a 4-methoxybenzyl group and a 2,4-dimethoxybenzyl group.

In the above reaction formulas (B), (C) and (D), when at least one of R ² CO—, R ^3a or R ³ is an acyl group, the following (1-1), (1) -2),
Deprotection can be performed by any of the methods (1-3) and (1-4).

(1-1) In the presence of an acid or an alkali, the reaction temperature is -10 ° C to 150 ° C, preferably 0 ° C to 1 ° C.
Solvolysis at 20 ° C.

Examples of the acid that can be used for the solvolysis include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, oxalic acid, fumaric acid, maleic acid, acetic acid, trifluoroacetic acid, and the like.
Trichloroacetic acid, p-toluenesulfonic acid, camphor
Organic acids such as sulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid are included.

Examples of the base used in the solvolysis include lithium hydroxide, sodium hydroxide,
Examples include potassium hydroxide, calcium oxide, barium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium t-butoxide, and ammonia water.

Solvents that can be used in the above solvolysis include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran, 1,4-dioxane, and diethoxyethane. -Tels, methanol, ethanol
Alcohol, iso-propanol, n-butanol, t-butanol and the like, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide,
Examples include dimethylacetamide, dimethylsulfoxide, water and the like. These solvents can be used alone or as a mixture.

(1-2) Water, methanol, ethanol
In an alcohol such as isopropanol, iso-propanol, n-butanol or t-butanol, the compound represented by the general formula (I)
a) reacting the aminobutene derivative of any of (I) and (I-1) with hydrazine at a reaction temperature of -10 ° C to 150 ° C;
C., preferably at 0 to 120.degree.

(1-3) An aminobutene derivative of any of the above formulas (Ia), (I) and (I-1) and lithium borohydride in one of the following solvents:
A method of reacting with a metal hydride such as sodium borohydride or lithium aluminum hydride. The reaction temperature is
The temperature is from -10 ° C to 150 ° C, preferably from 0 ° C to 120 ° C.

Solvents usable in the above reaction include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran, 1,4-dioxane and dimethoxyethane. , Methanol, ethanol, iso-
Examples thereof include alcohols such as propanol, n-butanol, and t-butanol, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and water. These solvents can be used alone or as a mixture.

(I-4) In the above reaction formulas (B), (C) and (D), among R ² CO—, R ^3a or R ³ ,
When at least one is a formyl group, the deprotection is carried out in any of the following aprotic solvents with a primary amine or a secondary amine and the above-mentioned general formula (Ia),
A method of reacting with either the aminobutene derivative (I) or (I-1). Reaction temperature is -10 ° C to 150 ° C
And preferably 0 ° C to 120 ° C.

The primary amine which can be used in the above reaction includes, for example, methylamine, ethylamine, propylamine, iso-propylamine, butylamine, iso-butylamine, s-butylamine, t-butylamine, cyclohexylamine, benzyl Amines. Examples of the secondary amine include dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, pyrrolidine, piperidine, morpholine, and piperazine.

Examples of the aprotic solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran, 1,4-dioxane and dimethoxyethane.
Examples thereof include ketones such as ters, acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like. These solvents can be used alone or as a mixture.

In the above reaction formulas (B), (C) and (D), when at least one of R ² CO—, R ^3a or R ³ is a formyl group, as an alternative method, it may be in any of the following solvents: Wherein the aminobutene derivative of any of the above general formulas (Ia), (I) or (I-1) is reacted with an oxidizing agent such as hydrogen peroxide at a reaction temperature of -10 ° C to 150 ° C, preferably 0 ° C to 120 ° C. Deprotection can be carried out by reacting at ° C.

Solvents that can be used in the above reaction include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, diethoxyethane and the like. Ethers, methanol, ethanol,
iso-propanol, n-butanol, t-butanol
And ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, water and the like. These solvents can be used alone or as a mixture.

In the above reaction formulas (B), (C) and (D), when at least one of R ² CO—, R ^3a or R ³ is a sulfonyl group, the following (2-1), (2-)
Deprotection can be performed by any of the methods 2) and (2-3).

(2-1) Reaction temperature -10 ° C. to 150
Solvolysis in the presence of an acid at 0 ° C, preferably 0 ° C to 120 ° C.

Examples of the acids that can be used in the above-mentioned solvolysis include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and perchloric acid, oxalic acid, fumaric acid, maleic acid, acetic acid, and the like. Trifluoroacetic acid, trichloroacetic acid, p
-Organic acids such as toluenesulfonic acid, camphor-sulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid.

Solvents that can be used in the solvolysis include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like. Ethers, methanol,
Ethanol, iso-propanol, n-butanol,
Examples thereof include alcohols such as t-butanol, ketones such as acetone and methyl ethyl ketone, and solvents such as acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water and acetic acid. These solvents can be used alone or as a mixture.

(2-2) In a solvent, any one of the aminobutene derivatives of the general formula (Ia), (I) or (I-1) is reacted with an alkali metal atom such as lithium or sodium at a reaction temperature of -78. ° C to 100 ° C, preferably -7
A method of reacting at 8 ° C to 0 ° C.

Examples of the solvent that can be used in the above reaction include liquid ammonia, alcohols such as methanol, ethanol, iso-propanol, n-butanol and t-butanol, and lower amines such as methylamine, ethylamine and ethylenediamine. Is mentioned.

(2-3) In a solvent, any of the aminobutene derivatives of the above general formula (Ia), (I) or (I-1) is reacted with sodium amalgam at a reaction temperature of -10.
A method in which the reaction is carried out at a temperature of from 0 to 150C, preferably from 0 to 120C.

As the solvent that can be used in the above deprotection reaction, for example, tetrahydrofuran, 1,4-
Examples thereof include ethers such as dioxane and dimethoxyethane, alcohols such as methanol, ethanol, iso-propanol, n-butanol and t-butanol, water, and acetic acid. These solvents can be used alone or as a mixture.

In the above reaction formulas (B), (C) and (D), at least one of R ² CO—, R ^3a or R ³ is
In the case of an alkoxycarbonyl group, deprotection can be performed by any of the following (3-1) or (3-2).

(3-1) A method of solvolysis in the presence of an alkali at a reaction temperature of -10 ° C to 150 ° C, preferably 0 ° C to 120 ° C.

Examples of the base that can be used in the solvolysis include sodium hydroxide, potassium hydroxide, calcium oxide, barium oxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, and the like. Potassium t-butoxide, aqueous ammonia and the like can be mentioned.

Solvents that can be used in the solvolysis include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like. Ethers, methanol,
Ethanol, iso-propanol, n-butanol,
Examples include alcohols such as t-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water and the like. These solvents can be used alone or as a mixture.

(3-2) A reaction temperature of -10 ° C. to 150 ° C., preferably 0 ° C. in the presence of an acid or an acid and a scavenger.
A method in which solvolysis is performed at a temperature of from 120C to 120C.

Examples of the acids that can be used in the above-mentioned solvolysis include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, oxalic acid, fumaric acid, maleic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid and p-toluene. Organic acids such as sulfonic acid, camphorsulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, aluminum chloride, zinc chloride, magnesium bromide, stannic chloride, titanium tetrachloride,
Acids such as boron oxyfluoride can be mentioned.

Solvents that can be used in the solvolysis include, for example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like. Ethers, methanol,
Ethanol, iso-propanol, n-butanol,
Examples thereof include alcohols such as t-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and water. These solvents can be used alone or as a mixture.

Examples of the scavenger that can be used in the above solvolysis include phenol, thiophenol, anisole, thioanisole, cresol, thiocresol, dimethyl sulfide, and the like.

In the above reaction formulas (B), (C) and (D), when at least one of R ² CO—, R ^3a or R ³ is a substituted alkyl, the following (4-1) and (4)
The deprotection can be performed by any of the methods of -2).

(4-1) An acid is reacted in the presence or absence of a solvent at a reaction temperature of -10 ° C to 150 ° C, preferably 0 ° C to 150 ° C.
A method of reacting at 120 ° C. and subjecting to solvolysis.

Examples of the acids that can be used in the above solvolysis include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid, tricroacetic acid, p-toluenesulfonic acid. And organic acids such as camphor-sulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid.

Solvents that can be used in the above solvolysis include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, and solvents such as tetrahydrofuran, 1,4-dioxane and dimethoxyethane. -Tels, methanol, ethanol,
iso-propanol, n-butanol, t-butanol
And ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide and water. These solvents can be used alone or as a mixture.

(4-2) In any one of the following solvents, any one of the aminobutene derivatives of the general formula (Ia), (I) or (I-1) is combined with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ),
Tetrachloro-1,2-benzoquinone, tetrachloro-
An oxidizing agent such as 1,4-benzoquinone is used at -10C to 150C.
Deprotection by reacting at 0 ° C, preferably 0 ° C to 120 ° C.

Examples of the solvent that can be used in the above oxidation reaction include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, and solvents such as tetrahydrofuran, 1,4-dioxane, and dimethoxyethane. -Tels, methanol, ethanol
Alcohol, such as iso-propanol, n-butanol, t-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide,
Examples include dimethylacetamide, dimethylsulfoxide, and water. These solvents can be used alone or as a mixture.

Specifically, the pyridyloxy derivative of the general formula (I-2) is produced by subjecting the acetimide derivative of the general formula (I-3) to the above deprotection according to the following reaction formula. be able to.

Embedded image (In the formula, R ¹¹ and R ¹² are the same as the groups defined above, and n is 0 or 1, 2.)

In the pyridyloxy derivative represented by the general formula (I-2), when n is 0 or 1, the compound represented by the general formula (I-
By oxidizing the pyridyl derivative of 2), a pyridyloxy derivative of the following general formula (I-2a) can be produced.

Embedded image (In the formula, R ¹¹ is the same as the group defined in the formula (I-2), m is n + 1, and n is 0 or 1.)

Further, according to the present invention, in the above reaction formula (A), R ¹ of any of the amino derivatives of the general formula (Ia), (I) or (I-1) is a hydroxyl-protecting group. Sometimes, the following (A-1), (A-2) and (A-3)
By any one of the above formulas (Ia) and (I)
Alternatively, an ammonobutenol derivative can be produced by deprotecting any of the aminobutene derivatives of (I-1).

(A-1) In the presence of an acid, an acid and a scavenger or an alkali, -10 to 150 ° C., preferably 0 to 150 ° C.
A method in which solvolysis is performed at a temperature of from 120C to 120C.

Examples of the acids that can be used in the above solvolysis include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, oxalic acid, fumaric acid, maleic acid, acetic acid, trifluoroacetic acid, trifluoroacetic acid, p-chloroacetic acid and the like. Organic acids such as toluenesulfonic acid, camphor-sulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, aluminum chloride, zinc chloride,
Examples of such acids include magnesium bromide, stannic chloride, titanium tetrachloride, and boron oxyfluoride.

Examples of the alkali that can be used in the solvolysis include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium oxide, barium oxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. , Sodium, potassium hydride,
Examples thereof include t-butoxide and ammonia water.

Examples of the solvent that can be used in the solvolysis include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, and the like.
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol, iso-propanol, n-butanol and t-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide; Examples include dimethylacetamide, dimethylsulfoxide, and water. These solvents can be used alone or as a mixture.

Examples of the scavenger that can be used in the solvolysis include phenol, thiophenol, anisole, thioanisole, cresol, thiocresol, and dimethyl sulfide.

(A-2) Water, methanol, ethanol
In an alcohol such as isopropyl, iso-propanol, n-butanol or t-butanol.
a) reacting any of the aminobutene derivatives of (I) or (I-1) with hydrazine at a reaction temperature of -10 ° C to 150 ° C;
Preferably, the reaction is carried out at 0 ° C to 120 ° C.

(A-3) In any one of the following solvents, the reaction temperature is from -10 ° C to 150 ° C, preferably from 0 ° C to
At 120 ° C., the above-mentioned general formula (Ia), (I) or (I-1)
With any of the aminobutene derivatives of
A method of reacting with a fluoride such as potassium fluoride, tetrabutylammonium fluoride, lithium boron fluoride or hydrofluoric acid to carry out solvolysis.

Examples of the solvent that can be used in the solvolysis include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, 1,4-dioxane, and the like.
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol, iso-propanol, n-butanol and t-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide; Examples thereof include dimethylacetamide and water. These solvents can be used alone or as a mixture.

[0115]

Embodiments of the present invention will be described below. These are for explaining the present invention, and the present invention is not limited by these examples.

Reference Example 1 (Z) -4-Piperidinomethyl-2- (4-tetrahydropyranyloxy-2-butenyloxy) -pyridine

Embedded image 1.10 g (0.025 mol) of sodium hydride in T
Suspended in 20 ml of HF and 4.31 g of 4-tetrahydropyranyloxy-2- (Z) -butenol (0.
025 mol) in THF (10 ml) was added dropwise.
Stirred for 0 minutes. 2.10 g (0.01 mol) of 2-chloro-4-piperidinomethylpyridine in THF (10 m
1) A solution was added, followed by DMF (2 ml), and the mixture was refluxed for 16 hours. After the reaction, the solvent was distilled off, and the residue was taken up in chloroform and extracted with a 1N aqueous hydrochloric acid solution. The aqueous layer was made basic by adding anhydrous potassium carbonate, and extracted with chloroform. The organic layer was washed with a saturated saline solution, dried, and the solvent was distilled off to obtain 3.10 g of (Z) -4-piperidinomethyl-2- (4-tetrahydropyranyloxy-2-butenyloxy) -pyridine (yield: 89). %)Obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.95 (8H, m), 2.35-2.55 (4
H, m), 3.47 (2H, s), 3.50-3.58.
(1H, m), 3.95-4.05 (1H, m), 4.
33 (2H, dd, J = 6 Hz), 4.90 (1H, b
rt, J = 2 Hz), 4.99 (2H, d, J = 7H)
z), 5.68-5.78 (1H, m), 5.84-
5.94 (1H, m), 6.77 (1H, s), 6.9
4 (1H, d, J = 5 Hz), 8.02 (1H, d, J
= 5Hz).

Reference Example 2 (Z) -4- [4- (Piperidinomethyl) pyridyl-2-oxy] -2-butenol

Embedded image 5.0 g (0.014 mol) of (Z) -4-piperidinomethyl-2- (4-tetrahydropyranyloxy-2-butenyloxy) -pyridine was dissolved in 60 ml of methanol, and p-toluenesulfonic acid / monohydrate was added under ice cooling. Japanese 6.
0 g (0.032 mol) was added and the mixture was stirred for 2 hours. After basifying with saturated aqueous sodium hydrogen carbonate, the solvent was concentrated and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 3.1 g of (Z) -4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (82% yield). Boiling point 177-179 ° C / 2 mmHg ¹ N-NMR (δ, CDCl ₃ ): 1.40-1.55
(2H, m), 1.55-1.70 (4H, m), 2.
35-2.55 (4H, m), 3.47 (2H, s),
3.90 (1H, br-s), 4.33 (2H, dd,
J = 5 Hz), 5.00 (2H, d, J = 7 Hz),
5.70-5.80 (1H, m), 5.84-5.94
(1H, m), 6.76 (1H, s), 6.93 (1
H, d, J = 5 Hz, 8.02 (1H, d, J = 5H)
z).

The compound was recrystallized from ethanol as oxalate. As mp 123.4-124.4 ° C. Elemental analysis molecular formula C ₁₇ H ₂₄ N ₂ O ₆

Reference Example 3 2-furfurylthioacetamide

Embedded image 11.4 g of 2-furfuryl mercaptan (0.1 mol
l), 9.4 g of 2-chloroacetamide (0.1 mol
l) was dissolved in 100 ml of acetonitrile, 13.8 g (0.1 mol) of anhydrous potassium carbonate was added, and the mixture was heated under reflux for 3 hours. After completion, the solvent was distilled off, the residue was taken up in ethyl acetate, washed with water (3 times) and saturated saline, the organic layer was dried, and the solvent was distilled off. The residue was recrystallized from a hexane-ethyl acetate mixed solvent to obtain 16.4 g (96% yield) of 2-furfurylthioacetamide.

Melting point: 66.9-67.6 ° C. (recrystallization solvent: hexane: ethyl acetate = 1: 1) ¹ N-NMR (δ, CDCl ₃ ): 3.21 (2H,
s), 3.79 (2H, s), 5.90-6.15 (1
H, br), 6.23 (1H, d, J = 3 Hz), 6.
32 (1H, dd, J = 3.2 Hz), 6.45-6.
80 (1H, br), 7.37 (1H, d, J = 2H
z). IR (ν, KBr): 3400, 3280, 1640,
1505, 1410, 1400, 1385, 1260,
1225, 1150, 1005, 940, 745. Elemental analysis Molecular formula: C ₇ H ₉ NO ₂ S Calculated for CH NS 49.10 5.30 8.18 18.73 Found 49.10 5.30 8.24 18.96

Reference Example 4 2-furfurylsulfinyl acetamide

Embedded image 3.1 g (10 mmol) of 2-furfurylsulfinyl acetic acid = p-nitrophenyl were suspended in 30 ml of ethanol, 20 ml of 28% aqueous ammonia was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain 1.2 g of 2-furfurylsulfinyl acetamide.

Melting point: 144.6-145.3 ° C. ¹ N-NMR (δ, CDCl ₃ ): 3.30 (1H,
d, J = 15 Hz), 3.62 (1H, d, J = 15H)
z), 4.22 (1H, d, J = 14 Hz), 4.26
(1H, d, J = 14 Hz), 5.48-5.66 (1
H, br), 6.41 (1H, dd, J = 4.2H)
z), 6.48 (1H, d, J = 4 Hz), 6.84-
6.96 (1H, m), 7.45 (1H, d, J = 2H
z).

Reference Example 5 N-acetyl-2-furfurylthioacetamide

Embedded image 8.56 g of 2-furfurylthioacetamide (0.05
mol), 5.61 g (0.055 mol) of acetic anhydride,
6.11 g of N, N-dimethylaminopyridine (0.05
mol) was dissolved in 50 ml of pyridine and stirred at 80 ° C. for 16 hours. The solvent was distilled off and the residue was taken up in ethyl acetate.
Washed with water, 1N-hydrochloric acid aqueous solution, water (three times) and saturated saline, the organic layer was dried, and the solvent was distilled off.
7.11 g of furfurylthioacetamide were obtained.

¹ N-NMR (δ, CDCl ₃ ): 2.3
5 (3H, s), 3.36 (2H, s), 3.79 (2
H, s), 6.22 (1H, d, J = 3 Hz), 6.3.
0 (1H, dd, J = 3.2 Hz), 7.36 (1H,
d, J = 2 Hz), 8.70-8.95 (1H, br-
s).

Reference Example 6 N-Formyl-2-furfurylthioacetamide

Embedded image 0.768 g (19.2 m) of 60% oily sodium hydride
mol) were suspended in tetrahydrofuran (50 ml), and 3 g of 2-furfurylthioacetamide (1
7.4 mmol) of tetrahydrofuran (100 ml)
The solution was added dropwise, and the mixture was further stirred at room temperature for 30 minutes. Under ice-cooling, 1.54 ml (19.2 mmol) of ethyl formate was added, and the mixture was further stirred at room temperature for 2 hours. Acetic acid 1.1
After stirring at room temperature for 10 minutes, the mixture was concentrated under reduced pressure. The obtained residue was treated with ethyl acetate (150
ml) -water (50 ml), and the organic layer was separated.
The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 2.4 g (yield 69%) of N-formyl-2-furfurylthioacetamide.

¹ N-NMR (δ, CDCl ₃ ): 3.3
2 (2H, s), 3.79 (2H, s), 6.23 (1
H, d, J = 3 Hz), 6.31 (1H, m), 7.3
6 (1H, d, J = 2 Hz), 8.80 to 9.10 (1
H, br), 8.98 (1H, br). IR (ν, KBr): 3224, 3180, 1734,
1684, 1478, 1384, 1258, 1234
750 cm ^-1 melting point: 51.0-52.1 ° C (recrystallized from ethyl acetate-hexane)

Reference Example 7 N-benzoyl-2-furfurylthioacetamide

Embedded image 12.11 g of 2-furfurylthioacetamide (0.0
7 mol) was dissolved in 30 ml of pyridine, and 9.94 g (0.07 mol) of benzoyl chloride was added.
For 15 hours. The solvent was distilled off, the residue was taken up in ethyl acetate, water (twice), 1N aqueous hydrochloric acid, water (three times),
Washed with saturated saline. The organic layer was dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 14.2 g of N-benzoyl-2-furfurylthioacetamide (yield 73%).

¹ N-NMR (δ, CDCl ₃ ): 3.2
2 (2H, s), 3.94 (2H, s), 6.30 (1
H, d, J = 3 Hz), 6.35 (1H, dd, J =
3.2Hz), 7.40 (1H, d, J = 2Hz),
7.48 (2H, dd, J = 7.7 Hz), 7.62
(1H, dd, J = 7.7 Hz), 8.12 (2H,
d, J = 7 Hz), 8.40-8.90 (1H, b
r).

Reference Example 8 Nt-butoxycarbonyl-2-furfurylthioacetamide

Embedded image 1.68 g of 60% oily sodium hydride (42.0 mm
ol) was suspended in 50 ml of tetrahydrofuran, and under ice-cooling, 3.00 g of 2-furfurylthioacetamide (1
(7.5 mmol) in tetrahydrofuran (50 ml) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. 4.8 ml (21.0 mmol) of di-t-butyl dicarbonate was added dropwise, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off, the residue was dissolved in water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-hexane to give Nt-butoxycarbonyl-2-furfurylthioacetamide.
08 g (yield 86%) was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
9 (9H, s), 3.52 (2H, s), 3.80 (2
H, s), 6.25 (1H, d, J = 2.8 Hz),
6.31 (1H, dd, J = 5.0, 1.9 Hz),
7.36 (1H, d, J = 2.0 Hz), 7.75 (1
H, br-s). IR (ν, KBr): 3272, 1750, 1692,
1532 cm ^-1 melting point 106.6-108.7 ° C

Reference Example 9 N-methoxycarbonyl-2
-Furfurylthioacetamide

Embedded image 60%-oily sodium hydride 1.29 g (0.032
mol) was suspended in 20 ml of tetrahydrofuran, and 5 g of 2-furfurylthioacetamide (0.029
mol) in tetrahydrofuran (50 ml) was added dropwise and stirred at room temperature for 30 minutes. 1. Dimethyl carbonate under ice cooling
7 ml (0.032 mol) was added dropwise and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in water.
After neutralization with hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from toluene to give 2.78 g (42% yield) of N-methoxycarbonyl-2-furfurylthioacetamide.

¹ N-NMR (δ, CDCl ₃ ): 3.5
5 (2H, s), 3.79 (3H, s), 3.80 (2
H, s), 6.25 (1H, d, J = 2.9 Hz),
6.31 (1H, dd, J = 2.0, 2.9 Hz),
7.37 (1H, d, J = 2.0 Hz), 7.86 (1
H, br-s). IR (ν, KBr): 3260, 3196, 1760,
1532 cm ^-1 melting point: 120.0-121.5 ° C

Reference Example 10 N-2,4-Dimethoxybenzyl-2- (furfurylthio) acetamide

Embedded image A solution of 3 g of chloroacetyl chloride in 30 ml of ethyl acetate and a solution of 7.35 g of potassium carbonate in 30 ml of water were mixed, and a solution of 2,4-dimethoxybenzylamine in 5.41 g of ethyl acetate in 10 ml was added dropwise and stirred for 1 hour. After completion of the reaction, the mixture was washed with water and saturated saline in this order, and after drying the organic layer,
The solvent was distilled off. The residue was dissolved in 50 ml of acetonitrile, 3 g of furfuryl mercaptan and 3.7 g of anhydrous potassium carbonate were added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solvent was distilled off, the residue was taken up in ethyl acetate, washed with water and saturated saline in this order, and after drying the organic layer, the solvent was distilled off. The residue was subjected to silica gel chromatography to give N-2,
6.9 g (90% yield) of 4-dimethoxybenzyl-2- (furfurylthio) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 3.1
9 (2H, s), 3.68 (2H, s), 3.80 (3
H, s), 3.84 (3H, s), 4.34 (2H,
d, J = 6 Hz), 6.15 (1H, d, J = 3H)
z), 6.26 (1H, dd, J = 3 Hz, J = 2H
z), 6.40-6.50 (2H, m), 7.15 (1
H, br-s), 7.16 (1H, d, J = 8 Hz),
7.28 (1H, d, J = 2 Hz).

Example 1 Synthesis of (Z) -4-amino-2-buten-1-ol.p-toluenesulfonate (Z) -N, N-diformyl-1-amino-4-
(Tetrahydropyranyl-2-oxy) -2-butene

Embedded image (Z) -4- (tetrahydropyranyl-2-oxy)-
10.33 g (60 mmol) of 2-buten-1-ol
To a solution of 9.1 g (90 mmol) of triethylamine and ethyl acetate (200 ml) was added dropwise 10.3 g (90 mmol) of methanesulfonyl chloride under ice-cooling, followed by stirring for 2 hours. The reaction solution was washed sequentially with 1N-hydrochloric acid, 1N-sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetonitrile (100 ml), and the solution was prepared according to the literature (Sy
7.6 g (80 mm) of sodium diformylamide synthesized according to the method of Nthesis, 1982 , 264).
ol) and heated to reflux for 2 hours. After cooling to room temperature,
The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give (Z) -N, N-diformyl-1-amino-4-.
(Tetrahydropyranyl-2-oxy) -2-butene 1
1.99 g (88% yield) was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
5-1.90 (m, 6H), 3.50-3.60 (m, 6H)
1H), 3.80-3.95 (m, 1H), 4.25
(D, J = 12 Hz, 7 Hz, 1H), 4.32 (d,
J = 7 Hz, 2H), 4.40 (dd, J = 12 Hz,
5Hz, 1H), 4.67 (t, J = 3Hz, 1H),
5.45-5.55 (m, 1H), 5.70-5.85
(M, 1H), 8.84 (s, 2H).

(Z) -4-Amino-2-butene-1
-All p-toluenesulfonate

Embedded image (Z) -N, N-Diformyl-1-amino-4- (tetrahydropyranyl-2-oxy) -2-butene 11.9
9.89 g (52%) of p-toluenesulfonic acid monohydrate was added to a solution of 9 g (52 mmol) of methanol (300 ml).
mmol) and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (10.78 g, yield 80%).
I got

¹ N-NMR (δ, CD ₃ OD): 2.3
6 (s, 3H), 3.64 (d, J = 7 Hz, 2H),
4.19 (d, J = 7 Hz, 2H), 5.55-5.6
5 (m, 1H), 5.85-6.00 (m, 1H),
7.24 (d, J = 8 Hz, 2H), 7.70 (d, J
= 8 Hz, 2H).

Example 2 Synthesis of (Z) -4-amino-2-buten-1-ol hydrochloride

Embedded image Literature (Chemica Scripta vol 2
4,7-dihydro-1,3,2-dioxathiepine-synthesized according to the method of 4,170-177, 1984).
To a solution of 1.34 g (10 mmol) of 2-oxide in toluene (50 ml) was added sodium diformylamide 1.0.
4 g (11 mmol) and 0.339 g (1 mmol) of tetrabutylammonium hydrogen sulfate were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the residue obtained by evaporating the solvent was dissolved in ethanol (50 ml), 10 ml of 12N hydrochloric acid was added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 0.537 g of the title compound (yield 50
%).

¹ N-NMR (δ, CD ₃ OD): 3.6
4 (d, J = 7 Hz, 2H), 4.19 (d, J = 7H
z, 2H), 5.55-5.65 (m, 1H), 5.8
5-5.75 (m, 1H)

Example 3 (Z) -4-Amino-2-buten-1-ol.p-toluenesulfonic acid salt

Embedded image Sodium methoxide -28% in 40 ml of formamide
15.35 ml (80 mmol) of a methanol solution was added, and the mixture was stirred at room temperature for 10 minutes and then heated at 90 ° for 1 hour to distill off methanol. 15.01 g (60 m) of (Z) -4- (tetrahydropyranyl-2-oxy) -2-buten-1-ol methanesulfonic acid ester was added to the reaction solution under ice cooling.
mol) in tetrahydrofuran (50 ml), and the mixture was stirred for 2 hours, heated to room temperature, and further stirred for 18 hours. The reaction solution was added to ice water and extracted twice with methylene chloride.
The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (Z) -N, N-diformyl-1-amino-4- (tetrahydropyranyl-2-
Oxy) -2-butene and (Z) -N-formyl-1-
Amino-4- (tetrahydropyranyl-2-oxy)-
15.1 g of a mixture of 2-butene was obtained. To a solution of the mixture in methanol (300 ml) was added 11.41 g (60 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 18 hours and concentrated under reduced pressure to give the title compound 13.53.
g was obtained. ((Z)-(4-tetrahydropyranyl-2
-Oxy) -2-buten-1-ol methanesulfonic acid ester, yield: 87%).

¹ N-NMR (δ, CD ₃ OD): 2.3
6 (s, 3H), 3.64 (d, J = 7 Hz, 2H),
4.19 (d, J = 7 Hz, 2H), 5.55-5.6
5 (m, 1H), 5.85-6.00 (m, 1H),
7.24 (d, J = 8 Hz, 2H), 7.70 (d, J
= 8Hz, 2H)

Example 4 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] acetamide

Embedded image (Z) -N-4 [4- (piperidinomethyl) pyridyl-
523 mg of 2-oxy] -2-butenol (2 mmol
l), 252 mg (2.5 mmol) of triethylamine
Was dissolved in 10 ml of toluene, and 286 mg (2.4 mmol) of methanesulfonyl chloride in toluene (2
ml) solution was added dropwise and stirred for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 132 mg of acetamide
(2.2 mmol) was dissolved in 10 ml of THF, and 247 mg (2.2 mmol) of potassium t-butoxide was added at room temperature.
Was added and stirred for 1 hour. The above reaction solution was added dropwise at room temperature, and tetra-n-butylammonium hydrogen sulfate 68 mg was used.
(0.2 mmol) was added and the mixture was further stirred for 1 hour. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 490 mg (yield 81%) of (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] acetamide.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.50 (2H, m), 1.55-1.68 (4
H, m), 2.00 (3H, s), 2.30-2.48
(4H, m), 3.44 (2H, s), 4.03 (2
H, t, J = 6 Hz), 4.93 (2H, d, J = 7H)
z), 5.65-5.75 (1H, m), 5.77-
5.87 (1H, m), 6.02-6.16 (1H, b
r-s), 6.75 (1H, s), 6.91 (1H,
d, J = 5 Hz), 8.05 (1 H, d, J = 5 Hz) IR (ν, film): 2940, 1658, 161
4,1564,1424,1288,1164,114
8,1114,1038.998 cm ^-1

Example 5 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] formamide

Embedded image (Z) -N-4 [4- (piperidinomethyl) pyridyl-
523 mg of 2-oxy] -2-butenol (2 mmol
l), 252 mg (2.5 mmol) of triethylamine
Was dissolved in 10 ml of toluene, and 286 mg (2.4 mmol) of methanesulfonyl chloride in toluene (2
ml) solution was added dropwise and stirred for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 132 mg formamide
(2.2 mmol) was dissolved in 10 ml of THF, and 247 mg (2.2 mmol) of potassium t-butoxide was added at room temperature.
Was added and stirred for 1 hour. The previous reaction solution was added dropwise at room temperature, and tetra-n-butylammonium hydrogensulfate 68 mg
(0.2 mmol) was added and the mixture was further stirred for 2 hours. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 220 mg of (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] formamide (yield 38%).

¹ N-NMR (δ, CDCl ₃ ): 1.3
8-1.52 (2H, m), 1.52-1.74 (4
H, m), 2.30-2.72 (4H, m), 3.49
(2H, s), 4.09 (2H, dd, J = 6.6H)
z), 4.94 (2H, d, J = 6 Hz), 5.64-
5.78 (1H, m), 5.80-5.92 (1H,
m), 6.24-6.40 (1H, m), 6.79 (1
H, s), 6.95 (1H, d, J = 5 Hz), 8.0
5 (1H, d, J = 5 Hz), 8.22 (1H, s). IR (ν, film): 2936, 1668, 161
4,1562,1424,1404,1314,116
4,1148,1038,996cm ^-1

Example 6 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] benzamide

Embedded image 523 mg of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (2 mmol
l), 252 mg (2.5 mmol) of triethylamine
Was dissolved in 10 ml of toluene, and 286 mg (2.4 mmol) of methanesulfonyl chloride in toluene (2
ml) solution was added dropwise and stirred for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 267mg benzamide
(2.2 mmol) was dissolved in 10 ml of THF, and 247 mg (2.2 mmol) of potassium t-butoxide was added at room temperature.
Was added and stirred for 1 hour. The previous reaction solution was added dropwise at room temperature, and tetra-n-butylammonium hydrogensulfate 68 mg
(0.2 mmol) was added and the mixture was further stirred for 30 minutes. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 520 mg (yield 71%) of (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] benzamide.

¹ N-NMR (δ, CDCl ₃ ): 1.3
8-1.50 (2H, m), 1.50-1.72 (4
H, m), 2.28-2.46 (4H, m), 3.43.
(2H, s), 4.25 (2H, dd, J = 6.6H)
z), 4.99 (2H, d, J = 6 Hz), 5.76 −
5.94 (2H, m), 6.60 (1H, br-s),
6.79 (1H, s), 6.88 (1H, d, J = 5H)
z), 7.39-7.50 (3H, m), 7.76-
7.78 (2H, m), 7.98 (1H, d, J = 5H)
z). IR (ν, film): 3336, 2936, 163
4,1578,1558,1532,1430,141
2,1318,1170,1150,1042,98
8,718 cm ^-1

Example 7 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] trifluoroacetamide

Embedded image 525 mg of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (2 mmol
l), 253 mg (2.5 mmol) of triethylamine
Is dissolved in 10 ml of toluene, and 275 mg (2.4 mmol) of methanesulfonyl chloride in toluene (2
ml) solution was added dropwise and stirred for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 249 mg (2.2 mmol) of trifluoromethylacetamide was dissolved in 10 ml of THF, and 247 mg of potassium t-butoxide was added at room temperature.
(2.2 mmol) was added and stirred for 1 hour. The above reaction solution was added dropwise at room temperature, and 68 mg (0.2 mmol) of tetra-n-butylammonium hydrogensulfate was added thereto, followed by further addition of 30 mg.
For a minute. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to give (Z) -N- [4-
[4- (piperidinomethyl) pyridyl-2-oxy]-
2-butenyl] trifluoroacetamide (410 mg)
(57% yield).

¹ N-NMR (δ, CDCl ₃ ): 1.3
8-1.52 (2H, m), 1.52-1.70 (4
H, m), 2.26-2.54 (4H, m), 3.43.
(2H, s), 4.16 (2H, dd, J = 6.6H)
z), 4.95 (2H, d, J = 7 Hz), 5.66-
5.76 (1H, m), 5.85-5.95 (1H,
m), 6.76 (1H, s), 6.92 (1H, d, J
= 5 Hz), 7.30-7.58 (1H, br-s),
8.02 (1H, d, J = 5 Hz). IR (ν, film): 2940, 1714, 166
4,1614,1564,1424,1344,131
4,1186,1040,998cm ^-1

Example 8 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image 2.61 g of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (0.01
mol), 1.21 g of triethylamine (0.012 m
ol) was dissolved in 50 ml of toluene, and a solution of 1.26 g (0.011 mol) of methanesulfonyl chloride in 10 ml of toluene was added dropwise with ice cooling, followed by stirring for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 1.71 g (0.01 mol) of 2-furfurylthioacetamide was dissolved in 20 ml of toluene, and 1.23 g (0.011 mol) of potassium t-butoxide was added at room temperature, followed by stirring for 1 hour. The above reaction solution was added dropwise at room temperature, and the mixture was further stirred for 3 hours. The reaction solution was washed with water (3 times) and saturated saline, dried, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography to give (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide.
74 g (yield 90%) was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.55 (2H, m), 1.55-1.80 (4
H, m), 2.35-2.65 (4H, m), 3.23.
(2H, s), 3.53 (2H, s), 3.75 (2
H, s), 3.99 (2H, dd, J = 6.6 Hz),
4.92 (2H, d, J = 7 Hz), 5.56-5.6
8 (1H, m), 5.80-5.92 (1H, m),
6.20 (1H, d, J = 3 Hz), 6.29 (1H, d, J = 3 Hz)
dd, J = 3.2 Hz), 6.78 (1H, s), 6.
88 (1H, br-s), 6.98 (1H, br-s)
s), 7.35 (1H, d, J = 2 Hz), 8.10
(1H, d, J = 4 Hz) IR (ν, film): 3300, 2940, 165
5,1620,1560,1420,1405,130
0,1150,1040,1010,740 cm ^-1 Further, N- [4- [4- (piperidinomethyl) pyridyl-2-oxy]-(Z) -2-butenyl] -2- (furfurylthio) acetamide is oxalic acid The salt was recrystallized from ethanol to obtain the following physical properties. C H N S Calculated mp 114-115 ° C. Elemental analysis molecular formula _{C 24 H 31 N 3 O 7} S 57.02 6.18 8.31 6.34 Found 56.80 6.19 8.05 6.57

Example 9 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylsulfinyl) acetamide

Embedded image 2.61 g of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (0.01
mol), 1.21 g of triethylamine (0.012 m
ol) was dissolved in 50 ml of toluene, and a solution of 1.26 g (0.011 mol) of methanesulfonyl chloride in 10 ml of toluene was added dropwise with ice cooling, followed by stirring for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 1.87 g (0.01 mol) of 2-furfurylsulfinyl acetamide
Was dissolved in 20 ml of toluene, and 1.23 g (0.011 mol) of potassium t-butoxide was added at room temperature, followed by stirring for 1 hour. The above reaction solution was added dropwise at room temperature, and the mixture was further stirred for 3 hours. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to give (Z) -N- [4-
[4- (piperidinomethyl) pyridyl-2-oxy]-
3.24 g (yield 75%) of 2-butenyl] -2- [furfurylsulfinyl) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.50 (2H, m), 1.50-1.65 (4
H, m), 2.30-2.45 (4H, m), 3.34.
(1H, d, J = 14 Hz), 3.40 (2H, s),
3.69 (1H, d, J = 14 Hz), 4.14 (1
H, d, J = 14 Hz), 4.15 (2H, dd, J =
6.6 Hz), 4.38 (1 H, d, J = 14 Hz),
4.93 (2H, dd, J = 6.6 Hz), 5.60 −
5.75 (1H, m), 5.80-5.90 (1H,
m), 6.40 (1H, dd, J = 3.2 Hz), 6.
47 (1H, d, J = 5 Hz), 6.73 (1H, d, J = 5 Hz)
s), 7.20 (1H, br-s), 7.44 (1H,
d, J = 2 Hz), 8.04 (1 H, d, J = 5 Hz) IR (ν, KBr): 3334, 2936, 1640,
1615, 1562, 1529, 1411, 1042c
m ^-1 melting point 72.7-73.4 ° C. elemental analysis molecular formula C ₂₂ H ₂₉ N ₃ O ₄ S calculated as CH N S 61.23 6.77 9.74 7.43 actual value 60.89 6. 72 9.51 7.43

Example 10 (Z) -N-acetyl-N
-[4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image 2.61 g of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (0.01
mol), 1.21 g of triethylamine (0.012 m
ol) was dissolved in 50 ml of toluene, and a solution of 1.26 g (0.011 mol) of methanesulfonyl chloride in toluene (10 ml) was added dropwise at room temperature, followed by stirring for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. N-acetyl-2
-Furfurylthioacetamide 2.13 g (0.01 m
ol) was dissolved in 20 ml of toluene, and potassium t was added at room temperature.
1.23 g (0.011 mol) of butoxide are added,
Stir for 1 hour. The above reaction solution was added dropwise at room temperature, and the mixture was further stirred for 3 hours. The reaction solution was washed with water (3 times) and saturated saline, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give (Z) -N-acetyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide. .50 g (76% yield) were obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.3
5-1.55 (2H, m), 1.55-1.85 (4
H, m), 2.41 (3H, s), 2.40-2.70.
(4H, m), 3.12 (2H, br-s), 3.72
(2H, s), 3.80 (2H, s), 4.54 (2
H, d, J = 5 Hz), 4.94 (2H, d, J = 5H)
z), 5.42-5.52 (1H, m), 5.82-
5.92 (1H, m), 6.23 (1H, d, J = 3H
z), 6.30 (1H, dd, J = 3.2 Hz), 6.
81 (1H, s), 7.07 (1H, br-s), 7.
35 (1H, d, J = 2 Hz), 8.10 (1H, d,
J = 5 Hz). IR (ν, neat): 2940, 1704, 161
4,1564,1422,1372,1122

(Example 11) (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image 457 mg of (Z) -N-acetyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy]-(Z) -2-butenyl] -2- (furfurylthio) acetamide
(1 mmol) was dissolved in 10 ml of methanol, 1 ml of a 1N aqueous solution of sodium hydroxide was added under ice cooling, and the mixture was stirred for 1 hour. After completion of the reaction, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water (three times) and saturated saline, and the organic layer was dried and the solvent was distilled off. The residue was purified by silica gel column chromatography, and (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide to 21
0 mg was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.55 (2H, m), 1.55-1.80 (4
H, m), 2.35-2.65 (4H, m), 3.23.
(2H, s), 3.53 (2H, s), 3.75 (2
H, s), 3.99 (2H, dd, J = 6.6 Hz),
4.92 (2H, d, J = 7 Hz), 5.56-5.6
8 (1H, m), 5.80-5.92 (1H, m),
6.20 (1H, d, J = 3 Hz), 6.29 (1H, d, J = 3 Hz)
dd, J = 3.2 Hz), 6.78 (1H, s), 6.
88 (1H, br-s), 6.98 (1H, br-s)
s), 7.35 (1H, d, J = 2 Hz), 8.10
(1H, d, J = 4Hz).

(Example 12) (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylsulfinyl) acetamide

Embedded image 415 mg (1 mmol) of (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide are dissolved in 5 ml of methylene chloride and 5 ml of acetic acid, and cooled with ice. Lower 30%
100 mg of aqueous hydrogen peroxide was added and the mixture was stirred for 1 hour. After completion, 10 ml of water was added and the mixture was extracted with ethyl acetate. The aqueous layer was made basic with potassium carbonate, and then extracted with ethyl acetate.
The organic layer was washed with water (three times) and saturated saline, and dried.
The solvent was distilled off, the residue was purified by silica gel column chromatography, and (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] was used.
-2- (furfurylsulfinyl) acetamide to 36
0 mg (83% yield) was obtained.

Melting point: 72.7-73.4 ° C. ¹ N-NMR (δ, CDCl ₃ ): 1.40-1.50
(2H, m), 1.50-1.65 (4H, m), 2.
30-2.45 (4H, m), 3.34 (1Hd, J =
14Hz), 3.40 (2H, s), 3.69 (1H,
d, J = 14 Hz), 4.14 (1H, d, J = 14H)
z), 4.15 (2H, dd, J = 6.6 Hz), 4.
38 (1H, d, J = 14 Hz), 4.93 (2H, d
d, J = 6.6 Hz), 5.60-5.75 (1H,
m), 5.80-5.90 (1H, m), 6.40 (1
H, dd, J = 3.2 Hz), 6.47 (1H, d, J
= 5 Hz), 6.73 (1H, s), 7.20 (1H,
7. br-s), 7.44 (1H, d, J = 2 Hz),
04 (1H, d, J = 5 Hz). IR (ν, KBr): 3334, 2936, 1640,
1615, 1562, 1529, 1411, 1042. Elemental analysis Molecular formula: C ₂₂ H ₂₉ N ₃ O ₄ S Calculated for CH NS: 61.23 6.77 9.74 7.43 Found 60.89 6.72 9.51 7.43

Example 13 (Z) -Nt-butoxycarbonyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -4- [4- (piperidinomethyl) pyridyl-2
-Oxy] -2-butenol 1.00 g (3.81 mm
ol), 0.66 ml of triethylamine (4.57 mm
ol) was dissolved in 30 ml of toluene, and 0.35 ml (4.57 mmol) of methanesulfonyl chloride was added dropwise under ice cooling, followed by stirring for 1 hour. The reaction solution was washed with water and a 1N aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate.
1.14 g (4.19 mmol) of Nt-butoxycarbonyl-2-furfurylthioacetamide was dissolved in 20 ml of tetrahydrofuran, and 1.14 g (4.19 mmol) of potassium t-butoxide was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Thereafter, 64 mg (0.19 mmol) of tetra-n-butylammonium hydrogen sulfate was added. The previous reaction solution was added dropwise at room temperature, and the mixture was further stirred for 4 hours. The reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to give (Z) -Nt-butoxycarbonyl-N-
1.69 g (86% yield) of [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.3
9-1.49 (2H, m), 1.50 (9H, s),
1.53-1.63 (4H, m), 2.30-2.42
(4H, m), 3.40 (2H, s), 3.77 (2
H, s), 3.79 (2H, s), 4.45 (2H,
d, J = 16.3 Hz), 4.98 (2H, d, J =
5.4 Hz), 5.52-5.63 (1H, m), 5.5.
80-5.90 (1H, m), 6.24 (1H, d, J
= 3.3 Hz), 6.30 (1H, dd, J = 5.0,
1.9 Hz), 6.71 (1H, s), 6.86 (1
H, d, J = 4.2 Hz), 7.36 (1H, d, J =
2.0 Hz), 8.05 (1H, d, J = 5.2 Hz) IR (ν, neat): 2936, 1736, 168
6,1614cm ^-1

(Example 14) (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -Nt-butoxycarbonyl-N- [4- [4
-(Piperidinomethyl) pyridyl-2-oxy] -2-
Butenyl] -2- (furfurylthio) acetamide 55
mg (0.11 mmol) was dissolved in 5 ml of methylene chloride, and at room temperature, 10.1 ml of trifluoroacetic acid (1.30 ml) was dissolved.
mmol) and stirred for 7 hours. After completion of the reaction, the mixture was neutralized with 10% potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to give (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2-
36 mg of (furfurylthio) acetamide (yield 80
%)Obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.55 (2H, m), 1.55-1.80 (4
H, m), 2.35-2.65 (4H, m), 3.23.
(2H, s), 3.53 (2H, s), 3.75 (2
H, s), 3.99 (2H, dd, J = 6.6 Hz),
4.92 (2H, d, J = 7 Hz), 5.56-5.6
8 (1H, m), 5.80-5.92 (1H, m),
6.20 (1H, d, J = 3 Hz), 6.29 (1H, d, J = 3 Hz)
dd, J = 3.2 Hz), 6.78 (1H, s), 6.
88 (1H, br-s), 6.98 (1H, br-s)
s), 7.35 (1H, d, J = 2 Hz), 8.10
(1H, d, J = 4 Hz) IR (ν, film): 3300, 2940, 165
5,1620,1560,1420,1405,130
0, 1150, 1040, 1010, 740 cm ^-1

Further, (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was converted into oxalate, which was recrystallized from ethanol. The following physical property values were obtained.

Melting point: 114-115 ° C. Elemental analysis: Molecular formula: C ₂₄ H ₃₁ N ₃ O ₇ S Calculated for CHNS: 57.02 6.18 8.31 6.34 Found 56.80 6.19 8.05 6.57

(Example 15) (Z) -N-formyl-N
-[4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -4- [4- (piperidinomethyl) pyridyl-2
-Oxy] -2-butenol 1.19 g (4.54 mm
ol), 0.79 ml of triethylamine (5.6 mmol)
l) was dissolved in 35 ml of toluene, and 0.421 ml (5.44 mmol) of methanesulfonyl chloride was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was washed with water and a 1N-sodium hydroxide solution, and dried over anhydrous sodium sulfate. 0.56 g of potassium t-butoxide (5.00 mm
ol) in tetrahydrofuran (15 ml),
Under ice-cooling, a solution of 1.0 g (5.00 mmol) of N-formyl-2-furfurylthioacetamide in 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 30 minutes, and then 84 mg (0.2 mg) of tetra-n-butylammonium hydrogen sulfate was added.
5 mmol) was added. The above toluene solution was added dropwise at room temperature, and the mixture was further stirred for 5 hours. The reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography,
(Z) -N-formyl-N- [4- [4-piperidinomethyl] pyridyl-2-oxy] -2-butenyl] -2-
1.6 g of (furfurylthio) acetamide (yield 79
%)Obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.3
5 to 1.50 (2H, m), 1.50 to 1.71 (4
H, m), 2.25 to 2.60 (4H, m), 3.46.
(2H, s), 3.53 (2H, s), 3.82 (2
H, s), 4.49 (2H, d, J = 6.9 Hz),
5.00 (2H, d, J = 6.3 Hz), 5.43-
5.55 (1H, m), 6.80-6.92 (1H,
m), 6.27 (1H, d, J = 2.9 Hz), 6.3
1 (1H, m), 6.74 (1H, s), 6.92 (1
H, d, J = 4.8 Hz), 7.37 (1H, d, J =
2 Hz), 8.07 (1H, d, J = 5.1 Hz),
9.19 (1H, s) IR (ν, KBr): 2928, 1660, 1614,
1556, 1308 cm ^-1 melting point: 68.1-70.3 ° C (recrystallized from ethyl acetate-diethyl ether)

(Example 16) (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -N-formyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2
-(Furfurylthio) acetamide 0.24 g (0.5
4 mmol) was dissolved in methanol (5 ml), and 0.226 g (1.19 m) of p-toluenesulfonic acid monohydrate was dissolved.
mol) was added and stirred for 14 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and (Z)
--N- [4- [4- (piperidinomethyl) pyridyl-
157 mg (yield 70%) of 2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.55 (2H, m), 1.55-1.80 (4
H, m), 2.35-2.65 (4H, m), 3.23.
(2H, s), 3.53 (2H, s), 3.75 (2
H, s), 3.99 (2H, dd, J = 6.6 Hz),
4.92 (2H, d, J = 7 Hz), 5.56-5.6
8 (1H, m), 5.80-5.92 (1H, m),
6.20 (1H, d, J = 3 Hz), 6.29 (1H, d, J = 3 Hz)
dd, J = 3.2 Hz), 6.78 (1H, s), 6.
88 (1H, br-s), 6.98 (1H, br-s)
s), 7.35 (1H, d, J = 2 Hz), 8.10
(1H, d, J = 4 Hz) IR (ν, film): 3300, 2940, 165
5,1620,1560,1420,1405,130
0, 1150, 1040, 1010, 740 cm ^-1

Further, (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was converted to oxalate and recrystallized from ethanol. The following physical property values were obtained.

[0173] mp 114-115 ℃ C H N S Calculated elemental analysis molecular formula _{C 24 H 31 N 3 O 7} S 57.02 6.18 8.31 6.34 Found 56.80 6.19 8.05 6.57

Example 17 (Z) -N-methoxycarbonyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -4- [4- (piperidinomethyl) pyridyl-2
-Oxy] -2-butenol] 0.5 g (1.9 mmol
l), 0.33 ml of triethylamine (2.3 mmol
l) was dissolved in 30 ml of toluene, and 0.18 ml (2.3 mmol) of methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was washed with water and a 1N aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. 0.24 mg of potassium t-butoxide (2.1 mm
ol) was suspended in 5 ml of tetrahydrofuran, a solution of 0.48 g (2.1 mmol) of N-methoxycarbonyl-2-furfurylthioacetamide in 15 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 0.048 g of decyltributylphosphonium
(0.095 mmol) was added. The above toluene solution was added dropwise at room temperature, and the mixture was further stirred for 3 hours. The reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give (Z) -N-methoxycarbonyl-N
0.86 g (95% yield) of-[4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.3
9-1.49 (2H, m), 1.53-1.67 (4
H, m), 2.32-2.40 (4H, m), 3.41
(2H, s), 3.78 (2H, s), 3.80 (3
H, s), 3.83 (2H, s), 4.50 (2H,
d, J = 7.2 Hz), 4.99 (2H, d, J = 7.
8 Hz), 5.51-5.63 (1H, m), 5.82
−5.93 (1H, m), 6.24 (1H, d, J =
2.7 Hz), 6.30 (1H, dd, J = 2.0,
2.7 Hz), 6.73 (1H, s), 6.88 (1
H, d, J = 5.2 Hz), 7.36 (1H, d, J =
2.0 Hz), 8.06 (1H, d, J = 5.2H)
z). IR (ν, neat): 2940, 1742, 169
0,1614,1562cm ^-1

(Example 18) (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide

Embedded image (Z) -N-formyl-N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2
-(Furfurylthio) acetamide 0.5 g (1.1 m
mol) was dissolved in 4 ml of tetrahydrofuran, and 2.3 ml of an isopropylamine tetrahydrofuran solution was added under ice cooling.
(2.3 mmol) was added dropwise, and the mixture was stirred at room temperature for 10 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide in 0.1%.
41 g (86% yield) were obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.55 (2H, m), 1.55-1.80 (4
H, m), 2.35-2.65 (4H, m), 3.23.
(2H, s), 3.53 (2H, s), 3.75 (2
H, s), 3.99 (2H, dd, J = 6.6 Hz),
4.92 (2H, d, J = 7 Hz), 5.56-5.6
8 (1H, m), 5.80-5.92 (1H, m),
6.20 (1H, d, J = 3 Hz), 6.29 (1H, d, J = 3 Hz)
dd, J = 3.2 Hz), 6.78 (1H, s), 6.
88 (1H, br-s), 6.98 (1H, br-s)
s), 7.35 (1H, d, J = 2 Hz), 8.10
(1H, d, J = 4 Hz) IR (ν, film): 3300, 2940, 165
5,1620,1560,1420,1405,130
0, 1150, 1040, 1010, 740 cm ^-1

Further, (Z) -N- [4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -2- (furfurylthio) acetamide was converted to oxalate and recrystallized from ethanol. The following physical property values were obtained.

Melting point: 114-115 ° C. Elemental analysis: Molecular formula: C ₂₄ H ₃₁ N ₃ O ₇ S Calculated for CHNS: 57.02 6.18 8.31 6.34 Found 56.80 6.19 8.05 6.57

Example 19 (Z) -N- [4- (tetrahydropyranyl-2-oxy) -2-butenyl] -2
-(Furfurylthio) acetamide

Embedded image (Z) -4- (tetrahydropyranyl-2-oxy)-
1.2 g of 2-buten-1-ol and 0.76 g of triethylamine were dissolved in 30 ml of ethyl acetate, and a solution of 0.86 g of methanesulfonyl chloride in 5 ml of ethyl acetate was added dropwise under ice-cooling, followed by stirring for 1 hour. After the reaction is completed, the reaction solution is
The organic layer was washed successively with saturated saline, dried, and then the solvent was distilled off. (1) Dissolve 0.79 g of 2-furfurylthioamide in 10 ml of tetrahydrofuran and add potassium t
-Butoxide (0.52 g) was added and stirred for 30 minutes. Further, 10 ml of tetrahydrofuran of the reaction product obtained in (1)
The solution was added dropwise and stirred for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was taken up in ethyl acetate, washed sequentially with water and saturated saline, and after drying the organic layer, the solvent was distilled off. The residue was subjected to silica gel chromatography to give (Z)-
N- [4- (tetrahydropyranyl-2-oxy) -2
-Butenyl] -2- (furfurylthio) acetamide (1.1 g, yield 78%) was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0 to 1.90 (6H, m), 3.21 (2H, s),
3.50-3.60 (1H, m), 3.74 (2H,
s), 3.70 to 3.95 (3H, m), 4.10 (1
H, dd, J = 10 Hz, 6 Hz), 4.30 (1H,
dd, J = 10 Hz, 6 Hz), 6.65 (1 H, t,
J = 3 Hz), 5.52 to 5.63 (1H, m), 5.
70 to 5.82 (1H, m), 6.21 (1H, d, J
= 3Hz)

Example 20 (Z) -N- (4-hydroxy-2-butenyl) -2- (furfurylthio) acetamide

Embedded image Dissolve 4.48 g of (Z) -N- [4- (tetrahydropyranyl-2-oxy) -2-butenyl] -2- (furfurylthio) acetamide in 50 ml of methanol and add p-
2.75 g of toluenesulfonic acid was added and stirred for 3 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was taken up in ethyl acetate, washed sequentially with water and saturated saline, and the solvent was distilled off after drying the organic layer. The residue was subjected to silica gel chromatography, and 3.3 g of N- (4-hydroxy- (Z) -2-butenyl) -2- (furfurylthio) acetamide was obtained.
(95% yield).

¹ N-NMR (δ, CDCl ₃ ): 3.2
1 (2H, s), 3.74 (2H, s), 3.88 (2
H, t, J = 6 Hz), 4.22 (2H, t, J = 6H)
z), 5.38-5.52 (1H, m), 5.78-
5.90 (1H, m), 6.21 (1H, d, J = 3H
z), 6.29-6.33 (1H, m), 6.95 (1
H, br-s), 7.37 (1H, d, J = 2 Hz)

Example 21 (Z) -N- [4- [4-
(Piperidinomethyl) pyridyl-2-oxy] -2-butenyl] -N-2,4-dimethoxybenzyl-2- (furfurylthio) acetamide

Embedded image 2.61 g of (Z) -N-4- [4- (piperidinomethyl) pyridyl-2-oxy] -2-butenol (0.01
mol), 1.21 g of triethylamine (0.012 m
ol) was dissolved in 50 ml of toluene, and a solution of 1.26 g (0.011 mol) of methanesulfonyl chloride in 10 ml of toluene was added dropwise with ice cooling, followed by stirring for 1 hour. After completion of the reaction, the precipitate was filtered, and the solid was further washed with 10 ml of toluene, and the filtrate and the washing were combined. 1. N-2,4-dimethoxybenzyl-2-furfurylthioacetamide
89 g (0.01 mol) was dissolved in 20 ml of toluene, and 1.23 g (0.0%) of potassium t-butoxide was dissolved at room temperature.
11 mol) and stirred for 1 hour. The above reaction solution was added dropwise at room temperature, and the mixture was stirred for 3 hours. The reaction solution was washed with water (3 times) and saturated saline, dried, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography to give N- [4- [4- (piperidinomethyl) pyridyl-2-oxy]-(Z) -2-butenyl] -N-2,
5.1 g (yield 90%) of 4-dimethoxybenzyl-2- (furfuryl) acetamide was obtained.

¹ N-NMR (δ, CDCl ₃ ): 1.4
0-1.65 (2H, m), 2.35 (4H, t, J =
6Hz), 3.37 (4H, s), 3.75 (3H,
s), 3.76 (3H, s), 3.88 (2H, s),
4.05 to 4.20 (2H, m), 4.43 (1H,
s), 4.57 (1H, s), 4.75 to 4.85 (2
H, m), 5.75 to 5.80 (1H, m), 6.22
６6.32 (2H, m), 6.35 to 6.45 (3H,
m), 6.66 (1H, s), 6.82 (1H, d, J
= 3 Hz), 7.31 (1H, s), 7.47 (1H,
d, J = 3Hz)

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ Identification code FI C07D 407/12 C07D 407/12 (72) Inventor Masakatsu Matsumoto 4-81-509, Shinisono, Shinisono, Sagamihara-shi, Kanagawa (72) Invention Person Yasuo Sekine 2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Inside Fuji Rebio Co., Ltd. (72) Inventor Masato Nishimura 2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Inside Fuji Rebio Corporation (72) inventor Akihiko Hosoda Tokyo Nishi-Shinjuku, Shinjuku-ku, 2-chome, No. 7 No. 1 Fuji Rebio within Co., Ltd. (56) reference Patent flat 1-193247 (JP, a) (58 ) investigated the field (Int.Cl. ⁷ , DB name) C07C 231/08 CA (STN) REGISTRY (STN)

Claims (19)

(57) [Claims] 1. A compound of the general formula And a butene derivative represented by the general formula: In Ru reacted to an amide derivative represented by the general formula ## STR3 ## A method for producing an aminobutene derivative represented by the formula: (Where R
¹ is a hydrogen atom, a hydroxyl-protecting group, a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and X is a hydroxyl group, a halogen atom, a sulfonyloxy group, an acyloxy group or an alkoxycarbonyloxy group. Or with R ¹ to form a cyclic sulfite,
A group forming a sulfate ester or a carbonate ester,
Is an alkali metal atom, an alkaline earth metal atom or a hydrogen atom, and R ² is a hydrogen atom, an alkoxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted heterocyclic group. A ring group,
R ³ is a hydrogen atom, a substituted or unsubstituted acyl group, an alkoxycarbonyl group, a sulfonyl group, or a substituted alkyl group. ). 2. The method according to claim 2, wherein the amide derivative is R ^Two Equivalent to CO group
Not R ^Three A non-symmetrical amide derivative having a group
2. The method for producing the aminobutene derivative according to 1. 3. The protecting group for a hydroxyl group represented by R ¹ is a tetrahydropyranyl group, a methoxymethyl group, a benzyloxymethyl group, an ethoxyethyl group, a 2-methoxyethyl group, a t-butyl group, a benzyl group or a benzyl group. -Methoxybenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, formyl group, acetyl group, n-propionyl group, iso-propionyl group, n-butyryl group, i
so-butyryl group, valeryl group, iso-valeryl group,
A pivaloyl group, a benzoyl group, a naphthoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an iso-butoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a phenyloxycarbonyl group. 1
The method for producing the aminobutene derivative described above. 4. The aromatic hydrocarbon group represented by R ¹ is a phenyl group, a naphthyl group, an anthranyl group, a 3- (tetrahydropyranyl-2-oxymethyl) phenyl group,
(Methoxymethoxymethyl) phenyl group, 3-formylphenyl group, 3- (diethoxymethyl) phenyl group, 3
-(1,3-dioxolan-2-yl) phenyl group, 3
-(Piperidinomethyl) phenyl group, 3- (dimethylaminomethyl) phenyl group, 4- (tetrahydropyranyl-2-oxymethyl) phenyl group, 4- (methoxymethoxymethyl) phenyl group, 4-formylphenyl group,
-(Diethoxymethyl) phenyl group, 4- (1,3-dioxolan-2-yl) phenyl group, 4- (piperidinomethyl) phenyl group, 4- (dimethylaminomethyl) phenyl group, 2- (tetrahydropyranyl- 2-oxymethyl) phenyl group, 2- (methoxymethoxymethyl) phenyl group, 2-formylphenyl group, 2- (diethoxymethyl) phenyl group, 2- (1,3-dioxolan-2)
The method for producing an aminobutene derivative according to claim 1, which is a -yl) phenyl group, a 2- (piperidinomethyl) phenyl group or a 2- (dimethylaminomethyl) phenyl group. 5. The heterocyclic group represented by R ¹ is a pyridyl group, a quinolyl group, an iso-quinolyl group, a thienyl group, a furyl group, a 3- (tetrahydropyranyl-2-oxymethyl) -2-pyridyl group , 3- (methoxymethoxymethyl) -2-pyridyl group, 3-formyl-2-pyridyl group, 3- (diethoxymethyl) -2-pyridyl group, 3-
(1,3-dioxolan-2-yl) -2-pyridyl group, 3- (piperidinomethyl) -2-pyridyl group, 3-
(Dimethylaminomethyl) -2-pyridyl group, 4- (tetrahydropyranyl-2-oxymethyl) -2-pyridyl group, 4- (methoxymethoxymethyl) -2-pyridyl group, 4-formyl-2-pyridyl group , 4- (diethoxymethyl) -2-pyridyl, 4- (1,3-dioxolan-2-yl) -2-pyridyl, 4- (piperidinomethyl) -2-pyridyl, 4- (dimethylaminomethyl ) -2-pyridyl group, 5- (tetrahydropyranyl-
2-oxymethyl) -2-pyridyl group, 5- (methoxymethoxymethyl) -2-pyridyl group, 5-formyl-2
-Pyridyl group, 5- (diethoxymethyl) -2-pyridyl group, 5- (1,3-dioxolan-2-yl) -2-
The method for producing an aminobutene derivative according to claim 1, which is a pyridyl group, a 5- (piperidinomethyl) -2-pyridyl group or a 5- (dimethylaminomethyl) -2-pyridyl group. 6. The aminobutene according to claim 1, wherein the sulfonyloxy group represented by X is a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or an imidazosulfonyloxy group. A method for producing a derivative. 7. An acyloxy group represented by X is a formyloxy group, an acetyloxy group, an n-propionyloxy group, an iso-propionyloxy group, an n-butyryloxy group, an iso-butyryloxy group, a valeryloxy group, an iso-valeryloxy group. Group, pivaloyloxy group,
The method for producing an aminobutene derivative according to claim 1, which is a benzoyloxy group or a naphthoyloxy group. 8. An alkoxycarbonyloxy group represented by X is a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an iso-butoxycarbonyloxy group,
The method for producing an aminobutene derivative according to claim 1, which is an allyloxycarbonyloxy group, a benzyloxycarbonyloxy group, a 9-fluorenylmethoxycarbonyloxy group, or a phenyloxycarbonyloxy group. 9. The method for producing an aminobutene derivative according to claim 1, wherein the alkoxy group represented by R ² is a methoxy group, an ethoxy group, a propoxy group, an iso-butoxy group, a t-butoxy group or a benzyloxy group. 10. The alkyl group represented by R ² is methyl, ethyl, propyl, butyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, benzyl, or furfurylthiomethyl. Group,
The method for producing an aminobutene derivative according to claim 1, which is a furfurylsulfinylmethyl group or a furfurylsulfonylmethyl group. 11. An aromatic hydrocarbon group represented by R ² is:
The method for producing an aminobutene derivative according to claim 1, wherein the aromatic hydrocarbon group is a phenyl group, a naphthyl group, or an anthryl group, and the aromatic hydrocarbon group may be substituted with an alkyl group, an alkoxyl group, a halogen atom, a nitro group, or an amino group. . 12. The heterocyclic group represented by R ² is a pyridyl group, a quinolyl group, an iso-quinolyl group, a thienyl group or a furyl group, wherein the heterocyclic group is an alkyl group, an alkoxyl group, a halogen atom, The method for producing an aminobutene derivative according to claim 1, which may be substituted with a nitro group or an amino group. 13. The acyl group represented by R ³ is a formyl group, acetyl group, propionyl group, butyl group, valeryl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, phenylacetyl group. The method for producing an aminobutene derivative according to claim 1, which is a benzoyl group, a naphthoyl group, a furoyl group, a thenoyl group, a nicotiyl group or an iso-nicotiyl group. 14. An alkoxycarbonyl group represented by R ³ is a methoxycarbonyl group, an ethoxycarbonyl group,
The method for producing an aminobutene derivative according to claim 1, which is an iso-butoxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, or a phenyloxycarbonyl group. 15. The method for producing an aminobutene derivative according to claim 1, wherein the sulfonyl group represented by R ³ is a methanesulfonyl group, a trifluoromethanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group or an imidazosulfonyl group. 16. The method for producing an aminobutene derivative according to claim 1, wherein the substituted alkyl group represented by R ³ is a benzyl group, a 4-methoxybenzyl group or a 2,4-dimethoxybenzyl group. 17. A compound of the general formula wherein R ³ is a hydrogen atom. The method according to claim 1, wherein the aminobutene derivative represented by the formula is produced. 18. R ¹ is represented by the following formula: (Wherein, R ¹¹ is a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, a piperidinomethyl It represents a group or a dimethoxy aminomethyl group.), and, X is a hydroxyl group, a halogen atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyl group, a p- toluenesulfonyl group or imidazo sulfonyl group, R ² Is (Wherein n represents 0, 1 or 2), and R ³ is hydrogen. The method according to claim 1, wherein the pyridyloxy derivative represented by the following formula is produced. 19. R ¹ is embedded image (Wherein, R ¹¹ is a hydroxymethyl group, a tetrahydropyranyl-2-oxymethyl group, a methoxymethoxymethyl group, a formyl group, a dimethoxymethyl group, a diethoxymethyl group, a 1,3-dioxolan-2-yl group, Represents a piperidinomethyl group or a dimethylaminomethyl group), and R ² is (Wherein n represents 0, 1 or 2), and R ³ is (Wherein, R ¹² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
Substituted or unsubstituted aromatic hydrocarbon group, having 1 to 6 carbon atoms
Represents an alkoxy group or a substituted or unsubstituted aryloxy group. ) Is a general formula The method according to claim 1, wherein the acetimide compound represented by the formula is produced.