JPH1036352A - (11e)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-5,9-methanocycloocta(b)pyridin-2-(1h)-one derivative and production intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound, reduced in adverse effects as a therapeutic agent for Alzheimer diseases and having expectable excellent effects on in vivo kinetics. SOLUTION: This new compound is represented by formula I [X<1> is hydroxymethyl, a helogenomethyl, a (substituted) alkyloxycarbonyl, an alkenyloxycarbonyl or an aralkyloxycarbonyl], e.g. (11E)-5-amino-11-ethylidene-7- fluoromethyl-5,6,9,10-tetrahydro-5,9-methanocycloocta[b]pyridin-2(1H)- one. The compound represented by formula I is synthesized by starting from 7,8,9,10- tetrahydro-7-methylene-11-oxo-5,9-metanocycloocta[b]pyridine-5(6H)-car boxylic acid ester derivative represented by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention shows potent enzyme inhibitory activity of acetylcholinesterase, and is expected to be used as a therapeutic agent for Alzheimer's disease, which is the most common example of senile dementia (11E) -5. -Amino-11-ethylidene-5,6,9,10-tetrahydro-5,9-
The present invention relates to a methanocycloocta [b] pyridin-2 (1H) -one derivative and a production intermediate thereof.

[0002]

2. Description of the Related Art Alzheimer's disease, which is a major cause of senile dementia, which is becoming a social problem with the advent of an aging society, has abnormalities in the production of neurotransmitters that play an important role in the central nervous transmission mechanism. It is thought that it will cause dementia symptoms. Therefore, focusing on the neurotransmitter acetylcholine, muscarinic drugs,
Attempts to develop acetylcholine releasing agents, acetylcholinesterase inhibitors and the like as anti-dementia agents have been actively made. Above all, research on acetylcholinesterase inhibitory active substances has recently been remarkably developed. [B
rossi, A .; Pei, X.-F .; Greig, NH Aust. J. Che
m., 48, 171 (1996).]

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound which has reduced side effects and is expected to have excellent pharmacokinetics as a therapeutic agent for Alzheimer's disease.

[0004]

Means for Solving the Problems The present inventors have studied in detail and found that the compound represented by the following general formula [I] exhibits a strong acetylcholinesterase inhibitory activity, and the compound represented by the following general formula [II] and They have found that the compound represented by [III] can be used as an intermediate for the production thereof, and have completed the present invention. That is, the present invention provides the following general formula [I]

[0005]

Embedded image

(Wherein, X ¹ represents a hydroxymethyl group; a halogenomethyl group; or an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group which may have a substituent.)
(11E) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one derivative represented by the following formula:
And a production intermediate of the general formula [II]

[0007]

Embedded image

(Wherein, R ¹ represents an alkyl group or a silyl group which may have a substituent. X ² is a hydroxymethyl group; a formyl group; a carboxyl group; an alkyl which may have a substituent. Y represents a carboxyl group; or an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group which may have a substituent, or an oxymethyl group, an alkenyloxymethyl group, or an aralkyloxymethyl group; An alkyloxycarbonyl group, an alkenyloxycarbonyl group or an aralkyloxycarbonyl group which may have a group; or an alkyloxycarbonylamino group, an alkenyloxycarbonylamino group or an aralkyloxycarbonylamino which may have a substituent Represents a group.) (11E) -11-ethylidene-
5,6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridine derivative and a compound represented by the general formula [II
I]

[0009]

Embedded image

(Wherein, R ¹ represents an alkyl group or a silyl group which may have a substituent. X ³ is a hydroxymethyl group; a halogenomethyl group; an alkyloxymethyl which may have a substituent. R ² represents an alkyl group, an alkenyl group, or an aralkyl group which may have a substituent), or an alkenyloxymethyl group or an aralkyloxymethyl group; 9,10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the formula [I] of the present invention can be prepared by the method described in the literature [AP Kozikowski et al.
Org. Chem., 58, 7660 (1993).].

[0012]

Embedded image

(Wherein, R ¹ represents an alkyl group or a silyl group which may have a substituent. R ² represents an alkyl group, an alkenyl group or an aralkyl group which may have a substituent. The following synthesis was carried out from a 7,8,9,10-tetrahydro-7-methylene-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid ester derivative represented by the following formula: It can be manufactured by a process.

[0014]

Embedded image

[0015]

Embedded image

[0016]

Embedded image

(In the formula, R ¹ represents an alkyl group or a silyl group which may have a substituent. R ² , R ⁴ , R ⁵ and R ⁶ are the same or different and have a substituent. Represents an alkyl group, an alkenyl group, or an aralkyl group which may be substituted, and R ³ represents an alkyl group, an alkenyl group, an aryl group, or an aralkyl group which may have a substituent.)

Examples of the alkyl group which may have a substituent in the above general formulas [I] to [IV] include a linear group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group and a t-butyl group. -Or branched lower alkyl groups, and these have a lower alkoxy group, a lower alkylthio group, a lower alkoxyalkoxy group, a halogen atom, a halogen-substituted lower alkoxy group, a silyl group, a cycloalkyl group, and a substituent such as an aralkyloxy group. Substituted alkyl groups such as methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, trifluoromethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl , Cyclohexylmethyl group, 1-ethoxyethyl group, 1-methyl-1
-Methoxyethyl group, benzyloxymethyl group; alkenyl groups which may have a substituent include allyl group, crotyl group, cinnamyl group and 4-nitrocinnamyl group; aralkyl groups which may have a substituent Is a benzyl group,
p-methoxybenzyl group, p-nitrobenzyl group, p-
Bromobenzyl group, trityl group, 2,4-dimethoxyphenylmethyl group, 2,4,6-trimethylphenylmethyl group, tetrafluorophenylmethyl group, 2-furfuryl group, 2-thenyl group, 1-naphthylmethyl group, 2 -Naphthylmethyl group, 2-phenylethyl group and the like. Examples of the silyl group which may have a substituent include a silyl group such as a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, and a nitro group and a cyano group. And a silyl group in which a lower alkoxy group, a halogen atom, a silyl group and the like are substituted with an alkyl group. Examples of the aryl group which may have a substituent include a phenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-bromophenyl group, m-chlorophenyl group, 2,4-dimethoxyphenyl group, 2,4 , 6-trimethylphenyl group, tetrafluorophenyl group, 2-furyl group, 2-thienyl group, 1-naphthyl group, 2-naphthyl group and the like. Examples of the acyloxymethyl group include an acetoxymethyl group, a propionyloxymethyl group, a trifluoroacetoxymethyl group, a benzoyloxymethyl group, and a p-toluoyloxymethyl group.

As described above, as R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ in the general formulas [I] to [IV], various ones are exemplified. R ¹ , R ² , R ³ and R ⁵ are
A methyl group is used, and R ⁶ is an ethyl group.
R ⁴ is a methoxymethyl group.

[First Step] In this step, 7,8,9,10-tetrahydro-7-methylene-11-oxo-5,9-methanocycloocta [b] represented by the general formula [IV] is used.
7 of pyridine-5 (6H) -carboxylic acid ester derivative
A bromonium ion on the exomethylene group,
7-bromomethyl- represented by the general formula [III-1]
This is to produce 9,10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative. In the general formula [IV], R ¹ and R ² are both methyl groups.
10-tetrahydro-2-methoxy-7-methylene-1
Methyl 1-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate was prepared according to the method described in the literature [AP Kozikowski et al., J. Org. Chem., 58, 7660.
(1993).]. A derivative having a group other than a methyl group in R ¹ and R ² can be produced according to this production method.

The derivation of an exomethylene group into an allyl bromide is accompanied by deprotonation by treating the exomethylene group under general bromohydroxylation conditions to directly obtain an allyl bromide. Bromohydroxylation can be performed by a known method (J. March, "Advanced Organ
ic Chemistry ", A Wiley-Interscience, New York, 199
2, pp814-816), and preferably, a method of treating with N-bromosuccinimide in the presence of a small amount of water is used. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but a polar solvent such as dimethyl sulfoxide or 1,4-dioxane is used. More preferably, 1,4-dioxane is used. The reaction proceeds smoothly at 0 ° C to 50 ° C.

[Second Step] This step is carried out according to the general formula [III-
1] converting the 7-bromomethyl group of the 7-bromomethyl-9,10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative represented by the formula: 7-acyloxymethyl-9,10-dihydro-11 represented by the general formula [III-2]
-Oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid ester derivative.

The allyl bromide is converted into an allyl ester by using a silver salt of a carboxylic acid such as silver acetate, silver trifluoroacetate or silver benzoate. Silver acetate is preferably used. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction.
Preferably, acetone is used. The reaction is performed at 0 ° C to 50
It proceeds smoothly at ° C.

[Third Step] This step is carried out according to the general formula [III-
Deprotection of the hydroxyl group at the 12-position of the 7-acyloxymethyl-9,10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative represented by the formula [2] And 9,10-dihydro-7-hydroxymethyl- represented by the general formula [III-3]
This is to produce an 11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid ester derivative.

The acyl group can be deprotected by a known method (TW Green, "Protect") depending on the type of the acyl group used.
ive Groups in Organic Synthesis ", A Wiley-Intersci
ence, New York, 1991, pp87-103).
For example, when the acyl group is an acetyl group, a method in which a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or ammonia is allowed to act in a hydroalcoholic solvent such as methanol or ethanol, or methanol or ethanol And a transesterification in the presence of an acid catalyst such as p-toluenesulfonic acid or camphorsulfonic acid in an alcoholic solvent such as Preferably, a method of reacting with potassium carbonate in methanol and deprotecting by transesterification is used. The reaction is 0
It proceeds smoothly from 100 to 100 ° C.

[Fourth Step] This step is carried out according to the general formula [III-
3] protecting the 12-position hydroxyl group of the 9,10-dihydro-7-hydroxymethyl-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative represented by the formula: 7-alkoxymethyl-9,10-dihydro-1 represented by the general formula [III-4]
This is for producing a 1-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid ester derivative.

As the protecting group for the primary hydroxyl group, those which are stably present in the fifth to seventh steps and which are rapidly removed in the eighth step without damaging other parts of the molecule are selected. Protecting groups that satisfy this requirement include methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl,
-Methoxycyclohexyl group, tetrahydrofuranyl group, 1-ethoxyethyl group, t-butyl group, allyl group,
Examples thereof include a benzyl group, a p-methoxybenzyl group, a diphenylmethyl group, and a trityl group, and a methoxymethyl group is preferably used.

These protecting groups may be introduced by a known method (TW Green, "Protective Groups in Organic Chemis").
try ", A Wiley-Interscience, New York, 1991, pp14-6
8). When the protecting group is a methoxymethyl group, it is generally treated with chloromethyl methyl ether in the presence of a tertiary amine such as triethylamine, ethyldiisopropylamine, pyridine or 4-dimethylaminopyridine, and dimethoxymethane in the presence of an acidic catalyst. A method of treating with chloromethyl methyl ether in the presence of ethyldiisopropylamine is preferably used. As the solvent used for the reaction,
Any solvent can be used as long as it does not participate in the reaction, but a halogenated hydrocarbon solvent such as dichloromethane or chloroform is preferably used. The reaction is -20
It proceeds smoothly from 50 ° C to 50 ° C.

[Fifth Step] This step is carried out according to the general formula [III-
Wittig (4) is added to the carbonyl group at the 11-position of the 7-alkoxymethyl-9,10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative represented by the formula (Wittig) Enhancement of two carbons by the action of a reagent, isomerization of a double bond, and (11E) -7- represented by the general formula [II-1]
Alkoxymethyl-11-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridine-5
(6H) -Carboxylic acid ester derivatives are produced.

A method for introducing an ethylidene group is a known method (J. March, "Advanced Organic Chemistry", A Wiley-
Interscience, New York, 1992, pp956-963) with Wittig reagent obtained from ethyltriphenylphosphonium bromide. Examples of the base to be used include sodium amide, butyllithium, phenyllithium, potassium-t-butoxide, sodium hydride and the like. Preferably, butyllithium is used. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, and diethyl ether, tetrahydrofuran, benzene, N,
N-dimethylformamide or the like is used, and preferably, tetrahydrofuran is used. Reaction is from -20 ° C to 7
It proceeds smoothly at 0 ° C.

The double bond isomerization is carried out by a method using thiophenol and α, α'-azobisisobutyronitrile. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but aromatic hydrocarbon solvents such as benzene, toluene, and xylene are used, and toluene is preferably used.
Also, thiophenol can be used as a solvent. The reaction proceeds smoothly at 0 ° C to 150 ° C.

[Sixth Step] This step is carried out according to the general formula [II-
(11E) -7-alkoxymethyl-1 represented by the formula
The 5-position carboxylate of 1-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate derivative is hydrolyzed to give a general formula [II-2] (11E) -7-Alkoxymethyl-11-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridine-5 represented by the following formula:
(6H) -carboxylic acid derivative is produced.

The conversion of the carboxylic acid ester to the carboxylic acid can be performed by a known method (TW Green, "Protective Groups in Organic") depending on the type of the carboxylic acid ester used.
Synthesis ", A Wiley-Interscience, New York, 1991,
pp224-276). For example, when the carboxylic acid ester is a methyl ester, an ethyl ester, a propyl ester or the like, the reaction is carried out by using sodium hydroxide, potassium hydroxide or the like as a base in a water-containing solvent such as methanol, ethanol or tetrahydrofuran. When the carboxylic acid ester is a t-butyl ester, the reaction is performed by using formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid or the like in tetrahydrofuran. When the carboxylic acid ester is a benzyl ester, a p-methoxybenzyl ester, a p-nitrobenzyl ester, or the like, palladium carbon, Raney nickel, palladium hydroxide, rhodium-in an organic solvent such as methanol, ethanol, or ethyl acetate. It is carried out by catalytic hydrogenation using a catalyst such as alumina.
The reaction proceeds smoothly at 0 ° C to 100 ° C.

[Seventh Step] This step is carried out according to the general formula [II-
2] (11E) -7-alkoxymethyl-1
The 5-carboxyl group of the 1-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid derivative is converted to give a compound of the general formula [II
(11E)-[7-Alkoxymethyl-11-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] represented by the following formula:
To produce carbamic acid ester derivatives.

As a method for converting a carboxylic acid into a carbamic acid ester, a known method (SR Sandler and W. K.
aro, "Organic Functional Group", Academic Press, N
ew York, 1983, pp414-420). For example, a method in which hydrazic acid is generated from sodium azide and sulfuric acid in the presence of a carboxylic acid to form an acyl azide, converted to isocyanate by thermal rearrangement, and then alcohol such as methanol, ethanol, propanol, or t-butanol is added. A carboxylic acid converted to an acid halide with thionyl chloride, oxalyl chloride or the like and then reacted with sodium azide to form an acyl azide, or reacted with hydrazine to convert to an acyl hydrazone, and then reacted with nitric acid to form an acyl azide; A method of treating in the same manner as above; a method of heating a carboxylic acid with a mixture of diphenylphosphoric acid azide and triethylamine and treating in the same manner as above is exemplified.
A method is used in which carboxylic acid and diphenylphosphoric acid azide are heated and then treated with methanol. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but an aromatic hydrocarbon solvent such as benzene, toluene and xylene is preferably used.
The reaction proceeds smoothly at 30 ° C to 150 ° C.

[Eighth Step] This step is carried out according to the general formula [II-
3] represented by (11E)-[7-alkoxymethyl-
11-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridin-5 (6H) -yl]-
The protecting group for the hydroxyl group at the 12-position of the carbamic acid ester derivative is deprotected to give (11E)-represented by the general formula [II-4].
This is for producing [11-ethylidene-9,10-dihydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] -carbamic acid ester derivative.

The deprotection of the primary hydroxyl group can be performed by a known method (TW
Green, "Protective Groups in Organic Synthesis", A
Wiley-Interscience, New York, 1991, pp14-118). When the protecting group is a methoxymethyl group, generally, a method of heating in a solvent under acidic conditions is used.
Preferably, a method of heating and refluxing in t-butanol in the presence of pyridinium p-toluenesulfonate is used. The reaction proceeds smoothly under reflux conditions.

[Ninth Step] This step is carried out according to the general formula [II-
(11E)-[11-ethylidene-9,
10-dihydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridin-5 (6H) -yl]-
By oxidizing the 7-position hydroxymethyl group of the carbamic acid ester derivative in two steps and further esterifying it,
(11E)-[7-Alkoxycarbonyl-11-ethylidene-9,10-dihydro-5,9-methanocycloocta [b] pyridine-5 represented by the general formula [II-5]
(6H) -yl] -carbamic acid ester derivative.

The oxidation reaction of the primary hydroxyl group to the aldehyde is
Known methods (J. March, "Advanced Organic Chemistry",
A Wiley-Interscience, New York, 1991, pp1167-117
Performed by 1). Preferably, a method of activating a primary alcohol using oxalyl chloride and dimethyl sulfoxide, followed by treatment with triethylamine (Swern oxidation)
Is used. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction.
Preferably, halogenated hydrocarbon solvents such as dichloromethane and chloroform are used. The reaction is carried out at -78 ° C to 0
It proceeds smoothly at ° C.

The oxidation reaction of the aldehyde to the carboxylic acid is
Known methods (J. March, "Advanced Organic Chemistry",
A Wiley-Interscience, New York, 1991, pp1167-117
Performed by 1). Preferably, an oxidation method using sodium chlorite in which sodium dihydrogen phosphate is used as a buffer and 2-methyl-2-butene coexists as a radical scavenger is used. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but a mixed solvent of t-butyl alcohol and water is preferably used. The reaction proceeds smoothly at 0 ° C to 50 ° C.

As the kind of the ester, an ester which is stably present in the tenth step, rapidly reduced in the eleventh step without damaging other parts of the molecule, and gives an alcohol is selected. Esters meeting this requirement include:
Examples thereof include ethyl ester, allyl ester, isopropyl ester, cyclopentyl ester, cyclohexyl ester, phenyl ester, and benzyl ester, and preferably, ethyl ester is used.

These esters can be introduced by a known method (TW Green, "Protective Groups in Organic Synth
esis ", A Wiley-Interscience, New York, 1991, pp227
-260). When the ester is an ethyl ester, it can be produced by a dehydration condensation reaction between carboxylic acid and ethanol or a nucleophilic substitution reaction between carboxylate and ethyl halide. Preferably, from the viewpoint of operability, a method is used in which carboxylic acid is converted to an acid chloride using oxalyl chloride and a catalytic amount of N, N-dimethylformamide, followed by treatment with ethanol to form an ethyl ester. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction.
An aromatic hydrocarbon solvent or a halogenated hydrocarbon solvent such as benzene, toluene, dichloromethane and chloroform is used. Preferably, dichloromethane is used. The reaction proceeds smoothly at -20 ° C to 50 ° C.

[Tenth Step] This step is carried out according to the general formula [II-
(11E)-[7-Alkoxycarbonyl-11-ethylidene-9,10-dihydro-5,9-
Deprotection of the 2-position hydroxyl group and the 5-position carbamic acid ester of the methanocycloocta [b] pyridin-5 (6H) -yl] -carbamic acid ester derivative was carried out to obtain a compound of the general formula [I
-1] represented by (11E) -5-amino-7-alkoxycarbonyl-11-ethylidene-5,6,9,10
-Tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one derivative.

The deprotection of the hydroxyl group can be performed by a known method (TW Green, "Protective Gro
ups in Organic Synthesis ", A Wiley-Interscience, N
ew York, 1991, pp14-118).

The deprotection of the carbamic acid ester can be performed by a known method (TW Green,
"Protective Groups in Organic Synthesis", A Wiley
-Interscience, New York, 1991, pp315-348). In the case where the 2-position is a methoxy group and the 5-position is methyl carbamate, a method of treating with a halogenated trimethylsilane is exemplified, and any solvent used in the reaction can be used as long as it does not participate in the reaction. But,
Halogenated hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane are used. Preferably, a method using trimethylsilane iodide in chloroform is used. The reaction proceeds smoothly at 0 ° C to 80 ° C.

[Eleventh Step] This step is carried out according to the general formula [I-
1] (11E) -5-amino-7-alkoxycarbonyl-11-ethylidene-5,6,9,10-
The 7-position alkoxycarbonyl group of the tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one derivative is reduced to give the compound of the formula [I-2] (11E)
-5-amino-11-ethylidene-5,6,9,10-
This is for producing tetrahydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridin-2 (1H) -one.

The reduction of the carboxylic acid ester can be carried out by a known method (J. March, "Advanced Organic Chemistry", A Wiley-
Interscience, New York, 1991, pp1214). For example, lithium aluminum hydride, diisobutylaluminum hydride, triethyllithium borohydride, a method using a metal hydride reagent such as lithium boron hydride is exemplified, preferably, diisobutylaluminum hydride is used . As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, and diethyl ether, tetrahydrofuran, dichloromethane, toluene and the like are used. Preferably, tetrahydrofuran is used. The reaction is -78
It proceeds smoothly from 0 ° C to 0 ° C.

[Twelfth Step] In this step, (11E) -5-amino-11-ethylidene- represented by the formula [I-2] is used.
5,6,9,10-tetrahydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridine-2
By fluorinating the 12-position hydroxyl group of (1H) -one, a compound of the formula [I
(11E) -5 which is a compound of the present invention represented by Formula [3].
-Amino-11-ethylidene-7-fluoromethyl-
This is to produce 5,6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one.

The conversion of a hydroxyl group to a fluorine atom is carried out by diethylaminosulfur trifluoride. As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but ether solvents such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; pentane, hexane , Benzene, toluene, xylene and the like. Preferably, dichloromethane is used. The reaction proceeds smoothly from -78 ° C to 0 ° C.

[0050]

According to the present invention, (11E) manufactured as described above.
-5-amino-11-ethylidene-7-fluoromethyl-5,6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one and its production intermediates Some (11E) -5-amino-
11-ethylidene-5,6,9,10-tetrahydro-
7-hydroxymethyl-5,9-methanocycloocta [b] pyridin-2 (1H) -one and (11E) -5
-Amino-7-ethoxycarbonyl-11-ethylidene-5,6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one is a potent acetylcholinesterase inhibitory activity test. Acetylcholinesterase inhibitory activity and confirmed to have use as a therapeutic drug for Alzheimer's disease (see Test Examples).

Hereinafter, the present invention will be described in detail with reference to Examples, but it goes without saying that the present invention is not limited to these.

[0052]

【Example】

 Example 1

[0053]

Embedded image

The method described in the literature [AP Kozikowski et a
l, J. Org. Chem., 58, 7660 (1993).], 7,8,9,10-tetrahydro-2-methoxy-
Methyl 7-methylene-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.80 g, 6.27 mmol) and N-bromosuccinimide (1.34 g, 7. 52 mmol) of 1,4
-Water (3.5 ml) was added to a dioxane (35 ml) solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water and extracted twice with ethyl acetate (80 ml). The organic layers were combined, washed with water (100 ml) and saturated saline (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 7-bromomethyl-9,10-dihydro-2-methoxy-11-oxo-5,9-methanocycloocta [b ] Methyl pyridine-5 (6H) -carboxylate (1.
(87 g, yield: 82%) as colorless prisms.

Mp 161.0-163.0 ° C. (n-hexane-AcOEt). IR (neat): 2950 (m), 1750 (s), 1735 (s), 1605 (s),
 1580 (m), 1480 (s), 1430 (m), 1330 (s), 1270 (s),
1220 (m), 1080 (m), 1030 (m), 920 (m), 830 (m), 74
0 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.15 (1H, d, J = 8.6Hz,
 C_Four-H), 6.64 (1H, d, J = 8.6Hz, C_Three-H), 5.89-5.87 (1
H, m, C₈-H), 3.91 (3H, s, OCH_Three), 3.83 (1H, d, J =
10.4Hz, CH_TwoBr), 3.79 (1H, d, J = 10.4Hz, CH_TwoBr),
3.78 (3H, s, CO_TwoCH_Three), 3.53 (1H, d, J = 17.4Hz, C₆-
H), 3.44 (1H, dd, J = 17.1, 4.8Hz, C _Ten-H), 3.25 (1
H, br t, J = 5.3Hz, C₉-H), 3.21 (1H, dd, J = 17.1,
 2.0Hz, C_Ten-H), 2.83 (1H, d, J = 17.4Hz, C₆-H).¹³ C-NMR (100 MHz, CDCl_Three): δ205.9 (C₁₁), 170.9 (CO
_TwoCH_Three), 163.3 (C_Two), 150.0 (C_10a), 137.8 (C_Four), 134.0
 (C_4a), 130.8 (C₈), 125.6 (C₇), 109.9 (C_Three), 59.7
(C_Five), 53.5 (OCH_Three), 52.8 (CO_TwoCH_Three), 46.0 (C₉), 43.0
(C₆), 40.0 (C_Ten), 35.1 (C₁₂) .EIMS (m / z): 367 (M + 1⁺, 6), 365 (M-1⁺, 7), 287 (17),
 286 (100), 258 (44), 230 (14), 226 (15), 199 (2
1), 198 (47), 184 (10), 170 (5), 154 (7), 128 (7),
 115 (6), 84 (8) .HREIMS (m / z): calcd for C₁₆H₁₆ ⁷⁹BrNO_Four (M⁺): 365.02
61 found: 365.0252.calcd for C₁₆H₁₆ ⁸¹BrNO_Four (M⁺): 367.0242.found: 36
7.0257. Anal.calcd for C₁₆H₁₆BrNO_Four : C, 52.48: H, 4.40:
N, 3.82: Br, 21.82: found: C, 52.20: H, 4.44: N,
3.71: Br, 22.04.

Embodiment 2

[0057]

Embedded image

7-bromomethyl-9,10-dihydro-
Methyl 2-methoxy-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.87 g, 5.11 mmol) and silver acetate (2.
14 g, 12.8 mmol) were suspended in acetone (40 ml) and stirred at room temperature for 6 hours. After concentrating the reaction solution, it was poured into water and extracted twice with ethyl acetate (80 ml). The organic layers were combined, washed with water (100 ml) and saturated saline (100 ml), and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain a residue. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1) to give 7-acetoxymethyl-9,
10-dihydro-2-methoxy-11-oxo-5,9
Methyl-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.43 g, yield 81%) was obtained as colorless prism crystals.

Mp 117.0-117.5 ° C (n-hexane-ether). IR (neat): 2950 (m), 1750 (s), 1600 (s), 1580 (m),
1480 (m), 1430 (m), 1380 (m), 1330 (m), 1250 (s),
. 1080 (m), 1040 ( m), 920 (m), 840 (m), 740 (m) cm -1 1 H-NMR (400 MHz, CDCl 3): δ7.13 (1H, d, J = 8.6Hz,
C ₄ -H), 6.64 (1H, d, J = 8.6 Hz, C ₃ -H), 5.79-5.77 (1
H, m, C ₈ -H), 4.41 (1H, d, J = 13.0Hz, CH ₂ OAc), 4.3
5 (1H, d, J = 13.0Hz, CH ₂ OAc), 3.92 (3H, s, OCH ₃ ),
3.78 (3H, s, CO ₂ CH ₃ ), 3.44 (1H, dd, J = 17.1, 4.8H
z, C ₁₀ -H), 3.43 (1H, d, J = 17.5Hz, C ₆ -H), 3.25 (1
H, br t, J = 4.9Hz, C ₉ -H), 3.21 (1H, dd, J = 17.1,
_{. 1.8Hz, C 10 -H),} 2.63 (1H, d, J = 17.5Hz, C 6 -H) 13 C-NMR (100 MHz, CDCl 3): δ206.3 (C 11), 171.1 (CO
₂ CH ₃ ), 170.4 (CH ₃ CO), 163.4 (C ₂ ), 150.3 (C _10a ), 13
7.7 (C ₄ ), 132.3 (C _4a ), 127.3 (C ₈ ), 125.9 (C ₇ ), 10
9.9 (C ₃ ), 66.1 (C ₁₂ ), 59.9 (C ₅ ), 53.5 (OCH ₃ ), 52.8
(CO ₂ CH ₃ ), 45.8 (C ₉ ), 41.3 (C ₆ ), 40.1 (C ₁₀ ), 20.8
(CH ₃ CO) .EIMS (m / z): 345 (M ⁺ , 49), 313 (35), 302 (10), 286
(21), 270 (5), 257 (35), 253 (45), 242 (9), 226 (5
7), 205 (14), 198 (100), 184 (13), 170 (9), 154 (1
2), 141 (6), 128 (9), 115 (8), 84 (14) .HREIMS (m / z): calcd for C ₁₈ H ₁₉ NO ₆ (M ⁺ ): 345.1211.
found: 345.1237.Anal.calcd for C ₁₈ H ₁₉ NO ₆ : C, 62.60: H, 5.55: N,
4.06: found: C, 62.54: H, 5.59: N, 3.98.

Embodiment 3

[0061]

Embedded image

Methyl 7-acetoxymethyl-9,10-dihydro-2-methoxy-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.43 g, 4.14 mmol) ) Of methanol (4
0 ml) solution at 0 ° C. with potassium carbonate (300 mg,
2.17 mmol) in methanol (3 ml) was added over 10 minutes and stirred for 2 hours. After concentrating the reaction solution,
It was poured into water and extracted twice with ethyl acetate (80 ml). The combined organic layers were combined with water (100 ml) and saturated saline (100 ml).
ml) and dried over anhydrous sodium sulfate.
The solvent was distilled off to obtain a residue. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
And purified using methyl 9,10-dihydro-7-hydroxymethyl-2-methoxy-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.17 g, (93% yield) as a colorless oil.

IR (neat): 3450 (m), 2950 (m), 1750
(s), 1730 (s), 1600 (s), 1580 (m), 1480 (s), 1430
(s), 1380 (s), 1260 (s), 1140 (m), 1080 (m), 1030
. (m), 835 (m ), 740 (m) cm -1 1 H-NMR (400 MHz, CDCl 3): δ7.13 (1H, d, J = 8.6Hz,
C ₄ -H), 6.62 (1H, d, J = 8.6 Hz, C ₃ -H), 5.75-5.73 (1
H, m, C ₈ -H), 3.97 (1H, d, J = 13.0Hz, CH ₂ OH), 3.90
(3H, s, OCH ₃ ), 3.89 (1H, d, J = 13.0Hz, CH ₂ OH),
3.77 (3H, s, CO ₂ CH ₃ ), 3.43 (1H, dd, J = 16.4, 4.8H
z, C ₁₀ -H), 3.39 (1H, d, J = 17.4Hz, C ₆ -H), 3.24 (1
H, br t, J = 4.7Hz, C ₉ -H), 3.21 (1H, dd, J = 16.4,
2.0Hz, C ₁₀ -H), 2.66 (1H, d, J = 17.4Hz, C ₆ -H), 1.6
3 (1H, br s, OH). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ207.0 (C ₁₁ ), 171.3 (CO
₂ CH ₃ ), 163.3 (C ₂ ), 150.5 (C _10a ), 137.8 (C ₄ ), 136.8
(C _4a ), 126.1 (C ₇ ), 123.9 (C ₈ ), 109.8 (C ₃ ), 65.0
(C ₁₂ ), 59.9 (C ₅ ), 53.5 (OCH ₃ ), 52.8 (CO ₂ CH ₃ ), 45.7
(C ₉ ), 42.4 (C ₆ ), 40.2 (C ₁₀ ) .EIMS (m / z): 303 (M ⁺ , 96), 285 (11), 271 (100), 258
(15), 244 (62), 240 (70), 226 (41), 216 (54), 205
(20), 198 (82), 186 (32), 172 (25), 154 (19), 142
(11), 128 (18), 115 (21), 102 (8), 89 (6), 77 (1
2) .HREIMS (m / z): calcd for C ₁₆ H ₁₇ NO ₅ (M ⁺ ): 303.1105.
found: 303.1123.

Embodiment 4

[0065]

Embedded image

Under an argon atmosphere, 9,10-dihydro-
7-hydroxymethyl-2-methoxy-11-oxo-
5,9-methanocycloocta [b] pyridine-5 (6
H) -Methyl carboxylate (975 mg, 3.22 mmol)
l) in dichloromethane (20 ml) at 0 ° C. in ethyldiisopropylamine (2.8 ml, 16.1 mm).
ol) and chloromethyl methyl ether (1.21 ml,
16.1 mmol) and stirred overnight at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate (50 ml). The organic layers were combined, and water (70 ml) and saturated saline (7
0 ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purified using 1) and 9,10-dihydro-2-methoxy-7- (methoxymethoxy) methyl-11-oxo-
5,9-methanocycloocta [b] pyridine-5 (6
H) -Methyl carboxylate (1.04 g, 93% yield) was obtained as a colorless oil.

IR (neat): 2950 (m), 1750 (s), 1730
(s), 1600 (s), 1580 (m), 1480 (s), 1430 (s), 1330
(s), 1260 (s), 1150 (s), 1110 (s), 1040 (s), 920
. (m), 830 (m ), 740 (m) cm -1 1 H-NMR (400 MHz, CDCl 3): δ7.13 (1H, d, J = 8.6Hz,
C ₄ -H), 6.62 (1H, d, J = 8.6 Hz, C ₃ -H), 5.76-5.74 (1
H, m, C ₈ -H), 4.44 (1H, d, J = 6.6 Hz, OCH ₂ OCH ₃ ), 4.
38 (1H, d, J = 6.6Hz, OCH ₂ OCH ₃ ), 3.91 (3H, s, OC
H ₃ ), 3.86 (2H, s, CH ₂ OMOM), 3.77 (3H, s, CO ₂ CH ₃ ),
3.43 (1H, dd, J = 17.0, 5.4Hz, C ₁₀ -H), 3.40 (1H, d
t, J = 17.5, 1.2Hz, C ₆ -H), 3.27 (3H, br s, OCH ₂ OCH
₃ ), 3.25-3.23 (1H, m, C ₉ -H), 3.21 (1H, dd, J = 17.
_{. 0, 1.9Hz, C 10 -H} ), 2.68 (1H, d, J = 17.5Hz, C 6 -H) 13 C-NMR (100 MHz, CDCl 3): δ206.7 (C 11), 171.3 ( CO
₂ CH ₃ ), 163.3 (C ₂ ), 150.5 (C _10a ), 137.8 (C ₄ ), 134.0
(C _4a ), 126.1 (C ₇ ), 126.1 (C ₈ ), 109.8 (C ₃ ), 95.2
(OCH ₂ OCH ₃ ), 69.1 (C ₁₂ ), 60.0 (C ₅ ), 55.4 (OCH ₂ OC
H ₃ ), 53.5 (OCH ₃ ), 52.8 (CO ₂ CH ₃ ), 45.9 (C ₉ ), 42.8 (C
_{. 6), 40.2 (C 10} ) EIMS (m / z): 347 (M +, 31), 315 (21), 302 (6), 285
(33), 270 (8), 257 (67), 244 (10), 226 (31), 214
(13), 205 (9), 198 (60), 186 (15), 170 (12), 154
(9), 143 (5), 128 (9), 115 (10), 84 (13), 69 (11),
45 (100) .HREIMS (m / z): calcd for C ₁₈ H ₂₁ NO ₆ (M ⁺ ): 347.1368.
found: 347.1377.

Embodiment 5

[0069]

Embedded image

Ethyltriphenylphosphonium bromide (5.29 g, 14.3 m) at 0 ° C. under an argon atmosphere.
mol) in a suspension of tetrahydrofuran (10 ml) in butyllithium (1.71 M in hexane).
(7.42 ml, 12.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, at 0 ° C., 9,10-dihydro-2-methoxy-7- (methoxymethoxy) methyl-1
Methyl 1-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (1.04 g, 3.
(0 mmol) in tetrahydrofuran (10 ml) and then stirred overnight at room temperature. A saturated aqueous ammonium chloride solution (10 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (50 ml). Combine the organic layers and add water (7
0 ml) and saturated brine (70 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 11-ethylidene-9,10-dihydro-2-methoxy-7-.
(Methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (802 mg, yield 75%) (11E: 11Z = 1: 4
) As a colorless oil.

11Z form: IR (neat): 2950 (m), 1730 (s), 1600 (s), 1580 (m),
 1480 (s), 1430 (s), 1320 (s), 1260 (s), 1150 (s),
1110 (m), 1040 (s), 920 (m), 830 (m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.10 (1H, d, J = 8.6Hz,
 C_Four-H), 6.53 (1H, d, J = 8.6Hz, C_Three-H), 5.72-5.71 (1
H, m, C₈-H), 5.52 (1H, q, J = 7.3Hz, C₁₃-H), 4.40
(1H, d, J = 6.5Hz, OCH_TwoOCH_Three), 4.32 (1H, d, J = 6.5
Hz, OCH_TwoOCH_Three), 3.88 (3H, s, OCH_Three), 3.80 (2H, s, CH
_TwoOMOM), 3.71 (3H, s, CO_TwoCH_Three), 3.26 (3H, s, OCH_TwoOC
H_Three), 3.19 (1H, dd, J = 15.8, 5.2Hz, C_Ten-H), 3.14
(1H, m, C ₉-H), 3.04 (1H, d, J = 17.0Hz, C₆-H), 2.8
4 (1H, d, J = 15.8Hz, C_Ten-H), 2.37 (1H, d, J = 17.
0Hz, C₆-H), 1.51 (3H, d, J = 7.3Hz, C₁₄-H).¹³ C-NMR (100 MHz, CDCl_Three): δ176.5 (CO_TwoCH_Three), 162.6
(C_Two), 152.5 (C_10a), 136.8 (C_Four), 135.8 (C_4a), 133.1
(C₇), 129.3 (C₈), 127.4 (C₁₁), 116.5 (C₁₃), 108.9
(C_Three), 94.9 (OCH_TwoOCH_Three), 70.1 (C₁₂), 55.2 (OCH_TwoOC
H_Three), 53.3 (OCH_Three), 52.2 (CO_TwoCH_Three), 50.6 (C_Five), 43.4
(C₉), 41.5 (C₆), 39.5 (C_Ten), 12.2 (C₁₄) .EIMS (m / z): 359 (M⁺, 35), 297 (26), 282 (13), 268
(13), 250 (7), 238 (100), 224 (18), 210 (14), 196
(6), 180 (5), 167 (4), 115 (5), 84 (23) .HREIMS (m / z): calcd for C₂₀H_{twenty five}NO_Five (M⁺): 359.1730.
found: 359.1730.

Embodiment 6

[0073]

Embedded image

Under an argon atmosphere, 11-ethylidene-
Methyl 9,10-dihydro-2-methoxy-7- (methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylate (817 mg,
To a solution of 2.28 mmol) (11E: 11Z = 1: 4) in toluene (10 ml) was added thiophenol (0.47 m
1,4.56 mmol) and α, α′-azobisisobutyronitrile (382 mg, 2.28 mmol),
Stirred at 85 ° C. for 43 hours. After the reaction solution was concentrated, it was poured into water and extracted twice with ethyl acetate (50 ml). The organic layers were combined, and water (70 ml) and saturated saline (70 ml)
After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give (11E) -11-ethylidene-9,10-
Dihydro-2-methoxy-7- (methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridine-5
(6H) -methyl carboxylate (817 mg, yield 100)
%) As a colorless oil.

11E form: IR (neat): 2950 (m), 1730 (s), 1600 (s), 1580 (m),
 1480 (s), 1430 (s), 1325 (m), 1250 (s), 1150 (s),
1105 (m), 1050 (s), 920 (m), 830 (m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.10 (1H, d, J = 8.5Hz,
 C_Four-H), 6.53 (1H, d, J = 8.5Hz, C_Three-H), 5.72 (1H, br
 d, J = 3.7Hz, C₈-H), 5.08 (1H, q, J = 6.7Hz, C₁₃-
H), 4.41 (1H, d, J = 6.5Hz, OCH_TwoOCH_Three), 4.33 (1H,
d, J = 6.5Hz, OCH_TwoOCH_Three), 3.88 (3H, s, OCH_Three), 3.80
(2H, s, CH_TwoOMOM), 3.75 (3H, s, CO_TwoCH _Three), 3.68 (1H,
br t, J = 5.1Hz, C₉-H), 3.27 (3H, s, OCH_TwoOCH_Three), 3.
10 (1H, dd, J = 17.1, 6.4Hz, C_Ten-H), 3.10 (1H, dd,
J = 17.1, 3.6Hz, C₆-H), 2.88 (1H, d, J = 17.1, 1.7H
z, C_Ten-H), 2.31 (1H, d, J = 17.1Hz, C₆-H), 1.70 (3
H, d, J = 6.7Hz, C₁₄-H).¹³ C-NMR (100 MHz, CDCl_Three): δ175.3 (CO_TwoCH_Three), 162.6
(C_Two), 152.5 (C_10a), 137.7 (C_Four), 137.0 (C_4a), 133.3
(C₇), 127.7 (C₁₁), 127.6 (C₈), 114.8 (C₁₃), 108.6
(C_Three), 94.9 (OCH_TwoOCH_Three), 70.1 (C₁₂), 55.2 (OCH_TwoOC
H_Three), 54.4 (C_Five), 53.3 (OCH_Three), 52.2 (CO_TwoCH_Three), 41.6 (C
₆), 39.3 (C_Ten), 32.8 (C₉), 12.8 (C₁₄) .EIMS (m / z): 359 (M⁺, 43), 327 (5), 314 (9), 297 (2
8), 282 (23), 268 (17), 254 (10), 238 (100), 224
(19), 210 (14), 198 (5), 186 (10), 167 (7), 154
(6), 115 (6), 84 (7), 69 (5), 45 (60) .HREIMS (m / z): calcd for C₂₀H_{twenty five}NO_Five (M⁺): 359.1730.
found: 359.1738.

Embodiment 7

[0077]

Embedded image

(11E) -11-ethylidene-9,10
-Dihydro-2-methoxy-7- (methoxymethoxy)
Methyl-5,9-methanocycloocta [b] pyridine-
Methyl 5 (6H) -carboxylate (817 mg, 2.28
mmol) in tetrahydrofuran-methanol (1:
The mixture was dissolved in the mixed solution (10 ml) of 1), and a 3N aqueous solution of sodium hydroxide (5 ml, 15 mmol) was added.
Heated to reflux for an hour. After concentrating the reaction solution, pour into water and add 1
After adjusting the pH to 4 with an aqueous solution of N-hydrochloric acid, ethyl acetate (50 m
Extracted twice in l). Combine the organic layers with water (70m
l), washed with saturated saline (70 ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (11E)
11-ethylidene-9,10-dihydro-2-methoxy-7- (methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid (633 mg, 81% yield) Was obtained as a colorless oil.

IR (neat): 2950 (m), 1730 (s), 1600
(s), 1580 (m), 1480 (s), 1430 (s), 1330 (s), 1270
(m), 1250 (m), 1150 (m), 1110 (m), 1040 (s), 920
(m), 830 (m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.27 (1H, d, J = 8.6Hz,
 C_Four-H), 6.57 (1H, d, J = 8.6Hz, C_Three-H), 5.73 (1H, br
 d, J = 3.6Hz, C₈-H), 5.34 (1H, q, J = 6.7Hz, C₁₃-
H), 4.41 (1H, d, J = 6.5Hz, OCH_TwoOCH_Three), 4.34 (1H,
d, J = 6.5Hz, OCH_TwoOCH_Three), 3.88 (3H, s, OCH_Three), 3.81
(2H, s, CH_TwoOMOM), 3.70 (1H, br t, J = 4.4Hz, C₉-H),
 3.26 (3H, s, OCH_TwoOCH_Three), 3.12 (1H, dd, J = 17.0,
5.1Hz, C _Ten-H), 3.05 (1H, d, J = 17.2Hz, C₆-H), 2.9
0 (1H, dd, J = 17.0, 3.3Hz, C_{1 0}-H), 2.34 (1H, d, J
 = 17.2Hz, C₆-H), 1.74 (3H, d, J = 6.7Hz, C₁₄-H).¹³ C-NMR (100 MHz, CDCl_Three): δ179.3 (CO_TwoH), 162.7 (C
_Two), 152.7 (C_10a), 137.9 (C_Four), 136.3 (C_4a), 133.2
(C₇), 127.7 (C₈), 127.2 (C₁₁), 115.2 (C₁₃), 108.6
(C_Three), 94.9 (OCH_TwoOCH_Three), 70.1 (C₁₂), 55.2 (OCH_TwoOC
H_Three), 54.3 (C_Five), 53.5 (OCH_Three), 41.3 (C₆), 39.2
(C_Ten), 32.7 (C₉), 12.8 (C₁₄) .EIMS (m / z): 345 (M⁺, 57), 313 (9), 300 (22), 283
(49), 268 (23), 254 (20), 238 (100), 224 (30), 210
 (21), 198 (11), 186 (13), 172 (8), 154 (8), 128
(7), 115 (7), 84 (9), 45 (75) .HREIMS (m / z): calcd for C₁₉H_{twenty three}NO_Five (M⁺): 345.1575.
found: 345.1590.

Embodiment 8

[0081]

Embedded image

Under an argon atmosphere, (11E) -11-ethylidene-9,10-dihydro-2-methoxy-7-
(Methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid (418
mg, 1.21 mmol) and triethylamine (0.2
5 ml, 1.82 mmol) in toluene (10 ml) was added to diphenylphosphate azide (0.26 ml, 1.2 ml).
1 mmol) and stirred at 85 ° C. for 2.5 hours.
Methanol (2 ml) was added, and the mixture was further heated under reflux for 4 hours. After the reaction solution was concentrated, it was extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with water (40 ml) and saturated saline (40 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (11E)-[11-ethylidene-9,10-dihydro-2-methoxy-7-.
Methyl (methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (269 mg, 59% yield) was obtained as a colorless oil.

IR (neat): 3330 (m), 2950 (m), 1730
(s), 1600 (s), 1580 (m), 1530 (s), 1480 (s), 1420
(s), 1320 (s), 1310 (m), 1260 (s), 1150 (s), 1100
(s), 1040 (s), 920 (m), 830 (m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.57 (1H, d, J = 8.6Hz,
 C_Four-H), 6.55 (1H, d, J = 8.6Hz, C_Three-H), 5.76 (1H, br
 d, J = 4.4Hz, C₈-H), 5.39 (1H, q, J = 6.8Hz, C₁₃-
H), 5.04 (1H, br s, NH), 4.38 (1H, d, J = 6.5Hz, O
CH_TwoOCH_Three), 4.30 (1H, d, J = 6.5Hz, OCH_TwoOCH_Three), 3.87
(3H, s, OCH_Three), 3.78 (1H, s, CH_TwoOMOM), 3.78 (1H, s,
 CH_TwoOMOM), 3.75 (1H, br s, C₉-H), 3.62 (3H, br s,
NHCO_TwoCH _Three), 3.25 (3H, s, OCH_TwoOCH_Three), 3.12 (1H, dd, J
 = 16.9, 4.0Hz, C_Ten-H), 2.85 (1H, dd, J = 16.9, 1.8
Hz, C_Ten-H), 2.59 (1H, d, J = 15.2Hz, C₆-H), 2.37
(1H, d, J = 15.2Hz, C₆-H), 1.72 (3H, d, J = 6.8Hz,
 C₁₄-H).¹³ C-NMR (100 MHz, CDCl_Three): δ162.6 (C_Two), 154.7 (NHC
O_TwoCH_Three), 152.9 (C_10a), 136.2 (C_4a), 135.4 (C_Four), 13
2.4 (C₇), 129.8 (C₁₁), 129.1 (C₈), 112.4 (C ₁₃), Ten
8.7 (C_Three), 94.8 (OCH_TwoOCH_Three), 69.9 (C₁₂), 58.5 (C_Five),
55.3 (OCH_TwoOCH_Three), 53.3 (OCH_Three), 52.2 (CO_TwoCH_Three), 45.3
(C₆), 39.1 (C_Ten), 33.9 (C₉), 12.6 (C_{1 Four}) .EIMS (m / z): 374 (M⁺, 26), 342 (7), 329 (12), 312
(100), 297 (26), 283 (9), 267 (17), 253 (13), 237
(92), 224 (43), 210 (13), 199 (7), 184 (6), 166
(6), 148 (5), 130 (5), 97 (8), 77 (6), 59 (10), 45
 (72) .HREIMS (m / z): calcd for C₂₀H₂₆N_TwoO_Five (M⁺): 374.1839.
 found: 374.1813.

Embodiment 9

[0085]

Embedded image

Under an argon atmosphere, (11E)-[11-
Ethylidene-9,10-dihydro-2-methoxy-7-
Methyl (methoxymethoxy) methyl-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (260 mg, 0.70 mmol) and pyridinium p-toluenesulfonate (1.8 g, 7. 2mmo
A solution of 1) in t-butanol (15 ml) was heated to reflux for 9 hours. The reaction mixture was concentrated, poured into water, adjusted to pH 7 with a saturated aqueous solution of sodium hydrogen carbonate, and then diluted with ethyl acetate (30%).
ml) twice. Combine the organic layers with water (40m
l), washed with saturated saline (40 ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (11E)
Methyl-[11-ethylidene-9,10-dihydro-7-hydroxymethyl-2-methoxy-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (150 mg, 65% yield) ) Was obtained as a colorless oil.

IR (neat): 3330 (m), 2940 (m), 1720
(s), 1600 (s), 1580 (m), 1530 (m), 1480 (s), 1420
(s), 1320 (s), 1260 (s), 1070 (m), 1040 (s), 830
(m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.57 (1H, d, J = 8.6Hz,
 C_Four-H), 6.55 (1H, d, J = 8.6Hz, C_Three-H), 5.73 (1H, d,
 J = 4.8Hz, C₈-H), 5.39 (1H, q, J = 6.8Hz, C₁₃-H),
 5.10 (1H, br s, NH), 3.88 (1H, dd, J = 13.3, 6.0H
z, CH_TwoOH), 3.87 (3H, s, OCH_Three), 3.81 (1H, dd, J = 1
3.3, 6.0Hz, CH_TwoOH), 3.74 (1H, br s, C₉-H), 3.62
(3H, br s, NHCO_TwoCH_Three), 3.12 (1H, dd, J = 16.8, 4.0H
z, C_Ten-H), 2.84 (1H, dd, J = 16.8, 1.8Hz, C_Ten-H),
2.61 (1H, br d, J = 15.2Hz, C₆-H), 2.37 (1H, d, J
= 15.2Hz, C₆-H), 1.72 (3H, d, J = 6.8Hz, C₁₄-H),
1.39 (1H, brt, J = 6.0Hz, OH).¹³ C-NMR (100 MHz, CDCl_Three): δ162.5 (C_Two), 154.7 (NHC
O_TwoCH_Three), 152.8 (C_10a), 136.3 (C_4a), 135.6 (C₇), 13
5.4 (C_Four), 129.7 (C₁₁), 126.6 (C₈), 112.3 (C ₁₃), Ten
8.7 (C_Three), 65.9 (C₁₂), 58.4 (C_Five), 53.3 (OCH_Three), 51.9
 (CO_TwoCH_Three), 44.8 (C₆), 39.1 (C_Ten), 33.6 (C₉), 12.5
(C₁₄) .EIMS (m / z): 330 (M⁺, 37), 312 (26), 299 (25), 283
(8), 267 (19), 255 (32), 237 (39), 224 (100), 210
(25), 195 (8), 184 (6), 167 (7), 115 (5), 84 (12) .HREIMS (m / z): calcd for C₁₈H_{twenty two}N_TwoO_Four (M⁺): 330.1577.
 found: 330.1567.

Embodiment 10

[0089]

Embedded image

Under an argon atmosphere, dimethyl sulfoxide (0.1 ml) was added to a solution of oxalyl chloride (0.17 ml, 1.94 mmol) in dichloromethane (1 ml) at −78 ° C.
9 ml, 2.68 mmol) and stirred for 10 minutes. (11E)-[11-ethylidene-9,10-dihydro-7-hydroxymethyl-2-methoxy-5,9-
Methyl methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (133 mg, 0.40 mmol
l) in dichloromethane (4 ml) was added and
Stir for 1 hour. Triethylamine (0.55 ml,
After addition of 3.94 mmol), the mixture was stirred at 0 ° C. for 30 minutes, poured into water, and extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with water (40 ml) and saturated saline (40 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue, 2-methyl-2-butene (1.4 g, 20 mmol) and anhydrous sodium dihydrogen phosphate (960 mg, 8 mmol) were dissolved in a mixed solution of t-butyl alcohol (10 ml) and water (3 ml). Sodium acid salt (purity 85%) (130
mg, 1.23 mmol) and stirred for 1 hour. The reaction solution was concentrated and extracted twice with ethyl acetate (30 ml). The combined organic layers were combined with water (40 ml) and saturated saline (4
0 ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was dissolved in dichloromethane (5 ml) and oxalyl chloride (17 ml) was added at 0 ° C.
5 μl, 2.0 mmol) and one drop of N, N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in ethanol (5 ml) and stirred at room temperature for 1 hour. After concentrating the reaction solution, pour into water,
After adjusting the pH to 7 with a saturated aqueous solution of sodium hydrogen carbonate, the mixture was extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with water (40 ml) and saturated saline (40 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1),
(11E)-[7- (ethoxycarbonyl) -11-ethylidene-9,10-dihydro-2-methoxy-5,9
Methyl methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (118 mg, 7
9%) as colorless prisms.

(11E)-[11-ethylidene-7-e
Lumyl-9,10-dihydro-2-methoxy-5,9-
Methanocycloocta [b] pyridine-5 (6H) -i
Methyl] carbamate: IR (neat): 3340 (m), 2940 (m), 2840 (m), 1720 (s),
 1680 (s), 1640 (m), 1600 (s), 1580 (m), 1520 (s),
1480 (s), 1420 (s), 1380 (m), 1320 (s), 1260 (s),
1185 (m), 1175 (m), 1140 (m), 1060 (m), 1040 (m),
840 (m), 730 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ9.35 (1H, s, CHO), 7.56
 (1H, d, J = 8.6Hz, C_Four-H), 6.85 (1H, dd, J = 5.2,
1.9Hz, C₈-H), 6.57 (1H, d, J = 8.6Hz, C_Three-H), 5.49
(1H, q, J = 6.8Hz, C₁₃-H), 5.18 (1H, br s, NH), 4.
03 (1H, br t, J = 4.9Hz, C₉-H), 3.86 (3H, s, OCH_Three),
 3.62 (3H, br s, NHCO_TwoCH_Three), 3.31 (1H, dd, J = 17.
0, 4.7Hz, C_Ten-H), 2.98 (1H, dd, J = 17.0, 1.8Hz, C
_Ten-H), 2.73 (1H, d, J = 16.2Hz, C₆-H), 2.50 (1H,
d, J = 16.2Hz, C₆-H), 1.75 (3H, d, J = 6.8Hz, C₁₄-
H).¹³ C-NMR (100 MHz, CDCl_Three): δ162.7 (C_Two), 154.5 (NHC
O_TwoCH_Three), 152.6 (C₈), 151.7 (C_10a), 138.9 (C_4a), 135.
7 (C_Four), 134.4 (C₇), 128.8 (C₁₁), 114.3 (C ₁₃), 109.
3 (C_Three), 57.8 (C_Five), 53.4 (OCH_Three), 52.1 (CO_TwoCH_Three), 40.
9 (C₆), 38.3 (C_Ten), 35.1 (C₉), 12.6 (C₁₄) .EIMS (m / z): 328 (M⁺, 100), 313 (11), 299 (20), 285
 (6), 267 (21), 253 (58), 238 (22), 224 (54), 210
(19), 195 (6), 167 (6), 84 (17) .HREIMS (m / z): calcd for C₁₈H₂₀N_TwoO_Four (M⁺): 328.1421.
 found: 328.1406.

(11E)-[7-carboxy-11-ethylidene-9,10-dihydro-2-methoxy-5,9
-Methyl methanocycloocta [b] pyridin-5 (6H) -yl] carbamate: IR (neat): 3330 (m), 2940 (m), 1710 (s), 1600 (s),
1580 (m), 1530 (m), 1480 (s), 1430 (m), 1320 (s),
. 1260 (s), 1030 ( m), 830 (m), 740 (m) cm -1 1 H-NMR (400 MHz, CDCl 3): δ7.56 (1H, d, J = 8.4Hz,
C ₄ -H), 7.09 (1H, m, C ₈ -H), 6.56 (1H, d, J = 8.4Hz,
C ₃ -H), 5.45 (1H, q, J = 6.5Hz, C ₁₃ -H), 5.16 (1H,
br s, NH), 3.86 (1H, br s, C ₉ -H), 3.86 (3H, s, OCH
₃ ), 3.62 (3H, brs, NHCO ₂ CH ₃ ), 3.20 (1H, br d, J =
16.9Hz, C ₁₀ -H), 2.94 (1H, d, J = 16.9Hz, C ₁₀ -H),
2.71 (1H, d, J = 16.3Hz, C ₆ -H), 2.61 (1H, br d, J
= 16.3Hz, C ₆ -H), 1.72 (3H, d, J = 6.5Hz, C ₁₄ -H),
. 1.23 (3H, t, J = 7.1Hz, CO 2 CH 2 CH 3) 13 C-NMR (100 MHz, CDCl 3): δ170.2 (CO 2 H), 162.7 (C
₂ ), 154.5 (NHCO ₂ CH ₃ ), 152.1 (C _10a ), 144.9 (C ₈ ), 13
5.6 (C ₄ ), 134.3 (C _4a ), 129.2 (C ₇ or C ₁₁ ), 128.9 (C ₇
or C ₁₁ ), 113.8 (C ₁₃ ), 109.2 (C ₃ ), 58.1 (C ₅ ), 53.4
(OCH ₃ ), 52.0 (CO ₂ CH ₃ ), 43.4 (C ₆ ), 38.2 (C ₁₀ ), 34.6
(C ₉ ), 12.6 (C ₁₄ ) .EIMS (m / z): 344 (M ⁺ , 96), 329 (16), 312 (11), 299
(16), 285 (23), 269 (69), 254 (39), 239 (23), 224
(100), 210 (22), 199 (10), 184 (7), 167 (8), 154
(7), 142 (5), 128 (5), 115 (7), 91 (8), 77 (9), 59
(26) .HREIMS (m / z): calcd for C ₁₈ H ₂₀ N ₂ O ₅ (M ⁺ ): 344.1370.
found: 344.1364.

(11E)-[7- (ethoxycarboni
11) -ethylidene-9,10-dihydro-2-meth
Toxi-5,9-methanocycloocta [b] pyridine-
Methyl 5 (6H) -yl] carbamate: mp 175.0-176.0 ° C (n-hexane-AcOEt). IR (neat): 3360 (m), 2980 (m), 2940 (m), 1710 (s),
 1650 (m), 1600 (m), 1580 (m), 1530 (m), 1475 (s),
1420 (m), 1320 (s), 1260 (s), 1220 (m), 1090 (m),
1040 (m), 830 (m), 740 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ7.58 (1H, d, J = 8.6Hz,
 C_Four-H), 7.00 (1H, dd, J = 5.4, 2.1Hz, C₈-H), 6.57
(1H, d, J = 8.6Hz, C_Three-H), 5.45 (1H, q, J = 6.8Hz, C
₁₃-H), 5.18 (1H, br s, NH), 4.16-4.04 (2H, m, CO_TwoC
H_TwoCH_Three), 3.89-3.87 (1H, br s, C₉-H), 3.87 (3H, s, O
CH_Three), 3.62 (3H, br s, NHCO_TwoCH_Three), 3.21 (1H, dd, J =
 16.9, 4.7Hz, C_Ten-H), 2.94 (1H, dd, J = 16.9, 1.5H
z, C_Ten-H), 2.77 (1H, d, J = 16.2Hz, C₆-H), 2.63 (1
H, d, J = 16.2Hz, C₆-H), 1.72 (3H, d, J = 6.8Hz, C
₁₄-H), 1.23 (3H, t, J = 7.1Hz, CO_TwoCH_TwoCH_Three).¹³ C-NMR (100 MHz, CDCl_Three): δ166.2 (CO_TwoCH_TwoCH_Three), 16
2.6 (C_Two), 154.5 (NHCO _TwoCH_Three), 152.1 (C_10a), 142.3 (C
₈), 135.7 (C_Four), 134.6 (C_4a), 129.1 (C₇ or C ₁₁), 12
8.3 (C₇ or C₁₁), 113.5 (C₁₃), 109.1 (C_Three), 60.7 (CO
_TwoCH_TwoCH_Three), 58.1 (C_Five), 53.4 (OCH_Three), 52.0 (CO_TwoCH_Three), Four
3.7 (C₆), 38.3 (C_Ten), 34.4 (C₉), 14.2 (CO_TwoCH_TwoCH_Three),
12.6 (C₁₄) .EIMS (m / z): 372 (M⁺, 82), 357 (10), 343 (22), 327
(23), 313 (16), 297 (35), 282 (22), 268 (38), 251
(19), 239 (19), 224 (100), 210 (14), 199 (7), 180
(6), 167 (5), 84 (34) .HREIMS (m / z): calcd for C₂₀H_{twenty four}N_TwoO_Five (M⁺): 372.1684.
 found: 372.1697.

Embodiment 11

[0095]

Embedded image

Under an argon atmosphere, (11E)-[7-
(Ethoxycarbonyl) -11-ethylidene-9,10
-Dihydro-2-methoxy-5,9-methanocycloocta [b] pyridin-5 (6H) -yl] carbamate (89 mg, 239 μmol) in chloroform (3
ml) solution into trimethylsilane iodide (0.34 m
1, 2.39 mmol) and heated under reflux for 8 hours.
Methanol (1 ml) was added, and the mixture was further heated under reflux for 4 hours. After concentrating the reaction solution, it was dissolved in ethyl acetate (50 ml), a 10% aqueous sodium thiosulfate solution was added until the color disappeared, and a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added.
ml), water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give (11E) -5-amino-7-ethoxycarbonyl-11-ethylidene-5,6,9,10-tetrahydro-5. , 9-Methanocycloocta [b] pyridin-2 (1H) -one (55.8 mg, yield 78%) was obtained as colorless prism crystals.

Mp 244.0-245.0 ° C. (AcOEt-MeOH). IR (neat): 3380 (m), 3280 (m), 2980 (m), 2940 (m),
1710 (s), 1660 (s), 1615 (s), 1560 (s), 1460 (s), 1
430 (m), 1410 (m), 1380 (m), 1310 (m), 1250 (s), 1
090 (m), 1140 (m), 1090 (s), 1050 (m), 840 (m), 74
0 (m), 660 (m) cm^-1.¹ H-NMR (400 MHz, CDCl_Three): δ 13.24 (1H, br s, CONH),
 7.92 (1H, d, J = 9.5Hz, C_Four-H), 6.93 (1H, dd, J =
5.4, 2.2Hz, C₈-H), 6.43 (1H, d, J = 9.5Hz, C_Three-H),
5.59 (1H, q, J = 6.8Hz, C₁₃-H), 4.12 (2H, q, J =
7.2Hz, CO_TwoCH_TwoCH _Three), 3.82 (1H, br t, J = 5.3Hz, C₉-
H), 3.02 (1H, dd, J = 17.1, 5.5Hz, C_Ten-H), 2.86 (1
H, dd, J = 17.1, 1.3Hz, C_Ten-H), 2.71 (1H, d, J = 1
7.3Hz, C₆-H), 2.26 (1H, d, J = 17.3Hz, C₆-H), 1.69
 (3H, d, J = 6.8Hz, C₁₄-H), 1.50 (2H, br s, NH_Two),
1.24 (3H, t, J = 7.2Hz, CO_TwoCH_TwoCH_Three).¹³ C-NMR (100 MHz, CDCl_Three): δ166.4 (CO_TwoCH_TwoCH_Three), 16
5.4 (C_Two), 142.2 (C_10a), 140.6 (C₈ and C₁₁), 140.4
(C_Four), 130.4 (C₇), 122.2 (C_4a), 117.6 (C_Three), 113.0 (C
₁₃), 60.7 (CO_TwoCH_TwoCH_Three), 54.0 (C_Five), 43.2 (C₆), 34.2
 (C_Ten), 33.2 (C₉), 14.2 (CO_TwoCH_TwoCH_Three), 12.3 (C₁₄) .EIMS (m / z): 300 (M⁺, 100), 285 (40), 271 (28), 255
 (20), 239 (12), 227 (90), 211 (47), 199 (12), 187
(70), 173 (19), 160 (12), 147 (9), 130 (5), 106
(7), 84 (22) .HREIMS (m / z): calcd for C₁₇H₂₀N_TwoO_Three (M⁺): 300.1472.
 found: 300.1470. Anal.calcd for C₁₇H₂₀N_TwoO_Three : C, 67.98: H, 6.71: N,
 9.33: found: C, 67.80: H, 6.73: N, 9.24.

Embodiment 12

[0099]

Embedded image

Under an argon atmosphere, (11E) -5-amino-7-ethoxycarbonyl-11-ethylidene-5,
6,9,10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one (80.7 m
g, 269 μmol) of tetrahydrofuran (2 ml)
Diisobutylaluminum hydride (0.93 M hexane solution) (2.89 ml, 2.6) was added to the solution at -78 ° C.
9 mmol) and stirred for 1 hour. After adding an aqueous solution of saturated potassium sodium tartrate (0.2 ml) to terminate the reaction, the mixture was diluted with ethyl acetate (30 ml) and filtered through celite. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by preparative silica gel thin-layer chromatography (tetrahydrofuran: methanol = 10: 1) to give (11E) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-7- Hydroxymethyl-5,9-methanocycloocta [b] pyridin-2 (1H) -one (47.6 mg,
(69% yield) as colorless prisms.

Mp 243.0-245.0 ° C. (AcOEt-MeOH). IR (neat): 3280 (m), 2930 (m), 1655 (s), 1610 (s),
1560 (m), 1460 (s), 1430 (m), 1300 (m), 1120 (m),
. 1070 (m), 930 ( m), 840 (m), 730 (m) cm -1 1 H-NMR (400 MHz, CD 3 OD): δ7.94 (1H, d, J = 9.5Hz,
C ₄ -H), 6.38 (1H, d, J = 9.5 Hz, C ₃ -H), 5.72 (1H, d,
J = 5.0Hz, C ₈ -H), 5.61 (1H, q, J = 6.8Hz, C ₁₃ -H),
3.84 (1H, d, J = 13.5Hz, CH ₂ OH), 3.79 (1H, d, J =
13.5Hz, CH ₂ OH), 3.75 (1H, brt, J = 4.9Hz, C ₉ -H),
2.85 (1H, dd, J = 17.1, 5.3Hz, C ₁₀ -H), 2.65 (1H,
dd, J = 17.1, 1.5Hz, C ₁₀ -H), 2.30 (1H, d, J = 16.6
Hz, C ₆ -H), 2.24 (1H, d, J = 16.6Hz, C ₆ -H), 1.72 (3
. H, d, J = 6.8Hz , C 14 -H) 13 C-NMR (100 MHz, CD 3 OD): δ165.8 (C 2), 144.2 (C
_10a ), 142.0 (C ₁₁ ), 141.8 (C ₄ ), 139.3 (C ₇ ), 125.4
(C ₈ ), 124.9 (C _4a ), 117.9 (C ₃ ), 113.3 (C ₁₃ ), 65.9 (C
₁₂ ), 55.0 (C ₅ ), 45.6 (C ₆ ), 36.1 (C ₁₀ ), 33.7 (C ₉ ),
12.5 (C ₁₄ ) .EIMS (m / z): 358 (M ⁺ , 90), 243 (40), 227 (100), 211
(32), 198 (16), 187 (72), 173 (27), 161 (23), 148
(11), 130 (8), 117 (6), 106 (7), 91 (10) .HREIMS (m
/ z): calcd for C ₁₅ H ₁₈ N ₂ O ₂ (M ⁺ ): 258.1366.found: 2
58.1364.Anal.calcd for C ₁₅ H ₁₈ N ₂ O ₂・ 1 / 2H ₂ O: C, 67.39: H,
7.16: N, 10.48: found: C, 67.37: H, 7.03: N, 10.2
9.

Embodiment 13

[0103]

Embedded image

Under argon atmosphere at −78 ° C. (11
E) -5-Amino-11-ethylidene-5,6,9,1
0-tetrahydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridin-2 (1H) -one (10.6 mg, 41 μmol) in dichloromethane (4
0 ml) solution, a solution of diethylaminosulfur trifluoride (66.0 mg, 410 μmol) in dichloromethane (2 ml) was added, and the mixture was stirred for 2 hours. After concentrating the reaction solution, a saturated aqueous solution of sodium hydrogen carbonate (1 ml) was added to adjust the pH to 7 or more, and the mixture was extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with saturated saline (3 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by preparative silica gel thin layer chromatography (ethyl acetate: methanol = 10: 1) to give (11E) -5-amino-11-ethylidene-7-fluoromethyl-5,6,9, 10-tetrahydro-5,9-methanocycloocta [b] pyridine-
2 (1H) -one (1.8 mg, yield 17%) was obtained as a colorless amorphous.

IR (neat): 3380 (m), 3280 (m), 2930
(m), 1660 (s), 1610 (s), 1560 (m), 1460 (s), 1430
(m), 1310 (m), 1120 (m), 980 (m), 840 (m), 730 (m)
^{. cm -1 1 H-NMR (} 400 MHz, CDCl 3): δ12.70 (1H, br s, CONH),
7.92 (1H, d, J = 9.5Hz, C ₄ -H), 6.43 (1H, d, J =
9.5Hz, C ₃ -H), 5.80 (1H, br s, C ₈ -H), 5.56 (1H, q,
J = 6.8Hz, C ₁₃ -H), 4.61 (2H, d, J _HF = 47.5Hz, C ₁₂
-H), 3.72 (1H, m, C ₉ -H), 2.95 (1H, dd, J = 17.1, 5.
4Hz, C ₁₀ -H), 2.75 (1H, dd, J = 17.1,1.3Hz, C ₁₀ -H),
2.32 (1H, d, J = 16.7Hz, C ₆ -H), 2.19 (1H, d, J =
16.7Hz, C ₆ -H), 1.70 (3H, d, J = 6.8Hz, C ₁₄ -H), 1.65
. (2H, br s, NH 2) 19 F-NMR (188 MHz, CDCl 3):. Δ-215.0 (t, J = 49Hz) EIMS (m / z): 260 (M +, 100), 245 ( 57), 227 (43), 211
(21), 198 (12), 187 (58), 173 (13), 160 (9), 147
(10), 130 (5), 106 (7), 106 (7), 84 (13) .HREIMS (m / z): calcd for C ₁₅ H ₁₇ FN ₂ O (M ⁺ ): 260.1324.
found: 260.1338.

Test Example (Measurement of Acetylcholinesterase Inhibitory Activity)

The brains extracted from SD rats (9 weeks old, male) were excised from 10 ml / g of 10 mM / 0.5% Triton X-100 / 80 mM Tris-HCl buffer (pH 8.0).
The supernatant homogenized in 0) and centrifuged at 10,000 xg for 1 hour was used as a source of acetylcholinesterase. Acetylcholinesterase activity was measured by Ellman.
[GL Ellman et al., Biochem. Pharmacol.,
7, 88-95 (1961).]. That is, 10 mM containing rat brain homogenate supernatant, test substance, 1.1 mM dithiobisnitrobenzoic acid (DTNB).
Ethylenediaminetetraacetic acid / 0.5% Triton X-10
0/80 mM Tris-HCl buffer (pH 8.0) 0.5 m
After incubation at 37 ° C. for 30 minutes, 1 mM acetylthiocholine was added as a substrate to start the reaction. Yellow 5-thio-2-nitrobenzoic acid produced by the reaction of thiocholine produced by acetylcholinesterase with dithiobisnitrobenzoic acid was quantified by absorbance at 412 nm, and the IC ₅₀ value was calculated. as a result,
(11E) -5-amino-11-ethylidene-7-fluoromethyl-5,6,9,10-tetrahydro-5,9
The IC ₅₀ value of -methanocycloocta [b] pyridin-2 (1H) -one was 2 × 10 ⁻⁷ M. Further, (11E) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-hydroxymethyl-5,9-methanocycloocta [b] pyridine- which is also a synthetic intermediate.
The IC ₅₀ value of 2 (1H) -on is ⁶ × 10 ⁻⁶ M, (11
E) -5-Amino-7-ethoxycarbonyl-11-ethylidene-5,6,9,10-tetrahydro-5,9-
The IC ₅₀ value of methanocycloocta [b] pyridin-2 (1H) -one was ⁶ × 10 ⁻⁶ M. Furthermore, each sample had 1X1 against butyrylcholinesterase.
No significant inhibitory effect was observed even at a concentration of 0 ^-4 M,
It was confirmed that the inhibitory action was specific to acetylcholinesterase.

Claims (3)

[Claims] 1. A compound of the general formula (Wherein, X ¹ represents a hydroxymethyl group; a halogenomethyl group; or an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group which may have a substituent). 1
1E) -5-Amino-11-ethylidene-5,6,9,
10-tetrahydro-5,9-methanocycloocta [b] pyridin-2 (1H) -one derivative. 2. A compound of the general formula (Wherein, R ¹ represents an alkyl group or a silyl group which may have a substituent. X ² is a hydroxymethyl group; a formyl group; a carboxyl group; an alkyloxymethyl group which may have a substituent. Or an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group which may have a substituent, wherein Y is a carboxyl group; An alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group which may be substituted; or an alkyloxycarbonylamino group, an alkenyloxycarbonylamino group, or an aralkyloxycarbonylamino group which may have a substituent. (11E)- 11-ethylidene-5,6,9,1
0-tetrahydro-5,9-methanocycloocta [b]
Pyridine derivatives. 3. A compound of the general formula (Wherein, R ¹ represents an alkyl group or a silyl group which may have a substituent. X ³ is a hydroxymethyl group; a halogenomethyl group; an alkyloxymethyl group which may have a substituent, alkenyl R ² represents an alkyl group, an alkenyl group, or an aralkyl group which may have a substituent), or an oxymethyl group or an aralkyloxymethyl group;
10-dihydro-11-oxo-5,9-methanocycloocta [b] pyridine-5 (6H) -carboxylic acid ester derivative.