JP3446899B2 - Process for producing halopyridyl-azabicycloheptane derivative and intermediate - Google Patents

Description

Detailed Description of the Invention

[0001]

[Field of Industrial Application] The present invention relates to the Journal of American Chemical Society (J. Am. Chem. Soc.), 10
2,830-836,1980. And ibid., 114,3475-3478, 1992., etc., halopyridyl-azabicycloheptane derivatives such as epibatidine having a non-opioid analgesic effect extracted from the skin of a poisonous frog. Further, it relates to a method for producing a salt thereof and an intermediate useful in the production thereof.

[0002]

2. Description of the Related Art Epibatidine is represented by the following chemical structural formula.

[0003]

[Chemical 11]

The halopyridyl-azabicycloheptane derivative typified by epibatidine is a natural product, and is obtained by extraction from the skin of a poisonous frog from Ecuador, South America.

[0005]

[Problems to be Solved by the Invention] As described above, since halopyridyl-azabicycloheptane derivatives such as epibatidine have a non-opioid analgesic action, they do not have the drawbacks as narcotics such as morphine. , Is expected as a clinically useful analgesic. However, the amount of these compounds existing in nature is extremely small and cannot be obtained in large amounts, and thus it has been impossible to proceed with pharmacological experiments and clinical trials. On the other hand, epibatidine is exo-2- (6'-chloro-3 '
-Pyridyl) -7-azabicyclo [2.2.1] heptane has the structure described in the above-mentioned [Journal of American Chemical Society (J.Am.Chem.So.
c.), 114, 3475-3478, 1992.], but the complete structure including the configuration (R or S) at the 2-position has not yet been determined.

However, the configuration at the 2-position of epibatidine is R
Or in any of S, dl-form (± form) is synthesized,
Since it may be optically resolved, synthesis of dl-epibatidine has been tried so far, but no successful report has been made yet. Therefore, there has been a demand for an industrial production method capable of producing a halopyridyl-azabicycloheptane derivative (II) such as epibatidine or a salt thereof with a high yield and a simple route.

[0007]

Therefore, the inventors of the present invention have earnestly studied a method for producing a halopyridyl-azabicycloheptane derivative (II) such as epibatidine or a salt thereof. As a result, a known compound, a sulfonyl-N-protected azabicycloheptene derivative (V
I) is reduced with sodium amalgam to an N-protected azabicycloheptene derivative (V), and then a halogenated pyridine is coupled in the presence of a dipalladium salt to form a pyridyl-N-protected azabicycloheptane derivative (V). IV),
Then, it is oxidized with hydrogen peroxide solution, peracid or organic peroxide to give N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III), and then reacted with a halogenating agent to give halopyridyl-N-protected azabicyclo. By using the heptane derivative (I) and deprotecting it, epibatidine (Epib
The present invention was completed by finding that a halopyridyl-azabicycloheptane derivative (II) such as atidine) or a salt thereof can be produced in high yield. The outline of the reaction route in the present invention is represented by the following chemical reaction formula.

[0008]

[Chemical 12]

DETAILED DESCRIPTION OF THE INVENTION Accordingly, an object of the present invention is to provide sulfonyl-N-protected azabicycloheptene derivative (VI), N-protected azabicycloheptene derivative (V), pyridyl-N-protected azabicyclo. Heptane derivative (IV), N-oxyhalopyridyl-
From N-protected azabicycloheptane derivative (III) or halopyridyl-N-protected azabicycloheptane derivative (I),
Provided is a method for industrially producing a halopyridyl-azabicycloheptane derivative (II) such as epibatidine or a salt thereof in a high yield. The present invention also provides an intermediate useful in the production thereof.

The salt of the halopyridyl-azabicycloheptane derivative (II) in the present invention includes, for example, hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, perchlorate, phosphate and the like. Inorganic acid addition salts, organic acid addition salts such as oxalate, maleate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate It means a salt or an addition salt of sulfonic acid such as camphor sulfonate.

The halopyridyl-N-protected azabicycloheptane derivative (I) in the present invention is represented by the following formula.

[0012]

[Chemical 13]

In the formula, R ¹ is a formyl group, a lower aliphatic acyl group, an aromatic acyl group, a vinyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, an allyloxycarbonyl group, an aralkyl group or a tri-lower alkylsilyl group, R ² means a halogen atom.

The lower aliphatic acyl group in the definition of the substituent R ¹ specifically includes, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group and the like. The group 6 is an aromatic acyl group such as a benzoyl group, a toluoyl group, a xyloyl group, a phenylacetyl group, a nitrobenzoyl group, a methoxybenzoyl group, a chlorobenzoyl group or a naphthoyl group, and a lower alkoxycarbonyl group such as a methoxy group. A group having in the molecule a lower alkyl group having 1 to 6 carbon atoms, such as a carbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and a butoxycarbonyl group, is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or methoxybenzyloxy group. Carbonyl group,
A nitrobenzyloxycarbonyl group, a chlorobenzyloxycarbonyl group, a bromobenzyloxycarbonyl group and the like, and an aryloxycarbonyl group such as a phenoxycarbonyl group and a nitrophenoxycarbonyl group,
Examples of the aralkyl group include benzyl group, methoxybenzyl group, nitrobenzyl group, chlorobenzyl group and the like, and examples of tri-lower alkylsilyl group include trimethylsilyl group, triethylsilyl group and triphenylsilyl group.
Among these groups, lower alkoxycarbonyl groups such as ethoxycarbonyl group are more preferable.

A halogen atom in the definition of R ² is
Specific examples thereof include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom, but a chlorine atom is more preferable.

Specific examples of the halopyridyl-N-protected azabicycloheptane derivative (I) include the following compounds. In the present invention, halopyridyl-
The N-protected azabicycloheptane derivative (I) is not limited to these. (1) Exo-2- (6'-chloro-3'-pyridyl)-
7-Ethoxycarbonylazabicyclo [2.2.1] heptane (2) exo-2- (6'-chloro-3'-pyridyl)-
7-Methoxycarbonylazabicyclo [2.2.1] heptane (3) exo-2- (6'-chloro-3'-pyridyl)-
7-Benzyloxycarbonylazabicyclo [2.2.
1] Heptane (4) exo-2- (6'-chloro-3'-pyridyl)-
7-Formylazabicyclo [2.2.1] heptane (5) exo-2- (6'-chloro-3'-pyridyl)-
7-Acetylazabicyclo [2.2.1] heptane (6) exo-2- (6'-chloro-3'-pyridyl)-
7-Benzylazabicyclo [2.2.1] heptane (7) exo-2- (5'-bromo-3'-pyridyl)-
7-Trimethylsilylazabicyclo [2.2.1] heptane (8) exo-2- (4'-bromo-3'-pyridyl)-
7-Triethylsilylazabicyclo [2.2.1] heptane (9) exo-2- (2'-fluoro-3'-pyridyl)
-7-Vinylazabicyclo [2.2.1] heptane

Next, the halopyridyl-azabicycloheptane derivative (II) is represented by the following formula.

[0018]

[Chemical 14]

In the formula, R ² is a halogen atom, and specific examples similar to the above can be mentioned. Specific examples of the halopyridyl-azabicycloheptane derivative (II) include:
The following compounds may be mentioned, but the halopyridyl-azabicycloheptane derivative (II) in the present invention is not limited thereto. (1) Exo-2- (6'-chloro-3'-pyridyl)-
7-azabicyclo [2.2.1] heptane (2) exo-2- (6'-bromo-3'-pyridyl)-
7-Azabicyclo [2.2.1] heptane (3) exo-2- (6'-fluoro-3'-pyridyl)
-7-Azabicyclo [2.2.1] heptane (4) exo-2- (6'-chloro-2'-pyridyl)-
7-azabicyclo [2.2.1] heptane (5) exo-2- (6'-chloro-4'-pyridyl)-
7-azabicyclo [2.2.1] heptane (6) exo-2- (5'-chloro-3'-pyridyl)-
7-azabicyclo [2.2.1] heptane (7) exo-2- (4'-chloro-3'-pyridyl)-
7-azabicyclo [2.2.1] heptane (8) exo-2- (2'-chloro-3'-pyridyl)-
7-azabicyclo [2.2.1] heptane

The N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III) is represented by the following formula.

[0021]

[Chemical 15]

In the formula, R ¹ and R ² have the same meanings as described above. Specific examples of the N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III) include the following compounds, and the N-oxyhalopyridyl-N-protected azabicycloheptane derivative of the present invention can be mentioned. (III) is not limited to these. (1) Exo-2- (3'-N-oxypyridyl) -7-
Ethoxycarbonylazabicyclo [2.2.1] heptane (2) exo-2- (3'-N-oxypyridyl) -7-
Methoxycarbonylazabicyclo [2.2.1] heptane (3) exo-2- (3'-N-oxypyridyl) -7-
Benzyloxycarbonyl azabicyclo [2.2.1]
Heptane (4) exo-2- (3'-N-oxypyridyl) -7-
Phenoxycarbonylazabicyclo [2.2.1] heptane (5) exo-2- (3'-N-oxypyridyl) -7-
Benzylazabicyclo [2.2.1] heptane (6) exo-2- (3'-N-oxypyridyl) -7-
Trimethylsilylazabicyclo [2.2.1] heptane (7) exo-2- (3'-N-oxypyridyl) -7-
Acetylazabicyclo [2.2.1] heptane (8) exo-2- (3'-N-oxypyridyl) -7-
Benzoylazabicyclo [2.2.1] heptane

The pyridyl-N-protected azabicycloheptane derivative (IV) is represented by the following formula.

[0024]

[Chemical 16]

In the formula, R ¹ has the same meaning as described above. Specific examples of the pyridyl-N-protected azabicycloheptane derivative (IV) include the following compounds, but the pyridyl-N-protected azabicycloheptane derivative (IV) in the present invention is not limited thereto. . (1) Exo-2- (3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane (2) Exo-2- (3'-pyridyl) -7-methoxycarbonylazabicyclo [2 1.2.1] Heptane (3) exo-2- (3'-pyridyl) -7-nitrobenzylcarbonylazabicyclo [2.2.1] heptane (4) exo-2- (3'-pyridyl) -7 -Anisoxycarbonylazabicyclo [2.2.1] heptane (5) exo-2- (3'-pyridyl) -7-benzylazabicyclo [2.2.1] heptane (6) exo-2- (3 '-Pyridyl) -7-triphenylsilylazabicyclo [2.2.1] heptane (7) exo-2- (3'-pyridyl) -7-formylazabicyclo [2.2.1] heptane (8) Exo-2- (3'-pyridyl) -7-propionylurea Zabicyclo [2.2.1] heptane

N-protected azabicycloheptene derivative
(V) is expressed by the following formula.

[0027]

[Chemical 17]

In the formula, R ¹ has the same meaning as described above. N-
The following compounds may be mentioned as specific examples of the protected azabicycloheptene derivative (V), but the N-protected azabicycloheptene derivative (V) in the present invention is not limited thereto. (1) 7-Ethoxycarbonylazabicyclo [2.2.
1] -4-Heptene (2) 7-methoxycarbonylazabicyclo [2.2.
1] -4-heptene (3) 7-benzyloxycarbonylazabicyclo [2.
2.1] -4-Heptene (4) 7-phenoxycarbonylazabicyclo [2.2.
1] -4-heptene (5) 7-benzylazabicyclo [2.2.1] -4-heptene (6) 7-triethylsilylazabicyclo [2.2.1]
-4-Heptene (7) 7-acetylazabicyclo [2.2.1] -4-heptene (8) 7-toluoylazabicyclo [2.2.1] -4-
Hepten

Further, the sulfonyl-N-protected azabicycloheptene derivative (VI) is represented by the following formula.

[0030]

[Chemical 18]

In the formula, R ¹ has the same meaning as described above, and R ³
Means a methyl group, an ethyl group, a phenyl group or a toluyl group. In the present invention, the mesyl (Ms) group means a methanesulfonyl group, and the tosyl (Ts) group means a p-toluenesulfonyl group. Specific examples of the sulfonyl-N-protected azabicycloheptene derivative (VI) include the following compounds, but the sulfonyl-N-protected azabicycloheptene derivative (VI) in the present invention is not limited thereto. Not limited. (1) Exo-2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -4-heptene (2) Exo-2-mesyl-7-ethoxycarbonylazabicyclo [2.2.1] -4 -Heptene (3) exo-2-ethanesulfonyl-7-ethoxycarbonylazabicyclo [2.2.1] -4-heptene (4) exo-2-benzenesulfonyl-7-ethoxycarbonylazabicyclo [2.2. 1] -4-heptene (5) exo-2-tosyl-7-methoxycarbonylazabicyclo [2.2.1] -4-heptene (6) exo-2-tosyl-7-benzyloxycarbonylazabicyclo [2] .2.1] -4-Heptene (7) Exo-2-tosyl-7-benzylazabicyclo [2.2.1] -4-Heptene (8) Exo-2-tosyl-7-trimethylsilylazabicyclo 2.2.1] -4-Heptene (9) exo-2-tosyl-7-formylazabicyclo [2.2.1] -4-heptene (10) exo-2-tosyl-7-acetylazabicyclo [ 2.2.1] -4-Heptene

The sulfonyl-N-protected azabicycloheptadiene derivative (VII) is represented by the following formula.

[0033]

[Chemical 19]

In the formula, R ¹ and R ³ have the same meanings as described above. Specific examples of the sulfonyl-N-protected azabicycloheptadiene derivative (VII) include the following compounds, but the sulfonyl-N-protected azabicycloheptadiene derivative (VII) in the present invention is Not limited. (1) Exo-2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -1,4-heptadiene (2) Exo-2-mesyl-7-ethoxycarbonylazabicyclo [2.2.1] -1,4-Heptadiene (3) Exo-2-ethanesulfonyl-7-ethoxycarbonylazabicyclo [2.2.1] -1,4-heptadiene (4) Exo-2-benzenesulfonyl-7-ethoxycarbonylaza Bicyclo [2.2.1] -1,4-heptadiene (5) exo-2-tosyl-7-methoxycarbonylazabicyclo [2.2.1] -1,4-heptadiene (6) exo-2-tosyl -7-Benzyloxycarbonylazabicyclo [2.2.1] -1,4-heptadiene (7) Exo-2-tosyl-7-benzylazabicyclo [2.2.1] -1,4-heptadiene (8) Exo-2-tosyl-7-trimethylsilylazabicyclo [2.2.1] -1,4-heptadiene (9) Exo-2-tosyl-7-formylazabicyclo [2.2.1] -1 , 4-heptadiene (10) exo-2-tosyl-7-butyrylazabicyclo [2.2.1] -1,4-heptadiene The above-mentioned compound, which is a starting material in the present invention, is an organometallic compound.・ Chemical synthesis (Orga
nometal.Chem.Syn.), 1 , 145, 1970. Tosyl acetylene produced by the method described in, Angewante Chemie International Edition English (Angew.Chem.Int.Ed.Engl.), 21 , 778, 1982. by reacting with N-protected pyrrole.

Next, each step of the production method according to the present invention will be described in detail below (see the chemical reaction formula [Chemical Formula 12]). Step 1 In this step, a sulfonyl-N-protected azabicycloheptadiene derivative (VII) is obtained. It is a step of reducing with a metal-hydrogen complex compound to give a sulfonyl-N-protected azabicycloheptene derivative (VI). Generally the Journal of Organic
Chemistry (J.Org.Chem.), 50 , 4340, 1985. can be carried out by the method described in, the metal hydrogen complex compound in the present invention, for example, sodium borohydride, cyanohydrogen Although sodium borohydride, potassium borohydride, lithium borohydride, etc. can be mentioned, sodium borohydride is more preferable. The amount of the metal-hydrogen complex compound used is not limited, but it is usually one of the sulfonyl-N-protected azabicycloheptadiene derivative (VII).
About 1 to 50 equivalents are used, preferably about 1 to 20 equivalents, more preferably about 1 to 10 equivalents, relative to the equivalents.

A solvent is preferably used in this reaction. The solvent that can be used in that case is not limited as long as it is inert to the sulfonyl-N-protected azabicycloheptadiene derivative (VII) or the metal hydrogen complex compound, and specifically, for example, methanol, ethanol, n -Propanol, i-propanol, tetrahydrofuran, 1,2-
Examples thereof include dimethoxyethane, ethyl ether, isopropyl ether, water and the like. Although the amount of the solvent used is not limited, it is usually about 0.2 to 100 per 1 weight of the sulfonyl-N-protected azabicycloheptadiene derivative (VII).
Volume, preferably about 0.5 to 50 volume, more preferably about 0.5 volume.
Use 1 to 20 volumes.

In this reaction, the sulfonyl-N-protected azabicycloheptadiene derivative (VII) is dissolved in a solvent, and a metal-hydrogen complex compound is added to react. The reaction temperature at that time is not limited, and the reaction can be carried out at −80 ° C. to solvent reflux temperature, but it is usually preferable to carry out under ice cooling. Although the reaction time varies depending on the temperature, it is usually completed in about 10 minutes to 4 hours. The obtained crude product of the sulfonyl-N-protected azabicycloheptene derivative (VI) can be further purified by a conventional method such as column chromatography or recrystallization.

Step 2 This step is a step of reacting the sulfonyl-N-protected azabicycloheptene derivative (VI) with sodium amalgam to produce an N-protected azabicycloheptene derivative (V). This step can be performed by a general reduction method using sodium amalgam. The concentration of sodium amalgam is not limited and may be arbitrary, but a commercially available product having a concentration of 5% can also be used. The amount of sodium amalgam used is not limited, and is usually about 1 to 50 equivalents, preferably about 1 to 20 equivalents, more preferably about 1 to the sulfonyl-N-protected azabicycloheptene derivative (VI). Use ~ 10 equivalents.

A solvent is preferably used in this reaction. The solvent that can be used in that case is not limited as long as it is inert to the sulfonyl-N-protected azabicycloheptene derivative (VI) or sodium amalgam,
Specific examples include methanol, ethanol, n-propanol, i-propanol and the like. Although the amount of the solvent used is not limited, it is usually about 0.2 per 1 weight of the sulfonyl-N-protected azabicycloheptene derivative (VI).
~ 100 volumes, preferably about 0.5-50 volumes, more preferably about 1-20 volumes are used.

This reaction comprises sulfonyl-N-protected azabicycloheptene derivative (VI) and sodium hydrogen phosphate (Na ₂ HPO ₄ ).
Is suspended in a solvent and sodium amalgam is added to react. The reaction temperature at that time is not limited, but it is usually preferable to carry out the reaction under ice cooling. The reaction is usually completed in about 30 minutes to 12 hours. The obtained crude product of the N-protected azabicycloheptene derivative (V) can be further purified by a conventional method such as column chromatography or vacuum distillation.

Step 3 In this step, the N-protected azabicycloheptene derivative (V) is
This is a step of coupling with a halogenated pyridine in the presence of a second palladium salt to give a pyridyl-N-protected azabicycloheptane derivative (IV). This reaction is generally described in Journal of Chemical Society Chemical Communication (J.Chem.Soc.Chem.Comm.), 1368, 198.
It can be performed according to the method described in 9. Specific examples of the halogenated pyridine used in the present invention include the following compounds. (1) 3-Brominated pyridine (2) 3-iodinated pyridine (3) 3-chloropyridine (4) 2-brominated pyridine (5) 4-brominated pyridine Is
About 1 to N-protected azabicycloheptene derivative (V)
50 equivalents, preferably about 1-20 equivalents, more preferably about 1-10 equivalents are used.

Specific examples of the second palladium salt in the present invention include second palladium acetate, second palladium chloride, second palladium nitrate, second palladium sulfate and the like. More preferable. Although the amount of palladium (II) acetate used is not limited, it is usually about 2% to the N-protected azabicycloheptene derivative (V).
1 to 50 equivalents, preferably about 1 to 20 equivalents, more preferably about 1 to 10 equivalents are used. Furthermore, this reaction is preferably carried out in the presence of an interlayer transfer catalyst such as tetrabutylammonium chloride and potassium formate.

A solvent is preferably used in this reaction. The solvent that can be used in that case is not limited as long as it is inert to the N-protected azabicycloheptene derivative (V), and specifically, for example, N, N, -dimethylformamide, dimethylsulfoxide, hexa Methylphosphoric triamide (HMPA), hexamethylphosphorus triamide (HMPT), tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 1,3-dioxolane and the like can be mentioned. Although the amount of the solvent used is not limited, it is usually about 1 part by weight of the N-protected azabicycloheptene derivative (V).
0.2 to 100 volumes, preferably about 0.5 to 50 volumes, and more preferably about 1 to 20 volumes are used.

In this reaction, the N-protected azabicycloheptene derivative (V), the second palladium salt, the interlayer transfer catalyst and potassium formate are dissolved in a solvent and reacted. Although the reaction temperature at that time is not limited, it is usually preferable to perform heating at 50 to 60 ° C. The reaction is usually completed in about 6 to 48 hours.
Obtained pyridyl-N-protected azabicycloheptane derivative
The crude product of (IV) can be further purified by a conventional method such as column chromatography.

Step 4 In this step, the pyridyl-N-protected azabicycloheptane derivative (IV) is oxidized with an aqueous hydrogen peroxide solution, a peracid or an organic peroxide to give an N-oxyhalopyridyl-N-protected azabicyclo. This is a step of producing a heptane derivative (III). This reaction can be carried out by a conventional method for synthesizing N-oxide with aqueous hydrogen peroxide, peracid or organic peroxide. Specific examples of the peracid in the present invention include m-chloroperbenzoic acid, performic acid, peracetic acid, perphthalic acid, and the like, and m-chloroperbenzoic acid is more preferable. Specific examples of the organic peroxide in the present invention include t-butyl peroxide and amyl peroxide. The amount of hydrogen peroxide solution, peracid or organic peroxide used is not limited, but is usually about 1 to 50 equivalents, preferably about 1 to 20 equivalents with respect to the pyridyl-N-protected azabicycloheptane derivative (IV). Equivalents, more preferably about 1-10 equivalents are used.

A solvent is preferably used in this reaction. The solvent that can be used in that case is not limited as long as it is inert to pyridyl-N-protected azabicycloheptane derivative (IV), peracid or organic peroxide, and specifically, for example, methylene chloride, Chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,
Examples include 1,1-trichloroethane and trichlene. Although the amount of the solvent used is not limited, it is usually about 0.2 to 100 volume, preferably about 0.5 to 50 volume, more preferably about 1 volume per 1 weight of the pyridyl-N-protected azabicycloheptane derivative (IV). Use ~ 20 volumes.

In this reaction, pyridyl-N-protected azabicycloheptane derivative (IV) is dissolved in a solvent, and a peracid or an organic peroxide is added to react. The reaction temperature at that time is not limited, but it is usually preferable to carry out the reaction under ice cooling. The reaction is usually completed in about 2 to 48 hours. The obtained crude product of the pyridyl-N-protected azabicycloheptane derivative (IV) can be further purified by a conventional method such as column chromatography.

Step 5 In this step, the N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III) is reacted with a halogenating agent to react with the halopyridyl-N-protected azabicycloheptane derivative (I).
And the process. This process is generally Weissburger
(Weissberger), Chemistry of Heterocyclic Compounds (Chemistry of Heterocyclic Compound
s, Pyridine and its Derivatives) '', Volume 14, special edition,
Part II, page 112. The halogenating agent used in the present invention is, for example, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus trichloride, pentachloride. Phosphorus, oxalyl chloride, phosgene, triphosgene, thionyl bromide, phosphorus tribromide and the like can be mentioned, but phosphorus oxychloride is more preferable.

In this reaction, either a solvent or no solvent may be used, but when used, it is not limited as long as it is inert to the halogenating agent. Specific examples include methylene chloride, chloroform, carbon tetrachloride, carbon disulfide, N, N, -dimethylformamide, benzene, toluene, xylene, hexane, octane and the like. Although the amount of the solvent used is not limited, it is usually the N-oxyhalopyridyl-N-protected azabicycloheptane derivative (I
About 0.2 to 100 volumes, preferably about 1 to 2 parts by weight of II)
0.5 to 50 volumes are used, more preferably about 1 to 20 volumes.

The amount of the halogenating agent used is not limited, but usually about 1 to 50 equivalents, preferably about 1 equivalent to 1 equivalent of the N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III). ~ 20 equivalents, more preferably about 1
Use ~ 10 equivalents.

In this reaction, the N-oxyhalopyridyl-N-protected azabicycloheptane derivative (III) is dissolved in a solvent as necessary, and a halogenating agent is added to react. Although the reaction temperature at that time is not limited, it can usually be carried out at room temperature to the reflux temperature of the solvent or the halogenating agent. Although the reaction time varies depending on the temperature, it is usually completed in about 30 minutes to 24 hours. The obtained crude product of the halopyridyl-N-protected azabicycloheptane derivative (I) can be further purified by a conventional method such as column chromatography.

In this step, the halopyridyl-N-protected azabicycloheptane derivative (I) is deprotected to give halopyridyl-
This is a step of producing an azabicycloheptane derivative (II), which can be carried out by acid hydrolysis according to a general method in organic synthesis. The acid used in that case is not limited, but is usually an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, phosphoric acid, or methanesulfonic acid, ethanesulfonic acid, benzene. Sulfonic acids such as sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like can be used.

Next, the N-protected azabicycloheptane derivative (VIII) represented by the following general formula is a novel compound and is useful as an intermediate in the production of the halopyridyl-azabicycloheptane derivative (II).

[0054]

[Chemical 20]

In the formula, R ¹ is a formyl group, lower acyl group, aromatic acyl group, vinyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, allyloxycarbonyl group, aralkyl group or tri-lower alkylsilyl group. R ⁴ is a hydrogen atom,
Lower alkylsulfonyl group, arylsulfonyl group or group represented by the following formula

[0056]

[Chemical 21]

(In the formula, R ² means a halogen atom.)
Means Specific examples of these groups are the same as above.
N is 0 or 1,

[0058]

[Chemical formula 22]

The bond represented by means a single bond or a double bond.

N-protected azabicycloheptane derivative (VIII)
The following compounds may be mentioned as specific examples, but the sulfonyl-N-protected azabicycloheptadiene derivative (VIII) in the present invention is not limited thereto. (1) Exo-2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -4-heptene (2) endo-2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -4 -Heptene (2) 7-ethoxycarbonylazabicyclo [2.2.
1] -4-heptene (3) exo-2- (3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane (4) exo-2- (3'-N-oxypyridyl) -7-
Ethoxycarbonylazabicyclo [2.2.1] heptane (5) exo-2- (6'-chloro-3'-pyridyl)-
7-Ethoxycarbonylazabicyclo [2.2.1] heptane

Next, production examples for producing the starting materials necessary for carrying out the present invention will be listed prior to the examples.

Production Example 1 2-Tosyl-7-ethoxycarb
Bonylazabicyclo [2.2.1] -1,4-heptadi
Synthesis of En

[0063]

[Chemical formula 23]

Organometal.Chem.Syn., 1 , 145, 1970.
Tosylacetylene synthesized by the method described in 41.
0 g (0.226 mol) and 1-ethoxycarbonylpyrrole 1.8
g (0.113 mol) was heated at 100 ° C. under a nitrogen stream for 4 hours.
After cooling, the reaction solution was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to obtain 27 g of the title compound as a colorless oil. (Yield: 75%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.0-1.
2 (3H, m), 2.4 (3H, s), 3.7-4.0 (1H, m), 5.2 (1H, s), 5.4 (1H, m
s), 6.9 (1H, s), 7.0 (1H, s), 7.4 (2H, s), 7.6 (1H, s), 7.8 (2H, s)
s)

Next, in order to specifically describe the present invention,
Examples will be given below, but it goes without saying that the present invention is not limited thereto.

EXAMPLES Example 1 2-Tosyl-7-ethoxycarbonylazabi
Synthesis of cyclo [2.2.1] -4-heptene

[0067]

[Chemical formula 24]

2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -1,4-heptadiene 34.0 g
(0.106 mol) was dissolved in ethanol (300 ml), and 4.0 g (0.105 mol) of sodium borohydride was added under ice-cooling and the reaction was carried out for 1 hour. After adding acetone to the reaction solution, the mixture was poured into water and extracted with ethyl ether to obtain a crude product of the title compound (exo form: endo form = mixture of about 4: 3). The crude product has sufficient purity for the next reaction without purification.

¹ H-NMR (400 MHz, CDCl ₃ ); Exoform δ (p
pm) 1.1-1.3 (3H, br-t), 1.6 (1H, br-S), 2.4 (3H, br-s), 3.0
(1H, br-s), 4.1 (2H, br-q), 4.8 (1H, br-s), 5.1 (1H, br-s),
6.3 (1H, br-s), 6.4 (1H, br-s), 7.4 (2H, d, J = 8.2Hz), 7.8 (2
H, br-d). End body δ (ppm) 1.2 (3H, t, J = 7.1Hz), 1.7 (1H, m), 2.2
(1H, m), 2.4 (3H, s), 3.7 (1H, m), 4.0 (2H, q, J = 7.1Hz), 4.8 (2
H, m), 6.4 (1H, m), 6.5 (1H, m), 7.4 (2H, d, J = 8.2Hz), 7.8 (2H,
(d, J = 8.2Hz)

Example 2 7-Ethoxycarbonyl azabi
Synthesis of cyclo [2.2.1] -4-heptene

[0071]

[Chemical 25]

2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -4-heptene 10.0 g (0.0311 m
ol) and sodium hydrogen phosphate (Na ₂ HPO ₄ ) 17.6g (0.124mo
l) is dissolved in methanol (100 ml) and cooled to 0 ° C.
5% Sodium amalgam 200.0g (0.894m under stirring)
ol) was added and the reaction was continued for 3 hours. The reaction solution was poured into water, extracted with ethyl ether, washed with water and dried to obtain a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to give 2.0 g of the title compound. (Yield; 38%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.1 (2
H, d, J = 8.8Hz), 1.2 (3H, t, J = 7.1Hz), 1.8 (2H, d, J = 8.8Hz),
4.0 (2H, q, J = 7.1Hz), 4.7 (2H, s), 6.2 (2H, s)

[0074]Example 3  Exo-2- (3'-Piriji
) -7-Ethoxycarbonylazabicyclo [2.2.
1] Synthesis of heptane

[0075]

[Chemical formula 26]

7-Ethoxycarbonylazabicyclo [2.2.1] -4-heptene 4.0 g (23.8 mmol), 3-
Pyridine bromide 3.76 g (23.8 mmol), tetra-n-butylammonium chloride 6.62 g (23.8 mmol), potassium formate 6.0 g
(71.4 mmol) and 280 mg (1.25 mmol) of palladium (II) acetate as N,
It was dissolved in N-dimethylformamide (50 ml) and reacted at 60 ° C for 24 hours. After cooling the reaction solution, it was poured into water and extracted with ethyl acetate. After drying, it was concentrated to give a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (toluene: ethyl acetate system) to give the title compound.
3.1g was obtained. (Yield; 53%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3
H, m), 1.6 (2H, m), 1.8 (3H, m), 2.0 (1H, m), 2.9 (1H, m), 4.1 (2
H, q, J = 7.3Hz), 4.3 (1H, s), 4.5 (1H, s), 7.2 (1H, m), 7.6 (1H,
d, J = 7.9Hz), 8.5 (2H, m)

[0078]Example 4  Exo-2- (3'-N-Oki
Cypyridyl) -7-ethoxycarbonylazabicyclo
[2.2.1] Synthesis of heptane

[0079]

[Chemical 27]

Exo-2- (3'-N-oxypyridyl) -7-ethoxycarbonylazabicyclo [2.2.
1] 5.82 g (23.6 mmol) of heptane in methylene chloride (50 ml)
Dissolved in 80% -m-chloroperbenzoic acid 7.64 g (35.
(4 mmol) was added and the reaction was continued for 24 hours. The reaction solution was returned to room temperature and purified as it was by silica gel column chromatography (methylene chloride: ethanol system) to obtain 4.8 g of the title compound. (Yield; 77%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3
H, t, J = 7.1Hz), 1.6 (2H, m), 1.8 (3H, m), 2.0 (1H, m), 2.8 (1H, m
m), 4.1 (2H, m), 4.3 (1H, s), 4.5 (1H, s), 7.2 (1H, m), 7.4 (1H, s
m), 8.2 (1H, d, J = 7.9Hz), 8.3 (1H, s)

Example 5 Exo-2- (6'-chloro-
3'-pyridyl) -7-ethoxycarbonylazavic
[2.2.1] Synthesis of heptane

[0083]

[Chemical 28]

Exo-2- (3'-N-oxypyridyl) -7-ethoxycarbonylazabicyclo [2.2.
1] 4.8 g (18.3 mmol) of heptane was added to 10.0 m of phosphorus oxychloride.
It was dissolved in 1 (108 mmol), heated to 80 ° C. and reacted for 1 hour. The reaction solution was cooled and then poured into ice water for neutralization. The pH was adjusted to weakly basic and extracted with ethyl acetate. After drying, it was concentrated to give a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to give the title compound (1.5 g). (Yield: 29
%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3
H, t, J = 7.2Hz), 1.6 (3H, m), 1.8 (3H, m), 2.0 (1H, m), 2.9 (1H, m
q, J = 5.2Hz), 4.1 (1H, q, J = 7.2Hz), 4.2 (1H, s), 4.4 (1H, s),
7.2 (1H, s), 7.6 (1H, d, J = 8.4Hz), 8.2 (1H, s)

Example 6 Exo-2- (2'-chloro-
3'-pyridyl) -7-ethoxycarbonylazavic
[2.2.1] Heptane and exo-2- (4'-
Chloro-3'-pyridyl) -7-ethoxycarbonyla
Synthesis of zabicyclo [2.2.1] heptane

[0087]

[Chemical 29]

[0088]

[Chemical 30]

When the crude product of Example 5 was purified by silica gel column chromatography, the above-identified 2 compounds were obtained.

(1) Exo-2- (2'-chloro-3'-
Pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane (yield; 28%) ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.2 (3H, br-t), 1.6-
2.2 (6H, m), 3.3 (1H, br-s), 4.1 (2H, br-q), 4.4 (1H, br-s),
7.2 (1H, dd, J = 7.9, 4.8Hz), 7.8 (1H, br-s), 8.2 (1H, dd, J =
4.8, 1.8Hz) MS; m / z 280 (MH ⁺ )

(2) Exo-2- (4'-chloro-3'-
Pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane (yield; 10%) ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.2 (3H, t, J = 7.2Hz) ,
1.6-2.0 (5H, m), 2.1 (1H, dd, J = 12.2, 9.7Hz), 3.3 (1H, dd, J
= 9.7, 4.8Hz), 4.1 (2H, q, J = 7.2Hz), 4.4-4.5 (2H, m), 7.3 (1
H, d, J = 5.4Hz), 8.4 (1H, d, J = 5.4Hz), 8.6 (1H, br-s) MS; m / z 280 (M + H ⁺ )

Example 7 Exo-2- (6'-chloro-
3'-pyridyl) -7-azabicyclo [2.2.1] he
Synthesis of butane dihydrochloride

[0093]

[Chemical 31]

Exo-2- (6'-chloro-3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.
2.1] Heptane (820 mg, 2.91 mmol) was added to 5N-hydrochloric acid (5 ml), and the mixture was heated under reflux for 24 hours. The reaction liquid was cooled and then concentrated under reduced pressure to obtain 780 mg of the title compound. (Yield: 95%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.1
(5H, m), 2.3 (1H, dd, J = 13.6, 9.6Hz), 3.3 (1H, dd, J = 9.6,
6.0Hz), 4.2 (1H, t, J = 4.4Hz), 4.4 (1H, d, J = 4.4Hz), 7.3 (1H,
d, J = 8.4Hz), 7.7 (1H, dd, J = 8.4, 2.8Hz), 8.2 (1H, d, J = 2.8H
z)

Example 8 Exo-2- (2'-chloro-
3'-pyridyl) -7-azabicyclo [2.2.1] he
Synthesis of butane dihydrochloride

[0097]

[Chemical 32]

Exo-2-in the same manner as in Example 7.
82 mg (0.29) of (2'-chloro-3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane
(78 mmol) to give 78 mg of the title compound. (Yield: 95%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.0
(5H, m), 2.4 (1H, dd, J = 13.6, 9.2Hz), 3.5 (1H, dd, J = 9.2,
6.0Hz), 4.2 (1H, t, J = 4.4Hz), 4.4 (1H, d, J = 4.4Hz), 7.3 (1H,
dd, J = 8.0, 4.8Hz), 7.8 (1H, dd, J = 8.0Hz, 1.6Hz), 8.1 (1H,
dd, J = 4.8, 1.6Hz) MS; m / z 208 (M + H ⁺ )

Example 9 Exo-2- (4'-chloro-
3'-pyridyl) -7-azabicyclo [2.2.1] he
Synthesis of butane dihydrochloride

[0101]

[Chemical 33]

Exo-2-
(4'-Chloro-3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane 82 mg (0.29
(76 mmol) to give 76 mg of the title compound. (Yield; 93%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.5-1.8
(5H, m), 2.0 (1H, dd, J = 13.5, 9.0Hz), 3.0 (1H, s), 3.2 (1H, m
m), 3.8 (1H, m), 3.9 (1H, m), 7.3 (1H, m), 8.3 (1H, m), 8.8 (1H, m
s) MS; m / z 208 (M + H ⁺ )

Example 10 Exo-2- (3'-pyridy
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0105]

[Chemical 34]

Exo-2-
78 mg of the title compound was obtained from 96 mg (0.39 mmol) of (3'-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane. (Yield; 81%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.1
(5H, m), 2.4 (1H, dd, J = 14.0, 10.0Hz), 3.6 (1H, dd, J = 10.0,
6.0Hz), 4.3 (1H, t, J = 4.4Hz), 4.6 (1H, d, J = 4.4Hz), 7.9 (1
H, dd, J = 8.4,5.6Hz), 8.4 (1H, d, J = 8.4Hz), 8.6 (1H, d, J = 5.
6), 8.7 (1H, s) MS; m / z 174 (M + H ⁺ )

Continuation of front page (56) References Tokuhyo 8-511768 (JP, A) Thomas F. Spande, et al. , Epibatidine: A novel (chloropyryl dyl) azabicyclohept anne with potent an alge sicity from Roman Ecuado, J .; Am. Chem. Soc. , Vol. 114, p. 3475-3478, 1992 Stephen F. Nelsen, et al. J., The Nitrogen Inversion Barrier of 7-methyl-7-az abicyclo [2.2.1] hep tan and the "bicy click effect", J. Chem. Am. Chem. Soc. , Vol. 111, p. 1776-1781, 1989 Hans-Josef Altenbach, et al. , Syntheses and photoelectron on specta of 7-aza norbornadiene and related compounds, an analysis with fra, Chem. Ber. , Vol. 124, p. 791-801, 1991 Robert R. et al. Fraser, et al. , Synthesis of 7-azabicyclo [2.2.1] heptane, exo-2-ch loro-7-azabicyclo [2.2.1. ] Heptane, and derivatives, Can. Chem. , Vol. 48, p. 2065-2074, 1970 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 487/08

Claims (6)

(57) [Claims] 1. An N-oxypyridyl-N-protected azabicycloheptane derivative (III) having the following general formula: [Wherein R ¹ is a lower aliphatic acyl group, an aromatic acyl group,
It means a vinyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an allyloxycarbonyl group, an aralkyl group or a tri-lower alkylsilyl group. However, the case where R ¹ is an acetyl group is excluded. ] By reacting with a halogenating agent to give a halopyridyl-N-protected azabicycloheptane derivative (I) represented by the following general formula, [In the formula, R ¹ has the same meaning as described above, and R ² represents a halogen atom. Provided that R ² is a chlorine atom and R
Except when ¹ is a methoxycarbonyl group. ] Then, it deprotects, The manufacturing method of the halopyridyl-azabicycloheptane derivative (II) represented by the following general formula, or its salt. [Chemical 3] [In the formula, R ² has the same meaning as described above, and X ⁻ represents an anion. ] 2. A pyridyl-N-protected azabicycloheptane derivative (IV) represented by the following general formula: [Wherein R ¹ has the same meaning as described above. ] Oxidized with aqueous hydrogen peroxide, peracid or organic peroxide to give N-oxypyridyl-N-protected azabicycloheptane derivative (III), then reacted with halogenating agent to give halopyridyl-N
-A method for producing a halopyridyl-azabicycloheptane derivative (II) or a salt thereof, which comprises deprotecting a protected azabicycloheptane derivative (I). 3. An N-protected azabicycloheptene derivative (V) represented by the following general formula: [Wherein R ¹ has the same meaning as described above. ] By reacting with a halogenated pyridine in the presence of a second palladium salt to give a pyridyl-N-protected azabicycloheptane derivative (IV),
Then, it is oxidized with hydrogen peroxide solution, peracid or organic peroxide to give an N-oxypyridyl-N-protected azabicycloheptane derivative (III), and then reacted with a halogenating agent to give a halopyridyl-N-protected azabicycloheptane. Derivative (I)
And further deprotection. A method for producing a halopyridylazabicycloheptane derivative (II) or a salt thereof. 4. A sulfonyl-N- represented by the following general formula:
The protected azabicycloheptene derivative (VI) was converted to [In the formula, R ¹ has the same meaning as described above, and R ³ represents a methyl group, an ethyl group, a phenyl group or a toluyl group. ] To react with sodium amalgam to give N-protected azabicycloheptene derivative (V), and then with halogenated pyridine in the presence of a second palladium salt to give pyridyl-N-protected azabicycloheptane derivative (IV), Then, it is oxidized with hydrogen peroxide solution, peracid or organic peroxide to give an N-oxypyridyl-N-protected azabicycloheptane derivative (III), and then reacted with a halogenating agent to give a halopyridyl-N-protected azabicycloheptane. A process for producing a halopyridyl-azabicycloheptane derivative (II) or a salt thereof, which is characterized in that the derivative (I) is further deprotected. 5. A sulfonyl-N-protected azabicycloheptadiene derivative (VII) represented by the following general formula: [Wherein R ¹ and R ³ have the same meanings as described above. ] Reduction with a metal hydrogen complex compound to give a sulfonyl-N-protected azabicycloheptene derivative (VI), followed by reaction with sodium amalgam to give an N-protected azabicycloheptene derivative
(V), followed by reaction with a halogenated pyridine in the presence of a second palladium salt to give a pyridyl-N-protected azabicycloheptane derivative (IV), followed by oxidation with aqueous hydrogen peroxide, peracid or organic peroxide. Then N-oxypyridyl-N
-A protected azabicycloheptane derivative (III), which is then reacted with a halogenating agent to give a halopyridyl-N-protected azabicycloheptane derivative (I), which is further deprotected, and a halopyridyl-azabicycloheptane derivative (III) II) or a method for producing a salt thereof. 6. The halopyridyl-azabicycloheptane derivative (II) is exo-2- (6′-chloro-3′-pyridyl) -7-azabicyclo [2.2.1] heptane. The manufacturing method described in any one of 1.