JPH06312989A - Production of (1rs, 2rs, 4rs)-2-(6-chloro-3-pyridyl)-7-azabicyclo(2.2.1)heptane - Google Patents

Abstract

PURPOSE:To obtain a new intermediate compound, composed of (1RS, 2RS, 4RS)-4-amino-2-(3-pyridyl)-1-cyclohexanols and derivatives thereof and useful as a synthetic intermediate, etc., for epibatidine useful as an analgesic agent. CONSTITUTION:3-Bromo-6-methoxypyridine is treated with t-butyl-lithium in dry THF at -78 deg.C and the resultant compound then reacts with 4-acetoxy-2- cyclohexenone in the presence of copper iodide and boron trifluoride-diethyl ether to provide a cvclohexanone derivative of formula 1 (R<1> is 1-4C alkyl or benzyl; R<3> is 1-4C alkyl, 2-5C aliphatic acyl, etc.), which is further treated with sodium cyanoborohydride. The produced amino group is protected to afford a new compound of formula II (Y is protecting group), which is then hydrolyzed to provide a new cyclohexanol compound of formula III. Furthermore, the resultant compound is then sulfonylated to afford a new compound of formula IV, which reacts with phosphorus oxychloride or phosgene to provide the objective intermediate compound of formula V.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing exo-2- (6-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane having an analgesic action, and this production method. And a novel pyridine derivative which is an intermediate for producing the raw material or the raw material used in 1.

[0002]

2. Description of the Related Art Conventionally, various analgesics, for example, a strong narcotic analgesic such as morphine, a weak narcotic analgesic such as codeine, a strong narcotic analgesic such as buprenorphine, pentazocine Such weak-acting opiate antagonistic analgesics have been used. Narcotic analgesics have a strong analgesic effect, but as a side effect, they develop resistance to the central nervous system depressant effect (analgesia, sedation, antitussive, respiratory depression, etc.) by continuous use, and further form psychological and physical dependence. However, there is a problem that withdrawal of medication causes strong withdrawal symptoms. There are similar problems with narcotic antagonistic analgesics. Although non-narcotic analgesics such as aspirin (non-opioid analgesics) have side effects such as gastrointestinal disorders and renal disorders, they are milder than the actions of narcotic analgesics, but have a weak analgesic effect. Therefore, there is a need for an analgesic drug that has neither tolerance nor dependence and has an analgesic action equivalent to or higher than that of morphine.

J. Am. Chem. Soc. Vol. 1
14, No. 9, 1992, pages 3475 to 3478, an alkaloid substance having an analgesic action about 200 times higher than that of morphine was isolated from the skin of a frog (Epipedobates tricolor) from Ecuador, and epibatidine was isolated.
It is reported that the effect of this substance is not antagonized by naloxone, does not bind to the μ receptor, and is a non-opioid analgesic. According to the above literature, epibatidine is represented by the following formula (Ep):

[0004]

[Chemical 9]

Exo-2- (6-chloro-3 represented by
-Pyridyl) -7-azabicyclo [2.2.1] heptane.

[0006]

The above literature does not describe a method for synthesizing epibatidine, and an object of the present invention is to provide a method for synthesizing epibatidine useful as an analgesic. Another object of the present invention is to provide a novel compound used as a raw material for the synthesis of epibatidine and a novel compound useful as an intermediate for synthesizing this compound.

[0007]

The present invention provides the following general formula (1):

[0008]

[Chemical 10]

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group and Y represents a protecting group) (1RS, 2RS, 4SR) -2- (3-pyridyl) −
A 7-azabicyclo [2.2.1] heptane derivative is reacted with phosphorus oxychloride or phosgene (1RS, 2RS, 4SR) -2- (6-chloro-3-).
Pyridyl) -7-azabicyclo [2.2.1] heptane.

Another aspect of the present invention is the following general formula (1):

[0011]

[Chemical 11]

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2RS, 4SR) -2- (3-pyridyl) −
It is a 7-azabicyclo [2.2.1] heptane derivative.

Another aspect of the present invention is the following general formula (2):

[0014]

[Chemical 12]

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group) (1RS, 2RS,
4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative.

Another aspect of the present invention is the following general formula (3):

[0017]

[Chemical 13]

(In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ² represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a tolyl group, and W represents a hydrogen atom or a protective group. Represents a group) (1RS, 2SR, 4RS)
It is a -4-amino-2- (3-pyridyl) -1-cyclohexanol derivative.

Another aspect of the present invention is the following general formula (4):

[0020]

[Chemical 14]

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and W represents a hydrogen atom or a protecting group) (1RS, 2SR, 4RS) -4-amino- It is a 2- (3-pyridyl) -1-cyclohexanol derivative.

Another aspect of the present invention is the following general formula (5):

[0023]

[Chemical 15]

(In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, and a ring substituent. Represents a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group which may have a halogen atom, Y represents a protecting group) (1RS, 2SR, 4RS) -4-amino-2- (3
-Pyridyl) -1-cyclohexanol derivative.

Another aspect of the present invention is the following general formula (6):

[0026]

[Chemical 16]

(In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, and a ring substituent. Represents a cyclohexylcarbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group optionally having a halogen atom) Represented by (1RS, 2S
R, 4RS) -4-Amino-2- (3-pyridyl) -1
A cyclohexanol derivative.

Another aspect of the present invention is the following general formula (7):

[0029]

[Chemical 17]

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a ring substituent) Represents a cyclohexylcarbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group optionally having a halogen atom) Represented by (3RS, 4S
R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative.

(1RS, 2RS, 4SR) -2 of the present invention
A method for producing-(6-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane (hereinafter sometimes referred to as "epibatidine") is represented by the general formula (1) ( It can be produced by reacting 1RS, 2RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) with phosphorus oxychloride or phosgene.

(1RS, 2RS, 4SR) -2- (3-
Pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is a novel compound, and from known compounds, (1RS, 2RS, 4SR) -2- (3-pyridyl)-
7-azabicyclo [2.2.1] heptane derivative (1)
Is synthesized, and this (1RS, 2RS, 4SR) -2-
A route for synthesizing epibatidine from (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is shown below.

[0033]

[Chemical 18]

[0034]

[Chemical 19]

[0035]

[Chemical 20]

In the above formula of the synthetic route, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and R ² represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a tolyl group. , R ³ is an alkyl group having 1 to 4 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent,
It represents an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a benzoyl group which may have a halogen atom, Y represents a protecting group, and W represents a hydrogen atom or a protecting group.

That is, from a pyridine derivative (9) obtained by reacting a known pyridine derivative (10) with organic lithium and copper iodide and a cyclohexenone derivative (8), (3RS, 4SR) -4 -Substituted oxy-3
A-(3-pyridyl) cyclohexanone derivative (7) was obtained, and (3RS, 4SR) -4-substituted oxy-3- (3-
The carbonyl group of the pyridyl) cyclohexanone derivative (7) is converted to an amino group by reductive amination (1RS, 2
SR, 4RS) -4-Amino-2- (3-pyridyl)-
A 1-cyclohexanol derivative (6) was obtained (1RS,
2SR, 4RS) -4-Amino-2- (3-pyridyl)
A protective group Y is bonded to the amino group of -1-cyclohexanol derivative (6) to obtain (1RS, 2SR, 4RS) -4-
Amino-2- (3-pyridyl) -1-cyclohexanol derivative (5) was obtained, (1RS, 2SR, 4RS) -4.
- amino-2- (3-pyridyl) -1--OR ³ group cyclohexanol derivative (5) by changing the -OH group (1
RS, 2SR, 4RS) -4-Amino-2- (3-pyridyl) -1-cyclohexanol derivative (4) is obtained,
(1RS, 2SR, 4RS) -4-amino-2- (3-
A pyridyl) -1-cyclohexanol derivative in which the —OH group is replaced with an —O—SO ₂ —R ² group to give a pyridine derivative (3)
To obtain (1RS, 2SR, 4RS) -4-amino-2-
Intramolecular cyclization of (3-pyridyl) -1-cyclohexanol derivative (3) to (1RS, 2RS, 4SR)-
2- (3-pyridyl) -7-azabicyclo [2.2.
1] A heptane derivative (2) is obtained, and (1RS, 2RS, 4
SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (2) or a protecting group Y bonded to its amino group (1RS, 2RS, 4S).
R) -2- (3-pyridyl) -7-azabicyclo [2.
2.1] From the heptane derivative (1), their —OR ¹
The group is changed to a chlorine atom, and the protecting group Y is eliminated, if necessary, to obtain epibatidine. Epibatidine has optical isomers, and in order to obtain an optically active substance, any compound in the above steps may be optically resolved.

In the general formula representing each of the above derivatives, R
Examples of the alkyl group having 1 to 4 carbon atoms represented by ¹ , R ² or R ³ include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.

Examples of the aliphatic acyl group having 2 to 5 carbon atoms represented by R ³ include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like, and cyclohexylcarbonyl group or benzoyl group. 1 to 4 carbon atoms as a ring substituent of
Examples of the alkyl group include those exemplified for R ¹ , and examples of the halogen atom include chlorine, bromine, iodine and the like.

The protecting group represented by Y or W may be a conventionally used protecting group, for example,
The following general formula (11), (12), (13) or (1
4):

[0041]

[Chemical 21]

Examples include groups represented by:

In the general formula (11), the group represented by R ¹¹ includes t-butyl, 1-adamantyl, cyclopentyl, diisopropylmethyl, 2-trimethylsilylethyl, 1-methyl-1-alkylethyl, 1,1
-Dimethyl-2-haloethyl, vinyl, benzyl, substituted benzyl (for example, p-methoxybenzyl, p-nitrobenzyl, etc.), diphenylmethyl, 9-anthrylmethyl, di (2-pyridyl) methyl, 4- (1, 4-dimethyl) piperidinyl and the like can be mentioned.

In the general formula (12), examples of the group represented by R ¹² include a hydrogen atom, methyl, substituted methyl (eg, monochloromethyl, dichloromethyl, trifluoromethyl, etc.), phenyl and the like. .

In the above general formula (13), the group represented by R ¹³ includes 2-tetrahydropyranyl and di (p-
Methoxyphenyl) methyl, triphenylmethyl, benzylidene, benzyl, substituted benzyl (for example, p-methoxybenzyl, p-nitrobenzyl, etc.), salicylidene, diphenylmethylene and the like can be mentioned.

In the general formula (14), examples of the group represented by R ¹⁴ include methyl and p-tolyl.

The above (1RS, 2RS, 4SR) -2-
The (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) to (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7) are all novel. It is a compound and has utility as an intermediate for the synthesis of epibatidine. Each pyridine derivative can be synthesized by utilizing a unit reaction known per se which can be understood from the above reaction route.

In the above reaction route, (3RS, 4S
As the R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7), a trans isomer was shown with respect to the pyridine ring and -OR ³ , but (3RS, 4S
The cis isomer is also obtained when synthesizing the (R) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7). In order to synthesize epibatidine, the trans-form (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative (7) is used separately from the mixture with the cis-form.

The manufacturing method of the present invention is (1RS, 2RS,
4SR) -2- (3-Pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) is reacted with phosphorus oxychloride or phosgene to produce epibatidine. Dimethylformamide may be used with phosphorus oxychloride. The reaction conditions for reacting (1RS, 2RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative (1) with phosphorus oxychloride or phosgene are similar to each other. The conditions known per se in the above can be used. For example, (1RS, 2RS, 4S
R) -2- (3-pyridyl) -7-azabicyclo [2.
2.1] When the heptane derivative (1) is reacted with phosphorus oxychloride and dimethylformamide, the reaction conditions of the Vilsmeier-Haack reaction can be used.

Epibatidine can also be synthesized by the reaction route shown below.

[0051]

[Chemical formula 22]

[0052]

[Chemical formula 23]

In each formula of the above reaction route, R ¹ , R ³
And Y are as defined above, R ⁴ and R ⁵ represent an alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom.

That is, the pyridine derivative (15) was synthesized by the step (A) or the step (B) to obtain the pyridine derivative (5).
Epibatidine can be synthesized from the pyridine derivative (15) by a method similar to the method of synthesizing epibatidine from. In addition, pyridine derivative (16) is synthesized in step (C), step (D) or step (E), and epibatidine is converted from pyridine derivative (16) by the same method as in the method of synthesizing epibatidine from pyridine derivative (5). Can be synthesized.

[0055]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 (3RS, 4SR) 4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone [trans form]

3-Bromo-6-methoxypyridine 35.
2 g (187 mmol) was dissolved in 580 ml of dry tetrahydrofuran (THF) under a nitrogen atmosphere, and -78
Stir at ℃. To this solution, 220 ml (374 mmol) of 1.7 M t-butyllithium-pentane solution was added dropwise over 2 hours, and the mixture was further stirred at -78 ° C for 1 hour. 18.0 g (93.6 mmol) of 99% copper iodide was added to this solution.
Was added as a powder and stirred at -78 ° C for 1.5 hours. To this mixture was further added boron trifluoride-diethyl ether 2
3.0 ml (185 mmol) was added dropwise over 5 minutes, and the mixture was stirred at -78 ° C for 3 hours. To the resulting mixture, 4
-Acetoxy-2-cyclohexenone 12.0 g (7
A solution of 7.8 mmol) in THF (16 ml) was added dropwise over 10 minutes, and the mixture was stirred at -78 ° C overnight. To this mixture, 40 ml of a saturated aqueous solution of ammonium chloride was added at -78 ° C, the mixture was allowed to stand at room temperature, the insoluble matter was filtered off using Celite, and the filtrate was extracted with ether. The obtained ether extraction layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a red crude oily substance. The oil was purified by medium pressure silica gel chromatography (eluent, hexane: ethyl acetate = 3: 2).
After recrystallization from ether, the title compound 3.8 was obtained.
0 g (yield 18.5%) was obtained as white crystals.

In the above chromatographic purification, from another fraction, 2.44 mg of (3RS, 4RS) 4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone [cis form] (yield 11 .9%)
Was also obtained as a colorless oil. The Rf value by TLC is about 0.4 trans form and about 0.3 cis form (developing solvent: hexane /
It was ethyl acetate = 1/1). Gas chromatographic analysis of the above red crude oil [column: Sili
cone OV-17; 2 m, carrier: nitrogen; 40 ml /
Min, column temperature: 230 ° C., injection temperature 250 ° C.] showed that the ratio of trans isomer / cis isomer in the crude oil was 2/1.

Trans form ¹ H NMR (CDCl ₃ ) δ; 1.93 (3H,
s), 1.8-2.0 (1H, m), 2.2-2.3.
(1H, m), 2.5-2.6 (2H, m), 2.6-
2.7 (2H, m), 3.23 (1H, dd, J = 9H
z, 17 Hz), 3.92 (3H, s), 5.26 (1
H, dt, J = 4Hz, 9Hz), 6.72 (1H,
d, J = 8.5 Hz), 7.45 (1H, dd, J =
2.5 Hz, 8.5 Hz, 8.00 (1H, d, J =
2.5 Hz) FAB-MS (m / e); 264 (M + 1) IR (KBr); 2956, 1724, 1608, 14
98, 1298, 1242, 1030. Melting point: 102-103 ° C

Cis isomer ¹ H NMR (CDCl ₃ ) δ; 2.06 (3H,
s), 2.0-3.1 (6H, m), 3.27 (1H,
ddd, J = 3 Hz, 5 Hz, 14 Hz), 3.92
(3H, s), 5.23-5.28 (1H, m), 6.
65-8.05 (3H, m), FAB-MS (m / e); 264 (M + 1).

Example 2 (1RS, 2SR, 4RS) -4-amino-2- (6-
Methoxy-3-pyridyl) -1-cyclohexyl acetate

Ammonium acetate 10.8 g (140 mmol) was dissolved in dry methanol 350 ml and this solution was prepared as in Example 1 (3RS, 4S).
R) -4-acetoxy-3- (6-methoxy-3-pyridyl) cyclohexanone 3.70 g (14.1 mmol) and 95% sodium cyanoborohydride.
94 g (14.2 mmol) was added, and the mixture was stirred at room temperature overnight. Methanol was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in 100 ml of dichloromethane, the solution was washed with 100 ml of saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted with dichloromethane (100 ml × 2), and the combined organic layers were saturated brine. 1
It was washed with 80 ml. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance 4.40.
g was obtained. This oil was purified by medium pressure silica gel chromatography (eluent, chloroform: methanol =
10: 1 to 3: 1) to give 1.59 g of the title compound (yield 4
2.6%) as a colorless oil.

In the above chromatographic purification, from the other fractions (1RS, 2SR, 4S
R) -4-Amino-2- (6-methoxy-3-pyridyl) -1-cyclohexyl acetate (0.71 g, yield 19.0%) was also obtained as a colorless oil. R by TLC
f value; (1RS, 2SR, 4RS) -body about 0.5, (1
RS, 2SR, 4SR) -body about 0.6 (developing solvent; chloroform / methanol / 28% ammonia water = 50/1)
0/1).

(1RS, 2SR, 4RS) -form ¹ H NMR (CDCl ₃ ) δ; 1.3-1.6 (5
H, m), 1.81 (3H, s), 1.9-2.2 (3
H, m), 2.73 (1H, td, J = 3Hz, 12H
z, 12 Hz), 2.94 (1H, tt, J = 4 Hz,
4 Hz, 11 Hz), 3.91 (3H, s), 4.84
(1H, td, J = 4.5Hz, 11Hz, 11H
z), 6.68 (1H, d, J = 8 Hz), 7.43
(1H, dd, J = 2Hz, 8Hz), 7.96 (1
H, d, J = 2 Hz) FAB-MS (m / e); 265 (M + 1)

(1RS, 2SR, 4SR) -body ¹ H NMR (CDCl ₃ ) δ; 1.32 (2H, br
s), 1.6-1.8 (4H, m), 1.83 (3H,
s), 1.85-2.0 (2H, m), 3.14 (1
H, td, J = 5 Hz, 5 Hz, 11 Hz), 3.37
(1H, quintet, J = 3Hz), 3.91 (3
H, s), 4.8-4.93 (1H, m), 6.67.
(1H, d, J = 8Hz), 7.44 (1H, dd, J
= 2.5 Hz, 8 Hz), 8.00 (1H, d, J =
2.5 Hz)

Example 3 (1RS, 2SR, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl acetate

Prepared as in Example 2 (1
RS, 2RS, 4RS) -4-Amino-2- (6-methoxy-3-pyridyl) -1-cyclohexylacetate 151 mg (0.57 mmol), sodium hydrogencarbonate 124 mg (1.48 mmol) and water 0.8 ml. 0.05 ml of carbobenzoxiclide at room temperature
A solution of (0.35 mmol) in 0.8 ml of chloroform was added dropwise, and the mixture was stirred for 2 hours. To this reaction mixture was further added 0.05 ml (0.35 mmol) of carbobenzoxylcolide.
And sodium hydrogen carbonate 62 mg (0.74 mmol)
Was added, stirred for 30 minutes, extracted with chloroform,
It was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 1/1) to obtain 227 mg of the title compound as a colorless oily substance in a quantitative yield.

¹ H NMR (CDCl ₃ ) δ; 1.3-
1.6 (3H, m), 1.81 (3H, s), 2.0-
2.3 (3H, m), 2.7-2.9 (1H, m),
3.6-3.8 (1H, m), 3.90 (3H, s),
4.7-4.9 (2H, m), 5.08 (2H, br
s), 6.66 (1H, d, J = 9Hz), 7.2-
7.4 (6H, m), 7.95 (1H, d, J = 3H
z)

Example 4 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexanol

Obtained in Example 3 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
217 mg (0.55 mmol) of -methoxy-3-pyridyl) -1-cyclohexyl acetate was dissolved in 2.3 ml of methanol, 0.7 ml of 1N aqueous sodium hydroxide solution was added to this solution, and the mixture was stirred at room temperature for 1.5 hours. did. After methanol was distilled off under reduced pressure from the reaction solution, the residue was extracted with ethyl acetate and washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
194 mg of the title compound was obtained as white crystals in quantitative yield.

¹ H NMR (CDCl ₃ ) δ; 1.3-
1.7 (3H, m), 2.0-2.2 (3H, m),
2.5-2.6 (2H, m), 3.5-3.7 (1H,
m), 3.92 (3H, s), 4.5-4.7 (1H,
br), 5.08 (2H, brs), 6.73 (1H,
d, J = 8 Hz), 7.3-7.4 (5H, m), 7.
44 (1H, dd, J = 8Hz), 8.03 (1H,
d, J = 2 Hz).

Example 5 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl methanesulfonate

Obtained in Example 4 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
-Methoxy-3-pyridyl) -1-cyclohexanol (194 mg, 0.55 mmol) was dissolved in dry dichloromethane (3.5 ml), and dry pyridine (1.4 m) was added to the solution.
1 was added and the mixture was stirred at 0 ° C. 0.76 ml (0.98 mmol) of methanesulfonyl chloride was added dropwise to this solution, and the mixture was stirred at room temperature for 17 hours. After distilling off the solvent from the reaction solution under reduced pressure, the residue was redissolved in 10 ml of dichloromethane,
After washing with 20 ml of water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 276 mg of a brown oily substance. This was purified by medium pressure silica gel chromatography (eluent, chloroform: methanol = 20: 1).
Then, 237 mg of the title compound was obtained as a yellow oily substance in a quantitative yield.

¹ H NMR (CDCl ₃ ) δ; 1.3-
1.6 (2H, m), 1.8-1.9 (1H, m),
2.1-2.2 (1H, m), 2.2-2.3 (1H,
m), 2.3-2.5 (1H, m), 2.37 (3H,
s), 2.84 (1H, m), 3.70 (1H, m),
3.91 (1H, s), 4.53 (1H, ddd, J =
4.4Hz, 11Hz, 11Hz), 4.71 (1H,
bs), 5.08 (2H, s), 6.73 (1H, d,
J = 8 Hz), 7.35 (1 H, dd, J = 2 Hz, 8
Hz), 8.02 (1H, d, J = 2 Hz). FAB-MS (m / e); 435 (M + 1)

Example 6 (1RS, 2RS, 4SR) -2- (6-methoxy-3)
-Pyridyl) -7-azabicyclo [2.2.1] heptane

Obtained in Example 5 (1RS, 2RS, 4R
S) -4-benzyloxycarbonylamino-2- (6
-Methoxy-3-pyridyl) -1-cyclohexyl methanesulfonate 18.0 mg (0.042 mmol)
Was dissolved in 0.1 ml of acetic acid, 0.2 ml of 47% hydrobromic acid aqueous solution and 0.2 ml of acetic acid were added to this solution, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off from this reaction solution, 7
The pH was adjusted to 9 by adding 1.5 ml of 0% aqueous ethanol solution and 1N aqueous sodium hydroxide solution, and the mixture was stirred at 70 ° C. for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure, followed by extraction with 5 ml of dichloromethane and washing with 5 ml of water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (8.0 mg, yield 93.0%) as a yellow oil.

¹ H NMR (CDCl ₃ ) δ; 1.4-
1.7 (6H, m), 1.8-1.9 (1H, m),
2.76 (1H, dd, J = 1 Hz, 22 Hz), 3.
53 (1H, s), 3.76 (1H, s), 3.91
(3H, s, J = 1Hz, 22Hz), 6.68 (1
H, d, J = 8 Hz), 7.64 (1H, dd, J = 2)
Hz, 8 Hz), 8.02 (1H, d, J = 2 Hz). FAB-MS (m / e); 205 (M + 1)

Example 7 (1RS, 2RS, 4SR) -7-Benzyloxycarbonyl-2- (6-methoxy-3-pyridyl) -7-azabicyclo [2.2.1] heptane

Obtained as in Example 6 (1R
S, 2RS, 4SR) -2- (6-Methoxy-3-pyridyl) -7-azabicyclo [2.2.1] heptane 2
To 1.9 mg (0.11 mmol), 0.1 ml of water and 24.0 mg (0.29 mmol) of sodium hydrogen carbonate.
Was added and stirred. A solution prepared by dissolving 0.01 ml (0.07 mmol) of carbobenzoxylcolide in 1 ml of chloroform was added to this reaction liquid, and the mixture was further stirred at room temperature for 1 hour. Furthermore, sodium bicarbonate 12.0 mg (0.
15 mmol) and carbobenzoxycyclolide 0.01
A solution prepared by dissolving ml (0.07 mmol) in 1 ml of chloroform and 0.1 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by thin-layer silica gel chromatography (eluent, hexane: ethyl acetate = 1: 1). Compound 3
2.5 mg (yield 87.3%) was obtained as a yellow oil.

¹ H NMR (CDCl ₃ ) δ; 1.5-
1.7 (2H, m), 1.7-1.9 (3H, m),
1.97 (1H, dd, J = 8.8Hz, 12.2H
z), 2.84 (1H, dd, J = 4.9 Hz, 8.8)
Hz), 3.90 (3H, s), 4.23 (1H, br
s), 4.47 (1H, brs), 5.10 (2H,
s), 6.63 (1H, d, J = 8.5 Hz), 7.2
-7.4 (5H, m), 7.49 (1H, dd, J =
2.4 Hz, 8.5 Hz), 7.99 (1H, d, J =
2.4 Hz).

Example 8 (1RS, 2RS, 4SR) -2- (6-chloro-3-)
Pyridyl) -7-azabicyclo [2.2.1] heptane

Obtained in Example 7 (1RS, 2RS, 4S
R) -7-Benzyloxycarbonyl-2- (6-methoxy-3-pyridyl) -7-azabicyclo [2.2.
1] 10.2 mg (0.030 mmol) of heptane was dissolved in 0.2 ml of dry dimethylformamide. To this solution, 6 μl (0.064 mmol) of phosphorus oxychloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours and then at 80 ° C. for 12 hours. After allowing the reaction solution to cool, 4 m of water was added to it.
The pH was adjusted to 7.5 by adding 1 and sodium hydrogen carbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent, chloroform: methanol = 9: 1 to 3: 1) to obtain 3.0 mg (yield 93.0%) of the title compound as a yellow oil.

¹ H NMR (CDCl ₃ ) δ; 0.88
-1.98 (7H, m), 2.81 (1H, m), 3.
64 (1H, s), 3.89 (1H, s), 7.24
(1H, m), 7.80 (1H, s), 8.28 (1
H, d, J = 2.4 Hz), FAB-MS (m / e); 209,211

Example 9 (1RS, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl)-
1-cyclohexyl p-toluene sulfonate

Obtained as in Example 4 (1R
55.0 mg (0.15 mmol) of S, 2RS, 4RS) -4-benzyloxycarbonylamino-2- (6-methoxy-3-pyridyl) -1-cyclohexanol was dissolved in 0.6 ml of dry pyridine. 35.0 mg (0.1%) of p-toluenesulfonyl chloride was added to the solution under ice cooling.
(8 mmol) was added, and the mixture was stirred as it was for 17 hours. Furthermore, p-toluenesulfonyl chloride 23.0 mg
(0.12 mmol) was added and stirring was continued at room temperature for 3 hours. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in chloroform and washed with water. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by preparative TLC (ethyl acetate: hexane = 1: 1) to give the title compound 7.
5 mg (yield 9.8%) was obtained as white crystals.

¹ H NMR (CDCl ₃ ) δ; 1.3-
1.9 (3H, m), 2.1 (2H, m), 2.39
(3H, s), 2.7-2.8 (1H, m), 3.6-
3.8 (1H, m), 3.90 (3H, s), 4.5-
4.7 (1H, br), 4.8-4.9 (1H, m),
5.06 (2H, brs), 6.34 (1H, d, J =
8 Hz), 7.0-7.1 (1 H, m), 7.2-7.
4 (9H, m), 7.74 (1H, d, J = 3Hz).

[0087]

INDUSTRIAL APPLICABILITY The present invention has an effect that epibatidine useful as an analgesic can be advantageously produced by a synthetic method.

Claims (8)

[Claims] 1. The following general formula (1): (Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2
RS, 4SR) -2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane derivative is reacted with phosphorus oxychloride or phosgene (1RS, 2
RS, 4SR) -2- (6-chloro-3-pyridyl)-
A method for producing 7-azabicyclo [2.2.1] heptane. 2. The following general formula (1): (Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y represents a protecting group) (1RS, 2
RS, 4SR) -2- (3-Pyridyl) -7-azabicyclo [2.2.1] heptane derivative. 3. The following general formula (2): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group) (1RS, 2RS, 4SR) -2
-(3-Pyridyl) -7-azabicyclo [2.2.1]
Heptane derivative. 4. The following general formula (3): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ² represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a tolyl group, and W represents a hydrogen atom or a protecting group. (1RS, 2SR, 4RS) -4-amino-2- (3-pyridyl) -1-cyclohexanol derivative represented by the formula (1). 5. The following general formula (4): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and W represents a hydrogen atom or a protecting group) (1RS, 2SR, 4RS) -4-amino-2- ( 3-
Pyridyl) -1-cyclohexanol derivative. 6. The following general formula (5): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. Represents a benzoyl group which may have and Y represents a protecting group) (1RS,
2SR, 4RS) -4-Amino-2- (3-pyridyl)
-1-Cyclohexanol derivative. 7. The following general formula (6): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. (Representing a benzoyl group which may be possessed) is represented by (1RS, 2SR, 4RS)-
4-Amino-2- (3-pyridyl) -1-cyclohexanol derivative. 8. The following general formula (7): (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R ³ represents an alkyl group having 1 to 4 carbon atoms, and 2 carbon atoms.
~ 5 aliphatic acyl group, a cyclohexylcarbonyl group which may have an alkyl group having 1 to 4 carbon atoms as a ring substituent, an alkyl group having 1 to 4 carbon atoms as a ring substituent, a nitro group or a halogen atom. A (3RS, 4SR) -4-substituted oxy-3- (3-pyridyl) cyclohexanone derivative represented by (representing a benzoyl group which may be possessed).