JP3123137B2 - Method for producing optically active 3-substituted-2-norbornanone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active 3-substituted-2-norbornanones useful as intermediates for synthesizing various physiologically active substances. For example, a thromboxane A2 receptor antagonist useful as a blood coagulation inhibitor can be synthesized using the present compound as an intermediate (Narisada et al., J. Med. Chem.,
31 , 1847 (1988)).

[0002]

2. Description of the Related Art In recent years, there has been an increasing need to synthesize physiologically active substances as optically active substances. When a plurality of optical isomers are present in these substances, differences are often observed in the activities among the isomers.However, one isomer usually shows strong activity, and the other isomer has no activity. Has been found to be weak or often exhibit undesirable toxicity. Therefore, in the case of synthesizing a physiologically active substance particularly as a pharmaceutical, selectively synthesizing a desired optical isomer is not only for expressing sufficient physiological activity,
It is strongly desired from the aspect of safety.

[0003]

SUMMARY OF THE INVENTION The optical activity 3 of the present invention
In order to efficiently synthesize substituted 2-norbornanone, it is necessary to efficiently obtain optically active 2-norbornanone. Regarding the method of synthesizing optically active 2-norbornanone, (1) racemic endo- or exo-2
-Optical resolution of norbornanol by the diastereomer method (Winstein et al., J. Am. Che
m. Soc. , 74, 1147 (1952), Bers.
on et al., ibid. , 83, 3986 (1961)),
(2) A method for asymmetric oxidation or asymmetric reduction of racemic exo-2-norbornanol or 2-norbornanone with horse liver alcohol dehydrogenase (Irwi
n. Am. Chem. Soc. , 98,8476
(1976)). However,
The method (1) requires repetition of recrystallization many times in order to improve the optical purity, and is not efficient. Also, (2)
In the method (1), the reagent is expensive, so that the method is not practical and the asymmetric yield is low.

As described above, none of these methods has been satisfactory for practical use on an industrial level. From the above, there has been a strong demand for the development of a simple method for producing useful optically active 3-substituted-2-norbornanone, which has a very wide range of applications as a synthetic intermediate for a physiologically active substance. The present inventors have conducted intensive studies to achieve the object of efficiently obtaining a large amount of optically active 3-substituted-2-norbornanone. As a result, the optically active 3-substituted-2-substituted-2-norbornen represented by the general formula (II) was obtained. The present inventors have found a method for efficiently producing norbornanone in large quantities and have led to the present invention.

[0005]

The present invention provides (1) a compound represented by the general formula (I):

[0006]

Embedded image Wherein R ² and R ^{3 in the group} are each independently C ₁ -C ₆
An alkyl or phenyl group, n is 0 or 1-3
It shows an integer and * shows asymmetric carbon. Optical activity represented by)
Acrylate in the presence of a Lewis acid in a solvent and
Reaction with cyclopentadiene at 78 ° C to room temperature
(2) this Diels-Alder adduct
The alder adduct is prepared in a solvent under basic conditions at 0 ° C to 50 ° C
Is hydrolyzed at the temperature of formula (VI)

[0007]

Embedded image (Wherein M is hydrogen or lithium, sodium or
Indicates a metal selected from potassium. Compound represented by)
And (3) dissolving the compound represented by the formula (VI).
In the presence of a hydrogenation catalyst in a medium and at a temperature of 0 ° C to 50 ° C
Catalytic hydrogenation gives formula (III)

[0008]

Embedded image (Wherein M is hydrogen or lithium, sodium or
Indicates a metal selected from potassium. Compound represented by)
And (4) converting the compound represented by the formula (III)
Using potassium permanganate at a temperature of 0 ° C to 100 ° C
Oxidize to formula (VII)

[0009]

Embedded image And (5) a compound represented by the formula (VII):
Using sodium bismuthate-phosphoric acid,
Subject to oxidative decarboxylation at room temperature to 60 ° C in a solvent.
Expression (IV)

[0010]

Embedded image (6) The compound represented by the formula (IV) is subjected to a base treatment to form an enol, and the thus obtained enolate is subjected to alkyl halide, alkenyl halide, at -78 ° C to room temperature in a solvent . or the formula which comprises reacting a halogenated hydrocarbon selected from aralkyl halides (II)

[0011]

Embedded image (Wherein R ⁴ represents an alkyl group, an alkenyl group, an alkynyl
Group, an aryl group or an aralkyl group. )
For producing an optically active 3-substituted-2-norbornanone.
You. Further, the present invention provides a compound represented by the formula (VII):

[0012]

Embedded image Using sodium bismuthate-phosphoric acid
Subject to oxidative decarboxylation at 0 ° C to 60 ° C in a solvent
Formula (IV) characterized by the following:

[0013]

Embedded image A method for producing optically active 2-norbornanone represented by
You. Next, the present invention will be described in detail. Optical activity of the present invention
The 3-substituted-2-norbornanone (II) having the following properties
It can be manufactured according to the process.

[0014]

Embedded image

(Wherein R ¹ and R ⁴ are the same as above)
M is hydrogen or lithium, sodium or potassium
Metal selected from the group consisting of ) The compound represented by (I), which is a starting material of the present invention, comprises (R)-(-)-or (S)-(+)-pantoyl lactone, and (S)-
By reacting (-)-or (R)-(+)-N-methyl-2-hydroxysuccinimide with acrylic acid chloride, it can be obtained with high optical purity (Poll et al., Tetrahedron Lett.,
30, 5595 ( 1989 ). ).

The compound represented by the formula (V) ((+) or
(-), The following formulas (VI), (III), (VII),
(Same in (IV) and (II)) can be synthesized by subjecting the compound represented by formula (I) to a Diels-Alder reaction with cyclopentadiene in the presence of a Lewis acid catalyst. Examples of the catalyst used for the reaction include titanium tetrachloride and the like. As the reaction solvent, methylene chloride,
A halogen-based solvent such as chloroform and dichloroethane, or a mixed solvent of these with a hydrocarbon-based solution such as pentane, hexane, heptane, and petroleum ether can be used. The reaction temperature is suitably from -78 ° C to room temperature, particularly preferably from -20 ° C to 0 ° C.

The compound of the formula (V) can be easily converted to the compound of the formula (VI) by hydrolysis under basic conditions. Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. As a reaction solvent, an ether solvent such as tetrahydrofuran is preferably used. The reaction temperature is suitably from 0 to 50 ° C,
Particularly preferably, it is around room temperature.

The compound represented by the formula (III) is represented by the formula (V
The compound represented by I) can be easily obtained by catalytic hydrogenation. Examples of the catalyst used for the reaction include palladium-carbon and the like. As a reaction solvent, an alcoholic solvent such as methanol, ethanol, solmix and the like can be used. Reaction temperature is 0-50
C is appropriate, and particularly preferably around room temperature.

The compound represented by the formula (VII) has the formula (I)
It can be obtained by oxidizing the compound represented by II). Examples of the oxidizing agent used for the reaction include potassium permanganate. As a reaction solvent, a two-phase system of a hydrocarbon solvent such as pentane, hexane, heptane, and petroleum ether and water can be used. The reaction temperature is suitably from 0 to 100 ° C, particularly preferably from room temperature to 7 ° C.
0 ° C.

The compound represented by the formula (IV) has the formula (VI)
It can be easily obtained by oxidizing the compound represented by I). Examples of the oxidizing agent used in the reaction include:
Examples include sodium bismuthate-phosphoric acid, lead tetraacetate, and chromic acid-sulfuric acid. These oxidizing agents can be used according to a conventional method. For example, when sodium bismuthate-phosphoric acid is used as the oxidizing agent, water can be used as a reaction solvent, and the reaction temperature is from room temperature to 60 ° C.
Is preferred.

The compound represented by the formula (II) has the formula (I)
It can be easily obtained by enolizing the compound represented by V) and then trapping with an alkyl halide. Examples of the base used for enolization include lithium diisopropylamide (LDA), lithium bis (trimethylsilyl) amide and the like. Examples of the alkyl halide include methyl chloride, methyl bromide, methyl iodide, allyl chloride, allyl bromide, allyl iodide,
Benzyl chloride, benzyl bromide, benzyl iodide, vinyl chloride, vinyl bromide, vinyl iodide and the like can be mentioned. An ether solvent such as tetrahydrofuran can be used as the reaction solvent. The reaction temperature is suitably from -78 ° C to room temperature, particularly preferably from -20 ° C to 0 ° C.

By the above operation, optically active 3-substituted-2
It is possible to produce norbornanone; The names of typical optically active 3-substituted-2-norbornanones obtained as described above are shown below. (+)-3-
Methyl-2-norbornanone, (+)-3-ethyl-2
-Norbornanone, (+)-3-allyl-2-norbornanone, (+)-3-vinyl-2-norbornanone,
(+)-3-benzyl-2-norbornanone, (+)-
3-phenyl-2-norbornanone,
(-)-3-methyl-2-norbornanone, (-)-3-ethyl-2-norbornanone, (-)-3-allyl-2-norbornanone, (-)
-3-vinyl-2-norbornanone, (-)-3-benzyl-2-norbornanone, (-)-3-phenyl-2
-Norbornanone and the like.

[0023]

The production method of the present invention provides an easily available asymmetric source,
It can be carried out using inexpensive raw materials and reagents, and it is possible to obtain a product with high optical purity in good yield by a simple operation. That is, the production method of the present invention is an excellent method for efficiently and in large quantities obtaining an optically active 3-substituted-2-norbornanone which is a useful compound having a very wide range of application as a synthetic intermediate of a physiologically active substance. Is the way.

[0024]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 Production of (−)-exo-3-allyl-2-norbornanone Step 1 46.8 g of (R)-(−)-pantoyllactone (36
0 mmol), 54.7 g of triethylamine (541 m
mol), 300 ml of methylene chloride, -25
41.2 g of acrylic acid chloride (455 mm
l) was added dropwise, and the mixture was stirred at −20 to −25 ° C. for 5 hours. Under ice-cooling, 500 ml of 0.5N hydrochloric acid was added to the reaction mixture to separate the organic layer, and the aqueous layer was methylene chloride (150 ml × 3).
Extracted. The organic layers were combined and washed sequentially with saturated aqueous sodium hydrogen carbonate, water, and saturated saline (250 ml each). After drying over anhydrous magnesium sulfate, the solvent was filtered and distilled off to obtain 64.5 g of a crude acrylic acid ester. Purification by silica gel column chromatography (hexane-ethyl acetate 3: 1) gave (R) -dihydro-3-acryloyloxy-
61.3 g of 4,4-dimethyl-2 (3H) -furanone
(333 mmol) was obtained. Yield 93%.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ 1.1 (s, 3H),
1.3 (s, 3H), 4.0 (s, 2H), 5.5
(S, 1H), 5.9-6.7 (m, 3H). Step 2 (R) -dihydro-3-acryloyloxy-4,4-
Dimethyl-2 (3H) -furanone 25.1 g (136 m
mol) was dissolved in 200 ml of a mixed solvent of methylene chloride-petroleum ether (7: 1), and 1.6 ml (14.6 mmol) of titanium tetrachloride (10 m
1) was added dropwise. After stirring at −10 to −15 ° C. for 30 minutes, 11.9 g of cyclopentadiene prepared at the time of use was prepared.
(180 mmol) was added dropwise and stirred at the same temperature for 3 hours. Sodium carbonate decahydrate 17.3 g (60.4 mm
ol) was added in small portions, and the temperature was gradually increased, followed by stirring at room temperature for 30 minutes. The insoluble material was removed by filtration, and the residue was washed with methylene chloride (100 ml × 3). The filtrate was combined with the washing solution and evaporated to obtain 34.0 g of a crude Diels-Alder adduct. Recrystallization from a mixed solvent (125 ml) of hexane-ethyl acetate (5: 3) gave 27.5 g (110 mmol) of a Diels-Alder adduct. Yield 81%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR δ: 1.0-2.2 (m, 4
H), 1.1 (s, 3H), 1.2 (s, 3H), 2.
8-3.3 (m, 3H), 4.0 (s, 2H), 5.3
(S, 1H), 5.8-6.0 (m, 1H), 6.2-
6.4 (m, 1H). Step 3 27.5 g of Diels-Alder adduct (110 mmo
l) in a tetrahydrofuran-water (5: 2) mixed solvent 42
0 ml, and potassium hydroxide (85%) 3
0.0 g (455 mmol) (dissolved in 120 ml of water) was added, and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the mixture was neutralized with 40 ml of concentrated hydrochloric acid and extracted with a mixed solvent of hexane-methylene chloride (98: 2) (150 ml × 4). After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to give crude 5-norbornene-2.
-15.7 g of carboxylic acid are obtained. Crude yield 100%.

This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.1-1.6 (m, 3H), 1.7-2.1 (m, 1H), 2.7-3.3
(m, 3H), 6.0 (dd, 1H), 6.2 (dd, 1H), 11.4 (brs, 1H). Step 4 15.7 g of crude 5-norbornene-2-carboxylic acid (110 mm
ol) was dissolved in 300 ml of ethanol, 1.55 g of 5% palladium-carbon powder was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. After the catalyst was removed by filtration, the solvent was distilled off, and the crude 2-
14.5 g of norbornanecarboxylic acid were obtained. Crude yield 94%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.1-1.9 (m, 8
H), 2.2-2.4 (m, 1H), 2.5-3.0
(M, 2H), 11.0 (brs, 1H). Step 5 24.1 g (367 mmol) of potassium hydroxide (85%)
l), 18.9 g (120 mmol) of potassium permanganate
1) was dissolved in 84 ml of water, and 84 ml of a petroleum ether solution of 8.36 g (59.6 mmol) of crude 2-norbornanecarboxylic acid was added dropwise under ice cooling. After heating under reflux for 6 hours, the mixture was stirred at room temperature for 18 hours. Under ice-cooling, the reaction mixture was slowly added to 120 ml of 6N sulfuric acid to make it acidic, and then 60 ml of an aqueous solution of 13.0 g of sodium hydrogen sulfite.
Was added and stirred at room temperature for 1 hour. Ether (100ml
× 4), and the extract was dried over anhydrous magnesium sulfate. The solvent was filtered off and evaporated to give crude 2-hydroxy-
8.34 g of 2-norbornanecarboxylic acid were obtained. Crude yield 90%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. 1H-NMR: δ1.0-2.3 (m, 10
H), 7.4 (brs, 2H). Step 6 8.25 g (52.8 mmol) of crude 2-hydroxy-2-norbornanecarboxylic acid, 19.5 g (55.7 mmol) of sodium bismuthate (80%) were added to water 8
Dissolved in 5 ml, phosphoric acid (85%) 18.0 g (156
mmol) is added dropwise at 45-50 ° C. for 8 hours and at room temperature for 1 hour.
Stir for 8 hours. The mixture was extracted with ether (100 ml × 4), and the extract was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline (100 m each).
After sequentially washing in 1), the resultant was dried over anhydrous magnesium sulfate. After ether was distilled off under normal pressure, distillation was carried out to give (−)-2-
3.09 g (28.1 mmol) of norbornanone were obtained. Yield 53%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.2-2.3 (m, 8
H), 2.5-2.9 (m, 2H). The physical properties were as follows. Boiling point: 174 ° C. Specific rotation: −28.5 ° (cl. 55, CHCl ₃ ) Step 7 Tetrahydrofuran of lithium diisopropylamide
To 3.4 ml (6.8 mmol) of a 2M hexane solution,
At 40 ° C., 500 mg of (−)-2-norbornanone
(4.54 mmol) in 1 ml of tetrahydrofuran solution
Was added dropwise, followed by stirring at −20 ° C. for 10 minutes. Subsequently, 1 ml of a tetrahydrofuran solution of 540 mg (4.46 mmol) of allyl bromide was added dropwise, and the mixture was stirred at −20 ° C. for 30 minutes, heated to room temperature, and further stirred for 1 hour. Under ice cooling, the reaction mixture was poured into 20 ml of 1N hydrochloric acid, and toluene (50 ml) was added.
ml × 4). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline (50 ml each), and dried over anhydrous magnesium sulfate. The solvent was filtered off and distilled off to obtain 980 mg of crude 3-allyl-2-norbornanone. Purification by distillation yielded 550 mg (3.66 mmol) of (-)-exo-3-allyl-2-norbornanone. Yield 8
1%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.2-2.8 (m, 11
H), 4.9-5.3 (m, 2H), 5.6-6.1.
(M, 1H). The physical properties were as follows. Boiling point: 70 to 73 ° C./3 mmHg Specific rotation: −89.1 ° (c 0.972, CHCl ₃ ) Example 2 Production of (+)-exo-3-allyl-2-norbornanone Step 1 (S)-( -)-N-methyl-2-hydroxysuccinimide 69.5 g (538 mmol), triethylamine 70.8 g (700 mmol), methylene chloride 400
ml of the mixture of acrylic acid chloride 6 at −25 ° C.
3.4 g (700 mmol) was added dropwise and -20 to -25
Stirred at 4.5 ° C. for 4.5 hours. Under ice-cooling, 170 ml of 1N hydrochloric acid was added to the reaction mixture to separate the organic layer, and the aqueous layer was extracted with methylene chloride (200 ml × 3). The organic layers were combined and washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine (150 ml each). After drying over anhydrous magnesium sulfate, the solvent was filtered off and distilled off to obtain 96.8 g of a crude acrylic acid ester.
Purified by silica gel column chromatography (ethyl acetate), 72.2 g of (S)-(-)-N-methyl-3-acryloyloxysuccinimide (394 mmol)
1) was obtained. 73% yield.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ 2.6-3.5 (m, 2
H), 3.0 (s, 3H), 5.5-5.7 (m, 1
H), 5.8-6.7 (m, 3H). Step 2 72.2 g (394 mmol) of (S)-(−)-N-methyl-3-acryloyloxysuccinimide was dissolved in 580 ml of a mixed solvent of methylene chloride and petroleum ether (7: 1), and the mixture was dissolved at -15 ° C. , 4.4 ml of titanium tetrachloride (4
0.1 mmol) (dissolved in 30 ml of petroleum ether) was added dropwise. After stirring at -10 to -15 ° C for 30 minutes, 32.4 g (490 mmo) of cyclopentadiene prepared at the time of use was prepared.
l) was added dropwise and stirred at the same temperature for 3.5 hours. After adding powder of 50.1 g (175 mmol) of sodium carbonate decahydrate in a small amount, the temperature was gradually increased, followed by stirring at room temperature for 1 hour. The insoluble material was removed by filtration, and the residue was filtered with methylene chloride (25%
0 ml × 3). The filtrate was combined with the washing solution and evaporated to obtain 99.6 g of a crude Diels-Alder adduct. Heptane-ethyl acetate (5: 3) mixed solvent (600
re-crystallized from Diels-Alder adduct 6
7.0 g (269 mmol) were obtained. Yield 68%.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR δ: 1.2-2.2 (m, 4
H), 2.4-3.4 (m, 5H), 3.0 (s, 3
H), 5.3-5.5 (m, 1H), 5.8-6.0.
(M, 1H), 6.1-6.3 (m, 1H). Step 3 Diels-Alder adduct 67.0 g (269 mmo
l) in a tetrahydrofuran-water (5: 2) mixed solvent 10
Dissolve in 40 ml and cool with ice, potassium hydroxide (85%)
70.5 g (1.08 mmol) (dissolved in 300 ml of water) was added, and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the mixture was neutralized with 94 ml of concentrated hydrochloric acid, and a mixed solvent of hexane-methylene chloride (98: 2) (200 ml ×
Extracted in 4). After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to obtain 38.8 g of crude 5-norbornene-2-carboxylic acid. Crude yield 100
%.

The compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.1-1.6 (m, 3H), 1.7-2.1 (m, 1H), 2.7-3.3
(m, 3H), 6.0 (dd, 1H), 6.2 (dd, 1H), 11.4 (brs, 1H). Step 4 38.8 g of crude 5-norbornene-2-carboxylic acid (269 mm
The ol), was dissolved in Solmix 740 ml, 5% palladium - Ca - adding carbon powder 1.92 g, under a hydrogen atmosphere at room temperature for 1
Stir for 7.5 hours. After filtering off the catalyst, the solvent was distilled off,
38.0 g of crude 2-norbornanecarboxylic acid were obtained. Crude yield 100%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.1-1.9 (m, 8
H), 2.2-2.4 (m, 1H), 2.5-3.0
(M, 2H), 11.0 (brs, 1H). Step 5 107 g of potassium hydroxide (85%) (1.63 mol)
l), 85.7 g (542 mmol) of potassium permanganate
l) was dissolved in 380 ml of water, and 380 ml of a petroleum ether solution of 37.9 g (271 mmol) of crude 2-norbornanecarboxylic acid was added dropwise under ice cooling. After heating under reflux for 8 hours, the mixture was stirred at room temperature for 18 hours. Under ice-cooling, the reaction mixture was slowly added to 544 ml of 6N sulfuric acid to make it acidic, and then 272 m of an aqueous solution of 62.2 g of sodium bisulfite was added.
was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (200
The extract was dried over anhydrous magnesium sulfate. The solvent was filtered and distilled off to obtain 38.5 g of crude 2-hydroxy-2-norbornanecarboxylic acid. Crude yield 92%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.0-2.3 (m, 10
H), 7.4 (brs, 2H). Step 6 Crude 2-hydroxy-2-norbornanecarboxylic acid 3
8.5 g (247 mmol) and 90.6 g (259 mmol) of sodium bismuthate (80%) in 400 m of water
of phosphoric acid (85%) (728 mm
ol) was added dropwise at 45 ° C to 50 ° C for 6 hours and at room temperature for 18 hours.
Stirred for hours. The mixture was extracted with ethyl acetate (200 ml × 4).
After sequentially washing in 1), the resultant was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under normal pressure, and then distilled to obtain (+)-
14.8 g (134 mmol) of 2-norbornanone was obtained. Yield 50%.

The compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.2-2.3 (m, 8
H), 2.5-2.9 (m, 2H). The physical properties were as follows. Boiling point: 174 ° C. Specific rotation: + 29.0 ° (cl. 51, CHCl ₃ ) Step 7 Tetrahydrofuran of lithium diisopropylamide
To 194 ml (388 mmol) of a 2M solution of hexane,
At + 40 ° C., 38.9 g of (+)-2-norbornanone (3
50 mmol of a tetrahydrofuran solution (53 mmol) was added dropwise, and the mixture was stirred at −20 ° C. for 10 minutes. Subsequently, 30 ml of a tetrahydrofuran solution of 47.0 g (388 mmol) of allyl bromide was added dropwise, and the mixture was stirred at −20 ° C. for 30 minutes.
The temperature was raised to room temperature, and the mixture was further stirred for 1 hour. Under ice-cooling, the reaction mixture was poured into 300 ml of 2N hydrochloric acid, and toluene (200 ml) was added.
ml × 4). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline (200 ml each), and then dried over anhydrous magnesium sulfate. The solvent was filtered off and evaporated to give crude 3-
77.6 g of allyl-2-norbornanone was obtained. Purification by distillation gave 42.5 g (134 mmol) of (+)-exo-3-allyl-2-norbornanone. Yield 8
0%.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.2-2.8 (m, 11
H), 4.9-5.3 (m, 2H), 5.6-6.1.
(M, 1H). The physical properties were as follows. Boiling point: 71-72.5 ° C./3 mmHg Specific rotation: + 87.3 ° (cl.08, CHCl ₃ ).

Example 3 Production of (+)-5-norbornene-2-carboxylic acid Step 1 (S) -A mixture of 59.0 g (499 mmol) of ethyl lactate, 55.7 g (550 mmol) of triethylamine and 200 ml of dichloroethane was added with- At 20 ° C., 49.8 g (550 mmol) of acrylic acid chloride (dissolved in 100 ml of dichloroethane) was added dropwise, and the mixture was stirred at −20 ° C. for 4.5 hours. Under ice cooling, 1N hydrochloric acid was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and washed sequentially with saturated aqueous sodium hydrogen carbonate and water. After drying over anhydrous magnesium sulfate, the solvent was filtered and evaporated, and crude (S) -ethyl 2-acryloyloxypropionic acid 7
5.0 g were obtained.

Step 2 67.5 g (392 mmol) of crude (S) -ethyl 2-acryloyloxypropionic acid was added to methylene chloride 15
0 ml, and titanium tetrachloride 5.0 ml at −20 ° C.
(45.6 mmol) (dissolved in 30 ml of hexane) was added dropwise. After stirring at −10 ° C. for 30 minutes, 31.1 g (470 mmol) of cyclopentadiene prepared for use (dissolved in 50 ml of methylene chloride) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. 20.0 g of sodium carbonate decahydrate (69.
After 9 mmol) of powder was added in small portions, the temperature was gradually raised and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, and the residue was washed with methylene chloride. The filtrate was combined with the washing solution and washed sequentially with saturated aqueous sodium hydrogen carbonate and water. After drying over anhydrous magnesium sulfate, the solvent was filtered off and distilled off to obtain 95.0 g of a crude Diels-Alder adduct quantitatively.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.2-1.5 (m, 10
H), 2.6-3.1 (m, 3H), 4.3 (q, 2
H), 5.1 (q, 1H), 6.0-6.2 (m, 2
H). Step 3 95.0 g of Diels-Alder adduct (392 mmo)
l) was dissolved in 950 ml of tetrahydrofuran, and 103 g (1.57 mol) of potassium hydroxide (85%) was added under ice-cooling.
1) (dissolved in 760 ml of water) was added and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, concentrated hydrochloric acid 13
Neutralized with 8 ml, hexane-methylene chloride (98: 2)
The mixture was extracted with a mixed solvent (200 ml × 4). After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to obtain 45.0 g of crude 5-norbornene-2-carboxylic acid.
I got 83% crude yield.

This compound was identified by ¹ H-NMR chart analysis. The data of ¹ H-NMR (CDCl ₃ ) is shown below. ¹ H-NMR: δ1.1-1.6 (m, 3
H), 1.7-2.1 (m, 1H), 2.7-3.3.
(M, 3H), 6.0 (dd, 1H), 6.2 (dd,
1H), 11.4 (brs, 1H).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ identification code FI C07M 7:00 (58) Investigated field (Int.Cl. ⁷ , DB name) C07C 45/29 C07C 49/433 C07C 49/647 C07C 49/653 C07C 49/67 C07B 53/00 C07M 7:00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) General formula I Wherein R ² and R ³ each independently represent a C _{1 to} C ₆ alkyl group or phenyl group, n represents 0 or an integer of 1 to 3, and * represents an asymmetric carbon. ) Is reacted with cyclopentadiene in a solvent at −78 ° C. to room temperature in the presence of a Lewis acid to obtain a Diels-Alder adduct. (2) The Diels-Alder adduct is obtained. Hydrolysis under basic conditions in a solvent and at a temperature of 0 ° C. to 50 ° C. yields the compound of formula (VI) (Wherein, M represents hydrogen or a metal selected from lithium, sodium or potassium). (3) The compound represented by the formula (VI) is dissolved in a solvent in the presence of a hydrogenation catalyst. Catalytic hydrogenation at a temperature of 50 ° C to 50 ° C, the formula (I
II) (Wherein M represents hydrogen or a metal selected from lithium, sodium or potassium). (4) The compound represented by the formula (III) is treated with potassium permanganate at 0 ° C. Oxidation at a temperature of 100 ° C. gives formula (VII) (5) The compound represented by the formula (VII) is subjected to an oxidative decarboxylation reaction using sodium bismuthate-phosphoric acid in a solvent at room temperature to 60 ° C. to obtain a compound represented by the formula (IV) ) (6) The compound represented by formula (IV) is treated with a base to form an enol, and the enol compound thus obtained is -78 in a solvent.
Reacting with a halogenated hydrocarbon selected from alkyl halides, alkenyl halides, or aralkyl halides at a temperature of from 0 ° C. to room temperature; (Wherein, R ⁴ is an alkyl group, an alkenyl Motoma other represents an aralkyl group.) Process for producing an optically active 3-substituted-2-norbornanone represented by. 2. A compound of the formula (VII) Wherein the compound of formula (IV) is subjected to an oxidative decarboxylation reaction in a solvent at a temperature of 0 ° C. to 60 ° C. using sodium bismuthate-phosphoric acid. A method for producing optically active 2-norbornanone represented by the formula: