JP3118939B2 - Method for producing optically active 2-hydroxy-2-norbornanecarboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active (+)-and (-)-useful as synthetic intermediates of various physiologically active substances.
The present invention relates to a method for producing 2-hydroxy-2-norbornanecarboxylic acid .

[0002]

2. Description of the Related Art In recent years, the importance of synthesizing a physiologically active substance as an optically active substance has been increasing. When a substance has multiple optical isomers, the activity is often different between the isomers, but one isomer usually shows strong activity, and the other isomers are active. Are known to be weak or often exhibit undesirable toxicity. Therefore, in the case of synthesizing a physiologically active substance, particularly as a pharmaceutical, it is strongly desired to selectively synthesize a desired optical isomer not only in order to exhibit sufficient physiological activity but also in view of safety.

The optically active 2-hydroxy- according to the present invention
2-norbornanecarboxylic acid is a novel compound synthesized for the first time by the present inventors. This novel compound is a very useful compound as a synthetic intermediate for various physiologically active substances. For example, (+) - 2-hydroxy-2-norbornane carboxylic acid (+) - by inducing a 2-norbornane, useful thromboxane _{A 2} receptor antagonists as anticoagulant (Narisada
J. et al. Med. Chem. , 31 , 1847 (198
8), Hamanaka et al., Tetrahedron
Lett. , 30 , 2399 (1989) ) can be synthesized. However, in the past, examples of racemic synthesis (Wilt et al., J. Am. Chem. So
c. , 90 , 6135 (1968)), but an industrially efficient and efficient optically active synthetic method was not known.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a novel optically active 2-hydroxy-2-norbornanecarboxylic acid discovered in the course of research for efficiently mass-producing this optically active substance, and a method for producing the same. To provide.

[0005]

The present invention provides the following formula (I):

[0006]

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An optically active (+)-2-hydroxy-2-norbornanecarboxylic acid represented by the following formula (I ′):

[0008]

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An optically active (-)-2-hydroxy-2-norbornanecarboxylic acid represented by the formula: Next, a method for producing the compound of the present invention will be described. The optically active (+)-2-hydroxy-2-norbornanecarboxylic acid (I) of the present invention can be produced according to the following reaction steps.

[0010]

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[0011]

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(R ¹ and R ^{2 each} represent an alkyl group, an aralkyl group, an aryl group, or a cycloalkyl group). M represents hydrogen or a metal atom such as lithium, sodium, and potassium. ]. The compound represented by (II), which is a starting material of the present invention, includes (S) -lactic acid ester and (S)-(+)-
By reacting pantoyl lactone or (S)-(-)-N-methyl-2-hydroxysuccinimide with acrylic acid chloride, it can be obtained with high optical purity (Poll et al., Tetrahedron Lett., 25 , 2191 (198
4); 30 , 5595 (1989)).

The compound represented by the formula (III) can be synthesized by subjecting the compound represented by the formula (II) 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, a halogen-based solvent such as methylene chloride, 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 (III) can be easily converted to the compound of the formula (IV) by hydrolysis under basic conditions. Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide,
Potassium hydroxide and the like. As the reaction solvent, an ether-based solvent such as tetrahydrofuran or a mixed solvent thereof with an alcohol-based solvent such as methanol, ethanol or solmix can be used. The reaction temperature is suitably from 0 to 50 ° C, particularly preferably around 20 to 30 ° C.

The compound represented by the formula (V) can be easily obtained by catalytic hydrogenation of the compound represented by the formula (IV). Examples of the catalyst used for the reaction include palladium-carbon and the like. Water, as a reaction solvent,
Alcohol solvents such as methanol, ethanol, and solmix, or a mixed solvent thereof can be used. The reaction temperature is suitably 0 to 50 ° C, preferably room temperature.

The compound represented by the formula (I) can be obtained by oxidizing the compound represented by the formula (V). Examples of the oxidizing agent used for the reaction include potassium permanganate. As a reaction solvent, water or a two-phase system of water and a hydrocarbon solvent such as pentane, hexane, heptane, petroleum ether and the like can be used. The reaction temperature is suitably from 0 to 100 ° C, particularly preferably from room temperature to 70 ° C.

By the above operation, optical activity (+)-2-
Hydroxy-2-norbornanecarboxylic acid (I) can be produced. Similarly, by using the compound represented by the formula (II ') as a starting material, the optical activity (-)-
2-hydroxy-2-norbornanecarboxylic acid (I ') can be produced.

[0018]

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(R ¹ and R ² represent an alkyl group, an aralkyl group, an aryl group or a cycloalkyl group). ].

[0020]

The compound of the present invention represented by the formula (I) or (I ') is a novel compound synthesized for the first time by the present inventors and can be used as an intermediate for synthesizing various physiologically active substances. For example, compound (I) can be induced to optically active (+)-2-norbornanone (VI) as follows. That is, the compound represented by the formula (VI) can be obtained by oxidizing the compound (I) using an oxidizing agent such as sodium bismuthate-phosphoric acid, lead tetraacetate, and chromic acid-sulfuric acid.

The compound represented by the formula (VI) is enolized with a base such as lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide and then trapped with an allyl halide to give a compound represented by the formula (VII). It can be easily converted to the represented compound. Through the further several steps from the compound (VII), useful thromboxane A ₂ receptor antagonists as anticoagulant (VIII), (I
X) can be obtained.

[0022]

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[0023]

EXAMPLES The present invention will be described in more detail with reference to the following Examples and Reference Examples, but the present invention is not limited by these Examples. Example 1 Production of (+)-2-hydroxy-2-norbornanecarboxylic acid Step 1 (S)-(-)-N-methyl-2-hydroxysuccinimide 69.5 g (538 mmol), triethylamine 70.8 g (700 m
mol) and 400 ml of methylene chloride at −25 ° C., 63.4 g (700 mmol) of acrylic acid chloride was added dropwise at −25 to −25.
The mixture was stirred at ℃ for 4.5 hours. Under ice cooling, add 1N hydrochloric acid to the reaction mixture.
The organic layer was separated by adding 170 ml, and the aqueous layer was diluted with methylene chloride (2.
00 ml × 3). The combined organic layers are combined with saturated aqueous sodium bicarbonate,
Washed sequentially with water and saturated saline (150 ml each). After drying over anhydrous magnesium sulfate, the solvent was filtered 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 (394 mmol) of (S)-(-)-N-methyl-2-propenoyloxysuccinimide was obtained. 73% yield. This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (C
The data of DCl ₃ ) are shown below. ¹ H-NMR: δ 2.6-3.5 (m, 2H), 3.0 (s, 3H), 5.5-5.7 (m,
1H), 5.8-6.7 (m, 3H).

Step 2 72.2 g (394 mmol) of (S)-(-)-N-methyl-2-propenoyloxysuccinimide was dissolved in 580 ml of a mixed solvent of methylene chloride-petroleum ether (7: 1). 15 ℃
At 4.4 ml (40.1 mmol) of titanium tetrachloride (30 ml of petroleum ether)
) Was added dropwise. After stirring at -10 to -15 ° C for 30 minutes, 32.4 g (490 mmol) of cyclopentadiene prepared at the time of use was prepared.
Was added dropwise and stirred at the same temperature for 3.5 hours. sodium carbonate
After powder of 50.1 g (175 mmol) of decahydrate was added in small portions, the temperature was gradually increased, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the residue was washed with methylene chloride (250 ml × 3).
The filtrate was combined with the washing solution and evaporated to obtain 99.6 g of a crude Diels-Alder adduct. Recrystallization from a heptane-ethyl acetate (5: 3) mixed solvent (600 ml) gave 67.0 g (269 mmol) of a Diels-Alder adduct. 68% yield.
This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR
(CDCl ₃ ) data is shown below. ¹ H-NMR δ: 1.2-2.2 (m, 4H), 2.4-3.4 (m, 5H), 3.0 (s,
3H), 5.3-5.5 (m, 1H), 5.8-6.0 (m, 1H), 6.1-6.3 (m, 1
H).

Step 3 67.0 g (269 mmol) of the Diels-Alder adduct was dissolved in 1040 ml of a mixed solvent of tetrahydrofuran-water (5: 2).
Under ice cooling, potassium hydroxide (85%) 70.5 g (1.08 mol) (water 3
(Dissolved in 00 ml) and 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 × 4).
Extracted. After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to give crude 5-norbornene-
38.8 g of 2-carboxylic acid were obtained. Crude yield 100%. This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ )
Are 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 (269 mm) of crude 5-norbornene-2-carboxylic acid
ol) was dissolved in 740 ml of Solmix, and 1.92 g of 5% palladium-carbon powder was added, followed by stirring under a hydrogen atmosphere for 17.5 hours. After removing the catalyst by filtration, the solvent was distilled off to obtain 38.0 g of crude 2-norbornanecarboxylic acid. Crude yield 100
%. This compound was identified by ¹ H-NMR chart analysis. ¹ H
-NMR (CDCl ₃ ) data are shown below. ¹ H-NMR: δ 1.1-1.9 (m, 8H), 2.2-2.4 (m, 1H), 2.5-3.0
(m, 2H), 11.0 (brs, 1H).

Step 5 107 g (1.63 mmol) of potassium hydroxide (85%) and 85.7 g (542 mmol) of potassium permanganate are dissolved in 380 ml of water, and 37.9 g (271 mmo) of crude 2-norbornanecarboxylic acid is cooled under ice-cooling.
380 ml of a petroleum ether solution of l) were added dropwise. 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 thereto was added 272 ml of an aqueous solution of 62.2 g of sodium bisulfite, followed by stirring at room temperature for 1 hour. The mixture was extracted with ethyl acetate (200 ml × 4), and the extract was dried over anhydrous magnesium sulfate. The solvent was filtered off and evaporated to give crude (+)-2-hydroxy-2.
38.5 g of norbornanecarboxylic acid were obtained. Crude yield 92%.

The compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.0-2.3 (m, 10H), 7.4 (brs, 2H). The steric configuration of the present compound is determined by comparing the sign of the optical rotation of 2-norbornanone obtained in Reference Example 1 with a literature value (Narisada et al., J. M.
ed. Chem., 31 , 1847 (1988)).

Example 2 Production of 5-norbornene-2-carboxylic acid Step 1 A mixture of 59.0 g (499 mmol) of (S) -ethyl lactate, 55.7 g (550 mmol) of triethylamine, and 200 ml of dichloroethane was added to acrylic acid at -20 ° C. 49.8 g (550 mmol) of 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 off and evaporated to obtain 75.0 g of crude (S) -ethyl 2-propenoyloxypropionate.

Step 2 67.5 g (382 mmol) of crude (S) -ethyl 2-propenoyloxypropionate were added to 150 ml of methylene chloride.
And 5.0 ml (45.6 mmol) of titanium tetrachloride (dissolved in 30 ml of hexane) was added dropwise at -20 ° C. After stirring at −10 ° C. for 30 minutes, 31.1 g (470 mmo) of cyclopentadiene prepared at the time of use was prepared.
l) (dissolved in 50 ml of methylene chloride) was added dropwise and stirred at the same temperature for 2 hours. After adding powder of 20.0 g (69.9 mmol) of sodium carbonate decahydrate in a small amount, the temperature was gradually increased, and the temperature was increased to 1 at room temperature.
Stirred 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 removed by filtration and the crude Diels-Alder adduct 9
5.0 g were obtained quantitatively. This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR δ: 1.2-1.5 (m, 10H), 2.6-3.1 (m, 3H), 4.3 (q,
2H), 5.1 (q, 1H), 6.0-6.2 (m, 2H).

Step 3 95.0 g (392 mmol) of the Diels-Alder adduct was dissolved in 950 ml of tetrahydrofuran, and 103 g (1.57 mol) of potassium hydroxide (85%) (1.57 mol) (dissolved in 760 ml of water) was added under ice-cooling. Stirred for hours. After distilling off tetrahydrofuran,
Neutralized with 138 ml of concentrated hydrochloric acid, 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 evaporated to obtain 45.0 g of crude 5-norbornene-2-carboxylic acid. 83% crude yield.

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). The crude 5-norbornene-2-carboxylic acid thus obtained can be used in place of the crude 5-norbornene-2-carboxylic acid used in Step 4 of Example 1,
Through the same steps 4 and 5, crude (+)-2-hydroxy-2-norbornanecarboxylic acid can be obtained.

Example 3 Production of (+)-2-hydroxy-2-norbornanecarboxylic acid Step 1 5.00 g (20.0 mmol) of the Diels-Alder adduct obtained from Step 2 of Example 1 was added to tetrahydrofuran-water (5:
4) Suspend in 45 ml of a mixed solvent and add sodium hydroxide under ice-cooling.
(93%) 1.85 g (43.0 mmol) was added and the mixture was stirred at room temperature for 24 hours. After distilling off tetrahydrofuran, the mixture was neutralized with concentrated hydrochloric acid. Subsequently, 280 mg of 5% palladium-carbon powder was added, and the mixture was stirred under a hydrogen atmosphere for 30 hours. After removing the catalyst by filtration and acidifying with concentrated hydrochloric acid, hexane-methylene chloride (98:
2) The mixture was extracted with a mixed solvent (50 ml × 4). After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to obtain 2.66 g of crude 2-norbornanecarboxylic acid. 95% crude yield. This compound was identified by ¹ H-NMR chart analysis.

Step 2 1.83 g (13.1 mmol) of crude 2-norbornanecarboxylic acid was dissolved in 10 ml of water, and 0.87 g of potassium hydroxide (85%) was added under ice-cooling.
g (13.1 mmol) was added and stirred for 6 hours. This reaction solution was added dropwise to a mixture of 5.22 g (79.5 mmol) of potassium hydroxide (85%), 4.57 g (28.9 mmol) of potassium permanganate, 10 ml of water and 20 ml of hexane. After heating and stirring at 40 to 50 ° C for 8 hours, the mixture was stirred at room temperature for 18 hours. Post-treatment was carried out in the same manner as in Step 5 of Example 1 to obtain 1.74 g of crude (+)-2-hydroxy-2-norbornanecarboxylic acid. 85% crude yield. This compound was identified by ¹ H-NMR chart analysis.

Example 4 Preparation of (+)-2-hydroxy-2-norbornanecarboxylic acid Step 1 5.00 g (20.0 mmol) of the Diels-Alder adduct obtained from Step 2 of Example 1 was added to tetrahydrofuran-methanol (1: 2). 1) Suspended in 40 ml of a mixed solvent, 1.86 g (43.3 mmol) of sodium hydroxide (93%) (dissolved in 4 ml of water) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Then 5% palladium-
280 mg of carbon powder was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The catalyst was removed by filtration, the solvent was distilled off, and the mixture was diluted with water. After acidification with concentrated hydrochloric acid, the mixture was extracted with a mixed solvent of hexane-methylene chloride (98: 2) (50 ml × 4). After the extract was dried over anhydrous magnesium sulfate, the solvent was filtered and distilled off to obtain 2.67 g of crude 2-norbornanecarboxylic acid. 95% crude yield. This compound was identified by ¹ H-NMR chart analysis.

Step 2 Crude 2-norbornanecarboxylic acid (9.59 g, 68.4 mmol) was dissolved in water (50 ml), and potassium hydroxide (85%) 4.55 was added under ice-cooling.
g (68.9 mmol) was added and stirred for 6 hours. This reaction solution was added dropwise to a mixture of 30.0 g (456 mmol) of potassium hydroxide (85%), 23.4 g (148 mmol) of potassium permanganate, and 50 ml of water. After heating and stirring at 40 to 50 ° C for 9 hours, the mixture was stirred at room temperature for 18 hours. Post-treatment was conducted in the same manner as in Step 5 of Example 1 to obtain 9.51 g of crude (+)-2-hydroxy-2-norbornanecarboxylic acid. 89% crude yield. This compound was identified by ¹ H-NMR chart analysis.

Reference Example 1 Production of (+)-2-norbornanone 38.5 g of crude (+)-2-hydroxy-2-norbornanecarboxylic acid obtained from step 5 of Example 1 (247 mmo)
l), sodium bismuthate (80%) 90.6g (259mmol)
Is dissolved in 400 ml of water, and 83.9 g of phosphoric acid (85%) (728 mmo)
l) was added dropwise, and the mixture was stirred at 45 to 50 ° C for 6 hours and at room temperature for 18 hours. The mixture was extracted with ethyl acetate (200 ml × 4), and the extract was washed successively with saturated aqueous sodium hydrogen carbonate, water, and saturated saline (200 ml each), and dried over anhydrous magnesium sulfate. After the ethyl acetate was distilled off under normal pressure, the residue was distilled to obtain (+)-2-norbornanone (14.8).
g (134 mmol) were obtained. Yield 50%.

This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.2-2.3 (m, 8H), 2.5-2.9 (m, 2H) The physical properties were as follows. Boiling point: 174 ° C Specific rotation: [α] _D + 29.0 ° (cl.51, CHCl ₃ ) Literature; [α] _D ²⁴ + 28.5 ± 0.5 ° (cl.5, CHCl ₃ ) (J. Med Chem., 31 , 1847 (1988)).

Example 5 Preparation of (-)-2-hydroxy-2-norbornanecarboxylic acid Step 1 46.8 g (360 mmol) of (R)-(-)-pantoyl lactone,
54.7 g (541 mmol) of triethylamine, methylene chloride 300
To a mixture of ml, at −25 ° C., 41.2 g of acrylic acid chloride
(455 mmol) 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 extracted with methylene chloride (150 ml × 3).
The combined organic layers are combined with saturated aqueous sodium bicarbonate, water, and saturated saline (250 m each)
Washing was performed sequentially in l). After drying over anhydrous magnesium sulfate,
The solvent was filtered and evaporated, and the crude acrylic ester 64.5 g
I got Purification by silica gel column chromatography (hexane-ethyl acetate 3: 1), (R) -dihydro-3-propenoyloxy-4,4-dimethyl-2 (3H)
61.3 g (333 mmol) of furanone were obtained. 93% yield. This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDC
l The data of 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 25.1 g (136 mmol) of (R) -dihydro-3-propenoyloxy-4,4-dimethyl-2 (3H) -furanone was dissolved in 200 ml of a mixed solvent of methylene chloride and petroleum ether (7: 1). Then, 1.6 ml (14.6 mmol) of titanium tetrachloride (dissolved in 10 ml of petroleum ether) was added dropwise at -15 ° C. After stirring at -10 to -15 ° C for 30 minutes, 11.9 g of cyclopentadiene prepared before use
(180 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. After powder of 17.3 g (60.4 mmol) of sodium carbonate decahydrate was added in small portions, the temperature was gradually increased and the mixture was stirred 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 hexane-ethyl acetate (5: 3) mixed solvent (125 ml) gave 27.5 g (110 mmol) of a Diels-Alder adduct. Yield 81%.
This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR
(CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.0-2.2 (m, 4H), 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 (110 mmol) of the Diels-Alder adduct was dissolved in 420 ml of a mixed solvent of tetrahydrofuran-water (5: 2).
Under ice cooling, potassium hydroxide (85%) 30.0 g (455 mmol) (water 12
(Dissolved in 0 ml) and 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 were obtained. 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 15.7 g of crude 5-norbornene-2-carboxylic acid (110 m
mol) 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 for 24 hours. After filtering off the catalyst, the solvent was distilled off to obtain 14.5 g of crude 2-norbornanecarboxylic acid. Crude yield 94%. This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDC
l The data of ₃ ) is shown below. ¹ H-NMR: δ 1.1-1.9 (m, 8H), 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%) and 18.9 g (120 mmol) of potassium permanganate are dissolved in 84 ml of water, and 8.36 g (59.6 mmol) of crude 2-norbornanecarboxylic acid is cooled under ice-cooling.
84 ml of petroleum ether solution of l) were added dropwise. 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, followed by stirring at room temperature for 1 hour. The mixture was extracted with ether (100 ml × 4), and the extract was dried over anhydrous magnesium sulfate. Filter the solvent,
Evaporation gave 8.34 g of crude (-)-2-hydroxy-2-norbornanecarboxylic acid. 90% crude yield.

This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.0-2.3 (m, 10H), 7.4 (brs, 2H) The configuration of this compound was obtained by (−)-in Reference Example 2.
The sign of the optical rotation of 2-norbornanone is shown in the literature (Narisada
J. Med. Chem., 31 , 1847 (1988)).

Reference Example 2 Production of (-)-2-norbornanone 8.25 g (52.8 mmol) of the crude (-)-2-hydroxy-2-norbornanecarboxylic acid obtained in Step 5 of Example 4.
Then, 19.5 g (55.7 mmol) of sodium bismuthate (80%) was dissolved in 85 ml of water, 18.0 g (156 mmol) of phosphoric acid (85%) was added dropwise, and the mixture was stirred at 45 to 50 ° C for 8 hours and at room temperature for 18 hours. did. Extract with ether (100 ml x 4), extract the extract with saturated aqueous sodium bicarbonate,
After washing with water and saturated saline solution (100 ml each), the mixture was dried over anhydrous magnesium sulfate. After ether was distilled off under normal pressure,
After distillation, 3.09 g (28.1 mmol) of (−)-2-norbornanone
I got Yield 53%.

This compound was identified by ¹ H-NMR chart analysis. ¹ H-NMR (CDCl ₃ ) data is shown below. ¹ H-NMR: δ 1.2-2.3 (m, 8H), 2.5-2.9 (m, 2H) The physical properties were as follows. Boiling point: 174 ° C Specific rotation: [α] _D −28.5 ° (cl.55, CHCl ₃ ) Literature; [α] _D ²⁴ −28.6 ± 0.3 ° (c2.2, CHCl ₃ ) (J. Med. Chem.) ., 31 , 1847 (1988)).

────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference US Pat. No. 3,931,984 (US, A) US Pat. 26, No. 7, pages 811-814 "Tetrahedron Lett." (1981), Vol. 22, No. 34, pages 3231-3234 "Org. Prep. Proced. Int." (1980), Vol. 12, No. 6, pages 357-360 "CHEMISTRY LETTER S" (1978), no. 1, pages 49-50 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 62/06 B01J 23/44 B01J 27/10 C07C 51/367 C07B 61/00 300 CA (STN) REGISTRY (STN )

Claims (2)

(57) [Claims] 1. A formula (II) ## STR1 ## (Wherein R ¹ and R ² represent an alkyl group, an aralkyl group, an aryl group, and a cycloalkyl group ) in a Diels-Alder reaction with cyclopentadiene in the presence of a Lewis acid catalyst, followed by hydrolysis, After catalytic hydrogenation,
Expression comprises the step of (I) oxide ## STR2 ## A method for producing an optically active (+)-2-hydroxy-2-norbornanecarboxylic acid represented by the formula: Wherein formula (II ') embedded image (Wherein R ¹ and R ² represent an alkyl group, an aralkyl group, an aryl group, and a cycloalkyl group ) in a Diels-Alder reaction with cyclopentadiene in the presence of a Lewis acid catalyst, followed by hydrolysis, After catalytic hydrogenation,
Expression comprising the step of oxidizing (I ') embedded image A method for producing an optically active (-)-2-hydroxy-2-norbornanecarboxylic acid represented by the formula: