JPH0769960A - Production of optically active norbornanone - Google Patents

Abstract

PURPOSE:To produce the subject compound industrically and simply by reacting a readily obtainable optically active dioxolan-4-one derivative with cyclopentadiene, then hydrolyzing, catalytically hydrogenating and finally decarboxylating oxidatively. CONSTITUTION:An optically active dioxolan-4-one derivative of formula 2 (R is an alkyl or an aryl; * is asymmetric carbon atom) is subjected to Diels-Alder reaction with cyclopentadiene to give a compound od formula 3a or 3b. Then the compound is hydrolyzed to give the optically active 2-hydroxynorbornene-2- carboxylic acid of formula 4a or 4b. Then the carboxylic acid is catalytically hydrogenated to give the compound of formula 5a or 5b. Finally, the compound is oxidatively decarboxylated to give the compound of formula Ia or 1b. Among these reactions, the reaction in which the readily obtainable optically active dioxolan-4-one derivative of formula 2 is subjected to Diels-Alder reaction with cyclopentadiene and the prepared reactional product is hydrolyzed to give the compound of formula 4a or formula 4b is utilized as the key reaction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing optically active 2-norbornanone useful as a raw material for synthesizing various optically active substances. The present invention also relates to a method for producing optically active 2-hydroxynorbornene-2-carboxylic acid, which is a synthetic intermediate for optically active 2-norbornanone.

[0002]

A thromboxane A2 receptor antagonist useful as a blood coagulant is an optically active 3-allyl-2.
-It has been reported that it can be synthesized from norbornanone (Narisada et al., J. Med. Ch.
em. , 31 , 1847 (1988).

Here, the optically active 3-allyl-2-norbornanone is usually produced by allylating the α-position of the carbonyl group of the optically active 2-norbornanone. Therefore, a thromboxane A2 receptor antagonist is obtained. Upon production, it is necessary to obtain optically active 2-norbornanone.

Conventionally, the following three types of methods have been proposed as methods for producing optically active 2-norbornanone.

That is, the first method is endo or exo.
2-The racemic 2-norbornanol is reacted with phthalic acid to form a half ester of phthalic acid, which is optically resolved by the diastereomer method. The resolved product is hydrolyzed and further oxidized to give optically active 2-norbornanone. It is obtained (Winstein et al., JA)
m. Chem. Soc. , 74 , 1147 (195
2)).

The second method is to obtain optically active 2-norbornanone by asymmetric oxidation or asymmetric reduction of racemic exo-2-norbornanol or 2-norbornanone by horse liver alcohol dehydrogenase (Irwin). et al., J. Am. Che.
m. Soc. , 98 , 8476 (1976)).

The third method is a Diels-Alder reaction of an optically active acrylic acid ester and cyclopentadiene to obtain an optically active norbornene-2-carboxylic acid ester, and the obtained ester is hydrolyzed to obtain the obtained optical Catalytic hydrogenation reaction is performed on active norbornene-2-carboxylic acid to obtain optically active norbornane-2-carboxylic acid, which is further oxidized to convert to optically active 2-hydroxynorbornane-2-carboxylic acid, and finally An optically active 2-norbornanone is obtained by carrying out an oxidative decarboxylation reaction (JP-A-5-51345).

[0008]

However, in the case of the above-mentioned first method, the optical purity of the optically active 2-norbornanone obtained is not sufficient, and in order to improve the optical purity, recrystallization or the like is required. It is necessary to repeat the complicated purification procedure of. As a result, the yield of the optically active 2-norbornanone is lowered, and conversely, the production cost is increased, which is problematic for industrial implementation.

Further, in the case of the second method, the horse liver alcohol dehydrogenase used is very expensive and the asymmetric yield is not sufficient, so that there was a problem in industrial implementation.

In the case of the third method, the optically active norbornane-2-carboxylic acid is oxidized in order to obtain the optically active 2-hydroxynorbornane-2-carboxylic acid. In the oxidation reaction, a heavy metal salt is used. Since a certain potassium permanganate is used, there is a great possibility that it will have an adverse effect on the environment, and there was also a problem in industrial implementation.

The present invention is intended to solve the above-mentioned problems of the prior art, and is used as a raw material for synthesizing various physiologically active substances including a thromboxane A2 receptor antagonist useful as a blood coagulation agent. It is an object of the present invention to make it possible to industrially and easily produce useful optically active 2-norbornanone.

Another object of the present invention is to make it possible to industrially and conveniently produce optically active 2-hydroxynorbornene-2-carboxylic acid, which is a raw material for the synthesis of optically active 2-norbornanone.

[0013]

[Means for Solving the Problems] The present inventors have conducted a Diels-Alder reaction of an easily available optically active dioxolan-4-one derivative with cyclopentadiene, and hydrolyzing the obtained product. Optical activity 2-
The present invention has been completed by finding that hydroxynorbornene-2-carboxylic acid can be easily obtained and that the above-mentioned object of the present invention can be achieved by utilizing this reaction as a key reaction.

That is, the present invention is Scheme 1

[0015]

[Chemical 9] (In the compound in Scheme 1, R is a substituted or unsubstituted alkyl group such as methyl, ethyl, tert-butyl, cyclohexyl or benzyl, or a substituted or unsubstituted aryl group such as phenyl, toluyl, naphthyl or furanyl. , * Represents an asymmetric carbon), in the method for producing the optically active 2-norbornanone represented by the formula (1a) or (1b): Formula (2)
The optically active dioxolan-4-one derivative represented by the formula (3) is reacted with cyclopentadiene to obtain the compound represented by the formula (3a) or (3
Step a to form a compound represented by b); Formula (3a)
Or a step b in which the compound of (3b) is hydrolyzed to be converted into an optically active 2-hydroxynorbornene 2-carboxylic acid represented by the formula (4a) or (4b); contact with a compound of the formula (4a) or (4b) Step c of forming a compound represented by formula (5a) or (5b) by subjecting to hydrogenation reaction; and formula (5a) or (5b) by oxidatively decarboxylating the compound obtained by formula (5a) or (5b). 1a) or (1
There is provided a production method comprising the step d) of forming the optically active 2-norbornanone of b).

The present invention also provides a method for producing an optically active 2-hydroxynorbornene-2-carboxylic acid represented by formula (4a) or (4b), which is a synthetic intermediate of optically active 2-norbornanone: 2) reacting an optically active dioxolan-4-one derivative with cyclopentadiene to form a compound represented by formula (3a) or (3b); and formula (3a) or (3)
There is provided a production method comprising a step b of hydrolyzing the compound of b) to form an optically active 2-hydroxy-norbornene-2-carboxylic acid of the formula (4a) or (4b).

Hereinafter, the present invention will be described in detail with reference to Scheme 1.

Step a In the present invention, first, the optically active dioxolan-4-one derivative of the formula (2) is subjected to a Diels-Alder reaction with cyclopentadiene to form a spiro compound of the formula (3a) or (3b). In this case, when the absolute configuration of the asymmetric carbon of the compound of formula (2) is (2S), the compound of formula (3a) is stereoselectively produced, and conversely, when the compound of formula (2R) is (2R).
The compound of b) is stereoselectively produced.

This Diels reaction is performed, for example, by the formula (2)
The mixture of the optically active dioxolan-4-one derivative and cyclopentadiene can be generally stirred by stirring at a temperature of 100 ° C. to quantitatively give a spiro compound of the formula (3a) or (3b). be able to. In this case, the optically active dioxolane-4 of formula (2)
1.5 mol of cyclopentadiene to 1 mol of the -one derivative
It is preferable to use ˜5.0 mol.

No solvent may be used during the Diels reaction, but aromatic hydrocarbons such as benzene and toluene, and aliphatic carbonization such as pentane, hexane and heptane, which do not adversely affect the reaction, if necessary. Hydrogen, ethers such as tetrahydrofuran and diethyl ether, aliphatic halides such as dichloromethane, chloroform and dichloroethane may be used.

The starting optically active dioxolan-4-one derivative of the formula (2) can be obtained by various methods. For example, when R is tert-butyl, pivalaldehyde and L can be obtained. -(-)-Or D-(+)
-It can be easily produced from those reacted with lactic acid ((J. Mattay et al., Chem.
Ber. 122 , 327 (1989); Org.
Chem. , 57 , 3380 (1992)).

Step b Next, the optically active spiro compound of the formula (3a) or (3b) is hydrolyzed to give the corresponding optically active 2-hydroxynorbornene represented by the formula (4a) or (4b). Convert to 2-carboxylic acid.

The hydrolysis reaction is preferably carried out under basic conditions, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metals such as calcium hydroxide and magnesium hydroxide. It can be carried out by stirring the spiro compound of the formula (3a) or (3b) in an aqueous solution of a metal hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate. By this hydrolysis, an optically active 2-hydroxynorbornene-2-carboxylic acid salt dissolved in the aqueous reaction solution can be obtained.

When carrying out the hydrolysis, an organic solvent may be added to the reaction solution in order to improve the rate of hydrolysis of the spiro compound of the formula (3a) or (3b). If an organic solvent that is miscible with water is used, a homogeneous reaction occurs, and if an organic solvent that is immiscible with water is used, a two-phase reaction occurs, but from the viewpoint of hydrolysis rate, safety, handleability, etc., methanol It is preferred to add lower alcohols such as ethanol, ethanol and propanol. Further, the reaction temperature and the reaction time can be set appropriately.

Further, if necessary, an organic solvent such as a lower alcohol is distilled off from the hydrolysis reaction solution in which the optically active 2-hydroxynorbornene-2-carboxylic acid salt is dissolved, and water is added to the residue. An extraction solvent such as hexane is added to extract the water-insoluble component by extracting it into the hexane phase. Then, the aqueous phase in which the 2-hydroxynorbornene-2-carboxylic acid salt is dissolved is acidified with a mineral acid such as sulfuric acid,
Preferably, the pH is adjusted to 1-2 to convert it into the 2-hydroxynorbornene-2-carboxylic acid of formula (4a) or (4b). Then, it is extracted with an extraction solvent such as isopropyl ether, and the extraction solvent is removed by a conventional method to isolate the optically active 2-hydroxynorbornene-2-carboxylic acid of the formula (4a) or (4b). This compound can be used as a raw material in the next step as it is, but since it has good crystallinity, it may be purified by recrystallization.

Step c Next, the optically active 2-hydroxynorbornene-2-carboxylic acid of the formula (4a) or (4b) is subjected to a catalytic hydrogenation reaction to give the corresponding (5a) or (5).
Reduction to optically active 2-hydroxynorbornane-2-carboxylic acid represented by b).

The catalytic hydrogenation reaction is carried out according to (4a) or (4
b) optically active 2-hydroxynorbornene-2-carboxylic acid, such as lower alcohols such as methanol, ethanol and propanol, esters such as ethyl acetate, propyl acetate and butyl acetate, hydrocarbons such as pentane, hexane and heptane. dissolved in a solvent, the solution of palladium - carried out by adding a catalytic hydrogenation catalyst such as carbon, generally ^1Kg / cm ^{2 ~50Kg} / cm 2 under a hydrogen atmosphere and stirred at a temperature of room temperature to 100 ° C. be able to.

After completion of the catalytic hydrogenation reaction, the catalyst for catalytic hydrogenation is filtered off, and the filtrate is concentrated to obtain the compound of formula (5a).
Or (5b) optically active 2-hydroxynorbornane-
A 2-carboxylic acid can be obtained.

Step d Next, the optically active 2-hydroxynorbornane-2-carboxylic acid of formula (5a) or (5b) is oxidatively decarboxylated to give the corresponding formula (1a) or (1b).
To form optically active 2-norbornanone.

Oxidative decarboxylation can be carried out by the formula (5a) or (5b)
The carboxylic acid can be treated with an oxidizing agent such as sodium hypochlorite, lead tetraacetate, chromic acid-sulfuric acid, sodium bismuthate-phosphoric acid by a conventional method. For example, when sodium hypochlorite is used as the oxidant, the aqueous carboxylic acid of the formula (5a) or (5b) is generally stirred with an aqueous solution of sodium hypochlorite at a temperature of -10 ° C to 40 ° C. It can be performed by dropping.

After decarboxylation, 2-norbornanone of the formula (1a) or (1b) is extracted from the reaction solution with an extraction solvent such as hexane, the organic phase is washed by a conventional method, dried and then extracted with an extraction solvent. Can be removed to obtain the optically active 2-norbornanone of the formula (1a) or (1b). This compound can be purified by vacuum distillation or recrystallization.

[0032]

Since the optically active dioxolan-4-one derivative used in the present invention has a double bond conjugated to α-carbonyl, it can easily undergo Diels-Alder reaction with cyclopentadiene. The optically active spiro compound obtained by this Diels-Alder reaction can be easily hydrolyzed into optically active 2-hydroxy-5-norbornene-2-carboxylic acid which is a raw material for producing optically active 2-norbornanone. Further, the optically active dioxolan-4-one derivative is an easily available compound. Therefore, according to the present invention, the optically active 2-norbornanone can be industrially produced easily.

[0033]

EXAMPLES Hereinafter, a method for producing an optically active dioxolan-4-one derivative which is a starting material of the production method of the present invention will be described as a reference example, and further with reference to Scheme 1,
The present invention will be specifically described with reference to examples.

Reference Example [(2S) -2-ter of Formula (2) ]
t-butyl-5-methylene-1,3-dioxolane-4
-Synthesis ] Step 1 To a solution of 86.0 g of pivalaldehyde in pentane, L-
45.0 g of (-)-lactic acid, 1.0 g of p-toluenesulfonic acid monohydrate and 2 drops of sulfuric acid were added. The reaction solution was heated and heated to reflux for 10 hours while removing generated water. After completion of the reaction, the reaction solution was washed with a saturated sodium hydrogen carbonate aqueous solution and then with a saturated saline solution, then pentane was distilled off from the reaction solution under reduced pressure, and the obtained distillation residue was recrystallized from hexane to obtain 48.0 g. (2S, 5S) -2-tert-
Butyl-5-methyl-1,3-dioxolan-4-one was obtained.

Step 2 (2S, 5S) -2-tert-butyl-5-methyl-1,3-dioxolan-4-one 4 obtained in Step 1
8.0 g was dissolved in 500 ml of carbon tetrachloride, 54.0 g of N-bromosuccinimide and 1.0 ml of benzoyl peroxide were added to the solution, and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool, then the insoluble matter was filtered off, and the filtrate was washed successively with 10% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. Carbon tetrachloride was distilled off from the filtrate under reduced pressure, and the obtained residue was recrystallized from hexane to give 70.5 g of (2S, 5S) -5-bromo-2-t.
ert-Butyl-5-methyl-1,3-dioxolane-
I got 4-on.

Step 3 (2S, 5S) -5-bromo-2-t obtained in Step 2
ert-Butyl-5-methyl-1,3-dioxolane-
Dissolve 70.5 g of 4-one in 500 ml of carbon tetrachloride,
50.0 g of triethylamine was added to the solution, and the mixture was heated under reflux for 4 hours. After allowing the reaction solution to cool, the insoluble matter was filtered off, carbon tetrachloride was distilled off from the filtrate under reduced pressure, and the obtained residue was recrystallized from hexane to give 29.5 g of (2S) -2.
-Tert-Butyl-5-methylene-1,3-dioxolan-4-one was obtained. The physical property data of this compound are shown below.

Boiling point: 59.0 to 61.5 ° C./6 Torr Specific rotation [α] ²⁵ _D : -14.8 ° (c = 1.51)
CHCl ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ , δ): 0.
97 (9H, s), 4.85 (1H, d, J = 2.7H
z), 5.12 (1H, d, J = 2.7 Hz), 5.4
5 (1H, s) ¹³ C-NMR (75.5 MHz, CDCl ₃ , δ):
24.4, 37.5, 92.6, 111.1, 146.
0,162.6.

Example [Synthesis of (+)-2-norbornanone of Formula (1a)] Step a (2S) -2-tert- of Formula (2) obtained in Reference Example.
Butyl-5-methylene-1,3-dioxolan-4-one (15.6 g) and cyclopentadiene (30.0 g) were placed in a sealed tube, and a Diels-Alder reaction was carried out at room temperature (20 to 25 ° C.) for 48 hours. After completion of the reaction, unreacted cyclopentadiene was distilled off from the reaction mixture under reduced pressure to obtain 46.0 g of a crude spiro compound of the formula (3a).

Step b To 46.0 g of the crude spiro compound obtained in step a, 100 ml of methanol, 10 ml of water and 6.
0 g was added, and the resulting mixture was stirred for 1 hour to carry out hydrolysis reaction. After completion of the reaction, methanol was distilled off from the mixture under reduced pressure, 100 ml of water was added to the obtained residue, and the mixture was washed twice with 100 ml of hexane. The pH of the washed aqueous phase was adjusted to 1-2 by adding sulfuric acid, and then extracted twice with 100 ml of isopropyl ether. Isopropyl ether was distilled off under reduced pressure from the obtained isopropyl ether extract, and the obtained residue was recrystallized from isopropyl ether to give milky white crystals.
3.8 g of 2-hydroxy-5-norbornene-2-carboxylic acid of formula (4a) was obtained. (2S) -2 of the formula (2)
The yield from -tert-butyl-5-methylene-1,3-dioxolan-4-one was 90%.

Step c 10.0 g of 2-hydroxy-5-norbornene-2-carboxylic acid of the formula (4a) obtained in step b was added to ethyl acetate 1
It is dissolved in 00 ml and 10 as a catalyst for catalytic hydrogenation.
% Palladium-carbon (0.5 g) was added, and the solution was stirred in a hydrogen gas atmosphere for 2 hours to carry out a catalytic hydrogenation reaction. After completion of the reaction, the catalyst was filtered off from the reaction solution, and ethyl acetate was distilled off from the filtrate under reduced pressure to obtain 14.5 g of crude 2-hydroxy-5-norbornane-2-carboxylic acid of the formula (5a).

Step d The crude 2-hydroxy-formula of formula (5a) obtained in step c.
While stirring 14.5 g of 5-norbornane-2-carboxylic acid, a 12% aqueous solution of sodium hypochlorite 5
Oxidative decarboxylation reaction was carried out for 1 hour by gradually dropping 0.0 g. During the reaction, the reaction solution was cooled to 10 to 1 by ice cooling.
Hold at 5 ° C. After completion of the reaction, the reaction solution was extracted with hexane, and the obtained organic layer was washed successively with a 10% sodium thiosulfate aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution. Hexane was distilled off under reduced pressure from the washed organic phase,
The obtained residue was distilled under reduced pressure to obtain 6.5 g of the optically active (+)-2-norbornanone of the formula (1a). The overall yield from starting material (2S) -2-tert-butyl-5-methylene-1,3-dioxolan-4-one of formula (2) was 82%. The physical property data of this compound are shown below.

Melting point: 96 to 97 ° C. Specific optical rotation [α] ²⁵ _D : + 27.5 ° (c = 1.51)
CHCl ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ , δ): 1.
38-1.60 (3H, m), 1.70-1.90 (4
H, m), 2.50 to 2.11 (1H, m), 2.59
(1H, br.s), 2.67 (1H, br.s) ¹³ C-NMR (75.5 MHz, CDCl ₃ , δ):
24.1, 271, 35.2, 37.6, 45.2
49.8, 218.2.

[0043]

INDUSTRIAL APPLICABILITY According to the present invention, optically active 2-norbornanone useful as a raw material for synthesizing various physiologically active substances can be industrially and conveniently produced. Further, according to the present invention, an optically active 2- which is a raw material for synthesizing optically active 2-norbornanone.
Hydroxynorbornene-2-carboxylic acid can be industrially and simply produced.

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Claims (2)

[Claims] 1. A formula (1a) or (1b): In the method for producing the optically active 2-norbornanone represented by: Formula (2) (In the formula, R represents a substituted or unsubstituted alkyl group or aryl group, and * represents an asymmetric carbon), and an optically active dioxolan-4-one derivative represented by the formula (3a) or (3b) [Chemical Formula 3] Step a to form a compound represented by the formula; a compound of formula (3a) or (3b) obtained in step a is hydrolyzed to give a compound of formula (4a) or (4b) (In the formula, R and * are as defined in formula (1))
Optically active 2-hydroxynorbornene-2 represented by
-Step b of converting to a carboxylic acid; a compound of formula (4a) or (4b) obtained in step b is subjected to catalytic hydrogenation reaction to give formula (5a) or (5b) And a compound of formula (1a) or (1b) obtained by oxidatively decarboxylating the compound of formula (5a) or (5b) obtained in step c; A production method comprising a step d for forming 2-norbornanone. 2. The formula (4a) or (4b): Optically active 2-hydroxynorbornene-2 represented by
In a method for producing a carboxylic acid: Formula (2) (In the formula, R represents a substituted or unsubstituted alkyl group or aryl group, and * represents an asymmetric carbon), and an optically active dioxolan-4-one derivative represented by the formula (3a) or (3b) embedded image And a compound of formula (3a) or (3b) obtained in step a is hydrolyzed to form an optically active 2-hydroxynorbornene-2- of formula (4a) or (4b). A production method comprising the step b of forming a carboxylic acid.