JPH1081678A - Production of optically active furanone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain the subject compound in a good yield by reacting an optically active glycidyl alcohol compound as a starting raw material with biphenyl acetic acid. SOLUTION: An optically active glycidyl alcohol derivative of formula I (R is an OH-protecting group; * is the position of an asymmetric carbon atom) is reacted with diphenyl acetic acid and subsequently subjected to an intermolecular dehydration reaction to obtain a 4,5-dihydro-2(3H)-furanone derivative of formula II. The OH-protecting group of the compound of formula II is released to obtain the optically active 4,5-dihydro-5-hydroxymethyl-3, 3- diphehnyl-2(3H)-furanone of formula III. The compound of formula III is useful as an intermediate for synthesizing an N-substituted-5-aminomethl-3,3-biphenyl-2(3 H)-furanone derivative having an antimuscarine action and useful as a medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active 4,5
The present invention relates to a method for producing -dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone and a production intermediate used therefor.

[0002]

2. Description of the Related Art 4,5-Dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone is an N-substituted compound having an antimuscarinic activity which is useful as a pharmaceutical.
5-aminomethyl-3,3-diphenyl-2 (3H)-
It is an industrially important compound as a synthetic intermediate of a furanone derivative (J. Med. Chem. 1992, 35 , 4415-4424).

[0003] Conventionally, such a method for producing 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone includes (i) optically active 2,2-dimethyl-4-furanone. (P-toluenesulfonyloxymethyl)-
2,2-dimethyl-4-iodomethyl-1,3 obtained by reacting sodium iodide with 1,3-dioxolane
-Reaction of dioxolane with diphenylacetic acid to give 3-
(2,2-Dimethyl-1,3-dioxolan-4-yl) -2,2-diphenylpropionic acid, followed by deprotection with hydrochloric acid and simultaneous ring closure (J. Med.
Chem. 1992, 35 , 4415-4424), (ii) 2,2-diphenyl-4-pentenoic acid obtained from allyl bromide and diphenylacetic acid, and formic acid-hydrogen peroxide (U.S. Pat.
And perbenzoic acid [J. Org. Chem. Soc., 24 , 934-938 (195
9)] to react with 4,5-dihydroxy-
There is known a method of obtaining 2,2-diphenyl-pentanoic acid and then performing a ring closing reaction.

[0004]

However, the above-mentioned production method (i), that is, the method of reacting 2,2-dimethyl-4-iodomethyl-1,3-dioxolane with diphenylacetic acid, is difficult for compounds having large steric hindrance. , The desired product can be obtained only in a very low yield. In addition, the production method of the above (ii), that is, the method of reacting 2,2-diphenyl-4-pentenoic acid with a peroxide requires not only the use of a peroxide which is dangerous for the reaction, but also the reaction results. Since the compound is obtained as a racemic form, it is necessary to obtain an optically active compound from the racemic form, which has the drawbacks of extremely difficult means and low yield.

Accordingly, an object of the present invention is to provide a method for producing 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone having a high optical purity in a high yield. It is to provide the intermediate.

[0006]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies and as a result, have found that an easily available optically active glycidyl alcohol derivative represented by the following general formula (1) is used as a starting material. Reaction with diphenylacetic acid to produce optically active 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone easily and in high yield. We have found and completed the present invention.

The present invention can be represented by the following reaction formula.

[0008]

Embedded image

[In the formula, R represents a hydroxyl-protecting group, and * represents the position of an asymmetric carbon.]

That is, according to the present invention, the glycidyl alcohol derivative represented by the general formula (1) is reacted with diphenylacetic acid (step 1) to obtain the 2,2 represented by the general formula (2).
-Diphenyl-4-hydroxycarboxylic acids are obtained, and the hydroxycarboxylic acids are subjected to an intramolecular dehydration reaction (Step 2) to give 4,5-dihydro-2 represented by the general formula (3).
Optically active 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl- (3H) -furanone derivative is obtained, and then the hydroxyl-protecting group of the compound is eliminated (Step 3). This is a method for producing 2 (3H) -furanone.

The present invention also provides a production intermediate represented by the above general formula (3).

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The method of the present invention will be described below for each of the above steps.

(1) Step 1 In the reaction of Step 1, for example, a metal salt of diphenylacetic acid is prepared by using about 2 equivalents of a metalating reagent in an inert solvent such as tetrahydrofuran, diethyl ether, dimethylformamide, and toluene. This is performed by dropping a glycidyl alcohol derivative therein. Examples of the metallizing reagent used here include organometallic reagents such as lithium diisopropylamide (LDA), n-butyllithium, and potassium t-butoxy, and inorganic metal reagents such as lithium hydride and metallic sodium. The reaction is -20 to
It is preferable to carry out at 50 ° C. for 1 to 24 hours.

R in the optically active glycidyl alcohol derivative (1) used as a raw material is not particularly limited as long as it is a commonly used protecting group for a hydroxyl group, and among them, especially R such as benzyl group and triarylmethyl group. An aralkyl group, an allyl group, a trialkylsilyl group, a tetrahydropyranyl group, a 2-thiolanyl group and the like are preferable, and an aralkyl group is particularly preferable.

The glycidyl alcohol derivative (1) used here has an asymmetric carbon atom, so that the R-form,
Although the S-isomer and a mixture thereof exist, in the present invention,
The configuration is such that the final product, 4,5-dihydro-
5-hydroxymethyl-3,3-diphenyl-2 (3
H) -furanone (4) is retained. That is, the desired 4,5-dihydro-5-hydroxymethyl-3,3
A glycidyl alcohol derivative (1) having a configuration according to the configuration of -diphenyl-2 (3H) -furanone (4) may be selected and used.

The 2,2-diphenyl-4- obtained here
The hydroxycarboxylic acid (2) may be isolated, but the reaction solution or extract is directly used in the next step 2 without isolation.
Can also be used.

(2) Step 2 The reaction in Step 2 is carried out in the presence or absence of a solvent at room temperature or under heating.
It is preferable to carry out the heating by distilling off the generated water.

(3) Step 3 In step 3, the desired optically active 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl-2 (3H) -furanone is obtained by removing a hydroxyl-protecting group. This is a reaction to obtain (4). The elimination reaction of the protecting group is carried out by a conventional method according to the protecting group, for example, by hydrogenolysis or hydrolysis.More specifically, in the case of an aralkyl group such as a benzyl group, a metal catalyst such as palladium carbon is used. It is carried out by hydrogenation in the presence. In the case of an allyl group, it is carried out by isomerizing to propenyl ether followed by acid-catalyzed hydrolysis. In the case of a trialkylsilyl group, tetrabutylammonium fluoride in tetrahydrofuran is used, in the case of a tetrahydropyranyl group, a silver salt is converted in the case of a 2-thiolanyl group by hydrolysis with an acid catalyst such as p-toluenesulfonic acid. Each is performed by using.

[0019]

According to the present invention, optically active 4,5-dihydro-5-hydroxymethyl-3,3-diphenyl-
2 (3H) -furanone can be easily produced in high yield.

[0020]

EXAMPLES Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.

Example 1 (R) -5-benzyloxymethyl-4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (3a)
Manufacturing of:

[0022]

Embedded image

Under a nitrogen stream, anhydrous tetrahydrofuran 20
In 0 ml, 37.5 g (0.18 mol) of diphenylacetic acid was added, and while cooling with ice, 180 ml of a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran (0.3 ml) was added.
(Equivalent to 6 mol) was slowly added dropwise. After completion, stirring was continued for 1.5 hours under ice cooling to prepare a dilithium salt. Then, 29.0 g (0.18 mol) of (R)-(-)-benzylglycidyl ether (1a) was slowly added dropwise under ice cooling, and after completion, stirring was continued for 40 minutes under ice cooling and at room temperature overnight. . The reaction solution was added to 1 liter of water, and a solution of 76.0 g (0.36 mol) of citric acid monohydrate in 300 ml of water was added to make the solution acidic, followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 75.4 g of compound (2a) as a yellow-brown oil.
To this oily substance was added 500 ml of toluene, and the mixture was heated and refluxed for 3 hours while distilling off generated water. After cooling, 66.9 g of a reddish brown oily substance obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (solvent: n-hexane / ethyl acetate), and 55.1 g (yield) of the title compound (3a) was obtained. 86%).

The yellow viscous oil _{^{1 H-NMR (CDCl 3)}} δ: 2.87 (1H, dd, J = 10.3 and 13.0Hz), 2.9
6 (1H, dd, J = 5.3 and 13.0Hz), 3.67 (1H, dd, J = 5.1 and 11.
0Hz), 3.73 (1H, dd, J = 3.8 and 11.0Hz), 4.51 ~ 4.58 (1H,
m), 4.59 (2H, s), 7.24-7.38 (15H, m)

Example 2 (R)-(+)-4,5-dihydro-3,3-diphenyl-5-hydroxymethyl-2 (3H) -furanone (4
Production of a):

[0026]

Embedded image

1.0 g (2.8 mm) of (R) -5-benzyloxymethyl-4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (3a) in 20 ml of ethanol.
ol) and 0.5 g of 5% palladium on carbon, and the mixture was stirred under a hydrogen atmosphere at room temperature for 21 hours. Then, the reaction solution was filtered to remove the catalyst, and the filtrate was evaporated under reduced pressure to obtain 0.86 g of a residue. The residue was purified by silica gel chromatography (solvent: chloroform) to give 0.75 g (yield: 100) of the title compound (4a) as an oil.
%)Obtained.

[Α] _D ²² : + 61.35 ° (c = 1.9, EtOH) [literature value + 54.6 ° (c = 1.9, EtOH)] IRν _max ^neat cm ⁻¹ : 3400, 1755 ¹ H-NMR ( CDCl ₃ ) δ: 2.02 (1H, t, J = 7.0 Hz), 2.89 (1H, dd, J =
5.5 and 12.9Hz), 2.97 (1H, dd, J = 10.3 and 12.9Hz), 3.71
(1H, ddd, J = 4.6 and 7.0 and 12.6Hz), 3.99 (1H, ddd, J = 2.
8 and 7.0 and 12.6Hz), 4.44 to 4.52 (1H, m), 7.26 to 7.38
(10H, m)

Claims (4)

[Claims] (1) The following general formula (3): [Wherein, R represents a hydroxyl-protecting group, and * represents the position of an asymmetric carbon atom] 4,5-dihydro-2 (3H)
The following general formula (4) characterized in that the hydroxyl protecting group of the furanone derivative is eliminated: [Wherein, * represents the same as above], the optically active 4,5-dihydro-5-hydroxymethyl-3,
A method for producing 3-diphenyl-2 (3H) -furanone. 2. The following general formula (2): [Wherein R represents a hydroxyl-protecting group and * represents the position of an asymmetric carbon] 2,2-diphenyl-4-hydroxycarboxylic acids represented by the following general formula (3) ): Wherein R and * are the same as defined above, and a hydroxyl group-protecting group is eliminated by the following step, wherein a 4,5-dihydro-2 (3H) -furanone derivative represented by the following formula: General formula (4): [Wherein, * represents the same as above], the optically active 4,5-dihydro-5-hydroxymethyl-3,
A method for producing 3-diphenyl-2 (3H) -furanone. 3. The following general formula (1): Wherein R represents a hydroxyl-protecting group and * represents the position of an asymmetric carbon. Diphenylacetic acid is reacted with an optically active glycidyl alcohol derivative represented by the following general formula (2): ] [Wherein, R and * are the same as defined above] to obtain 2,2-diphenyl-4-hydroxycarboxylic acids, which are subjected to an intramolecular dehydration reaction to obtain the following general formula (3): ] Wherein R and * are the same as defined above, and a hydroxyl group-protecting group is eliminated by obtaining a 4,5-dihydro-2 (3H) -furanone derivative represented by the following formula: General formula (4): [Wherein, * represents the same as above], the optically active 4,5-dihydro-5-hydroxymethyl-3,
A method for producing 3-diphenyl-2 (3H) -furanone. 4. The following general formula (3): [Wherein, R represents a hydroxyl-protecting group, and * represents the position of an asymmetric carbon atom] 4,5-dihydro-2 (3H)
-Furanone derivatives.