JP3300712B2 - Method for producing optically active 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active 2,2-dimethyl-5-phenyl useful as an intermediate of D-(-)-or L-(+)-mandelic acid and their esters and amides. The present invention relates to a method for producing -1,3-dioxolan-4-one.

[0002]

2. Description of the Related Art As a method for obtaining an optically active form of mandelic acid, asymmetric reduction using benzoylformic acid as a raw material and asymmetric cyanohydrin reaction using benzaldehyde as a raw material are known, but an expensive catalyst is required. Yes, not industrially suitable. On the other hand, as a method for obtaining optically active mandelic acid by optical resolution, α-phenethylamine [JP-A-55-147236 or J. Amer.
c., 55 , 411 (1933)], ephedrine [J. Amer. Chem. Soc.,
51 , 1906 (1929)] or cinchonine [J. Chem. Soc., 964
(1899)], the diastereomer separation method is known, but all of these methods have poor separation efficiency and have disadvantages as an industrial method. Also, a method in which a salt of (±) -2-amino-1-butanol and (±) -mandelic acid is used to alternately preferentially crystallize one of the salts of the optically active substance [JP-A-56-123936] Or a method of alternately preferentially crystallizing one of the optically active salts in the piperidine salt of (±) -mandelic acid or the N-methylcyclohexylamine salt [JP-A-56-122329] is known. However, these methods have low yields and require complicated operations.

[0003]

An object of the present invention is to provide an optically active 2,2-dimethyl-5-phenyl-1,3 useful as an intermediate of optically active mandelic acid and its derivatives.
-To provide a method for producing dioxolan-4-one in high yield and at low cost.

[0004]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies, and as a result, it has been found that 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one is a racemic mixture. And found that the substance can be preferentially crystallized. Also, 2,2-dimethyl-5-phenyl-
It has also been found that racemization easily occurs when a racemization accelerator is added to a solution in which a 1,3-dioxolan-4-one optically active substance is dissolved or melted in a solvent. As a result of repeated studies based on these findings, it was found that racemization and preferential crystallization proceed at the same time to obtain the target optical compound from a racemic mixture of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one. A method for obtaining the active substance in high yield was found.

Hereinafter, the present invention will be described in detail according to a manufacturing route.

[0006]

[Manufacturing route]

The process of the present invention comprises the step of reacting a racemic compound of the formula [2] or a mixture in which one optically active substance is present in excess of the other optically active substance in the presence of a racemization accelerator.
After being brought into a molten state or a dissolved state, one of the optically active substances is added as a seed crystal in a supercooled state to obtain a target optically active substance (compound represented by the formula [3a] or [3b]) Is preferentially crystallized. 2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-one of the formula [2] used as a raw material is, for example, a journal of
Organic chemistry, 55 , 5878-5881 (1990) and can be obtained in high yield from mandelic acid. The optically active 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (compound of the formula [3a] or [3b]) obtained by the racemization preferential crystallization method is described in Journal of Chemicals. -Can be easily led to optically active mandelamide and halostatin, as described in Sociati Parkin Transaction I2223-2228 (1984). Further, optically active mandelic acid or mandelic acid ester (formula [4a], [4
b], [5a] or a compound represented by the formula [5b])
[R represents an ester residue. ] Can also be obtained in high yield.

[0008] As the solvent used in this reaction, those in which the compound of the formula [2] shows appropriate solubility, for example,
Aliphatic hydrocarbons such as petroleum ether, benzine, ligroin, n-hexane and cyclohexane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and chlorobenzene; diethyl ether, diisopropyl ether; Ethers such as dibutyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; esters such as ethyl acetate and butyl acetate; secondary alcohols such as isopropanol and cyclohexanol. Tert
Tertiary alcohols such as -butanol and tert-amyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclopentanone; nitriles such as acetonitrile;
Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide; and a mixed solvent thereof. A mixed solvent of an aliphatic hydrocarbon and the above-mentioned solvent is particularly preferable.

As racemization accelerators, triethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.
0] non-5-ene (DBN), organic bases such as 1,4-diazabicyclo [2,2,2] octane and N-methylpiperazine; alkali metal alkoxides such as potassium tert-butoxy; and tetrabutyl Examples include quaternary ammonium salts soluble in organic solvents such as ammonium fluoride. Further, the amount of the racemization accelerator used is sufficient to be 0.1 to 10% by weight based on the compound of the formula [2] as the raw material.

The amount and the particle size of the seed crystal are not particularly limited, but usually, a powder obtained by crushing crystals of about 0.1 to 10% by weight based on the racemic form of the solution is used as it is or suspended in the same solvent system in advance. Use something. The operating temperature is not particularly limited, and can be up to the boiling point of the solvent. However, it is preferable to adjust the temperature according to the solubility of the compound of the formula [2] in the solvent to be used so as to obtain a stable supersaturated solution.

[0011]

EXAMPLES Next, Production Examples of the compound of the present invention will be described specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. In addition,% ee in optical purity is an enantiomeric excess.

Example 1 14.27 g of (±) -2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one is dissolved by heating in a mixed solution of 14.3 ml of n-hexane and 14.3 ml of isopropyl ether. This solution was added to 1,8-diazabicyclo [5.
4.0] -7-undecene (1.07 g) and then 27 ° C
And (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one [[α] _D = -82.7 ° (21.5 ° C., C = 1.
0, CHCl ₃ )]. 26 of the resulting mixture
After stirring at 1 ° C. for 1 hour, the mixture is gradually cooled to 20 ° C. over 4 hours, and then to 10 ° C. over 3 hours. The precipitated crystals are collected by filtration, dissolved in 50 ml of ethyl acetate under ice cooling, and washed with 50 ml of water. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pale yellow (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one as crude crystals (12.17 g). The yield excluding the added seed crystal is 82.3%. [Α] _D = -74.8 ° (21.5 ° C, C = 1.0, CHCl ₃ ) Optical purity 90.4
% Ee In addition, 11.61 g of the above-mentioned crude crystals was added to isopropyl alcohol 1
When recrystallized from 3.0 ml, colorless needles of (-)-2,2-
Dimethyl-5-phenyl-1,3-dioxolan-4-
You get 10.16g on. Melting point: 70.4-72.3 ° C [α] _D = -82.6 ° (21.5 ° C, C = 1.0, CHCl ₃ ) Optical purity 99.9
% Ee IR (KBr) ν _{C = O} ; 1809cm ^-1

Example 2 Using (+)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one as a seed crystal, (±) -2,2
-Dimethyl-5-phenyl-1,3-dioxolan-4
When 10.00 g of -one was treated in the same manner as in Example 1, 8.57 g of pale yellow (+)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one as crude crystals was obtained. The yield excluding the added seed crystal is 82.7%. [Α] _D = + 75.3 ° (18.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 89.5
% Ee 8.00 g of the crude crystals are recrystallized from 10.0 ml of isopropyl alcohol to give 6.69 g of (+)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one as colorless needles.
Get. Melting point: 70.0-72.3 ° C [α] _D = + 83.7 ° (18.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 99.
5% ee IR (KBr) ν _{C = O} ; 1809cm ^-1

Example 3 4.00 g of (±) -2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one was heated to 45 ° C. to be in a molten state, to which 1,8-diazabicyclo [ 54.0] -7
Add 0.20 g of undecene and cool to 40 ° C. At the same temperature, (-)-2,2-dimethyl-5-phenyl-1,3-
Dioxolan-4-one [[α] _D = -81.7 ° (26.0 ° C, C
= 1.0, CHCl ₃ )] at 35 ° C over 30 minutes
Cool. The whole solidified content is further cooled to 10 ° C. over 1 hour, dissolved in 50 ml of ethyl acetate, added with 50 ml of ice water, and adjusted to pH 3.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with water, a 5% aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with n-hexane to give 3.20 g of pale yellow (-)-2,2-dimethyl-5-phenyl-1,3-dioxolane crude crystals. Get. The yield excluding the added seed crystal is 77.5%. [Α] _D = -61.5 ° (26.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 75.3
% Ee The above crude crystals (2.00 g) were recrystallized from isopropyl alcohol (3.00 ml) to give colorless needles of (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (1.4%).
Get 6g. Melting point: 70.0-72.3 ° C [α] _D = -81.1 ° (26.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 99.3
% Ee IR (KBr) ν _{C = O} ; 1809cm ^-1

Reference Example 1 10.0 g of (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (optical purity 99.0% ee) was suspended in a mixture of 20 ml of acetone and 10 ml of water. Let it. After gradually adding 5.10 g of sulfuric acid under ice-cooling, the mixture is stirred at room temperature for 1.5 hours. 50 ml of ethyl acetate and 50 ml of water are added to the reaction mixture.
And the organic layer is separated. After the obtained organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixture of 50 ml of toluene and 5 ml of acetone to give colorless needles of (-)-mandelic acid 7.
08 g (89.4% yield) are obtained. Melting point: 132.6-133.9 ° C [α] _D = -156.5 ° (20.0 ° C, C = 1.0, H ₂ O) Optical purity 99.9
% Ee

Reference Example 2 7.02 g of (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (optical purity 99.9% ee) is suspended in 14.0 ml of methanol. Cool the mixture to 15 ° C,
After slowly adding 1.79 g of sulfuric acid, the mixture is stirred at 20 ° C. for 30 minutes. 50 ml of methylene chloride and 50 ml of water are sequentially added to the mixture, and the mixture is adjusted to pH 7.0 with a saturated sodium hydrogen carbonate solution.
The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
Recrystallization from a mixture of 30 ml of hexane and 9 ml of diisopropyl ether gives 5.40 g (yield: 89.0%) of (-)-mandelic acid methyl ester as colorless needles. Melting point: 54.7-56.1 ° C [α] _D = -149.7 ° (17.5 ° C, C = 1.0, MeOH)

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-61-238734 (JP, A) CHEMTRACTS-ORAGAN IC CHEMISTRY (1988), 1 (2), 139-140 Angew. Chem. Vol. 99, no. 12, pp. 1323-1325, 1987 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 317/34 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) 2,2-dimethyl-5-phenyl-1,3-
In the presence of a racemization accelerator, a racemic dioxolan-4-one or a supersaturated solution or melt of a mixture in which one optically active form is present in excess of the other optically active form,
An optically active 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-characterized by inoculating a crystal of the target optically active substance with preference to crystallize the target optically active substance. On manufacturing method.