JPH06199828A - Production of optically active 2,2-dimethyl-5-phenyl-1,3-dioxozolan-4-one - Google Patents

Abstract

PURPOSE:To obtain the subject compound by adding a racemization promoting agent to a solution of a racemic mixture of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4- one and seeding the solution with a crystal of the objective optically active substance, thereby simultaneously proceeding the racemization and the preferential crystallization. CONSTITUTION:A racemic mixture of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4one of formula 2 derived from mandelic acid of formula 1 or a mixture containing one of the optically active isomer in excess of the other optically active isomer is melted or dissolved in the presence of a racemization promoting agent. One of the optically active isomer is added to the mixture as a seed crystal in supercooled state to effect the preferential crystallization of the objective optically active isomer (a compound expressed by formula 3a or formula 3b). An optically active mandelic acid of formula 4a and formula 4b or mandelic acid ester of formula 5a and formula 5b can be produced from the compound of formula 3a and formula 3b in high yield.

Description

Detailed Description of the Invention

[0001]

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

[0002]

As a method for obtaining an optically active mandelic acid, an asymmetric reduction using benzoylformic acid as a starting material and an asymmetric cyanohydrin reaction using benzaldehyde as a starting material are known, but an expensive catalyst is required. Yes, it is not industrially suitable. On the other hand, as a method for obtaining an optically active mandelic acid by optical resolution, α-phenethylamine [JP-A-55-147236 or J. Amer. Chem. So.
c., 55 , 411 (1933)], ephedrine [J.Amer.Chem.Soc.,
51 , 1906 (1929)] or cinchonine [J.Chem.Soc., 964
(1899)], a diastereomer resolution method is known, but each method has a poor resolution efficiency and has a drawback as an industrial method. Further, a method in which a salt of (±) -2-amino-1-butanol and (±) -mandelic acid is used to preferentially crystallize the salt of either one of the optically active substances [JP-A-56-123936]. No.] or (±) -mandelic acid piperidine salt or N-methylcyclohexylamine salt, a method of preferentially crystallizing the salt of either optically active substance alternately [JP-A-56-122329] is known. However, these methods have low yields and require complicated operations.

[0003]

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

[0004]

In order to solve the above-mentioned problems, the inventors of the present invention have conducted diligent research, and as a result, 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one is a racemic mixture. It was found that it is a substance that can be preferentially crystallized. Also, 2,2-dimethyl-5-phenyl-
It was also found that racemization easily occurs when a racemization accelerator is added to an optically active substance of 1,3-dioxolan-4-one dissolved or melted in a solvent. As a result of repeated studies based on these findings, it was confirmed that the racemic mixture of 2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one can be used to achieve the desired optical properties by simultaneously promoting racemization and preferential crystallization. We have found a way to obtain actives in high yield.

The present invention will be described in detail below according to the manufacturing route.

[0006]

[Manufacturing route]

In the method of the present invention, a racemic compound which is a compound of the formula [2] or a mixture in which one optically active substance is present in excess relative to the other optically active substance is added in the presence of a racemization accelerator.
The target optically active compound (compound represented by the formula [3a] or the formula [3b]) can be obtained by adding either one of the optically active compounds as a seed crystal in a supercooled state after being brought into a molten state or a dissolved state. 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, 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 formula [3a] or [3b]) obtained by the racemization preferential crystallization method is a journal of chemicals. • Can readily lead to optically active mandelamides and halostatins, as described in Sociati Perkin Transaction I2223-2228 (1984). In addition, optically active mandelic acid or mandelic acid ester (formula [4a], [4a]
b], [5a] or a compound represented by the formula [5b])
[R represents an ester residue. ] Can also be obtained in high yield.

The solvent used in this reaction is one in which the compound of the formula [2] exhibits an 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; and sulfoxides such as dimethylsulfoxide and mixed solvents thereof, but mixed solvents of aliphatic hydrocarbons and the above-mentioned solvents are particularly preferable.

As a racemization accelerator, 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-butoxide; and tetrabutyl Examples thereof include quaternary ammonium salts that are soluble in organic solvents such as ammonium fluoride. Further, the amount of the racemization accelerator used is 0.1-10% by weight with respect to the compound of the formula [2] as the raw material.

The amount of seed crystals added and the particle size are not particularly limited, but powders obtained by crushing about 0.1-10% by weight of crystals with respect to the racemate in the solution are used as they are or suspended in the same solvent system in advance. Use one. The operating temperature is also not particularly limited and can be up to the boiling point of the solvent, but it is preferably adjusted according to the solubility of the compound of the formula [2] in the solvent used so that a stable supersaturated solution can be obtained.

[0011]

EXAMPLES Next, the production examples of the compound of the present invention will be specifically described 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 rate.

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. 1,8-diazabicyclo [5.
4.0] -7-undecene (1.07 g) was added, and then 27 ° C.
At (−)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one [[α] _D = -82.7 ° (21.5 ° C., C = 1.
0, CHCl ₃ )] crystals 0.43 g are added. The resulting mixture is 26
After stirring for 1 hour at 0 ° C, the solution is gradually cooled to 20 ° C in 4 hours and then to 10 ° C in 3 hours. The precipitated crystals are collected by filtration, added to 50 ml of ethyl acetate under ice cooling to dissolve, 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 12.17 g of pale yellow crude crystals of (-)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one. The yield excluding the added seed crystals is 82.3%. [Α] _D = -74.8 ° (21.5 ° C, C = 1.0, CHCl ₃ ) Optical purity 90.4
% Ee The crude crystal (11.61 g) above was mixed with isopropyl alcohol 1
If recrystallized from 3.0 ml, colorless needle-like (-)-2,2-
Dimethyl-5-phenyl-1,3-dioxolane-4-
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-dioxolane-4
If 10.00 g of -one is treated in the same manner as in Example 1, 8.57 g of crude yellow (+)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one is obtained. The yield excluding the added seed crystals is 82.7%. [Α] _D = + 75.3 ° (18.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 89.5
% Ee This crude crystal (8.00 g) was recrystallized from isopropyl alcohol (10.0 ml) to give colorless needle crystals of (+)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-one (6.69 g).
To 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 (±) -2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-one (4.00 g) was heated to 45 ° C. to be in a molten state, to which 1,8-diazabicyclo [ 5.4.0] -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 )] crystals 0.10 g, and it takes 30 minutes at 35 ℃
Cool to. The whole solidified content is further cooled to 10 ° C. over 1 hour, dissolved in 50 ml of ethyl acetate, 50 ml of ice water is added, and the pH is adjusted to 3.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with water, 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 pale yellow (-)-2,2-dimethyl-5-phenyl-1,3-dioxolane of crude crystals 3.20 g. To get The yield excluding the added seed crystals is 77.5%. [Α] _D = -61.5 ° (26.0 ° C, C = 1.0, CHCl ₃ ) Optical purity 75.3
% Ee The crude crystal (2.00 g) was recrystallized from isopropyl alcohol (3.00 ml) to give colorless needle crystals 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 mixed solution of 20 ml of acetone and 10 ml of water. Let After slowly 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 in the reaction mixture
Is added and the organic layer is separated. The obtained organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solution of 50 ml of toluene and 5 ml of acetone to give colorless needle crystals 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 was stirred at 20 ° C for 30 minutes. 50 ml of methylene chloride and 50 ml of water are sequentially added to the mixed solution, and the pH is adjusted to 7.0 with 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, and the obtained residue was n-
Recrystallization from a mixed solution of 30 ml of hexane and 9 ml of diisopropyl ether gives colorless needle-shaped (-)-mandelic acid methyl ester (5.40 g, yield 89.0%). Melting point; 54.7-56.1 ° C [α] _D = -149.7 ° (17.5 ° C, C = 1.0, MeOH)

Claims (1)

[Claims] 1. 2,2-Dimethyl-5-phenyl-1,3-
In the presence of a racemization accelerator in a supersaturated solution or a melt of a dioxolan-4-one racemate or a mixture in which one optically active substance is present in excess over the other optically active substance,
An optically active 2,2-dimethyl-5-phenyl-1,3-dioxolane-4-, which is characterized in that the optically active substance of interest is crystallized preferentially by inoculating the optically active substance of interest. On manufacturing method.