JP2003313153A - Method for producing optically active 2-acylated 1,2-diol compound derivative - Google Patents

Abstract

(57) [Problem] To optically resolve a dl-form 1,2-diol compound by a simple method without much concern for the purity of a raw material,
To develop a method for producing an optically active 1,2-diol compound in high yield. SOLUTION: The following general formula (I): (However, R ¹ independently represents an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a benzyl group.) In the presence of an optically active oxazoline-copper complex catalyst represented by
1) reacting a -1,2-diol compound with a carboxylic acid halide compound to optically resolve the (dl) -1,2-diol compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a dl-type 1,2-
By selectively protecting only one hydroxyl group of one of the isomers of the diol compound with a carboxylic acid halide compound, the two isomers are separated, and the optically active 2-acylated 1,
The present invention relates to a method for obtaining a 2-diol compound derivative or an optically active 1,2-diol compound.

[0002]

2. Description of the Related Art An optically active diol compound (hereinafter referred to as an optically active diol compound) in which two adjacent asymmetric carbons have the same absolute configuration is used as, for example, an intermediate of medicines and agricultural chemicals or an asymmetric ligand of a catalyst. Is an important compound.

Conventionally, various methods have been known as methods for synthesizing these optically active diol compounds, but one of the simplest production methods is optical resolution of a (dl) -1,2-diol compound. It can be manufactured by. As an optical resolution method of a dl-form using an optical resolving agent, one hydroxyl group of one isomer of the dl-form 1,2-diol compound in the presence of an optically active diamine catalyst, a tertiary amine compound and benzoyl chloride is benzoyl. Is known (enantiomer, vol. 5, 119-123 (20
00)).

[0004]

However, in such a method, only the optical resolution of the dl form of β-halohydrin is carried out, and an example of the optical resolution of the (dl) -1,2-diol form is shown. There is no. That is, although the optical resolution method of the dl body is already known, (dl)-
The method of optical resolution of 1,2-diol compound is not known. Further, in the above method, an optically active benzoylating agent is generated in the reaction system by activating benzoyl chloride with an optically active diamine, and the benzoylation reaction of alcohol is carried out. When monobenzoylation is performed,
If impurities such as a monoalcohol compound are present in the reaction system, it is expected that the benzoylation reaction to the monoalcohol compound will proceed preferentially and the reaction yield will decrease. Therefore, in order to improve the reaction yield,
It is necessary to use a highly pure dl diol compound.

Therefore, the dl-type 1,2-diol compound is optically resolved by a simple method without concern for the purity of the raw materials, and an optically active 1,2-diol compound is produced in a high yield. It was desired to develop a method of doing so.

[0006]

In view of such circumstances, the inventors of the present invention have conducted extensive studies, and as a result, have found that the optically active compound which has been used as a catalyst for asymmetric carbon-carbon bond reaction such as asymmetric Diels-Alder reaction has been conventionally used. By using an oxazoline-copper complex catalyst as an optical resolving agent, it was found that a dl-type 1,2-diol compound can be optically resolved in high yield, and the present invention has been completed.

That is, the present invention provides the following general formula (I)

[0008]

[Chemical 2]

(However, each R ¹ independently has 1 carbon atom.
5 represents an alkyl group, a phenyl group and a benzyl group. ) In the presence of an optically active oxazoline-copper complex catalyst and a base, a (dl) -1,2-diol compound is reacted with a carboxylic acid halide compound, and an optically active 2-acylated 1,2- A method for producing an optically active 2-acylated 1,2-diol compound derivative, which comprises separating the diol compound derivative.

The present invention also provides a method for producing an optically active 1,2-diol compound, which comprises separating the optically active 1,2-diol compound from the reaction solution obtained by the above method.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION As the dl 1,2-diol compound used in the present invention, any compound having a hydroxyl group bonded to an adjacent carbon atom can be used without any limitation. Suitably, the general formula (III)

[0012]

[Chemical 3]

(However, R ² represents an alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted phenyl group, and two R ²
May together form a ring. ) Is used.

Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, tert-amyl group, etc. Examples of the phenyl group include p-chlorophenyl group, p-fluorophenyl group, p-methylphenyl group, p-tert-butylphenyl group, p-dimethylaminophenyl group and the like. When two R ² 's together form a ring, examples of the ring include a cyclopentane ring, a cyclohexane ring, a cyclooctane ring and the like.

Specific examples of these 1,2-diol compounds include hydrobenzoin, p-fluorohydrobenzoin, p-chlorohydrobenzoin, p-methylhydrobenzoin, p-tert-butylhydrobenzoin and p-dimethyl. Aromatic 1,2-diol compounds such as aminohydrobenzoin and p-methoxyhydrobenzoin, 2,3-butanediol, 3,4-hexanediol, 2,5-dimethyl-3,4-hexanediol,
Examples thereof include dl form of aliphatic 1,2-diol compounds such as 2,2,5,5, -tetramethyl-3,4-hexanediol, cyclohexanediol, and cyclopentanediol.

Among the 1,2-diol compounds of these 1,2-diol compounds, the 1,2-diol compounds which are particularly preferably used are specifically exemplified by hydrobenzoin, p-fluorohydrobenzoin and p-chlorohydrobenzoin. ,
The dl form of an aromatic 1,2-diol compound such as p-methylhydrobenzoin, p-tert-butylhydrobenzoin and p-methoxyhydrobenzoin, and an aliphatic 1,2-diol compound such as cyclohexanediol and cyclopentanediol are , It is effective because it can be divided with high selectivity.

Some of these (dl) -1,2-diol compounds are available as reagents, but when they are not available, 1,2- which is a precursor of the (dl) -1,2-diol compound is available. It can be easily adjusted by reducing a diketone compound with a borane-methyl sulfide complex or oxidizing a stilbene derivative with osmium tetroxide.

As the carboxylic acid halide compound used in the present invention, generally, a carboxylic acid halide compound available as a reagent can be used without any limitation. The carboxylic acid halide compound selectively protects only one hydroxyl group of one isomer of the dl-type 1,2-diol compound to form an optically active 2-acylated 1,2-diol compound derivative. Let

Specific examples of these carboxylic acid halide compounds include acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, etc., preferably aliphatic carboxylic acid halide compounds having 2 to 7 carbon atoms, benzoyl chloride, Benzoyl bromide,
2-methylbenzoyl chloride, 3-methylbenzoyl chloride, 4-methylbenzoyl chloride, 4-
Preferable examples thereof include aromatic carboxylic acid halide compounds having 7 to 11 carbon atoms such as ethylbenzoyl chloride, 4-butylbenzoyl chloride and 4-tert-butylbenzoyl chloride. Among these,
An aliphatic carboxylic acid halide compound such as acetyl chloride and propionyl chloride, and an aromatic carboxylic acid halide compound such as benzoyl chloride and 4-methylbenzoyl chloride are preferably used because they exhibit high selectivity.

The amount of the above-mentioned carboxylic acid halide compound used is not particularly limited, but if the amount is small, unreacted substances remain and it is not efficient. Since 0.5 mol is a theoretical equivalent to 1 mol of the (dl) -1,2-diol compound, this amount is usually used from the viewpoint of reaction efficiency and avoiding excessive use of the carboxylic acid halide compound.

The bases used in the present invention are expected to act not only as a scavenger of hydrogen chloride generated in the reaction but also as a promoter. As the bases, bases usually available as reagents can be used without any limitation.

Specific examples of these bases include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [ 2.2.2] Octane, N, N, N ', N'-
Tetramethylethylenediamine, N, N, N ', N'-
Tetraethylethylenediamine, N, N, N ', N'-
Tetramethylpropanediamine, N, N, N ', N'-
Aliphatic tertiary amine compounds such as tetraethylpropanediamine, pyridine, N, N-dimethylbenzylamine, 4
-N, N-dimethylaminopyridine, N-methylpyrrole, N-ethylpyrrole, N-methylimidazole, N
-Aromatic tertiary amine compounds such as ethyl imidazole, inorganic carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, sodium hydroxide, and hydroxide Examples thereof include hydroxides such as potassium, lithium hydroxide, magnesium hydroxide and calcium hydroxide. Among these, especially, aliphatic tertiary amine compounds such as triethylamine, tripropylamine, tributylamine, diisopropylethylamine, etc., aromatic tertiary amine compounds such as pyridine, N, N-dimethylbenzylamine, sodium carbonate, potassium carbonate. Inorganic carbonates such as magnesium carbonate, calcium carbonate, lithium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and lithium hydrogencarbonate are preferably used because of high selectivity and yield.

The amount of the base used in the present invention is not particularly limited, but if the amount is too large, the post-treatment process becomes complicated and the possibility of contributing to the decomposition reaction of the product increases, and the amount is too large. If the amount is small, the conversion of the reaction will be low, so
0. 1 to 1 mol of the (dl) -1,2-diol compound.
It is good to select from the range of 5 to 5 mol, preferably 0.5 to 4 mol.

The following general formula (I)

[0025]

[Chemical 4]

(However, R ¹ independently has 1 carbon atom
5 represents an alkyl group, a phenyl group and a benzyl group. )
In the optically active oxazoline-copper complex catalyst represented by, the alkyl group having 1 to 5 carbon atoms represented by R ¹ is a methyl group, an isopropyl group, a tert-butyl group,
A tert-amyl group and the like can be mentioned. This optically active oxazoline-copper complex catalyst has the following general formula (II)

[0027]

[Chemical 5]

(However, each R ¹ independently has 1 carbon atom.
5 represents an alkyl group, a phenyl group and a benzyl group. )
Optically Active Oxazoline Derivatives and Copper (II) Chloride
Is reacted in a methylene chloride solvent, unreacted copper (II) chloride is filtered off, and the residue is recrystallized (hereinafter referred to as reaction A) to easily synthesize.

As the optically active oxazoline derivative used in the reaction A, an optically active oxazoline derivative available as a reagent can be used without any limitation. Specific examples thereof include 2,2-isopropylidene bis [(4
R) -4-Phenyl-2-oxazoline], 2,2-isopropylidene bis [(4R) -4-methyl-2-oxazoline], 2,2-isopropylidene bis [(4R)-
4-isopropyl-2-oxazoline], 2,2-isopropylidene bis [(4R) -4-tert-butyl-
2-oxazoline], 2,2-isopropylidene bis
[(4R) -4-benzyl-2-oxazoline], 2,2
-Isopropylidene bis [(4S) -4-phenyl-2
-Oxazoline], 2,2-isopropylidene bis [(4
S) -4-Methyl-2-oxazoline], 2,2-isopropylidenebis [(4S) -4-isopropyl-2-
Oxazoline], 2,2-isopropylidene bis [(4
S) -4-tert-Butyl-2-oxazoline],
2,2-isopropylidene bis [(4S) -4-benzyl-2-oxazoline] and the like can be mentioned.

Among these, 2,2-isopropylidene bis which exhibits high selectivity when used as a copper complex is particularly preferable.
[(4R) -4-phenyl-2-oxazoline], 2,2
-Isopropylidenebis [(4R) -4-tert-butyl-2-oxazoline], 2,2-isopropylidenebis [(4R) -4-benzyl-2-oxazoline],
2,2-isopropylidene bis [(4S) -4-phenyl-2-oxazoline], 2,2-isopropylidene bis [(4S) -4-tert-butyl-2-oxazoline], 2,2-isopropylidene Bis [(4S) -4-benzyl-2-oxazoline] and the like are particularly preferable.

The amount of the optically active oxazoline-copper complex used in this reaction is not particularly limited as long as it is equal to or less than 1 mol of the (dl) -1,2-diol compound for use as a catalyst. Is usually (dl) -1,2
-It may be selected from the range of 0.001 to 0.5 mol, preferably 0.005 to 0.1 mol, relative to 1 mol of the diol compound.

The present invention is usually carried out in an organic solvent.
The organic solvent used in the present invention includes (dl) -1,
Any solvent that does not react with the 2-diol compound and the carboxylic acid halide compound can be used without any limitation. Specific examples of these organic solvents include tetrahydrofuran, 1,4-dioxane, diethyl ether, and ter.
Ethers such as t-butyl methyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, nitriles such as acetonitrile and propionitrile, aromatic hydrocarbons such as benzene, toluene and xylene, acetone, Examples thereof include ketones such as methyl ethyl ketone, carbonates such as dimethyl carbonate, esters such as ethyl acetate and propyl acetate, and aliphatic hydrocarbons such as hexane and heptane.

Among these organic solvents, tetrahydrofuran, 1,
4-dioxane ethers, dichloromethane, chloroform halogenated hydrocarbons, benzene, toluene,
Aromatic hydrocarbons such as xylene and esters such as ethyl acetate are preferably used.

The amount of the organic solvent used in the present invention is not particularly limited, but if the amount is too large, the yield per batch is reduced, which is not economical. If the amount is too small, stirring or the like may be hindered. For this reason, the concentration of the (dl) -1,2-diol compound in the reaction solvent is usually 0.1 to 7
It is preferable to use an organic solvent so that the content of the organic solvent is 0% by weight, more preferably 1 to 60% by weight.

The reaction method in the present invention is not particularly limited, but a (dl) -1,2-diol compound, a base, an optically active oxazoline-copper complex catalyst and an organic solvent are charged in a reactor and the carboxylic acid halide compound is stirred. Can be suitably performed by adding.

At this time, the reaction temperature used is (d
l) -1,2-diol compounds, bases, and carboxylic acid halide compounds differ depending on the type, and therefore cannot be generally stated. However, if the temperature is too low, the reaction temperature becomes extremely small, and if the temperature is too high, side reactions are promoted. So normally
It is good to carry out in the range of -50 to 20 ° C, preferably -30 to 0 ° C.

The reaction time is not particularly limited, but 0.1-40 hours is sufficient.

The above reaction in the present invention is carried out under normal pressure, reduced pressure,
It can be carried out in any state of pressurization. Further, the reaction may be carried out in the air, or may be carried out under an atmosphere of an inert gas such as nitrogen, helium or argon.

Thus, a compound in which the hydroxyl group of either isomer of the (dl) -1,2-diol compound is acylated is produced. When an R-form compound is used as the trowel and the optically active oxazoline-copper complex, 1,
In the 2-diol compound, the (S, S) -form is selectively acylated, and the (S, S) -2-acylated 1,2-diol compound derivative and the (R, R) -1,2-diol compound are To generate. On the other hand, when the S-form compound is used as the optically active oxazoline-copper complex, the (R, R) -form is selectively acylated in the 1,2-diol compound,
A (R, R) -2-acylated 1,2-diol compound derivative and a (S, S) -1,2-diol compound are produced.

As a method for isolating and producing the above reaction product,
Any known method can be adopted without any limitation. For example, the reaction solution is poured into water, extracted with methylene chloride, the obtained organic solvent is dried with a desiccant such as magnesium sulfate, the solvent is distilled off, and the residue is subjected to silica gel chromatography to obtain an optically active 2-acyl ester. The compound 1,2-diol compound derivative can be separately produced. The obtained compound is
The optically active 1,2-
It may be used as a diol compound for various purposes such as intermediates for medical and agricultural chemicals.

At this time, the other unreacted isomer, the optically active 2-acylated 1,2-diol compound, is extracted into the organic phase. Therefore, if the non-acylated isomer is required any more, it can be separated and purified by further continuing the separation operation by silica gel chromatography.

[0042]

[Examples] The present reaction will be specifically described below with reference to Examples, but the present invention is not limited thereto. Example 1 In a 30 ml eggplant type flask, 0.214 g (1 mmol) of (dl) -hydrobenzoin, 0.129 g (1 mmol) of diisopropylethylamine, 2,2-isopropylidenebis [(4R) -4-phenyl-2- Oxazoline] copper complex 0.023 g (0.05 mmol) 5
It was dissolved in ml of methylene chloride and stirred. 0 this solution
The mixture was cooled to 0 ° C and 0.070 g of benzoyl chloride (0.
5 mmol) was added dropwise, and on thin layer chromatography,
The reaction was carried out at 0 ° C. until the benzoyl chloride spot disappeared. After completion of the reaction, the reaction solution was poured into 10 ml of water and extracted 3 times with 5 ml of methylene chloride. The extracts were collected and dried over magnesium sulfate, methylene chloride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (developing solution: n-hexane: ethyl acetate = 3:
When separated and purified in 1), 2-benzoyloxy-
0.148 g of 1,2-diphenylethanol (yield 9
6%) acquired. In addition, the optical purity of this compound was measured by liquid chromatography (developing solution: n-hexane: isopropyl alcohol = 5: 1) using an optical resolution column (Chiral Pack OJ manufactured by Daicel Chemical Industries).
It was 9% ee or more, and the absolute configuration was (S, S).

Further, as a result of continuing the separation operation by silica gel column chromatography after obtaining the above compound,
0.107 g of (R, R) -hydrobenzoin (yield 1
I was able to get it. Further, the optical purity of this compound was measured by liquid chromatography (developing solution: n-hexane: isopropyl alcohol = 5: 1) using an optical resolution column (Chiral Pack OJ manufactured by Daicel Chemical Industries), and it was 96% ee. there were.

Examples 2 to 6 The same operation as in Example 1 was carried out except that the (dl) -1,2-diol compound shown in Table 1 was used. The results are shown in Table 2.

[0045]

[Table 1]

Examples 7 to 10 The same operations as in Example 1 were carried out except that the optically active oxazoline-copper complex shown in Table 2 was used as a catalyst. The results are shown in Table 2.

[0047]

[Table 2]

Examples 11 to 12 The same operations as in Example 1 were carried out except that the bases shown in Table 3 were used. The results are shown in Table 3.

[0049]

[Table 3]

Example 13 In a 30 ml eggplant type flask, 0.214 g (1 mmol) of (dl) -hydrobenzoin, 0.010 g (0.05 mmol) of 1,2-diphenylethanol, 0.129 g (1 mmol) of diisopropylethylamine,
2,2-isopropylidene bis [(4R) -4-phenyl-2-oxazoline] copper complex 0.023 g (0.05
(mmol) was dissolved in 5 ml of methylene chloride and stirred. This solution was cooled to 0 ° C., 0.070 g (0.5 mmol) of benzoyl chloride was added dropwise, and the mixture was reacted at 0 ° C. until the spot of benzoyl chloride disappeared on thin layer chromatography. After completion of the reaction, the reaction solution was poured into 10 ml of water and extracted 3 times with 5 ml of methylene chloride. The extracts were collected and dried over magnesium sulfate, methylene chloride was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (developing solution: n-hexane: ethyl acetate = 3: 1). However, 2-benzoyloxy-1,2-diphenylethanol was added to 0.14
9 g (yield 97%) was obtained. In addition, this compound was subjected to liquid chromatography (developing solution: n-hexane: using an optical resolution column (Chiral Pack OJ manufactured by Daicel Chemical Industries)).
When the optical purity was measured with isopropyl alcohol = 5: 1), it was 98% ee, and the absolute configuration was (S, S). Further, a compound in which 1,2-diphenylethanol was benzoylated was not detected at all.

Comparative Example 1 In Example 13, 2,2-isopropylidene bis
0.023 g of [(4R) -4-phenyl-2-oxazoline] copper complex was added to 0.03 g of (S) -1-methyl-2-[(dihydroisoindol-2-yl) methyl] pyrrolidine
Example 1 except that it was replaced with 01 g (0.05 mmol)
The same operation as 3 was performed.

As a result, the yield of (S, S) -2-benzoyloxy-1,2-diphenylethanol was 0.1.
It decreased to 34 g (yield 87%). In addition, 0.015 g of 1-benzoyloxy-1,2-diphenylethane was obtained.

[0053]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active diol compound, which is an important compound as a ligand of an intermediate for medicines and agricultural chemicals or a catalyst, is prepared by combining an optically active derivative in which only one hydroxyl group is acylated with Unacylated 1,
It can be optically resolved efficiently with a 2-diol compound. At that time, each optically active compound can be obtained in high yield and high optical purity. Moreover, it is used as a raw material (dl)
The presence of monoalcohol in the -1,2-diol compound has no effect on the reaction.

That is, the present invention is a very useful resolution method for obtaining an optically active diol compound.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07M 7:00 C07M 7:00 F term (reference) 4H006 AA02 AC48 AC81 BA05 BA37 BA46 BB12 BJ20 BJ50 BM30 BM72 BN10 BN20 BP30 KA14 KC30 4H039 CA66 CD10

Claims (3)

[Claims] 1. The following general formula (I): (However, each R ¹ independently represents an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a benzyl group.) In the presence of an optically active oxazoline-copper complex catalyst and a base, (dl) -1, An optically active 2-acylated 1,2-diol compound characterized by reacting a 2-diol compound with a carboxylic acid halide compound to separate an optically active 2-acylated 1,2-diol compound derivative from a reaction solution. Method for producing derivative. 2. A method for producing an optically active 1,2-diol compound, which comprises separating the optically active 1,2-diol compound from the reaction solution obtained by the method of claim 1. 3. An optical resolving agent comprising an optically active oxazoline-copper complex represented by the general formula (I).