JPH0259130B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel optically active reducing agent and a method for producing the same. More specifically, the present invention relates to an optically active reducing agent useful in producing optically active substances that are important as synthetic intermediates such as physiologically active substances and ferroelectric substances, and a method for efficiently producing the same. It is. BACKGROUND TECHNIQUE Conventionally, the simplest method for producing optically active compounds by asymmetric reduction is known to be a method in which a normal non-optically active reducing agent is reduced in the coexistence of an optically active catalyst. Methods using quinine, its derivatives, optically active quaternary ammonium salts, bovine serum albumin, etc. as optically active catalysts have been proposed. Furthermore, a method of asymmetric reduction using an optically active reducing agent such as an optically active 1,4-dihydronicotinamide derivative has also been attempted. However, all of these methods have drawbacks such as low optical yield of the product, difficulty in obtaining the catalyst and reducing agent themselves, and the use of expensive natural extracts. Due to its low economic efficiency, it is currently hardly used except for the production of special compounds. Problems to be Solved by the Invention Under these circumstances, the present invention is directed to an asymmetric reduction that can be carried out in high yield using inexpensive and easily available raw materials, and that provides a product with high optical purity. The purpose of this invention is to provide an economically advantageous optically active reducing agent that can be used as an optically active reducing agent. Means for Solving the Problems As a result of extensive research in order to develop an optically active reducing agent having the above-mentioned preferable properties, the present inventors have found that they can use cyclodextrins, which are inexpensive and easily available, and ordinary reducing agents. The inventors have discovered that this objective can be achieved by forming an inclusion complex, and have completed the present invention based on this knowledge. That is, the present invention provides an optically active reducing agent for carbonyl compounds comprising an inclusion complex of cyclodextrin or a derivative thereof and an amine borane complex. According to the present invention, the optically active reducing agent can be produced by including the reducing agent in cyclodextrin or a derivative thereof in the presence of an aqueous or organic solvent. The present invention will be explained in detail below. The cyclodextrin used in the present invention is
It is a cyclic dextrin obtained by the action of special microorganisms or enzymes on starch or dextrin, and its characteristic feature is that it has a donut-shaped molecular structure and a cavity with a diameter of about 6 to 10 Å inside. Currently, three types of cyclodextrin are industrially isolated, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, depending on the number of constituent units of d-glucose, but in the present invention, Any of these three types may be used, or a mixture thereof may be used. In addition, modified cyclodextrins in which appropriate chemical groups are introduced into the side chains of these cyclodextrins, and polycyclodextrins in which cyclodextrins are cross-linked with epichlorohydrin or methacrylamide, or are not cross-linked, do not hinder inclusion. , and can be used as long as the reducing ability of the clathrate compound can be maintained. Such cyclodextrin derivatives include:
For example, 2,3,6-trimethyl-α-, β- and γ-cyclodextrin; 2,6-dimethyl-
α-, β- and γ-cyclodextrin; 2,
6-dicarboxymethyl-α-, β- and γ-cyclodextrin; 2,3,6-tricarboxymethyl-α-, β- and γ-cyclodextrin;

【formula】

【formula】

【formula】

【formula】

【formula】

α-, β-, and γ-cyclodextrin cap compounds linked by groups such as; poly α-, β-, and γ- having aminoalkyl groups, aminoalkylamino groups, carboxylmethyl groups, aminoalkyl sulfide groups, etc. Examples include cyclodextrin. These cyclodextrins and their derivatives are known to form clathrates with various substances, such as hydrocarbons, due to their donut-shaped molecular structure composed of glucose. On the other hand, regarding the reducing agent used in the present invention,
There are no particular limitations as long as it forms a stable inclusion complex with cyclodextrin or its derivatives and does not lose its reducing ability. For example, one type of reducing agent having such properties may be arbitrarily selected from known reducing agents, or two or more types may be used in combination. Among the above-mentioned known reducing agents, borohydride metal salts such as sodium borohydride and potassium borohydride and Lewis base complexes of borane are preferred, and Lewis base complexes of borane are particularly preferred.
This Lewis base complex of borane can be produced, for example, by adding various amines to a solution of borane in tetrahydrofuran or a metal borohydride solution ["Journal of the Society of Organic Synthetic Chemistry" No. 44]
Volume, pp. 896-906 (1986)]. Examples of the Lewis base complex of borane include ammonia borane, monomers such as t-butylamine, diethylamine, trimethylamine, and methylpropylamine;
Borane complexes of di- and trialkylamines; borane complexes of cycloalkylamines such as cyclohexylamine and bicyclo[3,3,1]nonylamine; pyridine, quinoline, isoquinoline, aminopyridine, 2,6-lutidine, N-fluorane Borane complexes of heterocyclic compounds such as enylmorpholine; aniline, dimethylaniline, 4-methyl-N-ethylaniline, 1-naphthylamine, 8-ethyl-
Examples include borane complexes of aromatic amines such as N-methyl-2-naphthylamine. These Lewis base complexes of borane may be used alone or in combination of two or more, and are not necessarily complexes with optically active amines. It may also be a complex with The optically active reducing agent of the present invention can be produced by including these reducing agents in the cyclodextrin or its derivative. There is no particular restriction on the method of inclusion, but a kneading method or a solution method is usually used. In the kneading method, an aqueous or organic solvent is usually added to the cyclodextrin or derivative.
After adding 0.05 to 10 times the weight and making it into a paste,
An optically active reducing agent can be produced by adding a reducing agent to be included and thoroughly kneading the mixture. As the organic solvent, for example, various ethers, dimethylacetamide, hexamethylphosphoric triamide, dimethylformamide, etc. can be used. Also, the kneading time is usually
The kneading time is selected within the range of 0.5 to 12 hours, preferably 2 to 8 hours, and the kneading temperature is not particularly limited, but room temperature is usually sufficient. Note that depending on the cyclodextrin derivative, the temperature may be changed depending on the kneading time. As the kneading device, for example, a crusher, a ball mill, a disper mill, an emulsifier, etc. are used. On the other hand, in the solution method, first a saturated aqueous solution of cyclodextrin or its derivatives is prepared,
Add the reducing agent for inclusion to this, and usually for 30 minutes or
An optically active reducing agent can be produced by stirring for 12 hours, preferably 1 to 4 hours to precipitate the inclusion complex, and then recovering it. The inclusion complex thus obtained is dried by a known method, such as a spray drying method or a vacuum drying method. The odor unique to each reducing agent has disappeared from the resulting powder, but if it is poured into hot water or treated with diethyl ether, it will emit the odor of being clathrated again, and the clathrate will dissolve. When the powder is dissolved in a solvent and H nuclear magnetic resonance is measured, a signal derived from the clathrated compound is observed, so it is clear that the reducing agent is clathrated in the powder. The ratio of the cyclodextrin or its derivative and the reducing agent differs depending on the combination of the two, but the target inclusion complex contains 0.5 to 0.5 to 1 reducing agent molecules in the cavity of one molecule of the cyclodextrin or its derivative. Since the compound is packaged in two pieces, it is desirable to use 0.5 mole or more of the reducing agent per mole of cyclodextrin or its derivative. The composition of the optically active reducing agent composed of the inclusion complex thus obtained can be confirmed by elemental analysis, NMR, IR, etc. The optically active reducing agent of the present invention can be used to reduce a carbonyl compound to an optically active alcohol according to the following formula. Such carbonyl compounds include, for example, ketols such as acetol and benzoin; aliphatic ketones such as methylcyclopropyl ketone; unsaturated ketones such as ethylheptenone; alicyclic ketones such as 2-cyanoethylcyclopentanone;
Heterocyclic ketones such as tropinone and pyrazolone; aminoketones such as adrenalone; keto acids and esters such as levulinic acid; diketones such as diacetyl; ferrocenyl ketones such as methylferrocenyl ketone; phenyl trifluoro Examples include halogen-substituted ketones such as methyl ketone. Effects of the Invention The optically active reducing agent of the present invention is an inclusion complex of a cyclodextrin or a derivative thereof and a reducing agent, and is capable of obtaining an optically active reduction product by treating a prochiral substance to be reduced. is possible,
For example, it is suitably used to produce optically active substances that are important as intermediates in the synthesis of physiologically active substances and ferroelectric substances. Moreover, the inclusion complex of the present invention is
It can also be used to increase stability in the formulation and use of products in the field of chemicals, which requires high stability against rapid oxidative decomposition of reducing agents. Furthermore, by including the reducing agent in cyclodextrin or its derivative, isolation of the reducing agent,
It can also be purified and stabilized. Note that after the reaction is completed, the cyclodextrin or its derivatives can be easily recovered and purified using an appropriate solvent and reused. Examples Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples in any way. Example 1 210g of α-cyclodextrin was placed in 1.5ml of water and heated to 25-30°C while stirring to form a homogeneous solution.Next, 20g of pyridine-borane complex was added to this, and after stirring for about 2 hours, The mixture was allowed to cool to room temperature, and the resulting precipitate was filtered to obtain an inclusion complex. The elementary yield after washing with cold water and air drying was 190 g, and the theoretical yield as a 1:0.5 product was 220 g, so the yield was about 86%. Figure 1 shows the IR spectrum of this inclusion complex measured by the KBr method. In this figure, the characteristic absorption of pyridine borane is 685 cm ^-1 , 750 cm ^-1 , 920 (small) cm
^-1 , 1090cm ^-1 , 1170 (δ _BH ) cm ^-1 , 1455 (ν _BN ) cm
^-1 , 1618 cm ^-1 , and 2370 (ν _BH ) cm ^-1 overlap with α-cyclodextrin except for the last absorption. On the other hand, ^{the 1} H-NMR (in DMSO- _d6 ) spectrum is shown in Figure 2. In this figure, the absorption derived from α-cyclodextrin is well separated from the absorption derived from pyridine/borane, and a comparison of the integral values reveals that it is a 1:0.5 complex. In addition, 8.56 ^W and 8.6 ^-W are BH ₃ , absorption of 7.6 to 8.4 ppm is H of the pyridine nucleus, and the others are protons derived from α-cyclodextrin. Moreover, the powder X-ray diffraction spectrum is shown in FIG. It is clear from this figure that it gives a completely different spectrum from α-cyclodextrin. From these results, the obtained complex is composed of one molecule of α-cyclodextrin and pyridine borane.
It can be confirmed that it is an inclusion compound consisting of 0.5 molecules. Example 2 130 g of β-cyclodextrin was added to 5 ml of water and heated to 50-60°C while stirring to obtain a homogeneous solution. After cooling to 30°C, 10 g of t-butylamine borane was added to the solution. The mixture was stirred at the same temperature for 2 hours, then cooled to room temperature, the resulting precipitate was filtered, and purified in the same manner as in Example 1 to obtain an inclusion complex. The elemental analysis values of this material are shown below.

[Table] From this result, it is considered that the inclusion complex is a 1:1 clathrate compound and contains about two water molecules in one molecule. Also, in the IR spectrum,
Characteristic absorption of t-butyl borane 440cm ^-1 , 860cm
^-1 , 1000cm ^-1 , 1120cm ^-1 , 1170 (δ _BH )cm ^-1 , 1400
cm ^-1 , 1470 (ν _BN ) cm ^-1 , and 2360 (ν _BH ) cm ^-1 overlap with the absorption of β-cyclodextrin except for the last absorption. ^1H -NMR in DMSO- _d6
The absorption spectrum shows absorption due to β-cyclodextrin at 3 to 6 ppm and separated methyl and
Absorption by BH ₃ appeared at 2 to 3 ppm, and the ratio of their integrated intensities revealed that it was a 1:1 complex. Furthermore, the X-ray diffraction pattern was also different from that of β-cyclodextrin. Example 3 Add 500 ml of water to 270 g of γ-cyclodextrin to make a slurry, add 35 g of 1-naphthylamine borane complex, knead at room temperature for 5 hours, and wash with cold ethyl ether and cold water. and air-dried to obtain an inclusion complex. The elemental analysis values of this material are shown below.

[Table] From this result, it is considered that the inclusion complex is a 1:1 clathrate compound and contains 2 to 3 water molecules in one molecule. The IR spectrum also shows an absorption of 2365 cm ^-1 (ν _BH ) due to 1-naphthylamine borane, but other absorptions overlap with absorption derived from γ-cyclodextrin. Also, DMSO-d ₆
In the ^1H -NMR absorption spectrum, 2.5~
Separated from the absorption caused by γ-cyclodextrin at 6.5 ppm, the absorption of naphthylamine/borane appears at 7 to 8.6 ppm, but from their intensity ratio,
For one molecule of γ-cyclodextrin, 1-
It can be seen that it is an inclusion compound containing 1.08 molecules of naphthylamine borane. Example 4 Tri-O-methyl β-cyclodextrin
Dissolve 300g in 1000ml of water, add 25g of 5-methylpentahydropyridyl borane complex,
After stirring at room temperature for 2 hours, heat to 50℃,
The resulting precipitate was filtered off, washed with hot water, and air-dried to obtain a complex. The elementary yield was 280 g, and the yield was 86%. As in Example 1, elemental analysis of this material,
IR and ¹ H-NMR spectroscopy and powder X-ray diffraction were performed, and from these results, the complex was 1:1
It was confirmed that it is a clathrate compound. Example 5 500 g of polyβ-cyclodextrin with an average molecular weight of 5500 was added to water 5 and stirred while heating to 50 to 60°C. The resulting solution was cooled to 40°C, and then 50 g of N-methylmorpholine borane complex was added. The mixture was stirred for about 4 hours, and then allowed to cool to below room temperature. The resulting precipitate was filtered, washed with cold water, and air-dried to obtain a complex. Elementary yield is 520g (yield is 95%)
It was hot. Elemental analysis, IR and ¹ H-NMR spectroscopy, and powder X-ray diffraction were performed in the same manner as in Example 1, and these results confirmed that the complex was a 1:1 clathrate. Reference Example After dispersing 110 g of the clathrate complex powder of α-cyclodextrin and pyridine borane obtained in Example 1 in a saturated saline solution, 13 g of methyl n-hexyl ketone was added thereto, and the mixture was stirred for 20 hours. Ta. Next, after filtering off the inclusion complex, the product was extracted with diethyl ether. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified using a silica gel column and a methylene chloride solution containing 20% by weight of hexane. Yield is 96
%, [α] _D ²⁵ measured at a concentration of 1.1 g/100 ml in ethanol is +5.51, and [S]- with an optical purity of 56%.
It was 2-octanol. Moreover, the elemental analysis values of this product were as follows.

【table】 [Brief explanation of the drawing]

Figure 1 is an IR spectrum diagram of an example of the α-cyclodextrin-pyridine-borane inclusion complex of the present invention and pyridine-borane, Figure 2 is a 1 H-NMR spectrum diagram of the inclusion complex, and Figure 2 is a ^1H -NMR spectrum diagram of the inclusion complex. Figure 3 is an X-ray diffraction spectrum diagram of the inclusion complex and α-cyclodextrin.

Claims (1)

[Scope of Claims] 1. An optically active reducing agent for carbonyl compounds comprising an inclusion complex of cyclodextrin or a derivative thereof and an amine borane complex. 2. A method for producing an optically active reducing agent for carbonyl compounds, which comprises including an amine borane complex in a cyclodextrin or a derivative thereof in the presence of an aqueous or organic solvent.