JPH01213234A - Optically active reducing agent and production thereof - Google Patents

Abstract

PURPOSE:To obtain the subject reducing agent of high optical purity, consisting of a clathrate complex of cyclodextrin and a reducing agent, capable of carrying out asymmetric reduction in high yield by using an inexpensive and readily available raw material and contriving increase in stability, etc., and useful as a synthetic intermediate for physiologically active substances, etc. CONSTITUTION:An optically active reducing agent consisting of a clathrate complex of cyclodextrin or a derivative thereof and a reducing agent. The reducing agent is included by a method for adding an aqueous solvent or organic solvent in an amount of normally 0.05-10 times based on the cyclodextrin or derivative thereof thereto, converting the resultant mixture into a pasty form, then adding the reducing agent to be included and thoroughly kneading the mixture. As an alternative method, a saturated aqueous solution of the cyclodextrin is prepared and the reducing agent to be included is added thereto and mixed to precipitate the resultant clathrate complex, which is then recovered to afford the aimed complex. Furthermore, ratio of the cyclodextrin and reducing agent used is preferably >=0.5mol. reducing agent based on 1mol. cyclodextrin.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application 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 ART 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. Also,
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 catalysts and reducing agents themselves, and the use of expensive natural extracts, making them uneconomical. Due to its low properties, it is currently rarely 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. This is something that was done for that purpose.

Means for Solving the Problems As a result of intensive research to develop an optically active reducing agent having the above-mentioned favorable properties, the present inventors have developed a method using inexpensive and easily available cyclodextrins and ordinary reducing agents. The inventors discovered that the objective could be achieved by forming an inclusion complex, and based on this knowledge, they completed the present invention.

That is, the present invention provides an optically active reducing agent comprising an inclusion complex of cyclodextrin or a derivative thereof and a reducing agent.

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 a cyclic dextrin obtained by the action of special microorganisms or enzymes on starch or dextrin, and its characteristic is that it has a donut-shaped molecular structure, with a diameter of approximately 6 to 1 mm inside.
It is to have 0 cavities. Cyclodextrins have a
-Three types of cyclodextrin, β-cyclodextrin, and γ-cyclodextrin are currently isolated industrially, but in the present invention, any of these three types may be used, or a mixture of these may be used. 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 white compound can be maintained.

Such cyclodextrin derivatives include, for example, 2,3,6-trimethyl-α-9β- and γ-cyclodextrin; 2,6-dimethyl-σ-9β- and γ-cyclodextrin;
-Cyclodextrin; 2,6-dicarboxymethyl-tricarboxymethyl-σ-1β- and γ-cyclodextrin; between the 6-positions -o C-C>-CO-1+
OC% C0-1-+ozs-+koΣko÷, +02
ff-, β- and γ-cyclodextrin cap compounds linked by groups such as S h O1+Ox S -Q-+-7CHβ-1-0, S +CH-CH+S Oβ-; aminoalkyl group, aminoalkylamino group,
Examples include polyα-9β- and γ-cyclodextrins having carboxylmethyl groups, aminoalkyl sulfide groups, and the like. 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, the reducing agent used in the present invention is not particularly limited 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 types may be used.
You may use combinations of more than one species.

Among the above-mentioned known reducing agents, borohydride metal salts such as sodium borohydride and potassium borohydride and Lewis base complexes of poran are preferred, and Lewis base complexes of poran are particularly preferred. This Lewis base complex of poran can be produced, for example, by adding various amines to a solution of poran in tetrahydrofuran or a metal borohydride solution ["Journal of the Society of Organic Synthetic Chemistry" No. 44]
Vol., pp. 896-906 (1986)]. Examples of the Lewis base complexes of poran include ammonia porane, borane complexes of mono-, di-, and trialkylamines such as t-butylamine, diethylamine, trimethylamine, and methylpropylamine; cyclohexylamine and bicyclo[3,3,1] Poran complexes of cycloalkylamines such as nonylamine; borane complexes of heterocyclic compounds such as pyridine, quinoline, inquinoline, aminopyridine, 2,6-lutidine, and N-phenylmorpholine;
Examples include poran complexes of aromatic amines such as aniline and dimethylamine. These Lewis base complexes of poran 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 crosstalk method, an aqueous solvent or an organic solvent is usually added to the cyclodextrin or its derivative at a concentration of 0.0S to 1S.
An optically active reducing agent can be produced by adding 0 times the amount by weight to form a paste, adding the reducing agent to be included therein, and thoroughly kneading the mixture. Examples of the organic solvent include various ethers, dimethylacetamide,
Hexamethylphosphoric triamide, dimethylformamide, etc. can be used. Further, the kneading time is usually selected in 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 crosstalk 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, a saturated aqueous solution of cyclodextrin or its derivatives is first prepared, a reducing agent for inclusion is added thereto, and the mixture is stirred for usually 30 minutes to 12 hours, preferably 1 to 4 hours, to form an inclusion complex. After precipitating the
By recovering, an optically active reducing agent can be produced.

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 when it is poured into hot water or treated with diethyl ether, signals originating from the clathrated compounds are observed. It is clear that the reducing agent is included in the powder.

The ratio of the cyclodextrin or its derivative and the reducing agent used varies depending on the combination of the two, but the intended 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 it is a compound containing two molecules, 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.

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 an optically active reduction product can be obtained by treating a brochiral substance to be reduced. For example, it can be suitably used to produce optically active substances that are important as intermediates in the synthesis of physiologically active substances and ferroelectric substances. In addition, the inclusion complex of the present invention can be used in the formulation aspect of products in the field of chemicals that require high stability against rapid oxidative decomposition of reducing agents, etc.
It can also be used to increase stability in use.

Furthermore, by including the reducing agent in cyclodextrin or its derivative, the reducing agent can be isolated, 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.
The present invention is not limited in any way by these examples.

Example 1 Complex 209 was added to α-cyclodextrin 2109 in 1.51 l of water, stirred for about 2 hours, then allowed to cool to room temperature, and the resulting precipitate was filtered to obtain an inclusion complex. The prime quantity after washing with cold water and air drying is +909, l:o
, the theoretical yield as 5 bodies was 2209, so the yield was about 86%.

The IR spectrum of this inclusion complex by the KBr method is shown in the first
As shown in the figure. In this figure, the characteristic absorption of pyridine porane is 685 cm-', 750 cm-', 920 (small) cm
-', 109109O', +170 (δB-H) c
m-', 1455 (y II-N) cm-', IN8
cm-', 23FO(Vl-M) CrR-' overlaps with α-cyclodextrin except for the last absorption.

On the other hand, FIG. 2 shows the Tomo H-NMR spectrum (in DMSO-ds). In this figure, the absorption derived from σ-cyclodextrin is well separated from the absorption derived from pyridine-borane, and a comparison of the integral values reveals that it is a 1:O,S complex. In addition, 156".

8.6-"l'1BHsj:,?,6~L4ppm('
) The absorption is ■ of the pyridine nucleus, and the others are protons derived from a-cyclodextrin.

Moreover, the powder X-ray diffraction spectrum is shown in FIG.

It is clear from this figure that it gives a spectrum completely different from that of σ-cyclodextrin.

From these results, it can be confirmed that the obtained complex is an inclusion compound consisting of one molecule of a-cyclodextrin and 0.5 molecules of pyridine poran.

Example 2 β-Cyclodextrin 1309 was added to water 5a and heated to 50 to 60°C while stirring to obtain a homogeneous solution. After cooling to 30°C, t-butylamine/
Poran 109 was added, stirred at the same temperature for about 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.

From this result, it is considered that the inclusion complex is a 1:l clathrate and contains about two water molecules in one molecule. In addition, in the IR spectrum, the characteristic absorptions of t-butyl porane are 440 cm-', 860 cm-', and 10010 cm-'.
0O', 1120cm-', 1170 (δm-o)
Cm-', eye 00cm-', eye 7G (v 1l-N)
cm-', 2360 (11,-,I) cm-Oni overlaps with the absorption of β-cyclodextrin except for the last absorption. In the '11-NMR absorption spectrum of DMSO-d, methyl and B11. absorption appears at 2 to 3 ppm, and from the integrated intensity ratio of the two,
It became clear that it was a 1:1 complex.

Furthermore, the X-ray diffraction pattern was also different from that of β-cyclodextrin.

Example 3 - 500 tl of water was added to γ-cyclodextrin 2709 to form a slurry, 1-naphthylamine-poran complex 359 was added thereto, and after kneading at room temperature for 5 hours,
This was washed with cold ethyl nityl and cold water, and then air-dried to obtain an inclusion complex. The elemental analysis values of this material are shown below.

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 2365cII+-' (ν81), which is caused by l-naphthylamine poran.
Other absorptions overlap with those derived from γ-cyclodextrin. In addition, in the 'H-NMR absorption spectrum in DMSO-da, it is separated from the absorption due to γ-cyclodextrin at 2.5 to 6.5 ppm, and 7 to 1 molecule of truffle has 1 l-naphthylamine poran. It turns out that it is an inclusion compound containing .08 molecules.

Example 4 Tri-0-methyl β-cyclodextrin 3009 was dissolved in 10100O of water, 5-methylpentahydropyridyl poran complex 259 was added thereto, stirred at room temperature for 2 hours, heated to 50°C, and the resulting The precipitate was filtered, washed with hot water, and air-dried to obtain a complex. The elementary yield is 2
809, yield was 86%. Similar to Example 1,
This product was subjected to elemental analysis, IR and 'If-NMR spectroscopy, and powder X-ray diffraction, and these results confirmed that the complex was a 1:1 clathrate.

Example 5 Polyβ-cyclodextrin 5 with an average molecular weight of 5500
00g in water 5a and stirred while heating to 50-60°C. After cooling the obtained solution to 40°C, N-
Methylmorpholine-poran complex 509 was added, stirred for about 4 hours, and then allowed to cool to room temperature or below. The resulting precipitate was filtered, washed with cold water, and air-dried to obtain a complex. The elementary yield is 5
209 (yield: 95%). Elemental analysis, IR and 1-NMR spectroscopy, and powder X-ray diffraction were conducted in the same manner as in Example 1, and from these results, it was found that the complex was 1:
It was confirmed that it is an inclusion compound of 1.

Reference Example After dispersing the inclusion complex powder +109 of σ-cyclodextrin and pyridine poran obtained in Example 1 in a saturated saline solution, methyl n-hexyl ketone 139 was added thereto and 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 added to a silica gel column and 20% by weight hexane.
It was separated and purified using a methylene chloride solution containing . The yield was 96%, the [α]D2s measured at a concentration of 1.19/1oOd in ethanol was +5.51, and the optical purity was 56%.
% of [5]-2-octatool. Also, this one

[Brief explanation of the drawing]

FIG. 1 shows an example of the a-cyclodextrin-pyridine poran inclusion complex of the present invention and the I of pyridine poran.
R spectrum diagram, Figure 2 shows the 'H-NM of the inclusion complex.
R spectrum and FIG. 3 are X-ray diffraction spectra of the inclusion complex and α-cyclodextrin. Patent applicant: Director of the Agency of Industrial Science and Technology Kozo Iizuka Figure 1 4000 3000 2000 1500
1000 “OCM”

Claims (1)

[Scope of Claims] 1. An optically active reducing agent comprising an inclusion complex of cyclodextrin or a derivative thereof and a reducing agent. 2. Production of an optically active reducing agent comprising an inclusion complex of a cyclodextrin or a derivative thereof and a reducing agent, which is characterized by including the reducing agent in a cyclodextrin or a derivative thereof in the presence of an aqueous or organic solvent. Method.