JPH01213235A - Production of optically active alcohol - Google Patents

Abstract

PURPOSE:To obtain the subject compound which is a synthetic intermediate for neurontransmitters, antitumor substances, etc., in high optical purity, by bringing a specific carbonyl compound into contact with a reducing agent complex prepared by including a reducing agent in cyclodextrin using a readily available and inexpensive raw material. CONSTITUTION:A reducing agent complex prepared by including a reducing agent in cyclodextrin in a powdery form is directly dispersed in a supersaturated aqueous solution of various inorganic salts or organic solvent by cutting off light and a carbonyl compound having an optional organic residue without interfering reductive reaction is added and reacted therewith at -60-90 deg.C, preferably -20-50 deg.C for 5-100hr to afford the aimed compound. Furthermore, the reducing agent used is preferably a Lewis base complex of borane. The clathrate compound of the reducing agent is obtained by, e.g., adding water (in an amount of about 0.1-6 times based on the cyclodextrin) to the cyclodextrin and kneading the resultant pasty mixture with a reducing agent compound to be included.

Description

[Detailed Description of the Invention] Industrial Application Field The present invention provides a method for synthesizing optically active secondary alcohols, which are important as intermediates for the synthesis of physiologically active substances such as neurotransmitters, antitumor substances, and insect pheromones. It is.

Therefore, it is suitable not only for medical and agrochemical related industries but also for fields related to sensor utilization.

Prior Art and Problems The simplest method to obtain optically active alcohols is to reduce carbonyl compounds such as ketones, ketoesters, and keto acids using ordinary reducing agents in the coexistence of optically active catalysts. It is publicly known. For example, methods using quinine or its derivatives, optically active quaternary ammonium salts, or bovine serum albumin as catalysts have been proposed. However, it has drawbacks such as low optical yield of the product, difficulty in synthesizing the catalyst, and the need to use expensive natural extracts. Furthermore, a method for synthesizing an optically active secondary alcohol using cyclodextrin, which has recently become easier to obtain, was proposed. (N, Baba, Y.

Matsumura, T., Sugimoto Te.
trahed, Lett,, (44) 4281
-4284 (1978): R. Fornasier.
F, Ren1evo, P, Scrim
in, U.

Toneilato; J, Org, Chem,
, 50. , 3209-3211 (1985)], which uses a cyclodextrin inclusion complex of a carbonyl compound, but the optical yield of the product was low. Furthermore, a method of reducing a carbonyl compound using an optically active reducing agent is also well known. That is, optically active 1.
4-dihydronicotinamide derivative-71M Since it is not easily available as a base agent and has high optical purity, it is not economical except for the synthesis of special compounds.

The present inventors have conducted extensive research to solve the above problems, and have found that asymmetric reduction of carbonyl compounds can be achieved with high yield even when using inexpensive and easily available cyclic oligosaccharides and ordinary reducing agents. It has been found that a secondary alcohol with high optical purity can be obtained.

The present invention was completed based on this knowledge.

In order to solve the problem, the present invention includes a reducing agent in cyclodextrin, and then disperses and reacts it in a solution containing carbonyl compounds such as ketones, ketoesters, and keto acids to produce optically active secondary alcohols. were successfully synthesized with high optical purity. Incidentally, after the reaction is completed, the cyclodextrin can be easily recovered and purified by filtering and washing, and can be reused.

represents the general formula R'COR2 (where R' % R2 is any organic residue that allows the compound of the formula to exist stably and does not prevent inclusion with cyclodextrin and does not prevent the reduction of the carbonyl group. These organic residues, which may be interconnected to form a ring, include nitro group, cyano group, halogen group, amino group, carboxyl group, carbonyl group, hydroxyl group, alkoxy group, aryloxy group, thio group. Alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkenyl, alkylcarbonyl, arylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkylcarbonyl, substituted or unsubstituted with a hydroxyl group, ferrocenyl group, etc. Alkoxycarbonyl, aryloxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, aralkenylcarbonyl, aralkinoxy The carbonyl group of the raw material used in the present invention,
(as a compound containing at least one compound in the molecule)
It is something that can be done.

For example, α- and β-1γ-ketols such as acetol, acetoin, acetoethyl alcohol, diacetone alcohol, phenacyl alcohol, benzoin; methyl ethyl ketone, propyl butyl ketone, methyl isopropyl ketone, methyl butyl ketone, binacolon, cyclopropyl methyl Aliphatic ketones such as ketones; methyl vinyl ketone, mesityl oxide, methyl hebutenone,
Unsaturated ketones such as asymmetrically substituted products of 4-(1-naphthyl)-3-buten-2-one, benzalacetone, and dibenzalacetone: 2-chloromethylcyclobutanone, 3-cyanoethylcyclopentanone, 3-nitro- 5-allylcyclohexanone, 3-methoxycyclohexanone, terpene ketone (camphor, fenchen), spiro (3,4
) Alicyclic ketones such as octanone-5 and steroid ketones; non-St-substituted carbonyl groups and carboxyl groups of acetophenone, propiophenone, butyrophenone, valerophenone, and benzophenone. However, asymmetrically substituted ketones, flavanones, 1.2.3.4-tetrahydro-4-ketophenanthrene, asymmetrically substituted xanthones, aromatic ketones such as 1.2.6.7-dibenzfluorenone, acetothienone and acetofuron Heterocyclic ketones such as , trobinone, pyrazolone, 4-methyl-5-acetylthiazole: adrenalone and 2.7-
Aminoketones such as diamitacridone; pyruvic acid, benzoylformic acid, phenylpyruvic acid, acetoacetic acid,
α- and β-1γ-keto acids and esters such as benzoylacetic acid, levulinic acid, 3-benzoylpropionic acid;
There are diketones such as diacetyl and benzyl. Also, 7 erocenyl ketones such as methylferrocenyl ketone and 4-7 erocenyl-3-buten-2-one: phenyl trifluoromethyl ketone, naphthyl chloromethyl ketone, anthryl bromomethyl ketone, chlorophenylethyl ketone, bromophenyl methyl ketone , naphthyl trifluoromethyl ketone, and 1; 1-substituted ketones -ft,'! ': can be given.

Among known reducing agents for carbonyl groups, the reducing agent used in the present invention may be any single one or 21 or more which forms a stable clathrate with cyclodextrin.
Can be used in combination of 1i or more.

However, depending on the raw material carbonyl compound, its substituent may change depending on the reducing agent, so it should be selected as appropriate and necessary. These known reducing agents and their characteristics are listed in the full volume of Nippon Chemistry, Experimental Chemistry Course 17 (Part 2) pi-1.
19, May 1950, Marukubi and Nippon Chemistry complete edition, Experimental Chemistry Course 19, p92-154, May 1960, detailed about Marukubi, preferred is the Lewis base complex of borane,
For example, it can be synthesized by adding various amines to a solution of borane in tetrahydrofuran or a metal borohydride solution.

[Yoshihisa Okamoto; Organic Synthetic Chemistry, 44(10), 896-9
06 (1986)), they include ammonia borane, t-butylamine, diethylamine, trime-4LI.
I-F y %7 J 4 II
--/F-I L/II Mako +7
Borane complexes of cycloalkylamines such as dichlorohexylamine and bicyclo[3,3,1]nonylamine; pyridine, quinoline, inquinoline, aminopyridine, 2,6-lutidine, Borane complexes of heterocyclic compounds such as N-phenylmorpholine, borane complexes of aromatic amines such as nearaniline, dimethylaniline, 4-methyl-N-ditylaniline, 1-naphthylamine, and 8-nityl-N-methyl-2-naphthylamine. be. Incidentally, from the spirit of the present invention, it is not necessary to be a complex with optically active amines, but it may be a complex of optically active amines.

The cyclodextrin used in the present invention is a cyclic dextrin obtained by the action of special microorganisms or enzymes on starch or dextrin.Its characteristic is that it has a donut-shaped molecular structure, and inside the cyclodextrin there is a
It is to have a cavity for 10 people. Cyclodextrins are complexed with borane of d-glue, di-, and trialkylamines, and 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 insolubilized, do not interfere with clathration and do not interfere with the reducing action of clathrate compounds. can be used as long as possible. That is, it is known that cyclodextrin forms clathrates with various substances, such as hydrocarbons, as a characteristic of its doughnut-shaped molecular structure composed of glucose.

There are various methods for inclusion, including the crosstalk method and the solution method.

In the cross-mixing method, water (approximately 0.1 to 6 times the weight of cyclodextrin) is added to cyclodextrin, and a reducing agent compound to be included in zero-order to form a paste is added and thoroughly kneaded. The kneading time is about 1 to 12 hours, preferably 2 to 8 hours, and the mixing time is about 1 to 12 hours, preferably 2 to 8 hours,
．． ,1%11Z+L//Yō1//)44V”kLgh-
V. A saturated aqueous solution of cyclodextrin is prepared, a reducing agent compound is added thereto, and the mixture is stirred for 30 minutes to 12 hours, preferably 1 to 4 hours, to obtain the clathrate compound as a precipitate.

The obtained clathrate compound can be used as it is, but if necessary, it may be dried by various methods, including spray drying and vacuum drying. The odor unique to each reducing agent compound has disappeared from the resulting powder, but when it is poured into hot water or treated with diethyl ether, it re-emits the odor of the clathrate compound. When the powder is dissolved in a dissolving 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 compound is clathrated in the powder.

1. The clathrate compound of the reducing agent thus obtained is shielded from light and left as a powder in the form of a supersaturated aqueous solution of various inorganic salts. , ゎえに；２. J1~90"C1□1oyoichi20'C~so"
React for 30 minutes to 150 hours, preferably 5 to 100 hours at It should be selected appropriately depending on the stability of the secondary alcohol produced. After the reaction, the cyclodextrin inclusion complex is appropriately removed, and the desired optically active alcohol is extracted with a suitable solvent such as diethyl ether. A second alcohol is obtained.

In addition, the inorganic salts used in the supersaturated aqueous solution of the present invention are those that do not interfere with the stability of the cyclodextrin complex powder of the reducing agent compound and the dispersibility in the solvent, and do not interfere with the reduction of the carbonyl group. All can be used alone or in combination of two or more. That is, Li%Nas K, Rb
s Alkali metals such as Cs, steps, Mg, Ca
, Sr, Ba and other alkaline earth metal groups, and F,
Halogens such as CI, Br, 1, and organic acids such as acetic acid, monochloroacetic acid, toluenesulfonic acid, tartaric acid, succinic acid, and phthalic acid; NO2, NO3, SO3, So, , H
3O4, N3, OCN%SCN, H3O,, CN%C
O8, HCO3, CrO2, HPO,, Sin, s
S20. , CIO, etc., and salts consisting of combinations of ion groups such as , CIO, etc.

Furthermore, the solvent used for dispersing the cyclodextrin inclusion complex powder of the reducing agent compound of the present invention stably disperses the inclusion complex powder without dissolving it, and does not interfere with the reduction of the carbonyl compound. Any of them can be used alone or in combination of two or more. For example, alcohols such as methanol and ethanol; saturated or unsaturated aliphatic hydrocarbons such as n-hexane, cyclohexane, and cyclohexene; halogenated hydrocarbons such as carbon tetrachloride, tetrachlorethylene, and trifluoroethylene; xylene aromatic hydrocarbons and their derivatives such as monochlorobenzene and nitrobenzene; ethers such as diglyme and anisole; and esters such as acetate. However, these should be selected as appropriate depending on the type of inclusion complex, the type of carbonyl compound, the reaction temperature, etc.

, 14. According to the method of the present invention, optically active secondary alcohols, which are important as raw materials or synthetic intermediates for various physiologically active substances, can be easily obtained with high purity.This method has a higher purity than conventional optically active catalysts. Not only does it use a cyclic oligosaccharide which is inexpensive, non-toxic, stable and can be used repeatedly, it is also characterized by high optical purity of the product. Therefore,
The product is easy to purify and there are no catalyst-derived toxicity problems, so the cost of producing an optically active secondary alcohol can be significantly reduced compared to conventional methods.

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 1 125 g of β-cyclodextrin was placed in 5 tons and heated to 60° C. while stirring. After cooling the homogeneous solution to 30°C, 9 g of t-butylamine borane was added: il:'
+ 1 lil l'·1 Stir at the same temperature for about 2 hours. The precipitate formed after cooling to room temperature was filtered to obtain an clathrate compound 1, which was determined by changes in the X-ray diffraction pattern using the powder method and I H- measured by dissolving this powder in deuterated dimethyl sulfoxide. It was confirmed from the NMR spectrum that it was a 1:1 inclusion complex. This inclusion complex powder was mixed with KCI and NaC1 at 0°C.
:6 (weight ratio) mixed salt was dispersed in 11 saturated aqueous solution, and 16 g of trifluoroacetophenone was added under light shielding, followed by stirring for 15 hours.

After filtering out the β-cyclodextrin 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 treated with a silica gel column and a 20% hexane methylene chloride solution. Separated and purified. Yield 98%, concentration in benzene 0.37g
The light intensity [α]3 measured at 7100 ml was -4.6, and the (R)-trifluoromethylphenylmethanol had an optical purity of 27.5%.

Elemental analysis value calculation value (C8H70F3): C=57.83%, H
=4.22%, F=QA IACN! - Comparative Example 1 Known method of Zaimoku et al. (N, Baba, Y, Mat
sumura, T.

Sugimoto ; Tetrahed, Let
For comparison, the results obtained in T. T., 4281 (1978) are shown below, using o,oi methyl borate at pH 9,
After dissolving 5 mmol of trifluoroacetophenone in a buffer solution adjusted to pH 2, 0.05 mol of β-cyclodextrin solution and 0.01 mol of t-butylamine borane solution were added, and the solution was incubated at 25°C in the dark. Stirred for 1 week at 0
After the reaction solution was extracted with diethyl ether, it was treated simultaneously with Example 1 to obtain the desired trifluoromethylphenylmethanol.

[α):==0, the chemical yield was 52%, which was not only inferior to Example 1, but also no optically active substance was obtained. Incidentally, even when the same procedure was carried out by changing the reducing agent to NaBH4, the chemical yield increased to 60%, but no optically active substance was obtained.

Example 2 200 g of dicyclodextrin is placed in 1.5 t of water and heated to 30° C. while stirring to form a uniform solution. To this was added 19 g of pyridine-borane complex, 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. In the same manner as in Example 1, it was confirmed that the precipitate was a 1=1 inclusion complex. This powder is cut off from light to 0~
Dispersed in 8000 m t of NaCl saturated aqueous solution at 5 °C,
Stir and add 33 g of n-butylphenyl ketone.
After reacting for 7 hours, the reaction mixture was treated in the same manner as in Example 1 to obtain the desired 1-phenylpentanoyl-1. Yield 96%
, measured at a concentration of 0.28g/100ml in benzene [
α]3 was +9.8, and there were 8 bodies with an optical purity of 32%.

Elemental analysis value calculation value (C11H1601): C=80.44%,
)l=9.83% Analysis value: C=80.52%, H=9
．． 74% Comparative Example 2 Separately obtained racemic 1-phenylpentanol-1,
The method of Cramer et al. (F, Cramer, W.

Dietsch; Chem, Ber, 9237
8 (1959)), optical resolution was carried out using α-cyclodextrin. The recovered material [d]1 at this time is -0
, 65, and the optical purity is as low as 2.1%. Therefore, it is clear that the results of Example 2 are not due to optical resolution.

Example 3 270 g of γ-cyclodextrin was made into a slurry by adding 500 ml of water, and 32 g of 1-naphthylamine.
Add the borane complex and knead for 6 hours at room temperature, then air dry. The obtained powder was confirmed to be a 1=1 clathrate in the same manner as in Example 1. This inclusion complex powder is
The mixture was dispersed in a 1:1 solution of carbon tetrachloride and cyclohexane at 2°C, 29 g of methyl and 2-phenylethynyl ketone were added, and the mixture was stirred for 20 hours. Thereafter, the same process as in Example 1 was carried out to obtain the desired second alroll. The yield is 98%,
[α]3 measured in chloroform at a concentration of 0.93 g/100 ml was +21.4, and (R
)-4-phenyl-3-buten-2-ol.

Elemental analysis value calculation value (C,.H,20): C=81.04%,)
[=8.16% prayer value: C=80.07%, H=8.
23% Comparative Example 3 Instead of the γ-cyclodextrin inclusion complex, 1
Using only the -naphthylamine-borane complex, 100% tearing of methyl and 2-7-ethyl alcohol was obtained in the same manner as in Example 3, but [α):6==o and no optically active product was obtained.

Example 4 A β-cyclodextrin inclusion complex powder of a dimethylamine-borane complex obtained in the same manner as in Example 1 was dispersed in a saturated saline solution at 0°C, and an equimolar amount of 2-year-old xo-2-phenylacetate methyl was added and stirred for 20 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired α-hydroxy ester.

Yield: 8, concentration in chloroform: 0.42g/100
[α]r measured with m1 was -44.1, and the optical purity of methyl (R)-2-phenylacetate was 26%.

Elemental Analysis Calculated Values” Mukai. O, ): C=65.05%, H=
6.07% Analysis value: C=66.01%, )(=6.1
5% Example 5 Using a β-cyclodextrin polymer with an average molecular weight of 5500 and an N-ethylaniline/borane complex, Example 3
Poly(β-cyclodextrin) inclusion complex powder of N-ethylaniline/borane complex obtained in the same manner as above,
Disperse in saturated saline solution at 0°C, equimolar methyl, n
-Hexylketone was added and stirred for 20 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired 2-octanol.

Yield: 95%, concentration in ethanol: 1.2g/100m
[α]5 measured in 1 is -5,51, and the optical purity is 5.
It was 6% (R) form.

Elemental analysis calculation value (CsHlaO): C=73.78%, )l
=13゜92% analysis value: C=73.03%, )(=1
3.80% Example 6 The N-methyl morphoconjugate complex obtained in the same manner as in Example 1 and the equimolar amount of trifluoromethyl anthryl ketone were added to a 10:1 mixture of carbon tetrachloride and ethyl acetate. The mixture was dispersed and reacted at 0°C for 30 hours. Thereafter, it was treated in the same manner as in Example 1 to obtain the desired second alcohol. Yield is 8
(a) 2Is is +6,7, measured at a concentration of 1 g/100 ml in chloroform, 2.2.2-) Refluoro-1- with an optical purity of 25%.
(Anthryl) ethanol.

Elemental analysis calculation value (C1sHoOF3): C=69.57%
, H = 3.99%, F = 20.65% Analysis value: (: = 69.73%, H = 3.90%, F
=20.41% Example 7 The α-cyclodextrin inclusion complex powder of hexahydropyridylporan obtained in the same manner as in Example 2 was mixed with the same mole of monobromomethyl phenyl ketone at 0°C as salt and calcium chloride. It was dispersed in a mixed saturated aqueous solution with a molar ratio of 10:1 and stirred for 24 hours. Thereafter, the process was carried out in the same manner as in Example 1 to obtain the β-cyclodextrin package of the target phosphorus-borane complex.
[α]r measured in 1 was +23.5, and the optical purity was 6.
It was 0% (S) form.

Elemental analysis calculation value (CsHeOBr): C=47.76%,
) l = 4.48%, B = 39.80% Analysis value: C = 47.94%, H = 4.40%, Br
=39.36% Reference Example 1 (+)-(S)-2-bromo-1- obtained in Example 7
A chloroform solution of phenylethanol was treated with an aqueous potassium hydroxide solution at 40°C for 3 hours to obtain (-)-(S)-styrene oxide with a chemical yield of 90% and an optical purity of 60%. That is, it was confirmed that the optically active monohalogeno alcohol was converted into the corresponding epoxide without reducing its optical purity.

Further, the cyclodextrin removed by filtration in the above example was extracted and washed with RI00 form, etc., and quantitatively recovered and could be reused.

As mentioned above, as shown in Comparative Example 2, it is clear that the present invention is not based on the optical resolution of a racemate. However, as shown in Comparative Examples 1 and 3, optically active secondary alcohols cannot be obtained using the two known methods.

In addition, the cyclodextrins used can be collected by filtration and reused, which is a resource-saving and energy-saving process.

Claims (1)

[Claims] 1. A method for producing an optically active secondary alcohol, which comprises bringing a reducing agent complex clathrated in cyclodextrin into contact with a carbonyl compound having any organic residue that does not interfere with a reduction reaction.