JPH032849B2 - - Google Patents

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 for obtaining optically active alcohols is to reduce carbonyl compounds such as ketones, ketoesters, and keto acids using an ordinary reducing agent in the coexistence of an optically active catalyst. 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, there are drawbacks such as a low optical yield of the product, difficulty in synthesizing the catalyst, and the need to use expensive natural extracts. Furthermore, a method for synthesizing optically active secondary alcohols using cyclodextrin, which has recently become easier to obtain, has been proposed. [N. Baba, Y.
Matsumura, T.Sugimoto Tetrahed.Lett.,
(44) 4281-4284 (1978): R. Fornasier, F.
Renievo, P.Scrimin, U.Toneilato; J.Org.
Chem., 50., 3209-3211 (1985)], which uses a cyclodextrin inclusion complex of a carbonyl compound, but not only the optical yield of the product is low, but also the cyclodextrin inclusion complex of a carbonyl compound. It has shortcomings such as being limited to compounds that form inclusion complexes and lacks generality. Furthermore, a method of reducing a carbonyl compound using an optically active reducing agent is also well known. That is, optically active 1,
Secondary alcohols with high optical purity have been obtained using 4-dihydronicotinamide derivatives as reducing agents, but these reducing agents are not easily available and are therefore not economical except for the synthesis of special compounds. .

The present inventors have conducted intensive research to solve the above-mentioned 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.

Means for Solving the Problems That is, 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.

The compound containing at least one carbonyl group as a raw material in the present invention has the general formula R ¹ COR ² (wherein R ¹ and R ² allow the compound of the formula to exist stably, and are similar to cyclodextrin). Any organic residues that do not hinder the inclusion of carbonyl groups or the reduction of carbonyl groups may be linked together to form a ring. Examples of these organic residues include nitro groups, cyano groups, and halogen groups. Alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, alkyl substituted or unsubstituted with a group, amino group, carboxyl group, carbonyl group, hydroxyl group, alkoxy group, aryloxy group, thiohydroxyl group, ferrocenyl group, etc. carbonyl, arylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl,
Included are aralkylcarbonyl, aralkenylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, aralkenoxycarbonyl, aralquinoxycarbonyl group and carboxyl group. However, R ¹ and R ² must not be the same residue at the same time.

For example, α- and β-acetol, acetoin, acetoethyl alcohol, diacetone alcohol, phenacyl alcohol, benzoin, etc.
-, γ-ketols; methyl ethyl ketone, propyl butyl ketone, methyl isopropyl ketone,
Aliphatic ketones such as methyl butyl ketone, binacolon, cyclopropyl methyl ketone; methyl vinyl ketone, mesityl oxide, methyl heptenone, 4-(1-naphthyl)-3-buten-2-one, benzalacetone, dibenzalacetone Unsaturated ketones such as asymmetrically substituted products of; 2-chloromethylcyclobutanone, 3-cyanoethylcyclopentanone, 3-nitro-5-allylcyclohexanone, 3-methoxycyclohexanone, terpene ketones (camphor, fentilone), spiro[3,4]
Alicyclic ketones such as octanone-5 and steroid ketones; asymmetrically substituted products of acetophenone, propiophenone, petirophenone, valerophenone, benzophenone, asymmetrically substituted products of acetonaphthone, benzonaphtone, dibenzyl ketone, flavanones and 1,2,3 ,4-tetrahydro-4-
Ketophenanthrene, asymmetrically substituted xanthone, aromatic ketones such as 1,2,6,7-dibenzfluorenone, acetothienone, acetofuron, trobinone, vilazolone, 4-methyl-5-
Heterocyclic ketones such as acetylthiazole; aminoketones such as adrenalone and 2,7-diaminoacridone; pyruvic acid, benzoylformate,
α- and β-, γ-keto acids and esters such as phenylpyruvic acid, acetoacetic acid, benzoylacetic acid, levulinic acid, 3-benzoylpropionic acid;
There are diketones such as diacetyl and benzyl.
Also, ferrocenyl ketones such as methyl ferrocenyl ketone and 4-ferrocenyl-3-buten-2-one; phenyl trifluoromethyl ketone, naphthyl chloromethyl ketone, anthryl bromomethyl ketone, and chlorophenyl ethyl ketone. , bromophenyl methyl ketone, naphthyl trifluoromethyl ketone, anthryl trifluoromethyl ketone, and other halogen-substituted ketones.

Among the reducing agents used in the present invention, among those known as reducing agents for carbonyl groups, any reducing agent that forms a stable clathrate with cyclodextrin can be used alone or in combination of two 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. The known reducing agents and their characteristics are listed in the Chemical Society of Japan, Experimental Chemistry Course 17 (Part 2) p1-119, May 1952, edited by Maruzen and the Chemical Society of Japan, Experimental Chemistry Course 19, p92-154.
May 1965, knowledgeable about Maruzen. Preferred is a Lewis base complex of borane, which can be synthesized, for example, by adding various amines to a solution of borane in tetrahydrofuran or a metal borohydride solution.
[Yoshihisa Okamoto; Organic Synthetic Chemistry, 44(10), 896-906
(1986)], they include ammonia borane and;
Borane complexes of mono-, di-, and tri-alkylamines such as butylamine, diethylamine, trimethylamine, and methylpropylamine; borane complexes of cycloalkylamines such as cyclohexylamine and bicyclo[3,3,1]nonylamine; pyridine and quinoline , isoquinoline, aminopyridine, 2,6-lutidine, N-phenylmorpholine, etc., borane complexes of heterocyclic compounds; aniline, dimethylaniline, 4-methyl-N-ethylaniline, 1-naphthylamine, 8-ethyl-
These include borane complexes of aromatic amines such as N-methyl-2-naphthylamine. Note that, 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
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. Three types of cyclodextrin are currently isolated, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, depending on the number of constituent units of d-glucose. Any of these may be used, or a mixture thereof may be used. Additionally, modified cyclodextrins with appropriate chemical groups introduced into the side complexes of these cyclodextrins and polycyclodextrins made of insolubilized cyclodextrins may also be used, as long as they do not interfere with inclusion and do not interfere with the reducing action of the inclusion compounds. , can be used. 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 a kneading method and a solution method.

In the kneading method, water (approximately 0.1 to 6 times the weight of cyclodextrin) is added to cyclodextrin to form a paste. Next, a reducing agent compound to be included is added and thoroughly kneaded. The kneading time is approximately 1 to 12 hours, preferably 2 to 8 hours, and the kneading temperature may be arbitrary, but room temperature is sufficient. A crusher, ball mill, disper mill, emulsifier, etc. are sufficient for kneading. on the other hand,
In the solution method, a saturated aqueous solution of cyclodextrin is prepared, a reducing agent compound is added thereto, and the solution 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 is, but
Drying may be performed by various methods if necessary. There are spray drying methods and vacuum drying methods. 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 has the same odor as 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.

The clathrate compound of the reducing agent obtained in this way is dispersed as a powder in a supersaturated aqueous solution of various inorganic salts or an organic solvent while shielding from light, then a carbonyl compound is added thereto, and the temperature is reduced to -60°C to 90°C, preferably. −20℃~
The reaction is carried out at 50°C for 30 minutes to 150 hours, preferably 5 to 100 hours. The reaction temperature and time are appropriately selected depending on the stability of the reducing agent clathrate, the reactivity of the clathrated reducing agent, the reactivity of the carbonyl compound, and the stability of the secondary alcohol produced. Should. After the reaction, the cyclodextrin inclusion complex is appropriately removed, and then extracted with a suitable solvent such as diethyl ether to obtain the desired optically active secondary alcohol.

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. In other words, alkali metals such as Li, Na, K, Rb, and Cs, alkaline earth metals such as Be, Mg, Ca, Sr, and Ba, halogens such as F, Cl, Br, and I, acetic acid, and monochloro Organic acids such as acetic acid, toluenesulfonic acid, tartaric acid, succinic acid, phthalic acid;
NO ₂ , NO ₃ , SO ₃ , SO ₄ , HSO ₄ , N ₃ , OCN,
SCN, HSO ₃ , CN, CO ₃ , HCO ₃ , CrO ₄ ,
These include salts consisting of combinations of ion groups such as HPO ₄ , SiO ₃ , S ₂ O ₃ , and ClO ₃ .

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; These include 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.

〔Effect of the invention〕

According to the method of the present invention, optically active secondary compounds, which are important as raw materials or synthetic intermediates for various physiologically active substances,
Alcohol can be easily obtained with high purity. Compared to conventional optically active catalysts, this method not only uses a cyclic oligosaccharide which is inexpensive, non-toxic, stable and can be used repeatedly, but also has the characteristics of high optical purity of the product. Therefore, the product can be easily purified, there is no problem of toxicity due to the catalyst, and 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 125g of β-cyclodextrin was added to 5 and heated to 60°C while stirring. After cooling the homogeneous solution to 30°C, 9 g of t-butylamine borane was added and stirred at the same temperature for about 2 hours. The precipitate formed by cooling to room temperature was filtered to obtain a clathrate compound. This substance was confirmed to be a 1:1 inclusion complex based on changes in the X-ray diffraction pattern using the powder method and the ¹ H-NMR spectrum measured by dissolving this powder in deuterated dimethyl sulfoxide. . This inclusion complex powder was dispersed in a saturated aqueous solution 11 of a mixed salt of KCl and NaCl (1:6 weight ratio) at 0°C, and 16 g of trifluoroacetophenone was added under light shielding and stirred for 15 hours. After filtering off 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 separated and purified using a silica gel column and a 20% hexane methylene chloride solution. yield
The optical density [α] ²⁵ _D measured at a concentration of 98% and benzene of 0.37 g/100 ml was -4.6, and it was (R)-trifluoromethylphenylmethanol with an optical purity of 27.5%.

Elemental analysis value Calculated value (C ₈ H ₇ OF ₃ ): C = 57.83%, H = 4.22
%, F=34.34% Analysis value: C=58.01%, H=4.16%, F=34.05
% Comparative Example 1 Known method by Sugimoto et al. [N, Baba, Y.
Matsumura, T.Sugimoto; Tetrahed.Lett,
4281 (1978)] are shown below for comparison. After dissolving 5 mmol of trifluoroacetophenone in a buffer adjusted to pH 9.2 with 0.01 molar borate, a 0.05 molar β-cyclodextrin solution and a 0.01 molar t-butylamine borane solution were added. The mixture was stirred for one week at 25°C in the dark. After the reaction solution was extracted with diethyl ether, it was treated simultaneously with Example 1 to obtain the desired trifluoromethylphenylmethanol. [α] ²⁵ _D = 0, the chemical yield is
The yield was 52%, and not only was the yield inferior to that of Example 1, but no optically active substance was obtained. In addition, the reducing agent
Even when the same procedure was carried out in place of NaBH ₄ , the chemical yield increased to 60%, but no optically active substance was obtained at all.

Example 2 200g of α-cyclodextrin was added to 1.5ml of water and heated to 30°C while stirring to form a uniform solution. 19 g of pyridine-borane complex was added thereto, and after stirring for about 2 and a half hours, it 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 was dispersed in 800 cm of a saturated aqueous solution of NaCl at 0 to 5°C with the light cut off, and 33 g of n-butyl phenyl ketone was added while stirring and reacted for 17 hours, followed by treatment in the same manner as in Example 1. The desired 1-phenylpentanol-1 was obtained. Yield 96%, measured at a concentration of 0.28 g/100 ml in benzene [α] ²⁵ _D is +
It was an s-isomer with an optical purity of 9.8 and an optical purity of 32%.

Elemental analysis values Calculated values (C ₁₁ H ₁₆ O ₁ ): C = 80.44%, H = 9.83% Analysis values: C = 80.52%, H = 9.74% Comparative example 2 Separately obtained racemic 1-phenylpentanol -1 by the method of Cramer et al. [F, Cramer, W.
Dietsch; Chem. Ber. 92 378 (1959)] using α-cyclodextrin. The [α] ²⁵ _D of the recovered product at this time had the opposite sign, −0.65, and the optical purity was 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 is made into a slurry by adding 500 ml of water, and 32 g of 1-naphthylamine-borane complex is added thereto, kneaded at room temperature for 6 hours, and then air-dried. The obtained powder was confirmed to be a 1:1 inclusion complex in the same manner as in Example 1. This inclusion complex powder was dispersed in a 1:1 solution of carbon tetrachloride and cyclohexane at -2 to 2°C.
29 g of 2-phenylethynyl ketone was added and stirred for 20 hours. Thereafter, the same process as in Example 1 was carried out to obtain the desired second alroll. The yield was 98%, measured at a concentration of 0.93 g/100 ml in chloroform [α]
²⁵ _D is +21.4, and [R]-4- has an optical purity of 85%.
It was phenyl-3-buten-2-ol.

Elemental analysis values Calculated values (C ₁₀ H ₁₂ O): C = 81.04%, H = 8.16% Analysis values: C = 80.07%, H = 8.23% Comparative example 3 Instead of the inclusion complex of γ-cyclodextrin, Using only the 1-naphthylamine-borane complex, methyl and 2-phenylethynyl ketone were treated for 4 hours in the same manner as in Example 3, and then treated in the same manner as in Example 1 to obtain a secondary alcohol as a reduced product. Although the yield was 100%, [α] ²⁵ _D =0 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 methyl 2-oxo-2-phenylacetate was dispersed in a saturated saline solution. add 20
It took up a lot of time. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired α-hydroxy ester.
Yield: 80%, concentration in chloroform: 0.42g/100ml
[α] ²⁵ _D measured at -44.1, optical purity 26
% of [R]-2-phenylacetate methyl.

Elemental analysis Calculated values (C ₉ H ₁₀ O ₃ ): C = 65.05%, H = 6.07% Analytical values: C = 66.01%, H = 6.15% Example 5 β-Cyclodextrin polymer with an average molecular weight of 5500 and N- Poly(β-cyclodextrin) inclusion complex powder of N-ethylaniline/borane complex obtained in the same manner as in Example 3 using ethylaniline/borane complex was dispersed in a saturated saline solution at 0°C. , molar equivalents of methyl and n-hexyl ketone were 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/100ml
[α] ²⁵ _D measured at -5.51, optical purity 56
% of the [R] form.

Elemental analysis Calculated values (C ₈ H ₁₈ O): C = 73.78%, H = 13.92% Analytical values: C = 73.03%, H = 13.80% Example 6 N-methylmorpholine obtained in the same manner as Example 1・The β-cyclodextrin inclusion complex of the borane complex and the equivalent mole of trifluoromethyl anthryl ketone are mixed with carbon tetrachloride and ethyl acetate in 10:
1 mixed liquid 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. The yield was 80%, the [α] ²⁵ _D measured at a concentration of 1 g/100 ml in chloroform was +6.7, and it was 2,2,2-trifluoro-1-(anthryl)ethanol with an optical purity of 25%. .

Elemental analysis Calculated value (C ₁₆ H ₁₁ OF ₃ ): C = 69.57%, H = 3.99
%, F=20.65% Analysis value: C=69.73%, H=3.90%, F=20.41
% Example 7 The α-cyclodextrin inclusion complex powder of hexahydropyridylborane obtained in the same manner as in Example 2 was mixed with the same mole of monobromomethyl phenyl ketone at 0°C as the mole of common salt and calcium chloride. ratio
It was dispersed in a saturated aqueous solution mixed with 10:1 and stirred for 24 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired 2-bromo-1-phenylethanol. Yield: 86%, concentration in chloroform: 0.3g/100
[α] ²⁵ _D measured in ml is +23.5, and the optical purity
It was 60% [S] form.

Elemental analysis Calculated value (C ₈ H ₉ OBr): C = 47.76%, H = 4.48
%, Br: 39.80% Analysis value: C = 47.94%, H = 4.40%, Br = 39.36
% Reference Example 1 A chloroform solution of (+)-(S)-2-promo-1-phenylethanol obtained in Example 7 was treated with an aqueous potassium hydroxide solution at 40°C for 3 hours to obtain a chemical yield of 90%. (-)-(S)-styrene oxide with an optical purity of 60% was obtained. That is, it was confirmed that the optically active monohalogeno alcohol was converted into the corresponding epoxide without reducing its optical purity.
In addition, the cyclodextrin removed by filtration in the above example was quantitatively recovered by extraction and washing with chloroform, etc., and could be reused.

As mentioned above, as shown in Comparative Example 2, it is clear that the present invention is not based on optical resolution of a racemate, and as shown in Comparative Examples 1 and 3, the two known methods do not rely on optically active secondary Alcohol is not available.
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 contacting a carbonyl compound having any organic residue that does not interfere with the reduction reaction with a reducing agent complex consisting of an amine borane complex clathrated in cyclodextrin.