JPH0224255B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to the production of optically active secondary alcohols. That is, the present invention provides a synthetic method for selectively obtaining D- and L-isomers of secondary alcohols, which are important intermediates for the synthesis of physiologically active substances such as neurotransmitters, antitumor substances, and insect pheromones.

[Conventional technology and problems]

It is well known that an optically active secondary alcohol can be obtained by reducing carbonyl compounds such as ketones and ketoesters using an optically active reducing agent. That is, although optically active 1,4-dihydronicotinamide derivatives are used as reducing agents to obtain secondary alcohols with high optical purity, these reducing agents have the disadvantage that they are not easily available. It is also known that a common reducing agent can be used together with an optically active catalyst. Thus, methods using kinine derivatives, optically active quaternary ammonium salts, and bovine serum albumin as catalysts have been proposed, but the optical yield of the product is low, the synthesis of the catalyst is difficult, and the use of expensive natural There remain drawbacks such as the need to use extracts. In addition, a method for synthesizing optically active secondary alcohols using cyclodextrin, which has recently become easier to obtain, was proposed [N. Baba, Y.
Matsumura, T. Sugimoto; Tetrahed, Lett.
(44) 4281-4284 (1978): R. Fornasier, F.
Reniero, P.Scrimin, U.Toneilato; J.Org.
Chem, 50 3209-3211 (1985)], but the optical yield of the product was low in any of the above methods.

The present inventors have conducted extensive research to solve the above problems, and have found that asymmetric reduction of carbonyl compounds can be carried out in high yields 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 problems]

That is, the present invention includes inclusion of carbonyl compounds such as ketones, ketoesters, and ketoacids in cyclodextrin, and then dispersion reaction in a reducing agent solution, followed by recovery of the reduced product from the clathrate, thereby achieving optical activity. We succeeded in synthesizing secondary alcohols with high optical purity.

Compounds containing at least one carbonyl group in the molecule used as raw materials in the present invention include:
General formula R ¹ COR ² (R ¹ and R ² in the formula are arbitrary organic residues that allow the compound of the formula to exist stably and do not interfere with inclusion with cyclodextrin and do not interfere with reduction of carbonyl group. , may be interconnected to form a ring. Examples of these organic acid groups include nitro group, cyano group, halogen group, amino group, carboxyl group,
carbonyl group, hydroxyl group, alkoxy group,
Alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl substituted or unsubstituted with aryloxy group, thiohydroxyl group, ferrocenyl group, etc.; alkylcarbonyl, arylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aralkylcarbonyl, aralkenyl Included are carbonyl, 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-, such as acetol, acetoin, acetoethyl alcohol, diacent alcohol, phenacyl alcohol, besozoin, etc.
γ-ketols; Aliphatic ketones such as methyl ethyl ketone, propyl butyl ketone, methyl isopropyl ketone, methyl butyl ketone, pinacolon; methyl vinyl ketone, mesityl oxide, methyl heptenone, 4-(1-naphthyl)-3-butene-2- 2-
Chlormethylcyclobutanone, 3-cyanoethylcyclopentanone, 3-nitro-5-allylcyclohexanone, 3-methoxycyclohexanone,
Alicyclic ketones such as terpene ketones (camphor, fentilone), spiro[3,4]octanone-5, and steroid ketones; acetophenone, propiophenone, butylophenone, valerophenone,
Asymmetrically substituted products of benzophenone, acetonaphthone, benzonaphthone, asymmetrically substituted product of dibenzyl ketone, flavanone, 1,2,3,4-tetrahydro-4-ketophenanthrene, asymmetrically substituted product of xanthone, 1,2,6,7- Aromatic ketones such as dibenzfluorenone; Heterocyclic ketones such as acetothienone, acetofurone, tropinone, pyrazolone, 4-methyl-5-acetylthiazole; Aminoketones such as adrenalone and 2,7-diaminoacridone; Pyruvate , benzoylformic acid, phenylpyruvic acid, acetoacetic acid, benzoylacetic acid, levulinic acid, 3-benzoylpropionic acid, and other α-, β-, and γ-keto acids and ketoesters; and diketones such as diacetyl and benzyl. Also, methylferrocenyl ketone and 4
-Ferrocenyl ketones such as ferrocenyl-3-buten-2-one; phenyl trifluoromethyl ketone, naphthyl chloromethyl ketone, anthryl bromomethyl ketone, chlorophenylethyl ketone, bromophenyl methyl ketone, naphthyl trifluoro Examples include halogen-substituted ketones such as methyl ketone and anthryl trifluoromethyl ketone.

As the reducing agent used in the present invention, any known reducing agent for carbonyl groups 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. These known reducing agents and their characteristics are listed in Nippon Kagaku ed., Experimental Chemistry Course 17 (Part 2), p.1-119.
May 1950, edited by Maruzen and Nippon Kagaku, Experimental Chemistry Course 19, p.92-154, May 1950, Maruzen details.
Preferred are complex metal hydrides such as sodium borohydride, potassium borohydride, and lithium borohydride. Sometimes dimethylamine borane,
Amine complexes of borane such as trimethylamine borane, t-butylamine borane, and pyridine borane are also effectively used.

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, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, are currently isolated depending on the number of constituent units of d-glucose. Any of these 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 hinder inclusion, and
It can be used as long as it does not interfere with the reduction reaction to the clathrate. 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, the carbonyl 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. Equipment for kneading is crusher, ball mill,
A disper mill, emulsifier, etc. is sufficient. On the other hand, in the solution method, a saturated aqueous solution of cyclodextrin is prepared, a carbonyl 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 resulting 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 resulting powder has lost its unique odor, but if it is poured into hot water or treated with diethyl ether, it will emit the same odor as before clathration, and the clathrate will dissolve. When it 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 unsaturated compound is clathrated in the powder.

The clathrate compound of the carbonyl compound thus obtained is shielded from light and dispersed as a powder in a supersaturated aqueous solution of various inorganic salts or an organic solvent, and then a reducing agent is added and the temperature is -60°C to 90°C, preferably - 20℃～50
The reaction is carried out at ℃ for 30 minutes to 150 hours, preferably for 1 to 100 hours. The reaction temperature and time depend on the stability of the clathrate compound, the reactivity of the clathrated carbonyl compound,
The reducing agent should be selected appropriately depending on the reactivity of the reducing agent and the stability of the secondary alcohol produced. After the reaction, the remaining unreacted reducing agent is appropriately removed, and then extracted with a suitable solvent such as diethyl ether to obtain the desired optically active secondary alcohol from the clathrate.

The inorganic salts used in the supersaturated aqueous solution of the present invention may be any inorganic salts as long as they do not interfere with the stability of the cyclodextrin complex powder of the carbonyl compound and the dispersibility in the solvent, and do not interfere with the reduction of the carbonyl group. They can be used alone or in combination of two or more. Namely, metal groups such as 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 monochloroacetic acid. , toluenesulfonic acid, tartaric acid, succinic acid, phthalic acid, and other organic acids; 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 carbonyl compound of the present invention is one that does not dissolve the inclusion complex powder, stably disperses it, and does not hinder the reduction of the carbonyl group. If any, they can all be used alone or in combination. For example, alcohols such as methanol and ethanol, saturated or unsaturated aliphatic hydrocarbons such as n-hexane and cyclohexane, halogenated hydrocarbons such as carbon tetrachloride, tetrachlorethylene and trifluoroethylene; xylene and monochlorobenzene. , aromatic hydrocarbons such as nitrobenzene and their derivatives; 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, reducing agent, reaction temperature, etc.

〔Effect of the invention〕

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. 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, it is easy to purify the product, there is no problem of toxicity due to the catalyst, and the cost of producing optically active secondary alcohols can be significantly reduced compared to conventional methods.

〔Example〕

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 is added to 1 part of water and heated to 70°C while stirring. 16 g of trifluoroacetophenone was added to the resulting solution and heated and stirred for about 2 hours to obtain a homogeneous solution.The mixture was then allowed to cool to room temperature and the resulting precipitate was filtered to obtain a clathrate compound. This product was confirmed to be a 1:1 inclusion complex based on the change in the X-ray diffraction pattern obtained by the powder method and the ¹ H-NMR spectrum measured after dissolving the powder in deuterated dimethyl sulfoxide. This clathrate powder was dispersed in KCl saturated aqueous solution 1 at 0°C and 4 g of NaBH ₄ was added.
After stirring and reacting for 3 hours, the starting carbonyl compound and the product were extracted with diethyl ether. After drying the separated organic layer over anhydrous magnesium sulfate, it was concentrated under reduced pressure, and then passed through a silica gel column for 20 minutes.
% hexane in methylene chloride solution.
The light absorption degree measured at a yield of 95% and a concentration of 0.42 g/100 ml in benzene was [α] ²⁵ _D = -7.6, and the optical purity was 45.4.
% (R)-trifluoromethyl, phenylmethanol. Elemental analysis value; Calculated value ( _C8H7OF3 ) C= _57.83 %, _H =4.22%,
F=34.34%; Analysis value C=57.52%, H=4.29%,
F=34.22% Comparative Example 1 Known method by Sugimoto et al. [N.Baba, Y.
Matsumura, T. Sugimoto; Tetrahed. Lett.,
4281 (1978)] are shown below for comparison.
5 mmol trifluoroacetophenone and 0.05 mmol trifluoroacetophenone in a buffer adjusted to PH 9.2 with 0.01 molar borate.
After dissolving mol of β-cyclodextrin, 0.01 mol of NaBH ₄ aqueous solution was added and stirred at 25°C in the dark for one week. After extracting the reaction solution with diethyl ether, it was treated in the same manner as in Example 1 to obtain the desired trifluoromethyl and phenylmethanol. [α] ²⁵ _D =0, the chemical yield was 60%, which was lower than in Example 1, and no optically active substance was obtained.

Example 2 200g of α-cyclodextrin is added to 1 water and heated to about 70°C while stirring to form a homogeneous solution. To this was added 33 g of n-butyl phenyl ketone, and the mixture was stirred and heated for about 3 hours to make it homogeneous, then allowed to cool to room temperature, and the resulting precipitate was filtered to obtain a clathrate compound. In the same manner as in Example 1, it was confirmed that the precipitate was a 1:1 inclusion complex. This powder is heated at 0~-5℃.
Disperse in 800 c.c. of NaCl saturated aqueous solution and stir while stirring.
After adding 12 g of KBH ₄ and reacting for 2 hours, Example 1
The desired 1-phenyl-pentanol-1 was obtained by treatment in the same manner as above. Yield 70%, concentration in benzene
[α] ²⁵ _D measured at 0.3 g/ml is -13.7, optical purity
It was 44.4% R-isomer. Elemental analysis values: Calculated values (C ₁₁ H ₁₆ O ₁ ) C = 80.44%, H = 9.83%; Analysis values C = 80.92%, H = 9.70%.

Example 3 Add 500 ml of water to 130 g of β-cyclodextrin to make a paste, and make ethyl phenyl ketone 15
g. Add 10 ml of diethyl ether, knead at room temperature for 5 hours, and then air dry. The obtained powder was confirmed to be a 1:1 inclusion complex in the same manner as in Example 1. This clathrate powder was mixed with Na ₂ SO ₄ at 0 to -5℃.
Dispersed in 900 ml of a 1:1 saturated aqueous solution with NaCl,
4.5 g of NaBH ₄ was added, stirred for 2 hours, left for 1 hour, and treated in the same manner as in Example 1. [α] measured at a concentration of 1 g/100 ml in diethyl ether with a yield of 85% ²⁵ _D
is -10.9 and the optical purity is 32.7% [S]-1-
It was phenyl-propanol-1. Elemental analysis: Calculated values (C ₉ H ₁₂ O ₁ ) C = 79.37%, H = 8.88%; Fractional values C = 79.91%, H = 8.80% Comparative example 2 Known method of Skrimin et al. [R. Fornasier, F.
Reniero, P.Scrimi, U.Toneilato; J.Org,
Chem., 50 3209 (1985)] are shown for comparison. That is, 0.4 mmol of the inclusion complex is dispersed in 3 ml of 0.2 M aqueous sodium carbonate solution, 0.8 mmol of NaBH ₄ is added at room temperature with vigorous stirring, and the reaction is allowed to proceed until the raw material is consumed. After the reaction, 10 ml of water was added and extracted with diethyl ether, followed by the same treatment as in Example 1. The yield was 80-90%, and the [α] ²⁵ _D measured at an ethanol concentration of 3.3 g/100 ml was +1.20 of the [R]-isomer, and the optical purity was 3.7%.
That is, the optical activity was also opposite to that of Example 1, and the optical purity was also quite low.

Example 4 Methyl phenyl ketone β-cyclodextrin inclusion complex powder obtained in the same manner as in Example 1 was dispersed in a 1:1 solution of carbon tetrachloride and cyclohexane containing equimolar NaBH ₄ and After stirring at 0°C for 15 hours, the solvent was removed and the mixture was extracted with diethyl ether. Thereafter, the same process as in Example 1 was carried out to obtain the corresponding second alcohol. [α] ²⁵ _D was measured at a yield of 98% and a concentration of 1 g/100 ml in dichloromethane.
16.6 and was [S]-1-phenyl-ethanol with an optical purity of 37%. Elemental analysis: Calculated values (C ₈ H ₁₀ O ₁ ) C = 78.65%, H = 8.25% Analysis values C = 78.07%, H = 8.29%.

Comparative Example 3 The results obtained by a known method similar to Comparative Example 2 are as follows. Yield 95% in dichloromethane
[α] ²⁵ _D measured at a concentration of 4.1 g/100 ml was −1.57, and the optical yield was 3.5%, and although the same [S] form was obtained, the optical yield was considerably lower than that of the example.

Example 5 A β-cyclodextrin inclusion complex powder of methyl and 2-phenylethenyl ketone obtained in the same manner as in Example 1 was dispersed in a saturated saline solution at 5 to 0°C, and an equimolar amount of NaBH ₄ was added. Stirred for 20 hours. After that, the same process as in Example 1 is carried out to obtain the desired second
Got alcohol. [S]-4-phenyl-3- with a yield of 90%, [α] ²⁵ _D measured in chloroform at a concentration of 1.3 g/100 ml, and an optical purity of 65%.
It was butene-2-ol. Elemental analysis: Calculated values (C ₁₀ H ₁₂ O) C = 81.04%, H = 8.16%; Analysis values C = 79.72%, H = 8.23%.

Comparative Example 4 The results obtained using a known method similar to Comparative Example 2 were as follows. Yield is 80%, 4.75 in ethanol
The [α] ²⁵ _D measured at the concentration of g/100 ml was -6.75 and the optical purity was 36.4%, giving the same [S] form, but both the yield and the optical purity were inferior to Example 5. .

Example 6 A β-cyclodextrin inclusion complex powder of methyl 2-oxo-2-phenylacetate obtained in the same manner as in Example 1 was dispersed in a saturated saline solution at 2 to -5°C, and the equimolar amount of NaBH ₄ was dispersed in a saturated saline solution. The mixture was added and stirred for 18 hours.
After that, the process is carried out in the same manner as in Example 1 to obtain the desired α
-Hydroxy ester was obtained. The yield was 75%, measured at a concentration of 0.3 g/100 ml in chloroform [α] ²⁵ _D
was +96.3 and was methyl [S]-2-hydroxy-2-phenylacetate with an optical purity of 56%. Elemental analysis: Calculated values (C ₉ H ₁₀ O ₃ ) C = 65.05%, H = 6.07%; Analysis values C = 64.65%, H = 6.11%.

Example 7 270 g of γ-cyclodextrin is added to 900 ml of water and heated to 70° C. with stirring to form a homogeneous solution. This is trifluoromethyl anthryl ketone.
Add 55 g of the solution and heat while stirring for about 4 hours to make a homogeneous solution, then let it cool to 0°C. When a trace amount of the precipitate was filtered and analyzed in the same manner as in Example 1, it was confirmed that it was a 1:1 inclusion complex. After adding salt equivalent to the saturation amount to the remaining inclusion complex precipitated aqueous solution, 2 to -2
8 g of NaBH ₄ was added at °C and reacted for 40 hours with stirring. Thereafter, it was treated in the same manner as in Example 1 to obtain the desired second alcohol. The yield was 75%, measured at a concentration of 0.8 g/100 ml in chloroform [α] ²⁵ _D was +13.6, and it was 2,2,2-trifluoro-1-(-anthryl)ethanol with an optical purity of 50.4%. . Elemental analysis: Calculated values (C ₁₆ H ₁₁ OF ₃ ) C=69.57%, H=3.99%,
F=20.65%; Analysis value C=69.68%, H=3.63%,
F=20.29%.

Example 8 A β-cyclodextrin inclusion complex powder of methyl and 1-naphthyl ketone obtained in the same manner as in Example 1 was dispersed in a saturated saline solution at 0°C to obtain an equimolar amount of
NaBH ₄ was added and stirred for 50 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired 1-(1-naphthyl)ethanol. The yield was 95%, the [α] ²⁵ _D measured at a concentration of 2.3 g/100 ml in ethanol was +51.5, and it was the [R] form with an optical purity of 70%. Elemental analysis; Calculated values (C ₁₂ H ₁₂ O) C = 83.69%, H = 7.02%; Analysis values C = 83.43%, H = 6.71%.

Comparative Example 5 The results obtained using a known method similar to Comparative Example 2 were as follows. Yield is 80%, concentration in ethanol
The [α] ²⁵ _D measured at 5.4 g/100 ml was +19.1, and although the same [R] form was obtained with an optical purity of 26%, the optical purity was lower than that of the example.

Example 9 A β-cyclodextrin inclusion complex powder of methyl and n-hexyl ketone obtained in the same manner as in Example 3 using a β-cyclodextrin polymer with an average molecular weight of 5000 and methyl and n-hexyl ketone was prepared. Disperse in saturated salt aqueous solution at 0℃ and make equimolar amount of
NaBH ₄ 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: 100%, concentration in ethanol: 1.7g/
[α] ²⁵ _D measured in 100 ml was −4.72, indicating that it was the [R] form with an optical purity of 48%. Elemental analysis: Calculated values (C ₈ H ₁₈ O) C = 73.78%, H = 13.92%; Analysis values C = 73.96%, H = 13.61%.

Example 10 The α-cyclodextrin inclusion complex powder of monobromomethyl and phenyl ketone obtained in the same manner as in Example 2 was dispersed in a 10:1 mixture of carbon tetrachloride and ethyl acetate at 0°C. Mol NaBH ₄
was added and stirred for 90 hours. Thereafter, the same treatment as in Example 4 was carried out to obtain the desired 2-bromo-1-phenylethanol. The yield was 42%, the [α] ²⁵ _D measured at a concentration of 0.1 g/100 ml in chloroform was -22.3, and it was the [R] form with an optical purity of 57%. Elemental analysis; Calculated values (C ₈ H ₉ OBr) C = 47.76%, H = 4.487%,
Br=39.80%; Analysis value C=47.69%, H=4.63%,
Br=39.27%.

Comparative Example 6 Separately obtained racemic 2-bromo-1-phenylethanol was prepared using the method of Cramer et al.
α in W. Dietsch; Chem, Ber, 92 378 (1959)]
-Optical resolution using cyclodextrin.
At this time, the recovered material [α] ²⁵ _D is +1.8, with the opposite sign.
The optical purity is also low at 4.6%. Therefore, Example 10
It is clear that the result is not due to optical resolution.

As mentioned above, as shown in Comparative Example 6, it is clear that the present invention is not based on optical resolution of a racemate, and as shown in Comparative Examples 1 to 5, the chemical yield is higher than that of the two known methods. It is a resource-saving and energy-saving process that not only provides an optically active secondary alcohol with high optical purity, but also allows the cyclodextrins used to be collected by filtration and reused.

Claims (1)

[Claims] 1 Does not prevent inclusion with cyclodextrin,
After including a carbonyl compound having any organic residue or organometallic residue that does not interfere with the reduction reaction of the carbonyl group in cyclodextrin,
A method for producing an optically active alcohol, which comprises bringing it into dispersion contact with a reducing agent.