JP2001348392A - Method for producing asymmetrically cyanosilylated product by using composition for asymmetrical synthesis catalyst - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an asymmetrically cyanosilylated product by using a catalyst composition for an asymmetric synthesis without extention of the reaction time. SOLUTION: When carrying out the asymmetrical cyanosilylation reaction of an aldehyde with a trimethylsilylcyanide by using a conventional catalyst composition for the asymmetrical synthesis, the asymmetrical cyanosilylation product can be obtained in a short time in high isolation yield and asymmetrical yield by adding a proton source to the reaction system.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an efficient method for producing an asymmetric cyanosilylation product using a catalyst composition for asymmetric synthesis which can be used in all fields utilizing asymmetric compounds as well as pharmaceutical intermediates.

[0002]

BACKGROUND OF THE INVENTION The present inventors have prepared a catalyst composition for asymmetric synthesis in which optically active binaphthols, diethylaluminum chloride and a phosphine oxide compound are added under anhydrous conditions, and this is used as a catalyst for asymmetric cyanosilylation reaction. I find it useful. When the amount of the aldehyde serving as the substrate is as small as 0.192 mmol,
It has been reported that the reaction yield and asymmetric yield of asymmetric cyanosilylation products formed from various aldehydes are good (J. Am. Chem. Soc., 1999, 121, 2641-2642). However, when this conventional method is diverted to an industrial scale, there is a problem that the reaction rate is remarkably reduced as the scale is increased, and the asymmetric yield is further reduced.

[0003]

SUMMARY OF THE INVENTION The present invention provides a catalyst composition for asymmetric synthesis by reacting an optically active binaphthol with a metal compound and a phosphine oxide compound. In a method of producing an asymmetric cyanosilylate by reacting an aldehyde and trimethylsilyl cyanide, even if the scale is increased to an industrial scale, the asymmetric cyanosilyl can be obtained at a high reaction yield and an asymmetric yield without extending the reaction time. To provide a method for producing a compound.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, prepared an asymmetric synthesis catalyst composition by reacting an optically active binaphthol with a metal compound and a phosphine oxide compound. However, by adding a proton source to the reaction system containing the catalyst composition for asymmetric synthesis, aldehyde and trimethylsilyl cyanide, the reaction yield which can satisfy the asymmetric cyanosilylation product without extending the reaction time and They have found that they can be obtained in asymmetric yields, and have completed the present invention.

That is, the present invention provides the following formula (1)

Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. An aldehyde represented by the following formula (2) may be reacted with trimethylsilyl cyanide in the presence of a catalyst composition for asymmetric synthesis.

Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. May be included)) or the following formula
(3)

Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. The present invention relates to a method for producing an asymmetric cyanosilylation product represented by the formula (1), wherein a proton source is added into a reaction system.

[0006] The asymmetric cyanosilylation reaction of the present invention is characterized in that a proton source is added to the reaction system in comparison with the conventional asymmetric cyanosilylation reaction.
The conventional asymmetric cyanosilylation reaction, as described in detail in the above-mentioned literature, describes the formation of an optically active binaphthol, diethylaluminum chloride and a phosphine oxide compound under anhydrous conditions. A catalyst composition for asymmetric synthesis is used.

The optically active binaphthols which are components of the catalyst composition for asymmetric synthesis of the present invention have the following formula (4)

Embedded image Or equation (5)

Embedded image Indicated by

The metal compound to be added to the catalyst composition for asymmetric synthesis includes the following formula (6)

Embedded image (Wherein, M represents an aluminum atom, a titanium atom, a zinc atom, a rare earth metal atom, etc., X represents a halogen atom, a cyano group, etc., Y represents an alkyl group, Z represents an alkoxyl group. a represents an integer of 1 to 10, b,
c and d each represent an integer of 0 to 10 that does not become 0 at the same time. )
Is used.

[0009] Specifically, Et_TwoAlCl, Et_TwoAlBr, Et_TwoA
lI, Me_ThreeAl, Et_TwoAlOEt, EtAlCl_Two, Me_TwoAlCl, Et_TwoAlC
N, TiCl_Four, Ti (O-i-Pr)_Four, Ti (O-t-Bu)_Four, Ti (O-i-Pr)
_TwoCl _Two, TiCl (O-i-Pr)_Three, Ti (O-n-Bu)_Four , Ti (OEt)_Four,
La (O-i-Pr)_Three, Yb (O-i-Pr)_Three, Zr (O-t-Bu)_Four, Zr (O-i-P
r)_Four, Zr (O-n-Pr)_Four, Zr (O-t-Bu)_Four, Sc (Tf)_Three, Yb (T
f)_Three, ZnI_TwoAnd the like.

In the present invention, a proton source is added to an asymmetric cyanosilylation reaction system using an aldehyde and trimethylsilyl cyanide in the presence of a conventional catalyst composition for asymmetric synthesis. In a system in which a proton source is not added to a conventional asymmetric cyanosilylation reaction system, the aldehyde is 0.19.
On a reaction scale of 2 mmol, the asymmetric cyanosilylation reaction proceeds at a satisfactory reaction rate, but when the reaction scale is increased to 1 mmol or more, the reaction time is extremely prolonged. In response to this phenomenon, by adding a proton source to the reaction system, an asymmetric cyanosilylation product can be obtained with a satisfactory reaction yield and asymmetric yield without extending the reaction time.

In the present invention, examples of the proton source added to the reaction system include water, hydrocyanic acid, alcohol, and binaphthols. Preferred are methanol, ethanol, propanol, isopropanol, butanol, or phenol. As a method for adding the proton source into the reaction system, a method for adding the proton source after mixing with trimethyl cyanide is preferable. Further, the amount of the proton source used in the present invention is preferably 0.01 mol% or more based on the aldehyde, and is preferably 0.01 to 20 mol%.
A mol% range is more preferred.

The aldehyde of the above formula (1) used in the process for producing an asymmetric cyanosilylate according to the present invention includes a aldehyde having 1 to 10 carbon atoms such as hexaaldehyde and heptaldehyde.
And the alkyl group may contain a double bond or a triple bond, or the alkyl group may be branched. Further, an aldehyde having an aromatic ring such as a phenyl group, a thienyl group, a pyrrolyl group, a furyl group, and a pyrrolidyl group may be used. Furthermore, alicyclic aldehydes, such as cyclohexyl aldehyde, can be mentioned.

The aldehyde of the formula (1) may have a substituent, such as a halogen atom such as a chlorine atom or a bromine atom, a lower alkyl group such as a methyl group or an ethyl group, or an alkenyl group. Group, alkynyl group, nitro group, etc.
Further, examples thereof include a heterocyclic group such as a thienyl group, a pyrrolyl group, a furyl group, and a pyrrolidyl group; and an aromatic hydrocarbon group such as a phenyl group.

[0014] The reaction temperature of the asymmetric cyanosilylation reaction of the present invention is preferably between -100 ° C and 50 ° C. Especially -50 ° C
A range of from -30C to -30C is particularly favorable from the viewpoint of the reaction yield and the asymmetric yield.

The asymmetric cyanosilylation reaction of the present invention is generally carried out in a solvent, but any solvent may be used without changing the catalyst for asymmetric synthesis. Specifically, ether solvents such as THF, diethyl ether and 1,4-dioxane, methylene chloride, chloroform,
Halogen solvents such as 1,1,1-trichloroethane and monochlorobenzene, fluorine solvents such as trifluorobenzene, hydrocarbon solvents such as benzene, toluene, n-hexane and n-heptane, ethyl acetate and methyl acetate; Fatty acid esters, dimethyl sulfoxide, N, N
Polar solvents such as dimethylformamide. These solvents can be used alone or in combination of two or more.

In the asymmetric cyanosilylation reaction of the present invention, a proton source is added to a reaction system for reacting trimethylsilyl cyanide with an aldehyde in the presence of a catalyst composition for asymmetric synthesis to form a cyanosilylation product. . The reaction yield and the asymmetric yield can be obtained by directly isolating the cyanosilylation product.However, after the asymmetric cyanosilylation reaction, when the trimethylsilyl cyanide used in excess is deactivated, it is simultaneously converted from the cyanosilylation product. The reaction yield and the asymmetric yield can also be determined by isolating the compound as a cyanohydrin compound corresponding to the cyanosilylate compound. Further, by reacting the cyanohydrinated compound with an acid anhydride or the like, the hydroxyl group of the cyanohydrinated compound is converted into a more stable ester or the like, and then the reaction yield and the asymmetric yield can be determined.

The trimethylsilyl cyanide used in the asymmetric cyanosilylation reaction of the present invention is preferably deactivated after completion of the reaction in order to avoid formation of hydrocyanic acid. Reagents used to deactivate trimethylsilyl cyanide include acids,
Bases, water, fluorides and the like are conceivable. By using these reagents, a cyanosilylation product produced by the asymmetric cyanosilylation reaction may be simultaneously converted to a corresponding cyanohydrination compound. In consideration of the stability of the cyanosilylate, deactivation by an acid such as acetic acid, hydrochloric acid, and sulfuric acid is generally preferred.

[0018]

EXAMPLES Hereinafter, a method for producing an asymmetric cyanosilylate will be described in detail with reference to the preparation of a catalyst composition for asymmetric synthesis, Examples and Comparative Examples. In addition, this Example and a comparative example do not limit this invention at all. The asymmetric yield in Examples and Comparative Examples was determined by HPLC (column; CHIRALPAK OD manufactured by Daicel Chemical Industries, Ltd .; eluent:
(Hexane / i-propanol).

(Preparation of Catalyst Composition A for Asymmetric Synthesis) 50 ° C.
Tributylphosphine oxide (36 mol% based on the substrate aldehyde) was vacuum-dried for 6 hours in methylene chloride under an argon atmosphere and cooled to 0 ° C., and the solution was added to commercially available diethylaluminum chloride (substrate). A hexane solution (9.5 mol% with respect to the aldehyde) is added dropwise to obtain a prepared mixed solution. Further, the mixed solution was cooled to 0 ° C. under an argon atmosphere,
Optically active binaphthols represented by the above formula (4) (vacuum dried at 6 ° C. for 6 hours, 9.0 mol based on substrate aldehyde)
%) In methylene chloride and stirred for 1 hour.
A catalyst composition A for asymmetric synthesis was prepared.

(Preparation of Catalyst Composition B for Asymmetric Synthesis) 50 ° C.
Diphenylmethylphosphine oxide (36 mol% based on the substrate aldehyde) dissolved in methylene chloride under an argon atmosphere and cooled to 0 ° C. under a vacuum atmosphere for 6 hours is then added to a commercially available diethylaluminum chloride ( (9.5 mol% based on the substrate aldehyde)
Was added dropwise to obtain a prepared mixed solution. Further, the mixed solution was cooled to 0 ° C. under an argon atmosphere,
Optically active binaphthols represented by the above formula (4) (vacuum dried at 50 ° C. for 6 hours) (9.0 m to substrate aldehyde)
ol%) of methylene chloride was added dropwise and the mixture was stirred for 1 hour, and then a catalyst composition A for asymmetric synthesis was prepared.

Example 1 Catalyst composition A for asymmetric synthesis was stirred at -40 ° C for 30 minutes.
Furthermore, at the same temperature, 0.148
mL (1.06 mmol) was added dropwise and methanol 4 μL was added.
After adding 0.170 mL (1.27 mmol) of trimethylsilyl cyanide mixed with (0.106 mmol) over 24 hours, the mixture was reacted at −40 ° C. with stirring. After 60 hours, 2 mL of 3N hydrochloric acid and 2 mL of ethyl acetate were added at −40 ° C., and the mixture was stirred at room temperature for 1 hour to complete the reaction, and at the same time, the trimethylsilyloxy group was converted to a hydroxyl group. Subsequently, subjected to extraction of the resulting product with methylene chloride, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, flash chromatography (SiO ₂ , Hexane / ethyl acetate = 100/1
Purification in 5) gave (S) -2-hydroxyoctanitrile. The isolation yield of the obtained compound was 95%.
Further, the obtained compound was converted into an ester form with benzoyl chloride and pyridine in methylene chloride, and the asymmetric yield was determined to be 97% ee.

Example 2 The catalyst composition B for asymmetric synthesis was stirred at -40 ° C for 30 minutes.
Further, at the same temperature, benzaldehyde 0.966
mL (9.50 mmol) was added dropwise, and methanol 19 μm was added.
After adding 1.52 mL (11.4 mmol) of trimethylsilyl cyanide mixed with L (0.475 mmol),
The reaction was carried out at −40 ° C. with stirring. -4 hours after 96 hours
After adding 10 mL of 3N hydrochloric acid and 10 mL of ethyl acetate at 0 ° C., the reaction was terminated by stirring at room temperature for 1 hour, and at the same time, the trimethylsilyloxy group was converted to a hydroxyl group. Subsequently, the obtained product was extracted with methylene chloride, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
₂ , hexane / ethyl acetate = 100/15),
(S) -Mandelonitrile was obtained. The isolation yield of the obtained compound was 96%. Further, the obtained compound was converted into an ester form with methylene chloride using ethyl chlorocarbonate and pyridine, and the asymmetric yield was determined. The asymmetric yield was 96% ee.

Comparative Example 1 The isolation yield of (S) -mandelonitrile obtained in the same manner as in Example 2 except that methanol was not added was 40%. Further, the obtained compound was converted into an ester form with ethyl chlorocarbonate and pyridine in methylene chloride, and the asymmetric yield was determined. The asymmetric yield was 86% ee.

Comparative Example 2 The isolation yield of (S) -mandelonitrile obtained in the same manner as in Example 2 except that methanol was not added and the reaction time was 320 hours was 95%. Further, the obtained compound was converted into an ester form with ethyl chlorocarbonate and pyridine in methylene chloride, and the asymmetric yield was determined. The asymmetric yield was 86% ee.

[0025]

According to the method of the present invention in which a proton source is added to an asymmetric synthesis reaction system to carry out an asymmetric cyanosilylation reaction, a high isolation yield and an asymmetric yield can be obtained without prolonging the reaction time. To give an asymmetric cyanosilylation product.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4G069 AA06 AA08 BA27B BC16B BE26B BE39B CB57 DA02 FA01 FB05 4H039 CA92 CF30 4H049 VN01 VP01 VQ41 VR23 VR41 VS41 VT08 VT32 VT33 VT35 VT36 VT40 VT44 V02V

Claims (6)

[Claims] [Claim 1] The following formula (1) (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. The aldehyde represented by the following formula (2) may be reacted with trimethylsilyl cyanide in the presence of a catalyst composition for asymmetric synthesis. (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. May be included.) Or the following formula
(3) (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. A method for producing an asymmetric cyanosilylation product represented by the formula (1), wherein a proton source is added to the reaction system. 2. The catalyst composition for asymmetric synthesis has the following formula (4): Is a catalyst composition for asymmetric synthesis obtained by reacting an optically active binaphthol represented by the formula (1) with a metal compound, wherein the asymmetric cyanosilylation product is represented by the following formula (2): (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. The method for producing an asymmetric cyanosilylate according to claim 1, which is a compound represented by the formula: 3. The catalyst composition for asymmetric synthesis is represented by the formula (5): Is a catalyst composition for asymmetric synthesis obtained by reacting an optically active binaphthol represented by the formula (1) with a metal compound, wherein the asymmetric cyanosilylation product is represented by the following formula (3): (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a benzyl group, and has a double bond or a triple bond. The method for producing an asymmetric cyanosilylate according to claim 1, which is a compound represented by the formula: 4. The proton source added to the reaction system is water,
The process for producing an asymmetric cyanosilylate according to any one of claims 1 to 3, wherein the process is a hydrocyanic acid, an alcohol or a binaphthol. 5. The method according to claim 1, wherein the proton source added to the reaction system is methanol, ethanol, propanol, isopropanol, butanol, or phenol.
A process for producing an asymmetric cyanosilylate according to any one of the preceding claims. 6. The process for producing an asymmetric cyanosilylate according to claim 1, wherein the proton source added to the reaction system is mixed with trimethyl cyanide and added.