JP2792639B2 - Catalyst for asymmetric nitroaldol reaction - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a catalyst for an asymmetric nitroaldol reaction containing an optically active lanthanum compound.

[0002]

2. Description of the Related Art The present inventors, under anhydrous conditions,
An optically active lanthanum compound was prepared from a dilithium salt of optically active 2,2'-dihydroxy-1,1'-binaphthyl and trivalent lanthanum chloride, and was found to be useful as a catalyst for an asymmetric nitroaldol reaction. ing. (Symposium on Progress in Reactions and Synthesis, sponsored by the Pharmaceutical Society of Japan, announced on November 7, 1991)

[0003]

However, the reaction yield or the asymmetric yield is not reproducible at all, and essentially the asymmetric nitroaldol reaction is extremely useful for providing an important raw material for synthesizing a physiologically active compound. Despite the difficult reaction, its usefulness could not be fully exhibited. Therefore, in order to industrially produce a drug that can be efficiently produced only by the asymmetric nitroaldol reaction, the reaction yield and the asymmetric yield are both high and the reproducible asymmetric It is necessary to develop a catalyst for the nitroaldol reaction.

An object of the present invention is to provide a catalyst for an asymmetric nitroaldol reaction, and to provide a reproducible active species in an asymmetric nitroaldol reaction.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on the type, purity, reaction conditions, and the like of the raw materials, and as a result, have found that the cause of the optically active lanthanum compound acting as an asymmetric catalyst in an asymmetric nitroaldol reaction is as follows. To determine that
An active species that maintains perfect reproducibility in this reaction was found, and the present invention was completed. Ie

The first catalyst for asymmetric nitroaldol reaction of the present invention has the formula (I _R )

Embedded image Or the formula (I _S )

Embedded image Optically active 2,2'-dihydroxy-1,1 'represented by
- dialkali metal salts of binaphthyl (to Isuzu was, wherein, M is Li, is K or Na), LaX ₃ (X is F, C
l, Br, I, NO ₃ or CH ₃ CO ₂ ), and MOR or MOH
(Wherein M is Li, K or Na, and R is isopropyl or t-butyl), characterized by being prepared from an alkali metal alkoxide or an alkali metal hydroxide in the presence of a hydrous solvent.

[0007] In a preferred embodiment, it is prepared in an ether solvent or a hydrous ether solvent. The molar ratio of the dialkali metal salt of the active 2,2'-dihydroxy-1,1'-binaphthyl, the lanthanum compound and the alkali metal alkoxide or alkali metal hydroxide is from 1: 1: 1 to 1: 1: 2. Is preferably within the range.

The method for using the second asymmetric nitroaldol reaction catalyst of the present invention is represented by the formula (II _R )

Embedded image Or formula (II _S)

Embedded image Optically active 2,2'-dihydroxy-1,1 'represented by
An active species obtained from lanthanum alkoxide represented by binaphthyl and La (OR) ₃ (R is isopropyl or t-butyl) is used in the presence of lithium chloride and a water-containing solvent.

In a preferred embodiment, it is desirable to use the active species in the presence of lithium chloride, water and an ether solvent. In addition, the optically active 2,2'-dihydroxy-1,
The molar ratio of 1'-binaphthyl and the lanthanum alkoxide can be used in the range of 2: 1 to 1: 1 but preferably 3: 2.

The optically active 2,2'-dihydroxy-1,1'- used in the catalyst for asymmetric nitroaldol reaction of the present invention.
Binaphthyl dialkali metal salt is prepared by adding optically active 2,2'-dihydroxy-1,1'-binaphthyl to an alkali hydride such as potassium hydride, sodium hydride or lithium hydride in an aprotic solvent such as THF. Method of reacting metal, or water, in a protic solvent such as alcohol, potassium hydroxide, sodium hydroxide,
Alternatively, it is prepared by any method of drying after allowing an alkali metal hydroxide such as lithium hydroxide to act.

The lanthanum compound represented by LaX ₃ used in the catalyst of the present invention is a lanthanum halide such as lanthanum chloride, a trivalent lanthanum compound such as lanthanum nitrate or lanthanum acetate.

As the alkali metal alkoxide, sodium tert-butoxide, potassium tert-butoxide,
Lithium-t-butoxide, potassium isopropoxide, sodium isopropoxide, lithium isopropoxide and the like are preferably used.

The water essential for the preparation of the catalyst of the present invention includes:
It can be introduced into the reaction system by any of the following methods. 1) hydrates of trivalent lanthanum compounds such as lanthanum chloride heptahydrate, lanthanum nitrate nonahydrate, and lanthanum acetate n-hydrate; 2) water-containing ethers such as water-containing THF, water-containing dioxane, and water-containing diethyl ether; solvent. The water added to the system promotes a smooth reaction between the trivalent lanthanum compound insoluble in the organic solvent and the binaphthyl derivative, and acts on the formation of an optically active lanthanum compound having a structure capable of exhibiting high asymmetric expression. I do. The amount of water used is preferably 1 to 20 molar equivalents, particularly preferably 10 molar equivalents, based on the trivalent lanthanum compound 1 as a raw material.

As the absolute configuration of the optically active 2,2'-dihydroxy-1,1'-binaphthyl used in the present invention, both R and S enantiomers can be used. Specifically, (R)-(+)-2,2 'represented by the above formula (II _R )
-Dihydroxy-1,1'-binaphthyl or a compound of the formula (II
Represented by _{S) (S) - (-} ) - 2,2 'dihydroxy-1,1'-binaphthyl.

The lanthanum alkoxide used in the catalyst of the present invention can be prepared by a known method (J. Am. Chem. Soc. 110, 1841 (198
Either method is possible even if it is prepared in a reaction system according to 8)) and used as it is or after isolation and purification.

The catalyst of the present invention contains an optically active lanthanum compound having a basic structural unit of lanthanum binaphthoxide represented by the following formula.

Embedded image

Embedded image

Embedded image Or

Embedded image In other words, because of the variety of bonding modes that are unique properties of lanthanum rare earth elements, this optically active lanthanum compound includes monomers, dimers having halogen atoms, lanthanum atoms or alkali metal atoms as bridging atoms, It may be a trimer to an oligomer, a polymer or a mixture thereof. These are only when water is present at the time of their preparation,
In terms of the structure and the composition ratio, the compound is stably generated as an active species having high catalytic activity against the asymmetric nitroaldol reaction.

The catalyst of the present invention can be easily obtained, for example, by the following method. Lanthanum tri-t-butoxide is suspended in aqueous THF, and this is added to the optically active 2,2 '.
-Dihydroxy-1,1'-binaphthyl is added at room temperature,
After stirring for another 2 hours, the mixture is prepared by adding water and lithium chloride. Alternatively, lanthanum trichloride heptahydrate is suspended in hydrated THF, and optically active 2,2'-dihydroxy-1,
It can also be prepared by adding the dilithium salt of 1'-binaphthyl, followed by the addition of sodium t-butoxide or an alkali metal hydroxide and water, and stirring the mixture at room temperature for 3 days. Hereinafter, the present invention will be described with reference to examples.

[0018]

EXAMPLE 1 A THF solution of lanthanum tri-t-butoxide (4.9 × 10 ⁻² mol · dm ⁻³ as a monomer) under a nitrogen atmosphere.
To 56 cm ³ (S) -2,2′-dihydroxy-1,
159 mg (0.56 mmol) of 1'-binaphthyl was added at room temperature, and the mixture was stirred for 2 hours to prepare a catalyst for asymmetric nitroaldol reaction. Removing the solvent of the catalyst,
¹ H-NM with JEOL GX-270 spectrum meter
R (THF-d ₈₎ and ^{13 C-NMR (THF-d} 8)
Was measured. The results are shown in FIG. 1 and FIG. 2, respectively.

Example 2 In a nitrogen atmosphere, 371 mg of lanthanum chloride / heptahydrate (1
mmol) in 9 cm ³ of a THF suspension.
298 mg (1 mmol) of dilithium salt of 2'-dihydroxy-1,1'-binaphthyl, 192 mg (2 mmol) of sodium t-butoxide, and 180 mg of water
(10 mmol) in THF (1 cm ³ ) was added in order, and the mixture was stirred at room temperature for 3 days to prepare an asymmetric nitroaldol reaction catalyst.

Example 3 Under a nitrogen atmosphere, a dilithium salt of (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl (1 mmol) was added to 9 cm ³ of a suspension of lanthanum chloride (1 mmol) in THF.
l), sodium t-butoxide (2 mmol) and then a solution of water (10 mmol) in 1 cm ³ of THF were added in that order, and the mixture was stirred at room temperature for 3 days to prepare a catalyst for an asymmetric nitroaldol reaction.

Example 4 A THF solution of lanthanum tri-t-butoxide in a nitrogen atmosphere (4.9 × 10 ^-2 mol · dm ^-3 as a monomer)
To 56 cm ³ (S) -2,2′-dihydroxy-1,
159 mg (0.56 mmol) of 1'-binaphthyl was added at room temperature, and the mixture was stirred for 2 hours and the resulting solution was 10 mol% (L
a), cyclohexylaldehyde and nitromethane (10 equivalents) are reacted in tetrahydrofuran at -42 ° C for 18 hours in the presence of 2 molar equivalents of LiCl (relative to La) and 10 molar equivalents of water (relative to La). Next formula

Embedded image 1-cyclohexyl-2-nitroethanol represented by the formula was obtained in a yield of 91%. 90% enantiomeric excess
ee.

Examples 5 to 6 Table 1 shows the results obtained in the same manner as in Example 4 except that the type of aldehyde was changed.

[0023]

[Table 1]

[0024]

Industrial Applicability The catalyst of the present invention is useful as an asymmetric catalyst for asymmetric nitroaldol reactions useful for the synthesis of β-hydroxynitro compounds, which are important raw materials for the synthesis of optically active compounds such as optically active compounds such as propranolol. Extremely useful.

[Brief description of the drawings]

[1] ¹ asymmetric nitroaldol reaction catalyst of the present invention
1 H-NMR spectrum.

FIG. 2 shows ^{13 of the} catalyst for asymmetric nitroaldol reaction of the present invention.
C-NMR spectrum.

Claims (8)

(57) [Claims] 1. A compound of the formula (I _R ) Or the formula (I _S ) Optically active 2,2'-dihydroxy-1,1 'represented by
- dialkali metal salts of binaphthyl (to Isuzu was, wherein, M is Li, is K or Na), LaX ₃ (X is F, C
l, Br, I, NO ₃ or CH ₃ CO ₂ ), and MOR or MOH
Wherein M is Li, K or Na, and R is isopropyl or t-butyl, prepared from an alkali metal alkoxide or an alkali metal hydroxide in the presence of a water-containing solvent. Embedded image Embedded image Or An asymmetric nitroaldol reaction catalyst having a basic structural unit represented by the formula: 2. The catalyst for asymmetric nitroaldol reaction according to claim 1, which is prepared in a hydrous ether solvent. 3. An optically active 2,2'-dihydroxy-1,
The molar ratio of the dialkali metal salt of 1'-binaphthyl, the lanthanum compound, and the alkali metal alkoxide or alkali metal hydroxide is from 1: 1: 1 to 1: 1: 2.
The catalyst for an asymmetric nitroaldol reaction according to claim 1, which is in the range of: 4. The catalyst for asymmetric nitroaldol reaction according to claim 1, wherein the lanthanum compound is a hydrate and the aqueous solvent is an aqueous ether solvent. 5. A compound of the formula (I _R ) Or the formula (I _S ) Optically active 2,2'-dihydroxy-1,1 'represented by
A dialkali metal salt of binaphthyl (where M is Li,
K or Na), lanthanum chloride heptahydrate and sodium t-butoxide or sodium hydroxide in an aqueous tetrahydrofuran catalyst for the asymmetric nitroaldol reaction according to claim 1. 6. A compound of the formula (II _R ) Or the formula (II _S ) Optically active 2,2'-dihydroxy-1,1 'represented by
An active species obtained from a lanthanum alkoxide represented by binaphthyl and La (OR) ₃ (R is isopropyl or t-butyl) in an ether solvent is used in the presence of lithium chloride and a water-containing solvent. How to use a catalyst for asymmetric nitroaldol reaction. 7. The method according to claim 6, wherein the catalyst is used in the presence of lithium chloride, water and an ether solvent. 8. The optically active 2,2′-dihydroxy-
The use of the catalyst for asymmetric nitroaldol reaction according to claim 6, wherein the molar ratio of 1,1'-binaphthyl and the lanthanum alkoxide is in the range of 2: 1 to 1: 1.