JPH11322649A - Production of optically active alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in a high yield, an optically active alcohol at a high enantiomer excess ratio using a small amount of a catalyst by the hydrogen- transfer type asymmetric reduction of a specific ketone by a specific amount of formic acid as a hydrogen donor in thepresence of a specific catalyst and an amine. SOLUTION: This composition shown by formula II is obtained by the hydrogen-transfer type asymmetric reduction of (A) a ketone shown by formula I [R<1> and R<2> are each a (substituted) aromatic hydrocarbon, an aliphatic hydrocarbon, an alicyclic hydrocarbon, or a heterocyclic group, or can form a ring together] by (B) formic acid at a 1-100 molar ratio to component A as a hydrogen donor in the presence of (C) a transition metal catalyst and (D) a tertiary amine (e.g. triethylamine) in an excess amount to component C and a 0.01-100 molar ratio to component A, with a B/D molar ratio being 2.2 or smaller in the reaction system.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an optically active alcohol. More specifically, the present invention relates to an improvement in a method for reducing ketones by a hydrogen transfer type asymmetric reduction reaction using formic acid as a hydrogen donor in the presence of an amine. The method of the present invention provides an optically active α- useful as a synthetic intermediate for pharmaceuticals and pesticides.
It is suitable for the synthesis of methylbenzyl alcohols.

[0002]

2. Description of the Related Art Optically active alcohols are important compounds as intermediates for pharmaceuticals and agricultural chemicals. As one of effective synthetic methods, a hydrogen-transfer type asymmetric reduction reaction using a ketone as a substrate is known. The hydrogen-transfer-type asymmetric reduction reaction is an asymmetric reduction reaction using a hydrogen-donating compound such as isopropanol or formic acid as a hydrogen source, and is more excellent in safety and economy than hydrogen gas reduction and borohydride reduction. .

Noyori et al. Am. Chem. S
oc. , 118, 2521 (1996).
A method for asymmetric reduction of ketones using a triethylamine azeotrope (formic acid: triethylamine = 5: 2 (molar ratio)) as a hydrogen source and a ruthenium compound as a catalyst is disclosed. In this reaction, carbon dioxide generated from formic acid is removed out of the system, so that a higher equilibrium conversion is achieved than when isopropanol is used as a hydrogen source, and a higher asymmetric yield is achieved by a molecular catalyst. I have.

[0004]

However, the hydrogen-transfer-type asymmetric reduction reaction including the above method is inherently slow in the reaction rate, and even when the molar ratio (S / C) of the substrate to the catalyst (S / C) is 200, it is about room temperature. There is a problem that a reaction time of 20 hours is required. An object of the present invention is to provide a method for producing an optically active alcohol capable of obtaining a high chemical yield and a high enantiomeric excess (hereinafter abbreviated as ee) with a smaller amount of catalyst in the case of industrial production.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, when reducing ketones by a hydrogen transfer type asymmetric reduction reaction using formic acid as a hydrogen donor, amines are reduced. The inventors have found that the reaction rate is significantly improved by reducing the molar ratio of formic acid from the azeotropic composition ratio, and have completed the present invention. That is, the gist of the present invention is the general formula (I)

[0006]

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(Wherein R ¹ and R ² are different from each other;
It represents an aromatic hydrocarbon group which may have a substituent, a saturated or unsaturated aliphatic hydrocarbon group, a cycloaliphatic hydrocarbon group or a heterocyclic group. And R ¹ and R ² may be combined to form a ring) in the presence of a transition metal catalyst and a tertiary amine. A general formula (II) characterized in that when the reduction is carried out by a simultaneous reduction reaction, the reaction is carried out in a molar ratio of formic acid to amine in the reaction system of 2.2 or less.

[0008]

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(Wherein R ¹ and R ² have the same meanings as in formula (I)). The present invention also provides a method for producing an optically active alcohol, comprising recovering an amine from a reaction solution obtained after completion of the reaction by distillation and recycling the amine to the reaction.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The starting ketone used in the present invention is represented by the formula (I). In the formula (I), R ¹ and R
² is specifically, for example, a monocyclic or polycyclic aromatic hydrocarbon group, a linear or branched alkyl group, an alkenyl group, an aliphatic hydrocarbon group such as a cycloalkyl group, nitrogen, oxygen, sulfur, etc. Represents a heterocyclic group containing an atom, and these groups may further have a substituent. However, R ¹ and R ² are not the same.

Particularly, ketones having high applicability in the method of the present invention include:
In the formula (I), R¹And R^TwoOne of the C₁
~ C_FourThe other is an XnAr- group (formula
In the formula, Ar represents an aromatic hydrocarbon group or a heterocyclic group;
Is a hydrogen atom, a halogen atom, C₁~ C_FourThe alkyl of
Group, C₁~ C_FourAn alkoxy group of C₁~ C_FourNo haloal
Kill group, C₁~ C_FourHaloalkoxy group, C₁~ C_Fourof
Alkylthio group, C_Two~ C ₆Alkynyloxy group,
Represents an ano group, a nitro group or an aryl group, and n is 1 to 3
Represents an integer. However, when n is 2 or 3, X is the same
But may be different, and two adjacent Xs are united
Which may form a condensed ring with Ar)
It is.

Specifically, the aromatic hydrocarbon group represented by Ar includes a phenyl group and a naphthyl group, and the heterocyclic group includes a pyridyl group, a thienyl group and a thiazolyl group. Examples of the halogen atom represented by X include a chlorine atom, a bromine atom and a fluorine atom; and examples of the C ₁ -C ₄ alkyl group or alkoxy group include a methyl group, an ethyl group,
n-propyl group, i-propyl group, n-butyl group, i-
Alkyl groups such as butyl group, sec-butyl group, t-butyl group and corresponding alkoxy groups; etc .; C ₁ -C ₄ haloalkyl groups and haloalkoxy groups include chloromethyl group, trifluoromethyl group, difluoro Ethyl group,
A haloalkyl group such as a pentafluoroethyl group and an alkoxy group corresponding thereto; and the C ₁ -C ₄ alkylthio group include the alkylthio groups corresponding to the aforementioned alkyl groups. Examples of the alkynyloxy group include a propargyloxy group and a butynyloxy group.

As for XnAr-, two adjacent Xs such as a methylenedioxyphenyl group and an ethylenedioxyphenyl group may combine to form a condensed ring with Ar. The most preferred specific examples of the raw material of the present invention include acetophenone, m-chloroacetophenone,
Examples include fluoroacetophenone, m-trifluoromethylacetophenone, m-trifluoromethoxyacetophenone, phenylethylketone, phenylisopropylketone, phenyl-n-propylketone, phenyl-n-butylketone, 1-indanone, α-tetralone, and the like. .

In the present invention, formic acid is used as a hydrogen donor. As formic acid obtained industrially, those having various water contents are available, but in this reaction, those having as small a water content as possible are desirable, and specifically, 99% by weight formic acid is exemplified. The molar ratio of formic acid to ketone as a raw material is 1 to 100 times, preferably 1 to 10 times.
Molar times, more preferably 1 to 1.2 times, are exemplified.

In this reaction, an equimolar amount of formic acid is consumed in the reaction. For the preparation method of formic acid,
There are a method in which an equimolar amount or an excess amount of formic acid is mixed at the time of charging, and a method in which the reaction proceeds while continuously or intermittently adding formic acid. It is useful to promote the reaction while adding formic acid in terms of improving productivity and avoiding a runaway reaction.

In the present invention, the reaction is carried out in the presence of an amine. As the amine, primary amines such as ammonia, methylamine and benzylamine, secondary amines such as dimethylamine and diethylamine, and tertiary amines such as trimethylamine, triethylamine, tri-n-propylamine and pyridine are used. Of these, tertiary amines are preferred, and trimethylamine, triethylamine,
Tertiary aliphatic amines such as tri-n-propylamine are preferred, and triethylamine is particularly preferred.

The amount of the amine must be at least an excess amount with respect to the catalyst, and the optimum amount of the amine to be used varies depending on the starting ketone and the amine to be used. Usually, the molar ratio of the amine to the starting ketone is 0.01 to 100; Preferably 0.1
To 2. The present invention is characterized in that the reaction is carried out within a molar ratio of formic acid to amine (hereinafter referred to as "formic acid / amine ratio") of 2.2 or less. The maximum charge of formic acid is determined according to the amount of amine present. Preferred formic acid /
The amine ratio is 1 or less. Since formic acid is consumed as the reaction proceeds, when the charged amount of formic acid is 1 or less with respect to the ketone, the formic acid / amine ratio becomes 0 as the reaction proceeds, and the reaction stops. The reaction is resumed by adding formic acid again.

It is also known that various tertiary amines form an azeotrope with formic acid (Journal of the Society of Synthetic Organic Chemistry, 34 , No. 2, 67 (1976)). It is also possible to use a formic acid-amine azeotrope as a supply method for the acid. The molar ratio of amine to formic acid in the azeotrope is usually from 2.3 to 2.5,
In the present invention, it is desirable to adjust the formic acid / amine ratio by adding an amine to the formic acid-amine azeotrope.

As the catalyst of the present invention, a generally known hydrogen transfer type asymmetric reduction catalyst is used. A common form of the catalyst is a transition metal compound having an optically active ligand, and examples thereof include US Pat.
3,521, JP-A-62-2738989, Tetrahedron Lett. 38 , no.
2,215 (1997), WO97 / 20789 and the like. Examples of the transition metal include ruthenium, rhodium, iridium, and samarium, and ruthenium is preferred.

As ligands, optically active phosphine derivatives, optically active amine derivatives, optically active aminophosphine derivatives, optically active amino alcohol derivatives, optically active amino acid derivatives and the like are known. The diphenylethylenediamine derivative is excellent. Generally, an optically active catalyst is prepared by reacting a ruthenium compound with an optically active ligand in a solvent in the presence or absence of a base. The ruthenium compound used as a raw material is [RuCl ₂ (cymene)] ₂ ,
[RuCl ₂ (Mesitylene)] ₂ , [RuC
l ₂ (benzene)] _{2 and the} like, and ruthenium phosphine complex such as RuCl ₂ (PPh ₃ ). The prepared optically active catalyst may be subjected to a reduction reaction as a concentrate of a prepared crude liquid containing it, but it is preferably further purified by recrystallization or the like and used as a pure optically active complex in the reaction. A typical example of a ruthenium complex having an optically active 1,2-diphenylethylenediamine derivative as a ligand is disclosed in WO97 / 20789. Typical ruthenium arene complexes, optically active ligands and optically active ruthenium complexes are shown in Tables 1, 2 and 3.

[0021]

[Table 1]

[0022]

[Table 2]

[0023]

[Table 3]

The amount of the catalyst varies depending on the substrate, but the reaction is carried out at a substrate / catalyst molar ratio (S / C) of 100 to 100,000, usually 200 to 10,000. The reaction temperature is not particularly limited because the optimum temperature range varies depending on the catalyst, but the reaction is preferably carried out in the range of -20 to 100 ° C. In order to obtain a practical reaction rate and a high ee, it is more preferable to carry out the reaction in the range of 10 to 60 ° C. In general, raising the reaction temperature shortens the reaction time and lowers the optical purity, but increasing the temperature as the reaction proceeds or in the final stage is a method for improving the chemical yield while maintaining the optical purity. It is valid.

Specific examples of the optically active alcohol represented by the formula (II) produced in the present invention include optically active 1
-Phenylethanol, optically active 1- (3-chlorophenyl) ethanol, optically active 1- (3-fluorophenyl) ethanol, optically active 1- (3-trifluoromethylphenyl) ethanol, optically active 1-phenylisopropanol, optically active Examples thereof include 1-phenyl-n-propanol, optically active 1-phenyl-n-butanol, optically active 1-indanol, optically active α-tetralonol, and the like.

In the present invention, after completion of the reaction, the amine is recovered from the reaction solution by direct distillation. The recovered amine can be reused for the reaction. The formic acid remaining in the reaction solution used after being added in excess can be recovered as an azeotrope with the amine, and can be reused in the reaction. Thus, recyclable amines include both the amines themselves and the formic acid-amine azeotropes. If necessary, the catalyst and the product can be separated. As a separation method, distillation or recrystallization of a product is generally performed.

It is conventionally known to perform extraction by adding water and an organic solvent after completion of the reaction, and it is also possible to separate the alcohol product and the reaction reagent by extraction. Any organic solvent can be used as long as liquid separation can be performed. Examples thereof include aliphatic hydrocarbon solvents such as hexane and cyclohexane, aromatic hydrocarbon solvents such as toluene and benzene, ethers such as ethyl ether and isopropyl ether, and ethyl acetate. And halogen-containing hydrocarbon solvents such as dichloromethane and chloroform. The extracted product is purified by a general purification method such as distillation, column chromatography, recrystallization and the like.

[0028]

EXAMPLES The present invention will be described in more detail with reference to examples and comparative examples, but the present invention is not limited to the following examples unless it exceeds the gist. In Examples, ee indicates an enantiomeric excess, and S
/ C indicates the molar ratio of the substrate to the catalyst.

Reference Example 1 Preparation method of catalyst Synthesis of [RuCl ₂ (cymene)] ₂ (M-2) 200 g of ethanol was added to 10 g of ruthenium chloride hydrate.
After adding 45 ml of α-terpinene and 22 ml of water and heating under reflux for 4 hours, most of the ethanol was removed by distillation under reduced pressure and concentrated. The crystals obtained by filtration were washed with a 1: 1 mixture of ethanol and hexane and dried under reduced pressure to obtain 11.5 g of red [RuCl ₂ (cymene)] ₂ (yield 92%).

(S, S) -p-toluenesulfonyldiphenylethylenediamine (SS-TsDPEN, L-
Synthesis of 2) 10.6 g of (S, S) -diphenylethylenediamine was dissolved in 100 ml of dichloromethane, 7 ml of triethylamine was added, and p-toluenesulfonyl chloride 9.5 was added.
g was added little by little while cooling with water. After stirring at room temperature for 2 hours, the mixture was filtered to remove insolubles, 50 ml of water was added to the filtrate, and the mixture was shaken to separate an organic layer. After repeating the washing operation, magnesium sulfate was added to dehydrate and concentrate. The precipitated crystals were separated by filtration, washed with a 1: 1 mixture of dichloromethane and hexane, and dried under reduced pressure to give 16.6 g (yield 90%) of white (S, S) -p-toluenesulfonyldiphenylethylenediamine. Obtained.

Optically active ruthenium complex (SS-TsDP)
Synthesis of EN-Ru, C-1) [RuCl ₂ (cymene)] ₂ 7.66 g and (S
S) -P-Toluenesulfonyldiphenylethylenediamine (9.16 g) was added with 2-propanol (150 ml) and triethylamine (7 ml), and the mixture was stirred at 80 ° C for 1 hour under nitrogen. After cooling with ice, the precipitated crystals were filtered and washed with a 1: 1 mixture of 2-propanol and hexane. Further, it was washed with water and dried under reduced pressure to obtain 12.6 g of orange crystals (yield 79).
%). After concentrating the filtrate after removing the crystals, 30 ml of dichloromethane was added, the generated white salt was further removed by filtration, and the obtained filtrate was concentrated, and the obtained brown solid was washed with water and dried under reduced pressure to give a brownish brown solid. 5.3 g of crystals were obtained. 50 ml of 2-propanol was added thereto, and the mixture was heated and stirred under nitrogen at 80 ° C. for 10 minutes. After cooling, the precipitated crystals were filtered, washed with a 1: 1 mixture of 2-propanol and hexane, and dried under reduced pressure. 1.9 g of colored crystals (yield 12%, total yield 91%) were obtained.

Example 1 135 g (2.93 mM) of formic acid and triethylamine 11
By distilling the solution mixed with 8 g (1.17 mM) under reduced pressure, 137 g of an azeotropic mixture (hereinafter abbreviated as TEAF) was obtained from a fraction having a boiling point of 119 ° C. at 45 mmHg. NMR analysis revealed that the molar ratio of formic acid to triethylamine in TEAF was approximately 5: 2.

[RuCl ₂ (cymene)] ₂ 12
4 mg (0.02 mM) and p-toluenesulfonyldiphenylethylenediamine 14.7 mg (0.008 m
M), 2 ml of 2-propanol dehydrated and distilled with calcium hydride and 11.2 μl of triethylamine
(0.08 mM), and the mixture was heated and stirred at 80 ° C. for 1 hour under nitrogen (hereinafter, referred to as a catalyst solution).

[0034] 0.3 ml (0.006 mM) of the catalyst solution was added to a flask having a volume of 10 ml, and the solvent was removed at room temperature under reduced pressure to obtain a red solid. To this, 1.0 ml of TEAF and 0.5 ml of triethylamine were added (formic acid / triethylamine = 1.43). Further, 0.564 g (3.0 mM, S / C500) of m-trifluoromethylacetophenone was added, and the mixture was stirred at room temperature for 25 hours. The reaction solution was analyzed by HPLC, and it was found that the chemical yield was 97.8% and ee 92.2%. Thus, the desired S-1- (3-trifluoromethylphenyl) ethanol was obtained.

Examples 2 to 5 and Comparative Example 1 A reaction was carried out at room temperature for 25 hours in the same manner as in Example 1 except that the ratio of formic acid to triethylamine was changed as follows.
The desired optically active alcohol was obtained with the chemical yield and ee shown in Table-4.

[0036]

[Table 4] Et ₃ N: triethylamine

EXAMPLE 6 109 g of TEAF was placed in a four-necked flask having a volume of 300 ml.
24.6 g of triethylamine (1.26 mol of formic acid, total of 0.75 mol of triethylamine, HCO ₂ H / Et
₃ N = 1.69), was added m- trifluoromethyl acetophenone 105g of (558mM). SS-TsDP
494 g (0.777 mM) of EN-Ru was added to 3 ml of DMF.
And immediately added to the reaction mixture, foaming started immediately. The reaction was carried out while keeping the temperature at 30 ° C. and following the reaction by optically active gas chromatography, and the conversion was 99 in 25 hours.
% Has been reached. After completion of the reaction, isopropyl ether 74
g, 1N hydrochloric acid (66 g) was added, and the mixture was stirred and allowed to stand. The lower aqueous layer was separated, and the oil layer was further washed with 79 g of 25% by weight saline. 13 g of anhydrous magnesium sulfate was added to the oil layer for dehydration, and then salts were removed by filtration. The filtrate was concentrated and distilled under reduced pressure to obtain the desired S-1- (3-trifluoromethylphenyl) ethanol at 17 mmHg and 100 to 102 ° C with a chemical yield of 95% and an ee of 93%.

Example 7 2 ml of TEAF, 2 ml of triethylamine (formic acid / triethylamine 0.98), 3.77 g of m-trifluoromethylacetophenone (hereinafter abbreviated as MTFA)
(20 mM, formic acid / MTFA = 1.16), 0.1 ml of a 1 M solution of SS-TsDPEN-Ru in DMF (S / C2000) was added, and the mixture was stirred at 50 ° C. for 5 hours. When the reaction solution was analyzed by optically active gas chromatography, the chemical yield was 96.2% and ee was 91.2%.
And the desired S-1- (3-trifluoromethylphenyl)
Ethanol (hereinafter abbreviated as S-BA) was obtained.

Examples 8 to 13 The reaction was carried out at 50 ° C. for 5 hours in the same manner as in Example 7 except that the ratio of formic acid to triethylamine was changed as follows.
S-BA was obtained with a chemical yield and ee as shown in Table-5.

[0040]

[Table 5]

Example 14 Ru catalyst SS-TsDPEN was placed in a 20 mL two-necked flask.
0.891 g (1.40 mmol) of Ru was weighed out,
A catalyst solution was prepared by adding 7.0 mL of DMF under nitrogen. 282.3 Triethylamine in a 1 L three-necked flask
g (2.79 mol), and formic acid (99
%) 133.9 g (2.88 mol) were added in small portions while cooling. Return to room temperature and MTFA 500.0g
(2.66 mol) and 6.65 ml (1.33) of the catalyst solution.
mmol), and the mixture was stirred at a bath temperature of 50 ° C. for 24 hours under a stream of nitrogen.
To obtain S-BA. The reaction solution was distilled under reduced pressure, and 250 g of triethylamine was recovered at a boiling point of 37 to 40 ° C./30 to 147 mmHg (recovery rate 95%).
477 g of S-BA (recovery rate 97%) at 11 mmHg
e obtained at 89.8%.

Example 15 3.19 g of triethylamine recovered in Example 14
(31.5 mM), formic acid 1.64 g (35.5 mM),
5.64 g (30 mM) of MTFA was mixed, and SS-Ts
DPEN-Ru 0.1M DMF solution 0.1ml
(S / C3000) was added and the mixture was stirred at 50 ° C. for 24 hours.
%.

Example 16 SS-TsDPEN-Ru was placed in a 10 ml three-necked flask.
1.7 mg (2.67 μM), MTFA 1.0 g (5.
4 mM), 0.19 ml of triethylamine (1.3 m
M). While the reaction solution was stirred at 50 ° C., 0.05 ml of formic acid (1.3 mM) was added. While following the reaction by gas chromatography, the same amount of formic acid was added four times every one hour, and 0.25 ml of synthesized formic acid was added in four hours. After 5 hours, S-BA has a chemical yield of 98.3%, e
e obtained at 89.5%. Table 6 shows changes in the formic acid input amount and the formic acid / amine ratio in the system in this example.

[0044]

[Table 6]

[0045]

According to the present invention, an optically active alcohol can be produced with a smaller amount of a catalyst in a high chemical yield and a high ee, which is advantageous in industrial production thereof.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (3)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ and R ² are different from each other and may have an aromatic hydrocarbon group, a saturated or unsaturated aliphatic hydrocarbon group, a cycloaliphatic hydrocarbon group, or a heterocyclic group. And R ¹ and R ² may combine to form a ring), and formic acid is used as a hydrogen donor in the presence of a transition metal catalyst and a tertiary amine. In the reduction by the hydrogen transfer type asymmetric reduction reaction, the reaction is carried out within a range of a molar ratio of formic acid to amine in the reaction system of 2.2 or less, wherein the reaction is carried out in a general formula (II). (Wherein R ¹ and R ² have the same meanings as in formula (I)). 2. In the general formula (I), ^one of R ¹ and R ² is an alkyl group having 1 to 4 carbon atoms,
The other is an XnAr- group (wherein, Ar represents an aromatic hydrocarbon group or a heterocyclic group, X represents a hydrogen atom, a halogen atom,
An alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, 6 represents an alkynyloxy group, a cyano group, a nitro group or an aryl group, and n is
Represents an integer of 1 to 3. However, when n is 2 or 3, X may be the same or different, and two adjacent Xs may be combined to form a condensed ring with Ar). Item 4. The method for producing an optically active alcohol according to Item 1. 3. The method for producing an optically active alcohol according to claim 1, wherein an amine is recovered from a reaction solution obtained after the completion of the reaction, and the amine is recycled to a reaction system.