JP2001131106A - Method for producing optically active 2-alkoxyalcohols - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method for asymmetric synthesis of an optically active 2-alkoxyalcohol in high productivity. SOLUTION: An α-alkoxy ketone is asymmetrically reduced by an asymmetric hydrogen transfer reduction by a catalyst of a metal compound of the group VIII containing an asymmetric ligand such as an asymmetric diphenylethylenediamine derivative, etc., to give an optically active 2- alkoxyalcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing optically active 2-alkoxy alcohols.

[0002]

2. Description of the Related Art Optically active 2-alkoxy alcohols are important compounds, for example, as intermediates in the synthesis of pharmaceuticals and agricultural chemicals, or as ligands in catalysts. Regarding the production of optically active 2-alkoxy alcohols, since the product has two asymmetric points, a total of four diastereomers are generated, and one of them can be selectively synthesized. Desired. The method of esterifying an optically active 1,2-diol is generally unsuitable for industrial practice since selective monoesterification does not proceed and a diester compound is mixed. Davis et al. Esterified the hydroxy group of an optically active α-hydroxyketone obtained by asymmetric oxidation of a chiral enolate, and further diastereoselectively reduced the ketone moiety with a hydride reagent,
Optically active 1,2-diphenyl-2-methoxyethanol has been obtained (J. Org. Chem. 1989, 54,
2021-2024). Vedej et al., Racemic 1,
The 2-diol is enantioselectively acylated with chiral phosphine, and the obtained optically active 2-acetoxyethanol is methylated and then hydrolyzed to obtain optically active 1,2-diphenyl-2-methoxyethanol. (J. Org. Chem. 1996, 6).
1,430-431). These methods are multi-step,
Not suitable for industrial practice.

On the other hand, Japanese Patent Application Laid-Open No. 9-157196 discloses an asymmetric reduction of a monoketone such as acetophenone with a hydrogen-donating compound in the presence of an asymmetric catalyst comprising a transition metal complex, a base and an optically active nitrogen-containing compound. Has proposed a method for producing an optically active monoalcohol. Thus, it was unclear whether such asymmetric reduction method can be applied to the production of optically active 2-alkoxy alcohols.

[0004]

SUMMARY OF THE INVENTION In view of the foregoing, it is an object of the present invention to provide a simpler and more selective method for producing optically active 2-alkoxy alcohols as compared with the prior art.

[0005]

Means for Solving the Problems The present inventors have responded to diketones in high yield and high selectivity by hydrogen transfer type asymmetric reduction in the presence of a ruthenium catalyst having a diamine type asymmetric ligand. (See Japanese Patent Application Nos. 10-184033 and 10-35).
5564). As a result of further study, it was found that under the conditions of the hydrogen transfer type asymmetric reduction, the desired optically active 2-alkoxy alcohol can be obtained in a high yield and a high selectivity from the racemic α-alkoxy ketone. Headings,
The present invention has been completed. That is, the gist of the present invention is represented by the following general formula (1)

[0006]

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(Wherein, R ¹ and R ² each independently represent an aromatic hydrocarbon group, an aromatic heterocyclic group or an aliphatic hydrocarbon group which may have a substituent. R ¹
And R ² may combine with each other or condense to form a ring. R represents an alkyl group which may have a substituent. )), And a periodic table V
The following general formula (2) characterized by reacting an asymmetric ligand having a group B element, a metal compound of group VIII of the periodic table, a hydrogen donor and a base.

[0008]

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(Wherein R ¹ and R ² have the same meanings as in the general formula (1), and * represents an asymmetric carbon). Exist.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The periodic table used herein is defined in the 1970 IUPAC
It is a long period table based on the nomenclature. Α which is a raw material of the present invention
-The alkoxy ketone is represented by the general formula (1). In the general formula (1), R ¹ and R ² represent an aromatic hydrocarbon group, an aromatic heterocyclic group or an aliphatic hydrocarbon group which may have a substituent. R ¹ and R ² may be bonded to each other or condensed to form a ring.

Specific examples of the aromatic hydrocarbon group include a phenyl group and a naphthyl group, and specific examples of the aromatic heterocyclic group include a pyridyl group, a furyl group and a thienyl group. Examples of the aliphatic hydrocarbon group include an alkyl group, an alkenyl group, and an alkynyl group. Examples of the alkyl group include a linear or branched alkyl group having 1 to 20 carbon atoms such as a methyl group, an ethyl group, an isopropyl group, and a hexyl group.
Examples of the alkenyl group include a linear or branched alkenyl group having 1 to 20 carbon atoms such as a vinyl group and a 2-methylvinyl group. Examples of the alkynyl group include a linear or branched alkynyl group having 1 to 20 carbon atoms such as an acetylenyl group and a methylacetylenyl group. As a substituent bonded to these aromatic hydrocarbon group, aromatic heterocyclic group or aliphatic hydrocarbon group, a substituent containing an aromatic hydrocarbon group, an aromatic heterocyclic group, a typical element and a transition metal element is exemplified. No. Specific examples of the substituent containing a typical element include a halogen atom such as fluorine, chlorine, bromine and iodine, and a halogen atom-containing hydrocarbon group such as a trifluoromethyl group; a hydroxyl group, for example, an alkoxy group such as a methoxy group and an ethoxy group. For example, an oxygen atom-containing substituent such as an acyl group such as an acetyl group, an alkoxycarbonyl group, and a carboxyl group; a nitrogen atom-containing substituent such as an amino group, an alkylamino group and a nitro group; and a silicon-containing substituent such as a trimethylsilyl group and a hydrosilyl group. Group: mercapto group, alkylthio group, 2,6-
Examples thereof include a sulfur atom-containing substituent such as a dithiacyclohexyl group; a phosphorus atom-containing substituent such as a phosphoryl group and a triphenylphosphinyl group. Specific examples of the substituent containing a transition metal element include iron-containing substituents such as a ferrocenyl group. Further, R ¹ and R ² may be bonded to each other to form, for example, a trimethylene group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, or the like, to form a ring.

R represents an alkyl group, specifically, a linear or branched alkyl group having 1 to 20 carbon atoms as described above. It is preferably a lower alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group. Specific examples of the α-alkoxy ketone of the general formula (1) include the compounds shown in Table 1 below, and those having particularly high applicability include benzoin methyl ether, acetoin methyl ether and 2-methoxycyclohexanone. You.

In the present invention, an optically active α-alkoxy ketone may be used as a raw material in advance, but a racemic form can be converted into a target optically active diol in a high yield.
That is, in the present invention, the stereoselective reduction of the prochiral ketone moiety is performed, and at the same time, the racemic ether moiety is converted to a chiral body, and the resulting 2-
Alkoxy alcohols have an excellent feature of having few meso bodies.

[0014]

[Table 1]

The asymmetric ligand constituting the catalyst used in the present invention is an asymmetric ligand having a VB group element in the periodic table.
Group VB elements include nitrogen and phosphorus, and an asymmetric ligand that functions as a catalyst component in an asymmetric hydrogen transfer reaction is used. A typical asymmetric hydrogen transfer catalyst is Che
m. Rev .. 1992, 92, 1051; Am.
Chem. Soc. , 1995, 117, 7562;
J. Am. Chem. Soc. , 1996, 118, 2
521; Chem. Commun. , 1996, 23
Page 3; Tetrahedron Lett. , 34,4
3, 6897 (1993); JP-A-9-24967.
7; Chem. Lett. , 957 (1997);
J. Org. Chem. , 1997, 62, 6104.
Page; Chem. Lett. , P. 491 (1998);
J. Org. Chem. , 1998, 63, 2749.
Page; Am. Chem. Soc. , 1998, 12
0,3817; Tetrahedron Asy
m. Chem., 9 (1998) p. 1143; Chem. Let
t. , P. 1199 (1998); WO 98/42643.
Is disclosed. In these asymmetric ligands, a diamine derivative represented by the following general formula (3) is preferably used.

[0016]

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[0017] (wherein, R ³ and R ⁴ are each independently an optionally substituted alkyl group, an aryl group or an aromatic heterocyclic group. The R ³ and R ⁴ are each R ⁵ and R ⁶ may be bonded or fused to form a ring.
Each independently represents a hydrogen atom, a lower alkyl group, an acyl group, a carbamoyl group, a thioacyl group, a thiocarbamoyl group, an alkyl or arylsulfonyl group. * Indicates an asymmetric carbon atom. )

In the general formula (3), examples of the alkyl group represented by R ³ and R ⁴ include a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group and an isopropyl group; Alternatively, a tetraethylene group in which R ³ and R ⁴ are combined (forming a cyclohexane ring) and the like can be mentioned. Examples of the aryl group represented by R ³ and R ⁴ include a phenyl group and a naphthyl group. Examples of the aromatic heterocyclic group represented by R ³ and R ⁴ include a furyl group and a pyridyl group. These groups may be substituted, examples of the substituent include a lower alkyl group such as a methyl group and an ethyl group,
One or two or more groups selected from a lower alkoxy group such as a methoxy group and an ethoxy group, and a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom. R ³ and R ⁴ are preferably a phenyl group or a substituted phenyl group.

When R ⁵ and R ⁶ represent a lower alkyl group,
It represents a linear or branched alkyl group having 1 to 4 carbon atoms.
In addition, in this specification, lower means C1-C4. When R ⁵ and R ⁶ represent an acyl group, examples thereof include an acetyl group, a propionyl group, and a benzoyl group.
When it represents a carbamoyl group, examples thereof include an N-methylcarbamoyl group and an N-phenylcarbamoyl group. R
^{When 5} , ⁶ represents a thioacyl group, for example, a thioacetyl group, a thiopropionyl group, a thiobenzoyl group and the like are exemplified. Is done.

When R ⁵ and R ⁶ represent an alkyl or arylsulfonyl group, examples thereof include an alkyl or arylsulfonyl group having 1 to 20 carbon atoms, such as a methanesulfonyl group, an ethanesulfonyl group, a benzenesulfonyl group and a toluenesulfonyl group. A 2,4,6-mesitylsulfonyl group, a 2,4,6-triisopropylbenzenesulfonyl group, a 4-methoxybenzenesulfonyl group, a 4-chlorobenzenesulfonyl group, and the like. As R ⁵ and R ⁶ , an arylsulfonyl group is preferable, and a toluenesulfonyl group is particularly preferable. Among the asymmetric ligands represented by the general formula (3), preferably, the following general formula (4)

[0021]

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Where R⁷ May have a substituent
An alkyl group or an aryl group; ⁸ Is a hydrogen atom or
Shows a lower alkyl group. R⁹ And R^TenAre independent
And an optionally substituted alkyl group, phenyl
A group or an aromatic heterocyclic group. * Indicates an asymmetric carbon atom
). More preferred
The asymmetric ligand has the following general formula (5)

[0023]

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(Wherein, R ¹² represents a hydrogen atom or a lower alkyl group, and R ¹¹ , R ¹³ and R ¹⁴ each independently represent
It represents a hydrogen atom, a lower alkyl group, a halogen atom, or a lower alkoxy group. l, m, and n each independently represent an integer of 1 to 5. * Represents an asymmetric carbon atom. ).

Examples of the alkyl group, aryl group, halogen atom and alkoxy group in the general formulas (4) and (5) are the same as those described above. Specific ligands are 1,2
-Diphenylethylenediamine, N-methyl-1,2-
Diphenylethylenediamine, N-tosyl-1,2-diphenylethylenediamine, N-methyl-N′-tosyl-1,2-diphenylethylenediamine, Np-methoxyphenylsulfonyl-1,2-diphenylethylenediamine, Np-chlorophenyl Sulfonyl-1,2
-Diphenylethylenediamine, N-p-mesitylsulfonyl-1,2-diphenylethylenediamine, N-
(2,4,6-tri-i-propyl) phenylsulfonyl-1,2-diphenylethylenediamine and the like.

Examples of the metal species of the Group VIII metal compound of the periodic table used in combination with these asymmetric ligands include ruthenium, rhodium, iridium and cobalt. Compounds include RuCl ₃ -3H ₂ O, [RuCl ₂ (p-cymen
e)] ₂ , [RuCl ₂ (benzene)] ₂ , [RuCl ₂ (mesytilene)] ₂ , [R
uCl ₂ (hexamethylbenzene)] ₂ , RuCl ₂ (PPh ₃ ) ₃ , [RuCl ₂ (c
od)] n, [RuCl ₂ (CO) ₃ ] ₂ , [Rh (cod) Cl] ₂ , [RhCl ₂ (pentam
ethylcyclopentadienyl)] ₂ , [Ir (cod) Cl] ₂ , CoCl _{2 and the} like, and preferably [RuCl ₂ (p-cymene)] ₂ .

In the above compound, Ph is a phenyl group, c
od represents cyclooctadiene. It is preferable that the asymmetric ligand and the Group VIII metal compound of the periodic table are reacted in advance to form a catalyst before use. Catalyst generation is J.Am.Chem.So
c. Known methods disclosed in 1995, 117, p7562 and the like can be used. For example, in a solvent such as isopropanol, in the presence of a base such as triethylamine, a complex in which an asymmetric ligand is coordinated to a metal atom by refluxing and heating the above-described asymmetric ligand and a Group VIII metal compound of the periodic table. Is obtained. You can use this as it is, or
Ent. Ed. Engl. 1997, 36, p285. The complex may be isolated as a crystal and used.

The asymmetric reduction reaction of the present invention is carried out by contacting a raw material with a hydrogen donor in the presence of a catalyst. Examples of the hydrogen donor include alcohol and formic acid.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol and sec.
Lower alcohols having a hydrogen atom at the α-position such as -butanol are used, and a preferred alcohol is isopropanol.

The asymmetric reduction reaction can be carried out in the absence of a base, but is preferably carried out in the presence of a base. The presence of a base stabilizes the catalyst, and can prevent a decrease in activity due to impurities. As the base, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium methoxide, sodium methoxide,
Examples thereof include alkali metal alkoxides such as potassium isopropoxide, and organic amines such as trimethylamine, triethylamine, and triisopropylamine. When a base is used, it is preferable to use an excess amount relative to the catalyst, for example, a molar ratio of 1 to 1000 times. Generally, when alcohol is used as the hydrogen donor, potassium hydroxide is used in a molar amount of 1 to 10 times, and when formic acid is used as the hydrogen donor, triethylamine is used in a large excess with respect to the catalyst, for example, 1 to 100 times.
It is performed using 0 mole times. Suitable hydrogen donor combinations include isopropanol / potassium hydroxide and formic acid / triethylamine, most preferred is formic acid / triethylamine.

When formic acid and amine are used in combination, it is preferable to prepare and use an azeotropic mixture of formic acid and amine in advance, because the influence of impurities in these raw materials can be suppressed. In the case of formic acid and triethylamine, since the molar ratio of the azeotrope is formic acid: triethylamine = 5: 2, it is preferable to further add formic acid or triethylamine to obtain an optimal formic acid / amine ratio. Normally, the hydrogen donor itself is used as the reaction solvent, but a non-hydrogen donor solvent such as toluene, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), or dimethyl sulfoxide may be used as a cosolvent to dissolve the raw materials. It is possible.

The amount of the catalyst used is usually the molar ratio of the substrate (starting material α-hydroxyketone) to the ruthenium atom (S /
C) is from 10 to 1,000,000, preferably 100
To 10,000. The amount of the hydrogen donor relative to the raw material is usually in the range of 1 mole to a large excess (usually 1000 moles). In general, when an alcohol is used as a hydrogen donor, a large excess is used also as a solvent, and formic acid is used as a hydrogen donor. When used, it is used in the range of 1 to 20 times.

The reaction temperature is selected from the range of -70 ° C to 100 ° C, preferably 0 ° C to 70 ° C. The reaction pressure is not particularly limited, and is usually 0.5 atm to 2 atm, preferably 1 atm.
It is performed under atmospheric pressure. As the reaction proceeds, ketones such as acetone are produced when a secondary alcohol such as isopropanol is used as a hydrogen donor, and carbon dioxide is produced when formic acid is used as a hydrogen donor. For efficient progress of the reaction, efficient removal of the product from these hydrogen donors is effective. In particular, the removal of acetone when isopropanol is used as a hydrogen donor is particularly effective for the progress of the reaction.

The reaction time is from 1 hour to 200 hours, usually from 5 hours to 72 hours. After the reaction, the optically active 2-alkoxy alcohol generated from the reaction solution can be separated and purified by generally known operations such as distillation, extraction, chromatography, and recrystallization.

[0034]

EXAMPLES Hereinafter, the embodiments of the present invention will be described in more detail by way of examples, but the present invention is not limited to the scope of the following examples unless it exceeds the gist. Note that ee
Represents the enantiomeric excess.

Example 1 To 7.66 g of [RuCl ₂ (p-cymene)] _{2 and} 9.16 g of (S, S) -Np-toluenesulfonyldiphenylethylenediamine, 150 m of 2-propanol was added.
and 7 ml of triethylamine were mixed and stirred at 80 ° C. for 1 hour under nitrogen. The crystals precipitated after cooling on ice were filtered and 2-
It was washed with a 1: 1 mixture of propanol and hexane. After washing with water and drying under reduced pressure, orange crystals (SS-TsD
12.6 g (referred to as PEN-Ru) (79% yield) was obtained. 50
benzoin methyl ether in a 3-ml three-necked flask.
26 g (10 mM) formic acid 1.43 g (31 mM) and triethylamine 2.63 g (26 mM) were added and mixed.
After replacing with nitrogen, 6.3 mg of SS-TsDPEN-Ru (0.01 mg
mM, S / C = 1000) and reacted at 40 ° C. for 24 hours. When the reaction solution was analyzed by optically active gas chromatography, (1R, 2R) -1,2-diphenyl-2-methoxyethanol was found to have a yield of 92% and an optical purity of 9
Obtained at 8% ee. Recrystallization with hexane, e
e improved to 99% ee.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 213/50 C07D 213/50 317/54 317/54 333/16 333/16 // C07B 53/00 C07B 53/00 B 61/00 300 61/00 300 (72) Inventor Kazuya Okano 8-3-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Prefecture F-term in Tsukuba Research Laboratory, Mitsubishi Chemical Corporation 4C055 AA01 BA02 BA30 BB02 CA01 DA01 4H006 AA02 AC41 AC81 BA20 BA22 BA23 BA24 BA43 BA46 BA69 GP01 GP10 4H039 CA60 CB20

Claims (9)

[Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ and R ² are each independently an optionally substituted aromatic hydrocarbon group, an aromatic heterocyclic group or an aliphatic hydrocarbon group. Further, the R ¹ R ² may be bonded to each other or condensed to form a ring, and R represents an alkyl group which may have a substituent.
-An alkoxyketone, an asymmetric ligand having an element of group VB of the periodic table, a metal complex of group VIII of the periodic table, and a hydrogen donor, which are acted on by the following general formula (2): (Wherein R ¹ , R ² and R have the same meaning as in the general formula (1), and * represents an asymmetric carbon atom). 2. The method for producing optically active 2-alkoxy alcohols according to claim 1, wherein the hydrogen donor is allowed to act in the presence of a base. 3. An asymmetric ligand represented by the following general formula (3): (Wherein, R ³ and R ⁴ each independently represent an alkyl group, an aryl group, or an aromatic heterocyclic group which may have a substituent. In addition, R ³ and R ⁴ are bonded to each other. R ⁵ and R ⁶ each independently represent a hydrogen atom, a lower alkyl group, an acyl group, a carbamoyl group, a thioacyl group, a thiocarbamoyl group, an alkyl or arylsulfonyl group. 3. The method for producing optically active 2-alkoxy alcohols according to claim 1, wherein * represents an asymmetric carbon atom. 4. An asymmetric ligand represented by the general formula (3):
Characterized by having a structure represented by the following general formula (4)
The optically active 2-alkoxy alcohol according to claim 3,
Manufacturing method. Embedded image(Where R⁷ Is an alkyl group which may have a substituent or
Represents an aryl group; ⁸ Is a hydrogen atom or lower alkyl
Represents a group. R⁹ And R^TenIs each independently a substituent
Alkyl group, aryl group or aromatic group which may have
Shows a heterocyclic group. * Indicates an asymmetric carbon atom. ) 5. The optically active 2-alkoxy alcohol according to claim 4, wherein the asymmetric ligand represented by the general formula (4) has a structure represented by the following general formula (5). Manufacturing method. Embedded image (Wherein R ¹² represents a hydrogen atom or a lower alkyl group;
¹¹ , R ¹³ and R ¹⁴ each independently represent a hydrogen atom, a lower alkyl group, a halogen atom, or a lower alkoxy group. l, m, and n each independently represent an integer of 1 to 5. * Indicates an asymmetric carbon atom. ). 6. The process for producing an optically active 2-alkoxy alcohol according to claim 1, wherein the metal compound of Group VIII of the periodic table is a ruthenium compound. 7. The method for producing an optically active 2-alkoxy alcohol according to claim 1, wherein the hydrogen donor is formic acid and the base is a tertiary amine. 8. R ¹ and R ^{2 in} the general formula (1) are each independently an aromatic hydrocarbon group or an aromatic heterocyclic group which may have a substituent. A method for producing the optically active 2-alkoxy alcohol according to any one of claims 1 to 7. 9. The method for producing an optically active 2-alkoxy alcohol according to claim 1, wherein the α-alkoxy ketone represented by the general formula (1) is benzoin methyl ether.