JP2000016954A - Production of optically active 1,2-diols - Google Patents

Abstract

PROBLEM TO BE SOLVED: To readily produce an optically active 1,2-diols useful as a synthetic intermediate or the like for a medicine or an agrochemical in high reaction yield, high racemic selectivity and high enantio selectivity by asymmetrically reducing a specific diketone by a hydrogen donor in the presence of a specified catalyst. SOLUTION: A diketone of formula I [R1 and R2 are each a (substituted) aromatic hydrocarbon or the like], (e.g. benzil) is asymmetrically reduced by using a hydrogen donor such as formic acid in the presence of a catalyst obtained by combining a group VIII metal compound in the periodic table e.g. [RuCl2(p-cymene)]2} with an asymmetric ligand of formula II [R3 and R4 are each a (substituted) alkyl or the like; R5 and R6 are each H or the like], [e.g. (S,S)-N-tosyl-1,2-diphenylethylenediamine], preferably in the presence of a base such as triethylamine, preferably at 0-70 deg.C for usually 5-72 hr to provide the objective compound of formula III [(*) represents an asymmetric carbon], [e.g. optically active 1,2-diphenylethane diol].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active 1,2-
The present invention relates to a method for producing diols. Specifically, the present invention relates to a method for producing optically active 1,2-diols by asymmetric hydrogen transfer reduction using an asymmetric catalyst.

[0002]

2. Description of the Related Art Optically active diols are important compounds, for example, as intermediates in the synthesis of pharmaceuticals and agricultural chemicals, or as ligands for catalysts. For example, an optically active 1,2-diarylethanediol having C2 symmetry in a molecule, particularly 1,2-diphenylethanediol, is useful as a ligand for a catalyst for asymmetric synthesis or a raw material thereof. What is important when selectively synthesizing such a compound is to reduce the selectivity of the optically inactive meso form among the obtained compounds and to determine the enantiomeric excess (ee) in the racemic form. ). Here, “racemic” means an optically active substance mixture.

However, for example, in J. Am. Che
m. Soc. , Vol. 110, no. 2, p629
(1988) discloses that various monoketones are hydrogenated to produce optically active alcohols by a ruthenium catalyst having a binaphthyl diphosphine ligand. On the other hand, when the same method is applied, the corresponding diol is obtained with a ratio of meso to racemic of 74:26, and the production amount of the target racemic diol is small.

[0004] Further, as a method for producing optically active 1,2-diphenylethanediol, 1) a method by optical resolution,
2) Method by asymmetric dihydroxylation of trans-stilbenes, 3) Method by asymmetric reduction of benzyls
Although the species are known, the conventional method has the following problems. That is, the optical division (Chem. Let
t. 1991, 763), the recovery rate is 50%
In addition to being inevitable, when diphenylethanediol as a raw material is obtained by reduction of benzyl,
In normal hydride reduction, meso form is selectively obtained,
The problem is that the yield of the desired racemate is low. t
asymmetric dihydroxylation of tran-stilbene (JO
rg. Chem. , 1994, 59, 8302) is an excellent method in terms of selectivity, but uses toxic osmium tetroxide in the reaction. Enzymatic asymmetric reduction of benzyl (Tetrahedron Lett. 1986, 2
7, 4453; Org. Chem. 1978, 4
3, 3319; Org. Chem. 1989, 5
4,968, Indian J. et al. Chem. , Sec
t. B. 1993, 32B, 131) and enzymatic asymmetric reduction of benzoin (Technol. Rep. Tohoku).
Univ. 1983, 48, 211) has a problem in practicality such as productivity. Asymmetric borohydride reduction of benzyl (J. Org. Chem. 1996, 61, 3).
888) has high optical purity, but the catalyst amount is 10 mol
% And the meso form in the product is as high as 12%.

[0005] JP-A-9-157196 discloses that a monoketone such as acetophenone is converted into a tertiary asymmetric catalyst comprising a transition metal complex, a base and an optically active nitrogen-containing compound.
A method for producing an optically active alcohol by hydrogen-transfer asymmetric reduction in the presence of a hydrogen-donating compound is disclosed, but there is no description about application to a diketone. Recently, Knochel et al. Used asymmetric ferrocenyldiamine as an optically active nitrogen-containing compound for ruthenium-catalyzed asymmetric hydrogen transfer reduction of benzyl (Tetrahedr).
on Asymmetry, 9 (1998) 1143)
However, the selectivity of the meso form is still higher at 69%, and the ee is still at a practical level of 50%.

[0006]

SUMMARY OF THE INVENTION In view of the foregoing, an object of the present invention is to provide a simpler and more selective method for producing optically active 1,2-diols as compared with the prior art.

[0007]

Means for Solving the Problems The present inventors have studied to achieve the above object, and as a result, have achieved a high reaction yield and a high racemic selection by asymmetric hydrogen transfer reduction using a metal catalyst using a specific ligand. The present inventors have found that desired optically active diols can be obtained with high enantioselectivity and high enantioselectivity, and completed the present invention. That is, the gist of the present invention is represented by the following general formula (1)

[0008]

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[0009] (wherein, R ¹ and R ² each independently represents an optionally substituted aromatic hydrocarbon group or an aromatic heterocyclic group. Further, R ¹ and R ² May be bonded to each other or condensed to form a ring), a metal compound of Group VIII of the periodic table and a compound represented by the following general formula (2)

[0010]

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[0011] (wherein, R ³ and R ⁴ are each independently an optionally substituted alkyl group, a phenyl group or an aromatic heterocyclic group. Further, 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. Asymmetric reduction with a hydrogen donor in the presence of a catalyst in combination with an asymmetric ligand represented by the following general formula (3):

[0012]

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

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION A diketone as a raw material of the method of the present invention is represented by the above general formula (1). In the general formula (1), when R ¹ and R ² are aromatic hydrocarbon groups, specific examples include a phenyl group and a naphthyl group. When R ¹ and R ² are aromatic heterocyclic groups, specific examples include Examples include a pyridyl group and a furyl group. As the substituents of these aromatic rings, a methyl group,
Carbon number 1 such as ethyl group, n-propyl group, i-propyl group, n-butyl group, sec-butyl group, t-butyl group, n-hexyl group, 2-ethylhexyl group, n-decyl group, etc.
A linear or branched alkyl group of 10 to 10; an alkoxy group having 1 to 10 carbon atoms corresponding to the alkyl group; a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom; a chloromethyl group, a trifluoromethyl group, A haloalkyl group having 1 to 10 carbon atoms such as a 2-dibromoethyl group and a perfluoropentyl group; an amino group; an alkylamino group. The number of these substituents is 1 or 2 or more, and when they have a plurality of substituents, they may be the same or different.
Specific examples of the diketone include benzyl, 3,3′-dimethylbenzyl, 4,4′-dimethylbenzyl,
3 ', 4'-tetramethylbenzyl, 3,3'-dimethoxybenzyl, 4,4'-dimethoxybenzyl,
4,3 ', 4'-tetramethoxybenzyl, 3,3'-
Dichlorobenzyl, 4,4'-dichlorobenzyl, 3,
4,3 ', 4'-tetrachlorobenzyl, 4,4'-bis (dimethylamino) benzyl, 2,2'-pyridyl,
2,2'-furyl and the like. R ¹ and R ² may be bonded to each other or condensed to form a ring. Such examples include the following diketones.

[0015]

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The catalyst constituting the catalyst used in the method of the present invention is
The asymmetric ligand is a diamine represented by the general formula (2).
You. In the general formula (2), R^Three, R^FourAl indicated by
As a kill group, an aromatic heterocyclic group or a substituent thereof
Is R¹, R^TwoAnd the same groups as in the case of Akira Amoto
In the detailed description, lower means C1-4.
R^Five, R⁶Represents a lower alkyl group;
Represents a linear or branched alkyl group. R^Five, R ⁶But
In the case of showing an acyl group, for example, acetyl group, propioni
And a carbamoyl group.
N-methylcarbamoyl group, N-phenylcar
A bamoyl group and the like are exemplified.

When it represents a thioacyl group, for example, a thioacetyl group, a thiopropionyl group, a thiobenzoyl group and the like are exemplified, and when it represents a thiocarbamoyl group, an N-methylthiocarbamoyl group, an N-phenylthiocarbamoyl group and the like are exemplified. . When R ⁵ and R ⁶ represent an alkyl or arylsulfonyl group, for example, a methanesulfonyl group,
Ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, 2,4,6-mesitylsulfonyl group,
2,4,6-triisopropylbenzenesulfonyl group,
4-methoxybenzenesulfonyl group, 4-chlorobenzenesulfonyl group and the like. Among the asymmetric ligands represented by the general formula (2), preferably, the following general formula (4)

[0018]

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(Wherein R⁷May have a substituent
An alkyl group or an aryl group; ⁸Is a hydrogen atom or
Shows a lower alkyl group. R⁹And R^TenAre independent
And an optionally substituted alkyl group, phenyl
A group or an aromatic heterocyclic group. With a diamine represented by
is there. More preferred asymmetric ligands are represented by the following general formula (5)

[0020]

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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. Among them, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently preferably a hydrogen atom or a lower alkyl group. In particular, R ¹¹ is a lower alkyl group and R ¹² , R ¹³ and R ¹⁴ are each a hydrogen atom. Particularly preferred. l, m, n are 1 to 5
Indicates an integer. When l, m, and n are 2 or more, R
¹¹ , R ¹³ and R ¹⁴ may be the same or different. ). In the general formulas (2) to (5), * represents an asymmetric carbon.

As the alkyl group, the aryl group, the halogen atom and the alkoxy group in the general formulas (4) and (5), the same as those described above can be mentioned. As specific ligands, for example, optically active 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-chlorophenylsulfonyl-1,2-diphenylethylenediamine,
N-mesitylsulfonyl-1,2-diphenylethylenediamine, N- (2,4,6-tri-i-propyl) phenylsulfonyl-1,2-diphenylethylenediamine and the like can be mentioned.

Examples of the metal species of the Group VIII metal compound used in combination with these asymmetric ligands include ruthenium, rhodium, iridium and cobalt. As the compound, RuCl ₃ -3H ₂ O, [RuCl
₂ (p-cymene)] ₂ , [RuCl ₂ (benz)
ene)] ₂ , [RuCl ₂ (mesytilen)
e)] ₂ , [RuCl ₂ (hexamethylben)
zene)] ₂ , RuCl ₂ (PPh ₃ ) ₃ , [RuC
l ₂ (cod)] _n , [RuCl ₂ (CO) ₃ ] ₂ ,
[Rh (cod) Cl] ₂ , [Ir (cod) C
l] ₂ , CoCl _{2 and the} like, and preferably [Ru
Cl ₂ (p-cymene)] ₂ . In the above compounds, Ph represents a phenyl group, and cod represents cyclooctadiene.

The formation of a catalyst from an asymmetric ligand and a metal compound is described in J. Am. Am. Chem. Soc. 1995, 117, p7
A known method disclosed in 562 or the like can be used. For example, by heating under reflux 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 can be obtained. This may be used as it is, or Angew.
Chem. Int. Ed. Engl. , 1997, 3
The complex may be isolated as crystals as described in 6, p285. The reaction is carried out by contacting the starting diketone with a hydrogen donor in the presence of a catalyst. Examples of the hydrogen donor include alcohol and formic acid. As the alcohol, a lower alcohol having a hydrogen atom at the α-position such as methanol, ethanol, n-propanol, isopropanol, n-butanol and sec-butanol is used, and a preferable alcohol is isopropanol.

The 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. Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide as bases,
Examples thereof include alkali metal alkoxides such as lithium methoxide, sodium methoxide, and potassium isopropoxide, and organic amines such as trimethylamine, triethylamine, and triisopropylamine. When a base is used, it is preferable to use an excess amount based on the catalyst.

Preferred combinations with hydrogen donors are isopropanol / potassium hydroxide and formic acid / triethylamine, most preferred formic acid / triethylamine. When formic acid and an amine are used in combination, it is preferable to prepare and use an azeotropic mixture of formic acid and an amine in advance because the influence of impurities in these raw materials can be suppressed. In the case of formic acid and triethylamine, the molar ratio of the azeotrope is formic acid: triethylamine =
Since the ratio is 5: 2, it is preferable to further add formic acid or triethylamine to obtain an optimal formic acid / amine ratio.

Usually, a hydrogen donor itself is used as a reaction solvent, but a non-hydrogen donating solvent such as toluene, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), or dimethyl sulfoxide is used as a cosolvent to dissolve the raw materials. It is also possible. The amount of the catalyst relative to the raw material is usually 1/10 to 1 / 1,000,000, preferably 1/100 to 1/1000 as a molar ratio of ruthenium atoms to the raw material. The amount of hydrogen donor relative to the raw material is usually in the range of 1 mole times to a large excess,
Generally, when alcohol is used as a hydrogen donor, a large excess is used also as a solvent, and when formic acid is used as a hydrogen donor, 1 is used.
The reaction is carried out in a molar range of 20 to 20 times.

The amount of the base relative to the catalyst is usually in the range of 1 mole to a large excess. Generally, when an alcohol is used as a hydrogen donor, 1 to 10 moles of potassium hydroxide is used. When formic acid is used as a hydrogen donor, triethylamine is used. With a large excess over the catalyst. Reaction temperature is from -70 ° C to 10
0 ° C, preferably selected from the range of 0 ° C to 70 ° C.
Reaction time is 1 hour to 200 hours, usually 5 hours to 7 hours.
2 hours.

After the reaction, the optically active diol formed from the reaction solution can be separated and purified by generally known operations such as extraction, chromatography and recrystallization.
The optically active 1,2-diol obtained by the present invention, for example, the optically active 1,2-diphenylethanediol can be used as an asymmetric ligand by itself, and can also be synthesized.
optically active 1,2-diphenylethylenediamine by a method as disclosed in is 1023 (1990).

[0030]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples unless it exceeds the gist. In the following examples, “%” means “% by weight” unless otherwise specified.

Reference Example 1 Synthesis of catalyst (optically active ruthenium complex) [RuCl ₂ (p-cymene)] _{2 was} added to 7.66 g and 9.16 g of (S, S) -N-tosyl-1,2-diphenylethylenediamine. -Add 150 ml of propanol and 7 ml of triethylamine, and add
Stirred for hours. Then, the reaction solution was cooled on ice and 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 (yield 79%) of orange crystals.

Example 1 135 g (2.93 mM) of formic acid and triethylamine 11
8 g (1.17 mM) mixed solution was distilled under reduced pressure.
A fraction having a boiling point of 119 ° C. at 5 mmHg (azeotrope, TEA
137 g). NMR analysis revealed that the molar ratio of formic acid to triethylamine in TEAF was approximately 5: 2. 50 ml four-necked flask TEAF1
8 ml, triethylamine 5.8 ml, benzyl 10.
08 g (47.95 mol) and DMF 11.2 ml were charged. After replacing with nitrogen, the catalyst 15 synthesized in Reference Example 1
When 3 mg (0.24 mM) was dissolved in 0.5 ml of DMF and added to the reaction solution, foaming started immediately. The reaction was carried out at room temperature and reached a conversion of 99% in 72 hours.
After completion of the reaction, isopropyl ether 18 was added to the reaction mixture.
0 ml, 60 ml of ethyl acetate and 40 ml of water were added,
The product was extracted. Further, the oil layer was washed with 40 ml of 1N hydrochloric acid and 20 ml of saturated saline. After anhydrous magnesium sulfate was added to the oil layer for dehydration, salts were removed by filtration. The filtrate was concentrated to obtain 10.18 g of a crude product. When analyzed by NMR, the ratio between the racemic form and the meso form was 94: 6. The crude product was dissolved by heating in 30 ml of 92% ethanol, cooled to room temperature, filtered and washed with cold 92% ethanol to obtain 7.20 g of colorless needle crystals of diphenylethanediol (meso body content: 0%). (Isolation yield 7
0%). As a result of analysis using an optically active column and a polarimeter, the obtained product was R or R form, and the optical purity was 97%.
%Met. The reaction was carried out in the same manner as in Example 1 except that 1,2-diketone shown in Table 1 was used in place of benzyl used in Example 1, whereby the optically active 1,2 shown in Table 1 was obtained. It is possible to produce diols.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

As is clear from the examples, according to the method of the present invention, 1,2-diketone is asymmetrically reduced to obtain a high yield, a high racemic selectivity, a high enantioselectivity and an optically active 1-diketone. , 2
A diol can be obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 35/37 C07C 35/37 41/26 41/26 41/32 41/32 43/23 43/23 A C07D 213/30 C07D 213/30 307/42 307/42 307/46 307/46 // C07B 61/00 300 C07B 61/00 300 C07M 7:00 (72) Inventor Hiroshi Iwane Amicho, Inashiki-gun, Ibaraki Prefecture 8-3-1 F-term in Tsukuba Research Laboratory, Mitsubishi Chemical Corporation 4C037 HA04 HA06 4C055 AA01 BA02 BA16 BA18 CA01 DA01 GA10 4G069 AA15 BA26A BA26B BA27A BA27B BC67B BC70A BC70B BC74B BD12B BE25B BE37B BE42B BE46A ACB BA20 BA22 BA23 BA24 BA29 BA32 BA46 BA51 FC52 FC56 FE11 FE12 FE73 FE75 GP03 GP10 4H039 CA60 CB20

Claims (4)

[Claims] [Claim 1] The following general formula (1) (Wherein, R ¹ and R ² each independently represent an aromatic hydrocarbon group or an aromatic heterocyclic group which may have a substituent. In addition, R ¹ and R ² are bonded to each other. Or a condensed ring may be formed) to form a diketone represented by the following general formula (2): (Wherein, R ³ and R ⁴ each independently represent an alkyl group which may have a substituent, a phenyl group or an aromatic heterocyclic group. Further, R ³ and R ⁴ are bonded to each other or 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. Asymmetric reduction with a hydrogen donor in the presence of a catalyst in combination with an asymmetric ligand represented by the formula (3): (Wherein R ¹ and R ² have the same meanings as in formula (1), and * represents an asymmetric carbon).
-A method for producing diols. 2. An asymmetric ligand represented by the following general formula (4):
The optical activity according to claim 1, wherein
For producing a hydrophobic 1,2-diol. Embedded image(Where R⁷Is an alkyl group which may have a substituent or
Represents an aryl group; ⁸Is a hydrogen atom or lower alkyl
Represents a group. R⁹And R^TenIs each independently a substituent
Alkyl group, phenyl group or aromatic group which may have
Shows a heterocyclic group. ) 3. The method for producing an optically active 1,2-diol according to claim 2, wherein the asymmetric ligand has a structure represented by the following general formula (5). Embedded image (Wherein R ¹² represents a hydrogen atom or a lower alkyl group;
¹¹ , R ¹² 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. ) 4. The process for producing an optically active 1,2-diol according to claim 1, wherein the metal belonging to Group 8 of the periodic table is ruthenium.