JP2962668B2 - Method for producing optically active alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing optically active alcohols. More specifically, the present invention relates to a new method for producing optically active alcohols useful in various applications such as synthetic intermediates of pharmaceuticals and liquid crystal materials, which is excellent in practicality.

[0002]

2. Description of the Related Art Conventionally, methods for asymmetrically synthesizing an optically active alcohol include 1) a method using an enzyme such as baker's yeast, and 2) a method for asymmetric hydrogenation of a carbonyl compound using a metal complex catalyst. Have been. Particularly in the method 2), many examples of asymmetric catalysis have been reported. For example, (1) Asymmetric Catalysis In Organic
Synthesis, pp. 56-82 (1994) Ed. R. Noyori
(2) Chem. Rev., Vol. 92, pp. 1051-1069 (1) Asymmetric hydrogenation of carbonyl compounds having a functional group using an optically active ruthenium catalyst described in detail in
992) Method by hydrogen transfer type reduction reaction using an asymmetric complex catalyst of ruthenium, rhodium and iridium (3) Oil Chemistry, 882-831 (1980) and Advances in Catalysis, Vol. 32, 215 (198)
3) Method for asymmetric hydrogenation using tartaric acid-modified nickel catalyst described in Ed. Y. Izumi (4) Asymm
etric Synthesis, Vol. 5, Chap. 4 (1985) Ed.
JD Morrison and J. Organomet. Chem, Vol. 346,
413-424 (1988), a method by asymmetric hydrosilylation (5) J. Chem. Soc., Perki
n Trans. 1, pp. 2039-2044 (1985) and
J. Am. Chem. Soc., Vol. 109, pp. 5551-5553 (1987), a method of reducing porane in the presence of an asymmetric ligand is known.

[0003]

However, the conventional method using an enzyme can obtain an alcohol having a relatively high optical purity, but is limited in the reaction substrate, and the absolute configuration of the obtained alcohol is also limited to a specific one. limited. In addition, a method using a transition metal asymmetric metal hydride complex catalyst can produce an optically active alcohol with high selectivity, but requires a pressure-resistant reactor because hydrogen gas is used as a hydrogen source, which makes the reaction operable and safe. There are difficulties in terms of. In the case of a method based on an asymmetric hydrogen transfer type reduction reaction using an existing metal complex catalyst, there are drawbacks in that the reaction conditions are heating and the selectivity of the reaction is insufficient, which is not suitable for practical use.

For this reason, it has been desired to realize a new synthesis method using a highly versatile, highly active and highly selective catalyst which does not depend on hydrogen gas for producing optically active alcohols. .

[0005]

In order to solve the above-mentioned problems, the present invention provides a method for converting a carbonyl compound into ruthenium.
Moarene complex and base , optically active aminoalcoholization
Compound, optically active aminophosphine compound and optically active
Production of optically active alcohols by hydrogen-transfer type asymmetric reduction in the presence of at least one optically active amine compound among diamine compounds and an organic or inorganic compound capable of donating hydrogen. A method for producing an optically active alcohol is provided.

Further, according to the present invention, in the above method, the following general formula (a)

[0007]

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(R ¹ is an aromatic monocyclic or aromatic polycyclic hydrocarbon group which may have a substituent, a saturated or unsaturated aliphatic group which may be unsubstituted or may have a substituent, An aromatic hydrocarbon group or a cyclic hydrocarbon group, or a heteromonocyclic or heteropolycyclic group containing a heteroatom such as nitrogen, oxygen, or a sulfur atom, wherein R ² has a hydrogen atom or a substituent. A saturated or unsaturated chain or cyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group; and R ¹ and R ² may be combined with each other to form a ring). Asymmetric reduction of the carbonyl compound represented by the general formula (b)

[0009]

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[0010] The present invention provides a method for producing an optically active alcohol, characterized by producing an optically active alcohol represented by the formula (R ¹ and R ² represent the same organic groups as described above). And also, the present invention is or a hydroxide or a salt of salt groups alkali metals or alkaline earth metals 4
The grade ammonium salt der Turkey and the like is set to one of its aspects.

[0011]

Embodiments of the present invention will be described below in more detail. First, the carbonyl compound as a raw material of the present invention can be represented by, for example, the above-mentioned general formula (a), but is not necessarily limited thereto. Looking at the general formula (a), R
¹ is unsubstituted or may have a substituent, an aromatic monocyclic or aromatic polycyclic hydrocarbon group, an unsubstituted or may have a substituent, a saturated or unsaturated aliphatic A hydrocarbon group or a cyclic hydrocarbon group, or nitrogen,
It may be a heteromonocyclic or heteropolycyclic group containing a hetero atom such as oxygen or sulfur atom, specifically, a phenyl group, 2-
Methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-tert-butylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-vinylphenyl, 3-methylphenyl, 3-ethylphenyl, 3-isopropylphenyl, -Methoxyphenyl, 3-chlorophenyl, 3-vinylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,
4-tert-butylphenyl, 4-vinylphenyl,
Aromatic, monocyclic or polycyclic groups such as cumenyl, mesityl, xylyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, indenyl, thienyl, furyl, pyranyl, xanthenyl, pyridyl, pyrrolyl, imidazolinyl, indolyl, carbazoyl, Examples thereof include a heteromonocyclic or polycyclic group such as phenanthronyl and a ferrocenyl group.

As in these examples, the substituent may have various types of substituents, such as hydrocarbon groups such as alkyl, alkenyl, cycloalkyl and cycloalkenyl, halogen atoms, alkoxy groups, carboxyl groups, and the like. It may be an oxygen-containing group such as an ester group, a nitro group, a cyano group, or the like. Further, R ² may be a hydrogen atom, which may have a substituent, a saturated or unsaturated chain or cyclic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group containing a hetero atom. Is, for example, an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; an unsaturated hydrocarbon such as vinyl and allyl; ^{The same as 1} can be shown. Furthermore, for example, a β-keto acid derivative having a functional group at the β-position can be exemplified. R ¹ and R ²
Are bonded to form a ring, for example, a cyclopentanone, cyclohexanone, cycloheptane, cyclopentenone, cyclohexenone, saturated and unsaturated alicyclic group giving a cyclic ketone such as cycloheptenone,
And a saturated or unsaturated alicyclic group having a substituent having a chain or cyclic hydrocarbon group containing a hetero element, such as an alkyl group, an aryl group, an unsaturated alkyl group, or a hetero element at each carbon.

In the present invention, the ruthenium oxide
Lane complex is the base and the optically active amine compound together with <br/> constitutes a asymmetric reduction catalyst ternary ruthenium arene complex of this is preferably in particular, for example, the general formula ( c)

[0014]

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[0015] (M is Le Teniu beam, .m X represents hydrogen, halogen atom, carboxyl group, hydroxy group, an alkoxy group, etc., L is indicating that the ligand aromatic compounds,
n shows an integer. The complex body where Ru can be represented by), as the base, the general formula (d)

[0016]

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(M ¹ represents an alkali metal or an alkaline earth metal, Y represents a hydroxy group, an alkoxy group, a mercapto group or a naphthyl group) or a quaternary ammonium salt; Those which are used together with a compound to constitute a three-element asymmetric catalyst are exemplified.

The aromatic compound as a neutral ligand is, for example, a monocyclic aromatic compound represented by the following general formula (e). Here, R ^{3 to} R ⁸ are the same or different, and can represent hydrogen, a saturated or unsaturated hydrocarbon group, an allyl group, or a functional group containing a heteroatom. For example, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Functional groups containing a hetero atom such as a group such as an unsaturated hydrocarbon such as benzyl, vinyl, and allyl, and a hydroxyl group, an alkoxy group, and an alkoxycarbonyl group can be shown. The number of the substituents is any number from 1 to 6, and any place can be selected.

[0019]

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The ruthenium array according to the present invention
The amount of the complex used varies depending on the size of the reaction vessel, its type, and economy, but is approximately 1/100 to 1/100, in molar ratio, to the carbonyl compound as the reaction substrate.
000, preferably 1/500 to 1 /
The range is 5,000. In the base represented by the general formula (d) as described above, specifically, KOH, KOCH ₃ ,
KOCH (CH ₃ ) ₂ , KOC (CH ₃ ) ₃ , KC ₁₀ H
₈ , LiOH, LiOCH ₃ , LiOCH (C
H ₃ ) ₂ , LiOC (CH ₃ ) ₃ , NaOH, NaOC
H ₃ , NaOCH (CH ₃ ) ₂ , NaC ₁₀ H ₈ , NaO
C (CH ₃ ) _{3 and the} like are exemplified. Further, quaternary ammonium salts can also be used.

The amount of the base used is about 0.5 to 50 equivalents, preferably 2 to 10 equivalents, based on the transition metal complex.
Is equivalent. Further, in this invention, the use of an optically active amine compound <br/> was the asymmetry catalyst system, this compound, the Ruteni
It is presumed that it exists and acts as an asymmetric ligand to the um arene complex. Such optically active amine of <br/> compound may For example other following general formula (f)

[0022]

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(R ⁹ , R ¹⁰ , R ¹⁵ and R ¹⁶ are hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group or a sulfonyl group, and R ¹¹ , R ¹² , R ¹³ and R ¹⁴
Are the same or different groups such that the carbon to which these substituents are attached is an asymmetric center, and may be hydrogen or an alkyl group, an aromatic monocyclic and polycyclic group, a saturated or unsaturated hydrocarbon group, and Shows a cyclic hydrocarbon group. further,
Any one of R ¹¹ and R ¹² may be bonded to any one of R ¹³ and R ¹⁴ to form a ring. ) Is an optically active diamine compound. For example, such compounds include optically active 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine,
2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl- 2,2-di (p-methoxyphenyl) ethylenediamine, 1-isobutyl-2,2-
Di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-benzyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-methyl-2,2 −
Dinaphthylethylenediamine, 1-isobutyl-2,2
-Dinaphthylethylenediamine, 1-isopropyl-
Optically active diamine compounds such as 2,2-dinaphthylethylenediamine and one of the substituents of R ⁹ to R ¹⁵
An optically active diamine compound in which one or two are a sulfonyl group, an acyl group or a urethane group can be exemplified. Preferably, an optically active diamine compound having one sulfonyl group can be used. Further, the optically active diamine that can be used is not limited to the exemplified optically active ethylenediamine derivatives, and optically active propanediamine, butanediamine, and phenylenediamine derivatives can be used.

As the optically active amine compound, an optically active amino alcohol compound represented by the following general formula (g) can be used.

[0025]

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Here, at least one of R ¹⁷ and R ¹⁸ is a hydrogen group, and the other one is hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group, a sulfonyl group, and R ^{19 to} R ²² Are the same or different groups such that the carbon to which these substituents are attached is an asymmetric center, and may be hydrogen or an alkyl group, an aromatic monocyclic and polycyclic group, a saturated or unsaturated hydrocarbon group, and R ²³ represents a hydrogen or alkyl group, an aromatic monocyclic or polycyclic group, a saturated or unsaturated hydrocarbon group, or a cyclic hydrocarbon group. Further, any one of R ¹⁹ and R ²⁰ may be bonded to any one of R ²¹ and R ²² to form a ring, or any one of R ¹⁷ and R ¹⁸ And any one of R ²⁰ and R ²¹ may combine to form a ring. Specifically, optically active amino alcohols shown in Examples described later can be used. Further, as the optically active amine compound, the following general formula (h)
An aminophosphine compound represented by the following formula can be used.

[0027]

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[0028] Here, R ^24, R ²⁵ is hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group, a sulfonyl group, an acyl group, (CR ₂ ²⁶⁾ _n is by these substituents are bonded Hydrogen or an alkyl group, an aromatic monocyclic and polycyclic group, a saturated or unsaturated hydrocarbon group, and a cyclic hydrocarbon group; R ²⁷ and R ^{28 each} represent hydrogen, a saturated or unsaturated hydrocarbon group, or an allyl group. Specifically, the optically active aminophosphines shown in Examples can be used.

For example, the amount of the optically active amine compound which can be exemplified as described above is used in a ruthenium array.
About 0.5 to 20 equivalents, preferably 1 to
It is in the range of 4 equivalents. The three components of the ruthenium arene complex, the base, and the optically active amine compound used as a catalyst as described above are components essential for smoothly performing an asymmetric reduction reaction and achieving a high asymmetric yield. , 1
If the components are insufficient, an alcohol having a sufficient reaction activity and a high optical purity cannot be obtained.

Further, the hydrogen-donating organic or inorganic compound used in the process for producing optically active alcohols by hydrogen-transfer-type asymmetric reduction in the present invention may be thermally reacted.
Alternatively, it refers to a compound capable of donating hydrogen by a catalytic action. Such a hydrogen donating compound is not particularly limited in its kind, but is preferably methanol, ethanol, 1- Alcohol compounds such as propanol, 2-propanol, butanol and benzyl alcohol; formic acid and salts thereof, for example, those comprising a combination of amines; unsaturated hydrocarbons and heterocyclic compounds having partially saturated carbon bonds such as tetralin and decalin; There are hydroquinone and phosphorous acid. Among them, alcohol compounds are preferable, and 2-propanol is more preferable. The amount of the organic compound serving as a hydrogen source to be used is determined based on the solubility and economical efficiency of the reaction substrate. Usually, the substrate concentration can be used at about 0.1 to 30% by weight depending on the type of the substrate, but it is preferably used at 0.1 to 10% by weight. When using a mixture of formic acid and formic acid and an amine as a hydrogen source, a solvent may not be used,
When used, aromatic compounds such as toluene and xylene, halogen compounds such as dichloromethane, and organic compounds such as DMSO, DMF and acetonitrile can be used.

In the present invention, hydrogen pressurization is not essentially required, but hydrogen pressurization may be performed depending on the reaction situation. However, even when hydrogen is pressurized, the pressure may be about 1 atm to several atm due to the extremely high activity of the catalyst system.
The reaction temperature can be set to about −20 ° C. to about 100 ° C. in consideration of economy. More practically, the reaction can be carried out at around room temperature of 25 to 40 ° C. The reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, temperature and pressure, but the reaction is completed in several minutes to 100 hours.

The ruthenium arene complex used in the present invention can be used by mixing with an optically active amine compound before the start of the reaction.
A ruthenium arene complex can be synthesized and used. That is, for example, an optically active amine compound and a ruthenium arene complex are added to an alcohol, and the mixture is heated and stirred under an inert gas. The obtained solution is cooled, treated under reduced pressure, and then recrystallized to form an asymmetric complex catalyst. Get.

Hereinafter, the present invention will be described in more detail with reference to Examples. In addition, Table 1, Table 2 and Table 3 collectively illustrate the reaction substrate, the ruthenium arene complex, and the optically active amine compound as the asymmetric ligand, which are used as typical examples. The instrument analysis was based on the following models. NMR: JEOL GSX-400 / Varian G
emini-200 (1H-NMR standard sample: TM
S, ³¹ P-NMR standard sample: phosphoric acid) GLC: SHIMAZU GC-17A (columnu)
n: chiral CP-Cyclodextrin-
b-236-M19) HPLC: JASCO GULLIVER (column
un: CHIRALCEL OJ, OB-H, OB, O
D)

[0034]

[Table 1]

[0035]

[Table 2]

[0036]

[Table 3]

Examples 1 to 19 0.05 mmol of various amino alcohol compounds shown in Table 3 as optically active amine compounds as chiral ligands were added to 5.0 ml of dry 2-propanol which had been frozen and degassed.
0.0125 mmol of ruthenium arene complex shown in
After stirring at 80 ° C. for 20 minutes under argon, the mixture was returned to room temperature and frozen and degassed. Dry 2-propanol 45.
0 ml, degassed distilled various carbonyl compounds 5 in Table 1
Then, 2.5 ml (0.125 mmol) of a 0.05 M KOH2-propanol solution were added in this order, followed by stirring at room temperature. After completion of the reaction, the mixture was acidified by adding dilute hydrochloric acid, most of 2-propanol was distilled off under reduced pressure, saturated saline was added, and the mixture was extracted with ethyl acetate, washed with saturated saline several times, and dried over anhydrous sodium sulfate. ¹ H-NMR (CDCl ₃ ) was measured on the solvent after the solvent was distilled off, and the conversion was calculated. Next, this was purified by thin-layer silica gel chromatography, and the optical purity and absolute configuration of the fractionated alcohol were determined by HPLC or GLC. The results are summarized in Table 4. The conversion and the optical purity of the sampled reaction solution can be simultaneously calculated by GLC. Examples 20 to 23 Using the same method as in Example 1, a reaction was carried out using an aminophosphine compound as the optically active amine compound.
The results are summarized in Table 4.

[0038]

[Table 4]

Examples 24 to 41 Using the same method described in Example 1, an asymmetric Ru complex shown in Table 2 was synthesized using an optically active amine compound.
This complex catalyst, carbonyl compound and formic acid were added to a mixture of triethylamine (5: 2) and reacted at room temperature for a predetermined time. After completion of the reaction, the reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off, and then 1H-NMR (CDC
l ₃ ) was measured and the conversion was calculated. Optical purity and absolute configuration were determined by HPLC or GLC. The results are summarized in Table 5. The conversion and the optical purity of the sampled reaction solution can be simultaneously calculated by GLC.

[0040]

[Table 5]

[0041]

As described in detail above, according to the present invention, it is possible to produce optically active alcohols having a high synthesis yield and high optical purity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 33/05 C07C 33/05 33/18 33/18 35/23 35/23 37/20 37/20 39/02 39/02 39/12 39/12 39/18 39/18 67/31 67/31 69/732 69/732 Z 255/56 255/56 C07D 215/18 C07D 215/18 311/22 311/22 495/04 111 495 / 04 111 // B01J 31/16 B01J 31/16 X C07B 61/00 300 C07B 61/00 300 C07M 7:00 (72) Inventor Takao Ikariya 8-1 Uchiyacho, Chikusa-ku, Nagoya-shi, Aichi Saka Coaters 907 (72) Inventor Jun Takehara 1-11-4-105, Chuo, Ami-cho, Inashiki-gun, Ibaraki Pref. 1505 Tobitani, Nagakute-cho, Aichi-gun, Japan Habitation 3-B (72) Inventor Ryoji Noyori Nisshin-shi, Aichi 135-417, Nitta, Umemori-cho (56) Reference Chemical Reviews, 1992, Vol. 92, No. 5, p. 1051-1069 Am. Chem. Soc. , 1995, 117, p. 2675-2676 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07C 29/136-29/149 C07B 41/02 C07B 53/00

Claims (4)

(57) [Claims] 1. The method of claim 1, wherein the carbonyl compound is a ruthenium array.
The emission complexes and a base, the optically active amino alcohol compound, light
Active aminophosphine compounds and optically active diamines
At least one optically active amine compound of the compounds,
And a method for producing optically active alcohols, comprising producing an optically active alcohol by asymmetric hydrogen-transfer reduction in the presence of a hydrogen-donating organic or inorganic compound. 2. Formula (a): ## STR1 ## (R ¹ may have a substituent, may be an aromatic monocyclic or aromatic polycyclic hydrocarbon group, may be unsubstituted or may have a substituent, may be a saturated or unsaturated aliphatic hydrocarbon, Group or a cyclic hydrocarbon group, or nitrogen, oxygen, a heteromonocyclic or heteropolycyclic group containing a heteroatom such as a sulfur atom,
R ² may be a hydrogen atom or may have a substituent;
It represents a saturated or unsaturated chain or cyclic hydrocarbon group, aromatic hydrocarbon group or heterocyclic group. Further R ¹ and R
² may combine to form a ring. Asymmetric reduction of the carbonyl compound represented by the general formula (b) ^2. The method according to claim 1, wherein an optically active alcohol represented by the formula (R ¹ and R ² represents the same organic group as described above) is produced. 3. The base is an alkali metal or alkaline earth.
Metal hydroxides or their salts or quaternary ammonium
3. The method according to claim 1, which is a sodium salt. 4. The method according to claim 1, wherein the hydrogen-donating organic or inorganic compound is
Alcohol compounds, formic acid, formate, hydrocarbon compounds, complex
Ring compounds, hydroquinone or phosphite claim
The method of 1 or 2.