JP2731377B2 - Method for producing optically active alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing optically active alcohols. More particularly, 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 optically active alcohols include 1) a method using an enzyme such as baker's yeast, and 2) asymmetric hydrogenation of a carbonyl compound using a metal complex catalyst. There are known methods for making such.
Especially in the latter method, many examples of asymmetric catalysis have been reported so far. For example, (1) Asymme
tric Catalysis in Organic Synthesis, pp. 56-82 (1994) Ed. R. Noyori, a method for asymmetric hydrogenation of carbonyl compounds having a functional group using an optically active ruthenium catalyst, and (2) Chem. Rev. ., Vol.9
2, 3101-1069 (1992), a method by a hydrogen transfer type reduction reaction using an asymmetric complex catalyst of ruthenium, rhodium, and iridium, (3) Oil Chemistry 88
2-831 (1980) and Advances in Catalysi
s, Vol. 32, p. 215 (1983) Ed. Y. Izumi, a method for asymmetric hydrogenation using tartaric acid-modified nickel catalyst, (4) Asymmetric Synthesis. Vol.
5, Chap. 4 (1985) Ed. JD Morrison and J.
Organomet, Chem. Vol. 346, 413-424 (1
988), a method by asymmetric hydrosilylation described in (5) J. Chem Soc., PerkinTrans.
-2044 (1985) and J. Am Chem Soc., Vo.
I. 109, 5551-5553 (1987), a method of reducing borane in the presence of an asymmetric ligand is known.

[0003] However, the method using an enzyme can obtain alcohols having a relatively high optical purity, but it is limited in the type of a reaction substrate, and the absolute configuration of the obtained alcohol is limited to a specific one. There is. In the case of a method using an asymmetric hydrogenation catalyst for a transition metal, optically active alcohols can be produced with high selectivity for a substrate containing a functional group in the molecule, for example, a keto acid, but the reaction is difficult. There is a drawback in terms of speed, and it is not effective for relatively simple carbonyl compounds having no functional group in the molecule.

For this reason, it has been desired to realize a new synthesis method using a highly active and highly active catalyst for producing an optically active alcohol.

[0005]

To solve the above-mentioned problems, a general formula (a)

[0006]

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(R ¹ is an aromatic monocyclic or polycyclic hydrocarbon group which may have a substituent, or a heteromonocyclic or polycyclic group containing a hetero atom, and R ² is ,hydrogen,
Or a saturated or unsaturated chain, cyclic or aromatic hydrocarbon or heterocyclic group which may have a substituent. Further, R ¹ and R ² may combine to form a ring. Wherein the asymmetric hydrogenation of the carbonyl compound represented by the formula (b) is carried out by reacting the asymmetric hydrogenation catalyst of a transition metal with hydrogen in the presence of a base and an optically active nitrogen-containing compound.

[0008]

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(R ¹ and R ² represent the same organic groups as described above). Further, the present invention provides that the above-mentioned asymmetric hydrogenation catalyst is a complex of a Group VIII metal, for example, a metal complex having an optically active ligand, or that the base is a hydroxide of an alkali metal or an alkaline earth metal. One of the embodiments is that the compound is a compound or a salt thereof or a quaternary ammonium salt, and the optically active compound as the nitrogen-containing asymmetric compound is an optically active amine compound.

The asymmetric hydrogenation catalyst is, for example, of the general formula (c)

[0011]

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(M ¹ is a Group VIII transition metal such as ruthenium, rhodium, iridium, palladium, platinum and the like;
Represents a hydrogen, a halogen atom, a carboxyl group, a hydroxy group, an alkoxy group or the like, and L represents an optically active phosphine ligand, an optically active organic arsenic compound ligand or the like. m and n represent integers), and the base is represented by, for example, the general formula (d)

[0013]

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(M ² represents an alkali metal or an alkaline earth metal, and Y represents a hydroxy group, an alkoxy group, a mercapto group, or a naphthyl group) or a quaternary ammonium salt. The carbonyl compound as a raw material of the present invention is represented by the general formula (a), wherein R ¹ is an unsubstituted or substituted aromatic monocyclic and polycyclic hydrocarbon group, or nitrogen, oxygen, sulfur A heteromonocyclic or polycyclic group containing a hetero atom such as an 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, 3-methoxyphenyl, 3-chlorophenyl, 3-
Vinylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-vinylphenyl, cumenyl, mesityl, xylyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, indenyl group Aromatic monocyclic or polycyclic groups such as thienyl, furyl, pyranyl, xanthenyl, pyridyl, pyrrolyl, imidazolinyl, indolyl, carbazoyl, phenanthroyl and other heteromonocyclic or polycyclic groups such as ferrocenyl group. it can. Further, R ² can represent hydrogen, a saturated or unsaturated hydrocarbon group, an allyl group, or a functional group containing a hetero atom, for example, an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyne, heptyl, cyclopropyl, etc. And cycloalkyl groups such as cyclobutyl, cyclopentyl and cyclohexyl; and unsaturated hydrocarbons such as benzyl, vinyl and allyl. Furthermore, for example, a β-keto acid derivative having a functional group at the β-position can be exemplified.
When R ¹ and R ² combine to form a ring, a saturated and unsaturated alicyclic group which gives a cyclic ketone such as cyclopentanone, cyclohexanone, cycloheptane, cyclohexenone cycloheptenone, etc .; Saturated and unsaturated alicyclic groups having a substituent having a chain or cyclic hydrocarbon group containing a carbon alkyl group, an aryl group, an unsaturated alkyl group, or a hetero element can be exemplified. In the present invention, M ¹ in the transition metal complex represented by the general formula (c) is a Group VIII transition metal such as ruthenium, rhodium, iridium, palladium, and platinum, with ruthenium being particularly desirable. X is hydrogen,
It represents a halogen atom, a carboxyl group, a hydroxy group, or an alkoxy group. L is an optically active phosphine ligand or the like, for example, BINAP: 2,2′-bis- (diphenylphosphino) -1,1′-binaphthyl, and BINA
BINAP derivatives having an alkyl or aryl group substituent on the naphthyl ring of P include, for example, H ₈ BINAP and BINA
An alkyl group substituent on the phosphorus atom-like benzene ring of P
5-day BINAP derivatives such as @ Tol-BIN
AP: 2,2'-bis- (di-p-tolylphosphino)
-1,1'-binaphthyl, and B having a fluorine substituent
INAP derivative, BICHEP: 2,2'-bis- (dicyclohexylphosphino) -6,6'-dimethyl-
1,1'-biphenyl, BPPFA: 1- [1'2-bis- (diphenylphosphino) ferrocenyl] ethyldiamine, CHIRAPHOS: 2,3-bis- (diphenylphosphino) butane, CYCPHOS: 1-cyclohexyl-1 , 2-bis- (diphenylphosphino) ethane, DEGPHOS: 1-substituted-3,4-bis- (diphenylphosphino) pyrrolidine, DIOP: 2,3-
O-isopropylidene-2,3-dihydroxy-1,4
-Bis- (diphenylphosphino) butane, DIPAM
P: 1,2-bis [(o-methoxyphenyl) phenylphosphino] ethane, DuPHOS: (substituted-1,2-
Bis (phosphorano) benzene), NORPHOS: 5
6-bis- (diphenylphosphino) -2-norbornene, PNNP: N, N'-bis- (diphenylphosphino) -N, N'-bis [1-phenylethyl] ethylenediamine, PROPHOS: 1,2-bis -(Diphenylphosphino) propane, SKEWPHOS: 2,4-
Bis- (diphenylphosphino) pentane and the like. Further, the monodentate optically active phosphine ligand represented by the general formula PR ³ R ⁴ R ⁵ (where R ³ R ⁴ R ⁵ is an optically active phosphine ligand comprising three different substituents, or at least one group is optically active) (Optically active phosphine ligand). In the case of a bidentate phosphine ligand, n is 1-2, and in the case of a monodentate phosphine ligand, it is 3-4. Of course, the optically active phosphine ligand that can be used in the present invention is not limited to these, and the metal is not limited to ruthenium.

The Group VIII transition metal in the present invention
The amount of complex used depends on the reaction vessel, the type of reaction and the economics.
Therefore, it differs from carbonyl compound as a reaction substrate.
Even 1/100 to 1 / 100,000 in molar ratio
And preferably 1/500 to 1 / 10,000
Within the range. The general formula M used in the present invention
^TwoM in the base represented by Y^TwoIs an alkali metal
Is an alkaline earth metal, Y is a hydroxyl group or
Represents an alkoxy group, a mercapto group, or a naphthyl group;
Physically KOH, KOCH_Three, KOCH (CH_Three)_Two,
KC_TenH₈, LiOH, LiOCH_Three, LiOCH (C
H _Three)_TwoEtc. are exemplified. In addition, quaternary ammonium salts
Available.

The base is used in an amount of 0.5 to 100 equivalents, preferably 2 to 4 equivalents, based on the Group VIII transition metal complex.
It is 0 equivalent. In the present invention, a nitrogen-containing compound such as an optically active amine compound is used. This is, for example, an amine compound represented by the general formula NR ⁶ R ⁷ R ⁸ , wherein at least one of the substituents is an optically active group. The remainder is hydrogen or an optically active monoamine having a saturated or unsaturated hydrocarbon group or an aryl group, or a compound represented by the general formula (e):

[0017]

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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, a sulfonyl group, etc., and R ¹¹ , R ¹² , R ¹³ , 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 And a cyclic hydrocarbon group. )). For example, optically active 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-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-2,
Examples thereof include an optically active diamine compound such as 2-dinaphthylethylenediamine and an optically active diamine compound in which one or two of the substituents of R ⁹ to R ¹⁵ are a sulfonyl group or a urethane group. Further, the optically active diamines that can be used are not limited to the optically active ethylenediamine derivatives exemplified above, and optically active propanediamine, butanediamine, and phenylenediamine derivatives can be used. The amount of the optically active amine compound used is in the range of 1 to 4 equivalents, preferably 2 to 4 in the case of the monoamine compound, based on the transition metal complex.
4 equivalents are preferable, and in the case of a diamine compound, 0.5 to
2.5 equivalents, preferably in the range of 1-2 equivalents.

In the present invention, the combination of the absolute structure of the optically active ligand and the absolute configuration of the optically active nitrogen-containing compound in the asymmetric hydrogenation catalyst as a catalyst component is important for obtaining a high asymmetric yield. Yes, for example, as shown in a comparative example described below, the combination of an S-phosphine ligand and S, S-diamine is optimal and gives an alcohol of the (R) form. S−
The combination of phosphine ligand and R, R-diamine is
Although the reaction proceeds, the asymmetric yield is extremely reduced.

As described above, in the present invention, the three components of the optically active transition metal complex, the base and the optically active nitrogen-containing compound used as the catalyst smoothly proceed with the asymmetric hydrogen reaction and achieve a high asymmetric yield. In order to carry out the reaction, alcohol components having sufficient reaction activity and high optical purity cannot be obtained if any one component is insufficient. In the present invention, an appropriate liquid solvent can be used as long as it can solubilize the reaction raw materials and the catalyst system. Examples include aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether and tetrahydrofuran, methanol, ethanol, and 2-propanol. , Butanol, alcoholic solvents such as benzyl alcohol, acetonitrile, DMF
And an organic solvent containing a hetero atom such as DMSO. Since the product is an alcohol, an alcohol-based solvent is preferred. Still more preferably, it is 2-propanol. When the reaction substrate is hardly solubilized in a solvent, it can be selected from the above solvents and used as a mixed solvent.

The amount of the solvent is determined by the solubility of the reaction substrate and the economics. In the case of 2-propanol, the reaction can be carried out at a substrate concentration of as low as 1% or less depending on the substrate and in a state close to no solvent.
It is desirable to use 0% by weight. The pressure of hydrogen in the present invention is sufficient to be 1 atm because the present catalyst system is extremely active.
A range of 100 atm, preferably a range of 3 to 50 atm is desirable, but it is also possible to maintain a high activity even at 10 atm or less in consideration of economy of the whole process.

The reaction temperature is from 15 degrees to 1 in consideration of economy.
The reaction is preferably carried out at a temperature of 00 degrees, but the reaction can be carried out at around room temperature of 25 to 40 degrees. However, the present invention is characterized in that the reaction proceeds even at a low temperature of -30 to 0 degrees. Although the reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, the temperature, and the pressure, the reaction is completed in several minutes to 10 hours. Specific examples will be described in Examples.

The reaction in the present invention can be carried out either in a batch system or a continuous system.

[0024]

The present invention will be described in more detail with reference to the following examples. Table 1 shows optically active phosphines, diamine ligands and reaction substrates that can be used as representative examples. Example 1 In a Schlenk reaction tube, a 0.5 M solution of KOH in 2-propanol (40 μL), (S, S) -diphenylethylenediamine (2.1 mg, 0.01 mmol) and 1′-acetonaphthone (Table 1: compound 10) ( 85 0 mg, 5.
0 mmol) and 3 ml of 2-propanol were introduced under a stream of argon, and after degassing and purging with argon, RuCl ₂ ((S) -binap) (dmf) was further added to the solution.
_n (9.6 mg, 0.01 mmol) is added to adjust the reaction solution. The solution was repeatedly degassed and replaced with argon to completely dissolve, and then transferred to a 100 ml glass autoclave, and hydrogen was injected to a predetermined pressure to start the reaction. After stirring at 28 ° C. for 6 hours, the temperature was returned to room temperature, and the reaction compound was analyzed by gas chromatography and H ¹ NM.
The product was identified and the reaction yield (99% or more) was determined by R analysis. Further obtained (R) -1- (1-naphthyl)
The optical purity of ethanol can be determined by HPL using an optically active column.
C and gave a result of 97% ee. Examples 2 to 14 In the same manner as in Example 1, a carbonyl compound shown in Table 1 was used as a reaction substrate, and a phosphine ligand and a diamine ligand shown in Table 2 were used. The reaction was carried out under the reaction conditions for the reaction time, and the corresponding optically active alcohols were obtained in high yield. Table 3 summarizes the results.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

Example 15 In the same manner as in Example 1, hydrogen was added using p-diacetylbenzene as a reaction substrate and (S) -isopropyl-2,2-di (p-methoxyphenyl) ethylenediamine as an optically active diamine. 1. Pressure at 4 atm, 28 ° C.
The reaction was performed for 5 hours. The ratio of the optically active substance and the meso form of the obtained diol was 85:15. The optical purity of the optically active substance was 99% ee or more. Example 16 The reaction was carried out by scaling up Example 1 about 35 times.
(R) -1- (1-naphthyl) ethanol was 27.90 from 30 g of 1'-acetonaphthone (Table 1: Compound 10).
g were obtained. The reaction product was distilled under reduced pressure (98 to 101 degrees /
0.5 mmHg) and an optical purity of 95% ee
To obtain a pure product. Comparative Example 1 A reaction was carried out under exactly the same conditions as in Example 1 except that ethylenediamine was used instead of (S, S) -diamine. The corresponding optically active alcohol was obtained with an optical purity of 57% ee. Examples 17 to 22 By the same experimental procedure as in Example 1, hydrogenation was carried out using an unsaturated carbonyl compound having a carbon-carbon double bond in the same molecule as a reaction substrate, and the corresponding optically active alcohol was obtained in high yield. Obtained. At this time, the carbon-oxygen unsaturated bond was hardly hydrogenated, and only the carbonyl group was hydrogenated. Table 3 above summarizes the optically active ligands used and the reaction results. Example 23 Hydrogenation was carried out by the same experimental procedure as in Example 1 using cyclic unsaturated ketone 16 (0.35 g, 2.5 mmol) as a reaction substrate to quantitatively obtain the corresponding optically active unsaturated alcohol. As shown in Table 3, the optical purity was 93% e.
e.

Example 24 The amount of KOH added was 0.2 mmol (0.4 M, 2-M
Hydrogenation was carried out using racemic 2-methylcyclohexanone 17 (0/57 g, 5.0 mmol) as a reaction substrate in the same manner as in Example 1, except that the solvent was changed to a propanol solution (444 μl). The reaction proceeded with dynamic optical resolution for the asymmetric carbon at the 2-position, and the cis isomer was preferentially formed at a ratio of 97.7: 2.3 of the cis and trans optically active alcohols. As shown in Table 3, the optical purity of the cis form was 80% ee. Example 25 By the same experimental procedure as in Example 24, hydrogenation was carried out using racemic compound 18 (1.05 g, 5 mmol) as a reaction substrate. The reaction proceeded with dynamic optical resolution as in Example 24, and the anti-form alcohol and the syn-form alcohol were preferentially produced at a conversion of 97.0: 3.0 at 100% conversion. . The optical purity of the obtained anti-alcohol was 91% ee as shown in Table 3.

[0030]

As described in detail above, according to the present invention, it is possible to obtain various optically active alcohols with higher purity and higher yield.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location // C07B 61/00 300 C07B 61/00 300 (73) Patent holder 594200323 Nobuo Seito Yokohama-shi, Kanagawa 95-14, Honmura-cho, Asahi-ku 202 No. 3 Shinozaki 202, 72 (72) Inventor Takao Ikariya 8-1 Yuchiya-cho, Chigusa-ku, Nagoya, Aichi Prefecture Chaya-ga-Zaka Coaters 907 (72) Inventor Hirohito Ooka Meito-ku, Nagoya-shi, Aichi 3-79 Heiwagaoka 2nd Keiraku Building 2A (72) Inventor: Shohei Hashiguchi 4-302, Shinto-ku, Nagoya-shi, Aichi Prefecture (72) Inventor: Takeshi Okuma 1505 Totagaya, Nagakute-cho, Aichi-gun, Aichi Prefecture Habilitation 3- B (72) Inventor Nobuo Seito 95-14 Kimuracho, Asahi-ku, Yokohama-shi, Kanagawa Prefecture 202 3rd Corp. Shinozaki 202 (72) Inventor Ryoji Noyori 135-417, Nitta, Umemori-cho, Nisshin-shi, Aichi Prefecture

Claims (6)

(57) [Claims] 1. A compound of the general formula (a) (R ¹ is an aromatic monocyclic or polycyclic hydrocarbon group which may have a substituent, or a heteromonocyclic or polycyclic group containing a heteroatom, and R ² is hydrogen, Or a saturated or unsaturated chain, cyclic, or aromatic hydrocarbon or heterocyclic group which may have a substituent, and further, R ¹ and R ² are bonded to form a ring; Asymmetric hydrogenation by reacting the carbonyl compound represented by the general formula (b) with hydrogen in the presence of a transition metal asymmetric hydrogenation catalyst, a base and an optically active nitrogen-containing compound. (Wherein R ¹ and R ² represent the same organic groups as described above). 2. The method of claim 1 wherein the asymmetric hydrogenation catalyst is a complex of a Group VIII metal. 3. The method according to claim 1, wherein the asymmetric hydrogenation catalyst has an optically active ligand. 4. The method according to claim 3, wherein the optically active ligand is a phosphine ligand. 5. The method according to claim 1, wherein the base is an alkali metal or alkaline earth metal hydroxide or a salt thereof, or a quaternary ammonium salt. 6. The method according to claim 1, wherein the optically active nitrogen-containing compound is an optically active amine compound.