JP2007297285A - Method for preparing optically active hydroxy compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparing an optically active hydroxy compound high in yield and optical purity. <P>SOLUTION: The method for preparing an optically active hydroxy compound represented by formula (4) (wherein R<SP>4</SP>is a hydrocarbon group or a heterocyclic group which may have a substituent; R<SP>5</SP>is an alkyl group; and * is an asymmetric carbon atom) comprises reacting an aldehyde compound with a dialkylzinc in the presence of an optically active Schiff base, and then treating the reaction mixture with an acid. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel process for producing optically active hydroxy compounds. An optically active hydroxy compound, for example, a compound useful as a raw material or synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.

Conventionally, as a method for producing an optically active hydroxy compound by reacting an aldehyde compound with dialkylzinc using an optically active Schiff base, for example, an optically active Schiff base (substituted on the carbon of the imine bond) is used. And a method of reacting benzaldehyde with diethylzinc in the presence of titanium tetraisopropoxide to obtain optically active 1-phenyl-1-butyl alcohol (for example, Non-Patent Document 1). reference). However, in this method, titanium tetraisopropoxide must be used, and the optical purity of the target product is not necessarily high, and there is no mention of application to aliphatic aldehydes. Furthermore, a method for obtaining an optically active hydroxy compound by reacting various aldehyde compounds with diethylzinc in the presence of (-)-3-exo- (dimethylamino) isoborneol is disclosed (for example, non- Patent Document 2). However, in this method, it is difficult to synthesize an optically active ligand to be used, and in addition, when n-heptanal (aliphatic aldehyde) is used as the aldehyde compound, the optical yield of the target product is low. There was a problem of getting worse.
Synlett., 1441 (1998) J. Am. Chem. Soc., 108, 6071 (1986)

  An object of the present invention is to solve the above problems and to provide a method for producing an optically active hydroxy compound having a high yield and optical purity.

  The subject of this invention is general formula (1).

（式中、Ｒ^１は、水素原子又は炭化水素基を示し、Ｒ^２及びＲ^３は、炭化水素基を示す。又、＊は、不斉炭素原子を示す。）
で示される光学活性なシッフ塩基の存在下、一般式（２）

(In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, R ² and R ³ represent a hydrocarbon group, and * represents an asymmetric carbon atom.)
In the presence of an optically active Schiff base represented by the general formula (2)

（式中、Ｒ^４は、置換基を有していても良い炭化水素基又は複素環基（縮合していても良い）を示す。）
で示されるアルデヒド化合物と一般式（３）

(In the formula, R ⁴ represents a hydrocarbon group or a heterocyclic group which may have a substituent (which may be condensed).)
An aldehyde compound represented by the general formula (3)

（式中、Ｒ^５は、アルキル基を示す。）
で示されるジアルキル亜鉛とを反応させた後に、反応混合物を酸で処理することを特徴とする、一般式（４）

(In the formula, R ⁵ represents an alkyl group.)
The reaction mixture is treated with an acid after the reaction with the dialkylzinc represented by the general formula (4):

（式中、Ｒ^４及びＲ^５は、相異なって、前記と同義であり、＊は、不斉炭素原子を示す。）
で示される光学活性なヒドロキシ化合物の製法によって解決される。

(In the formula, R ⁴ and R ⁵ are different and have the same meanings as above, and * represents an asymmetric carbon atom.)
It solves by the manufacturing method of the optically active hydroxy compound shown by these.

  According to the present invention, a method for producing an optically active hydroxy compound having a high yield and optical purity can be provided.

The aldehyde compound used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R ⁴ is a hydrocarbon group or a heterocyclic group which may have a substituent. The heterocyclic group may be condensed. The carbon number of the hydrocarbon group is generally 1-30, in particular 1-20. Specific examples of the hydrocarbon group include, for example, alkyl groups, particularly carbon such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl group. A linear or branched alkyl group of 1 to 15; a cycloalkyl group, in particular, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or the like, and a cycloalkyl group having 3 to 10 carbon atoms An alkenyl group, particularly a straight chain or branched alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a propenyl group or a butenyl group; an alkynyl group, particularly 2 to 6 carbon atoms such as an ethynyl group, a propynyl group or a butynyl group; A linear or branched alkynyl group of 7 to 2 carbon atoms such as an aralkyl group, particularly a benzyl group, a phenethyl group, and a phenylpropyl group Aralkyl group; an aryl group, especially phenyl group, p- tolyl group, a naphthyl group, and an aryl group having 6 to 20 carbon atoms such as an anthryl group.

  Examples of the hetero atom in the heterocyclic group (which may be condensed) are an oxygen atom, a nitrogen atom, and a sulfur atom. The number of ring atoms in the heterocycle is generally 3-18. The number of carbon atoms of the heterocyclic group is 2 to 25, for example 3 to 20, particularly 4 to 15. Specific examples of the heterocyclic group include furyl, benzofuryl, thienyl, pyrrolyl, pyridyl, quinolyl, pyrimidyl, piperidyl, morpholyl, thiazolyl, benzothiazolyl, imidazolyl, and triazolyl. Groups and the like. These groups include various isomers.

  The hydrocarbon group and heterocyclic group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

  Examples of the substituent formed through the carbon atom include a linear or branched alkyl having 1 to 15 carbon atoms such as an alkyl group, particularly a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. A cycloalkyl group, particularly a cycloalkyl group having 3 to 10 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group; an alkenyl group, particularly a vinyl group, an allyl group, a propenyl group, C2-C6 linear, branched or cyclic alkenyl groups such as cyclopropenyl, cyclobutenyl and cyclopentenyl; heterocyclic groups, in particular quinolyl, pyridyl, pyrrolidyl, pyrrolyl, furyl, thienyl A heterocyclic group having 3 to 18 ring atoms having at least one oxygen atom, nitrogen atom or sulfur atom, such as a group; A reel group, particularly a phenyl group, a tolyl group, a fluorophenyl group, a xylyl group, a biphenylyl group, a naphthyl group, an anthryl group, a phenanthryl group and the like; an aryl group (which may be acetalized); ), Especially an acetyl group, a propionyl group, an acryloyl group, a pivaloyl group, a cyclohexylcarbonyl group, a benzoyl group, a naphthoyl group, a toluoyl group, etc., an acyl group having 1 to 20 carbon atoms; a carboxyl group; an alkoxycarbonyl group, particularly a methoxycarbonyl An alkoxycarbonyl group having 1 to 6 carbon atoms such as an ethoxycarbonyl group; an aryloxycarbonyl group, particularly an aryloxycarbonyl group having 7 to 21 carbon atoms such as a phenoxycarbonyl group; an alkyl halide group, particularly trifluoromethyl 1-15 carbon atoms such as group Halogenated linear or branched chain (e.g., fluoride, chloride, bromide or iodide) alkyl group; a cyano group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include a hydroxyl group; a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group and the like. Examples thereof include a chain or branched alkoxyl group; an aralkyloxyl group having 7 to 15 carbon atoms such as a benzyloxyl group; and an aryloxyl group having 6 to 20 carbon atoms such as a phenoxyl group, a toluyloxyl group, and a naphthyloxyl group. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include a primary amino group having 1 to 20 carbon atoms such as a methylamino group, an ethylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, and a naphthylamino group. A secondary amino group having 2 to 20 carbon atoms such as a dimethylamino group, a diethylamino group, a dibutylamino group, a methylethylamino group, a methylbutylamino group, a diphenylamino group or an N-methyl-N-methanesulfonylamino group; A heterocyclic amino group having 5 to 20 carbon atoms such as a group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group, indolyl group; imino group. These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxyl group having 1 to 20 carbon atoms such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thiophenoxyl group and a thiotoluyloxyl group. And a thioaryloxyl group having 6 to 20 carbon atoms such as a thionaphthyloxyl group. These groups include various isomers.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The dialkylzinc used in the reaction of the present invention is represented by the general formula (3). In the general formula (3), R ⁵ is an alkyl group (generally having 1 to 20 carbon atoms), preferably, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, etc. Examples thereof include an alkyl group having 1 to 6 carbon atoms. These groups include various isomers.

  The amount of the dialkyl zinc used is preferably 1 to 5 mol, more preferably 2 to 3 mol, per 1 mol of the aldehyde compound.

  The optically active Schiff base of the present invention has the general formula (1)

(Wherein R ¹ , R ² , R ³ and * are as defined above.)
Indicated by

In the general formula (1), R ¹ is a hydrogen atom or a hydrocarbon group (the carbon number is generally 1 to 30, particularly 1 to 20). Specific examples of the hydrocarbon group include, for example, alkyl groups, particularly carbon such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl group. A linear or branched alkyl group of 1 to 15; a cycloalkyl group, in particular, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or the like, and a cycloalkyl group having 3 to 10 carbon atoms An alkenyl group, particularly a straight chain or branched alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a propenyl group or a butenyl group; an alkynyl group, particularly 2 to 6 carbon atoms such as an ethynyl group, a propynyl group or a butynyl group; A linear or branched alkynyl group of 7 to 2 carbon atoms such as an aralkyl group, particularly a benzyl group, a phenethyl group, and a phenylpropyl group Aralkyl group; an aryl group, especially phenyl group, p- tolyl group, a naphthyl group, and an aryl group having 6 to 20 carbon atoms such as an anthryl group. These groups include various isomers.

R ² and R ³ are hydrocarbon groups and have the same meanings as those described above for R ¹ . * Represents an asymmetric carbon atom.

  The amount of the optically active Schiff base used is preferably 0.5 to 100 mmol, more preferably 0.8 to 70 mmol, with respect to 1 mol of the aldehyde compound.

  The optically active Schiff base is represented by the reaction process formula (1)

(Wherein R ¹ , R ² , R ³ and * are as defined above, and X represents a halogen atom.)
As shown in the above, the 3-tert-butyl-2-hydroxybenzaldehyde compound is converted into a (3-tert-butyl-2-hydroxyphenyl) methanol compound using a Grignard reagent and then oxidized to give 3 It is a compound obtained by making -tert-butyl-2-hydroxy-1-ketobenzene compound and then reacting it with an optically active leucinol compound.

  These reactions for the production of the Schiff base may be carried out in the presence or absence of a solvent as exemplified below, which does not adversely influence the reaction. In the reaction using a Grignard reagent, there are 2-3 moles of Grignard reagent per mole of 3-tert-butyl-2-hydroxybenzaldehyde compound, the reaction temperature is 0 to 80 ° C., and the reaction time is 1 to 24. It may be time. In the oxidation reaction, it is preferable to use a metal catalyst, particularly a palladium catalyst such as palladium carbon (for example, 5 to 50 parts by weight with respect to 100 parts by weight of (3-tert-butyl-2-hydroxyphenyl) methanol compound). An atmosphere is preferred, the reaction temperature may be 50-120 ° C., and the reaction time may be 1-48 hours. In the reaction using the optically active leucinol compound, the optically active leucinol compound is 1 to 1.1 mol per 1 mol of the 3-tert-butyl-2-hydroxy-1-ketobenzene compound, and the reaction temperature is 80 to 150 ° C. The time may be 1 to 48 hours.

  Among the optically active Schiff bases used in the reaction of the present invention, those having the following substituents are novel compounds.

(Wherein R ¹ , R ² and R ³ are any of the following cases.
(1) R ¹ = hydrogen atom, R ² and R ³ are the same or different hydrocarbon groups,
(However, R ¹ = hydrogen atom, R ² = phenyl group, R ³ = except isopropyl group)
(2) R ¹ = t-butyl group, R ² = α-naphthyl group, R ³ = t-butyl group)

  Examples of the acid used in the present invention include inorganic acids and organic acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, etc., preferably inorganic acids such as hydrochloric acid and sulfuric acid are used. . In addition, you may use these acids individually or in mixture of 2 or more types.

  The amount of the acid used is preferably 3 to 100 mol, more preferably 10 to 30 mol, per 1 mol of the aldehyde compound.

  Although the reaction of the present invention is carried out in the presence or absence of a solvent, the use of a solvent is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic carbonization such as pentane, hexane, heptane and the like. Hydrogen (including branched and cyclic); Halogenated aliphatic hydrocarbons (including branched and cyclic) such as methylene chloride and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene are exemplified, but aliphatic hydrocarbons are preferably used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity of reaction and stirrability, but is generally 1 to 300 g, preferably 10 to 100 g, and more preferably 15 to 60 g with respect to 1 g of the aldehyde compound.

  The present invention provides, for example, reaction process formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and * are as defined above. Note that n is 1 or 2.)
In the presence of an optically active Schiff base, the dialkylzinc and the aldehyde compound are reacted and then the reaction mixture is treated with an acid. The reaction temperature at that time is preferably -70 to 30 ° C, more preferably -50 to 25 ° C, particularly preferably -40 to 15 ° C. The reaction is generally performed in a liquid phase, and the reaction pressure is not particularly limited. Although the reaction time is not particularly limited, the time for reacting the dialkylzinc is 0.1 to 2 hours, the time for reacting the aldehyde compound is 1 to 48 hours, and the time for treating with the acid is 0.1 to 1 hour. It is.

As a preferred embodiment of the present invention, an optically active Schiff base and dialkyl zinc (excess amount with respect to the ligand) are reacted to form a zinc complex, and then an aldehyde compound is added to react with the remaining dialkyl zinc. Then, an optically active hydroxy compound is obtained by treating with an acid.

  According to the present invention, an optically active hydroxy compound is obtained, which can be isolated and purified by a general method such as hydrolysis, neutralization, extraction, filtration, concentration, distillation, recrystallization, column chromatography and the like. The

  The zinc complex obtained by reacting the optically active Schiff base of the present invention with dialkylzinc is represented by the general formula (5).

(Wherein R ¹ , R ² , R ³ , * and n are as defined above.)
It is a novel compound shown by these.

  The zinc complex is a monomer or a dimer. Monomers (the chemical formula on the left) and dimers (the chemical formula on the right) are considered to have the following chemical structures.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto. In addition, the optical purity of the optically active hydroxy compound obtained by the reaction of the present invention was measured under the following conditions by high performance liquid chromatography using an optically active column.

Column: CHIRALPAK OD-H (Daicel)
Solvent: Hexane / 2-propanol (= 97.5 / 2.5 (volume ratio))
Flow rate: 1.0ml / min.
Wavelength: 254nm

Synthesis Example 1 (Synthesis of 3-tert-butyl-2-hydroxybenzaldehyde)
In an eggplant flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a reflux condenser, 25.0 g (166 mmol) of 2-t-butylphenol, 16.2 g (16.6 mmol) of paraformaldehyde of 92.3% purity, 6.18 g of 4-picoline ( 66.3 mmol) and 300 ml of toluene were added, and the mixture was reacted at 95 ° C. for 6 hours with stirring in an argon atmosphere. Next, the reaction solution was cooled to room temperature, and the oily substance in the lower layer of the reaction solution was removed by decantation. The supernatant was washed twice with 60 ml of 1 mol / l hydrochloric acid and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting concentrate was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (= 100/3 (volume ratio))) to give 3-tert- 13.1 g of butyl-2-hydroxybenzaldehyde was obtained (isolation yield; 44%).

Synthesis Example 2 (Synthesis of (3-tert-butyl-2-hydroxyphenyl) phenylmethanol)
To an eggplant flask having an internal volume of 100 ml equipped with a stirrer, a dropping device and a reflux condenser, add 1.0 g (16.5 mmol) of magnesium pieces and 15 ml of tetrahydrofuran, and gently add 6.5 g (41.3 mmol) of bromobenzene in a nitrogen atmosphere. The solution was added dropwise to prepare phenylmagnesium bromide. Next, 2.9 g (16.5 mmol) of 3-tert-butyl-2-hydroxybenzaldehyde synthesized in Synthesis Example 1 was slowly added dropwise at 0 ° C. with stirring, and reacted at room temperature for 1 hour and at 80 ° C. for 15 minutes with stirring. I let you. After completion of the reaction, the reaction solution was cooled to 0 ° C., and 50 ml of 1 mol / l hydrochloric acid was slowly added to make the reaction solution acidic. The resulting reaction solution was extracted three times with 50 ml of diethyl ether and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting concentrate was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (= 25/1 (volume ratio))) to give (3-tert- 4.1 g of butyl-2-hydroxyphenyl) phenylmethanol was obtained (isolation yield: 97%).

Synthesis Example 3 (Synthesis of 3-tert-butyl-2-hydroxybenzophenone)
In an ampoule tube with an internal volume of 25 ml equipped with a stirrer, 1.17 g of 10% by mass palladium carbon, 3.9 g (15.2 mmol) of (3-tert-butyl-2-hydroxyphenyl) phenylmethanol synthesized in Synthesis Example 2 and 20 ml of acetonitrile And was allowed to react at 100 ° C. for 7 hours with stirring in an ethylene atmosphere. After completion of the reaction, the reaction mixture was filtered and concentrated, and the resulting concentrate was purified by silica gel column chromatography (developing solvent: hexane) to give 3.2 g of 3-tert-butyl-2-hydroxybenzophenone as a yellow liquid. Obtained (isolation yield; 83%).

Production Example 1 ([R ¹ = hydrogen atom, R ² = phenyl group, R ³ = t-butyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butyl-phenyl)- Synthesis of phenyl-methylene] -amino} -3,3-dimethyl-1-butanol
In a eggplant flask having an internal volume of 100 ml equipped with a stirrer and a reflux condenser, 1.9 g (7.4 mmol) of 3-tert-butyl-2-hydroxybenzophenone synthesized in Synthesis Example 3 and 1.0 g (8.5 mmol) of L-tert-leucineol were synthesized. ), 2.0 g (14.2 mmol) of sodium sulfate and 10 ml of toluene were added and reacted at 115 ° C. for 24 hours with stirring. After completion of the reaction, the reaction solution was filtered and concentrated, and the resulting concentrate was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (= 15/1 (volume ratio))) to give a yellow solid, 2.4 g of (S) -2- {N-[(2-hydroxy-3-tert-butyl-phenyl) -phenyl-methylene] -amino} -3,3-dimethyl-1-butanol was obtained (isolated product). Rate; 92%)
Note that (S) -2- {N-[(2-hydroxy-3-tert-butyl-phenyl) -phenyl-methylene] -amino} -3,3-dimethyl-1-butanol has the following physical property values: It is a novel compound shown.

Melting point: 143 ° C
Specific rotation: [α] ²⁹ _D -44.2 ° (c 1.0, CHCl ₃ )
IR (KBr method, ν _max (cm ⁻¹ )); 3476, 2960, 1593, 1442, 1324, 1288, 1254, 1214, 1141, 919, 752, 706
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.93 (s, 9H), 1.48 (s, 9H), 2.04 (s, 1H), 3.25 (dd, 1H, J = 7.99, 4.00 Hz), 3.86 ~ 3.82 (m, 2H), 6.60 (dd, 2H, J = 20.78,7.59Hz), 7.45 ~ 7.17 (m, 6H), 16.23 (s, 1H)
¹³ C-NMR (CDCl ₃ , δ (ppm)); 27.1, 29.5, 33.9, 35.0, 63.5, 70.9, 128.0, 128.2, 128.3, 128.6, 129.0, 129.4, 130.3, 134.5, 137.9, 163.0, 175.9

  In addition, the following various optically active Schiff bases were synthesized by the same method as in Synthesis Examples 1 to 3 and Production Example 1.

Comparative Production Example 1 ([R ¹ = t-butyl group, R ² = hydrogen atom, R ³ = isopropyl group]; (S) -2- [N- (2-hydroxy-3 ′, 5′-di-tert -Butylsalicylidene) -amino] -3-methyl-1-butanol)
Isolation yield of the final process; 89%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.94 (d, 3H, J = 6.7 Hz), 0.96 (d, 3H, J = 6.7 Hz), 1.31 (s, 9H), 1.45 (s, 9H ), 1.60 (brs, 1H), 1.90 (m, 1H), 3.00 (m, 1H), 3.80 (m, 2H), 7.14 (s, 1H), 7.41 (s, 1H), 8.38 (s, 1H) , 13.5 (brs, 1H)

Production Example 2 ([R ¹ = t-butyl group, R ² = phenyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3,5-di-tert-butyl Synthesis of phenyl) -phenyl-methylene] -amino} -3-methyl-1-butanol
Final process isolation yield; 83%

Production Example 3 ([R ¹ = t-butyl group, R ² = 4-t-butylphenyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3,5- Synthesis of di-tert-butylphenyl)-(4-tert-butylphenyl) -methylene] -amino} -3-methyl-1-butanol
Isolated yield of the final process: 62%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.87 (d, 3H, J = 7.1 Hz), 0.93 (d, 3H, J = 7.1 Hz), 1.38 (s, 9H), 1.48 (s, 9H) ), 1.78 to 1.88 (m, 1H), 3.29 to 3.41 (m, 1H), 3.71 to 3.84 (m, 2H), 6.60 (d, 1H, J = 2.7Hz), 7.36 (d, 1H, J = 2.7 Hz), 7.09-7.54 (m, 4H), 16.0 (brs, 1H)

Production Example 4 ([R ¹ = t-butyl group, R ² = α-naphthyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3,5-di-tert -Butylphenyl)-(1-naphthyl) -methylene] -amino} -3-methyl-1-butanol)
Final process isolation yield; 56%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.78 (d, 3H, J = 7.1 Hz), 0.91 (s, 9H), 1.22 (d, 3H, J = 7.1 Hz), 1.58 (s, 9H) ), 1.88 to 2.02 (m, 1H), 3.02 to 3.19 (m, 1H), 3.61 to 3.79 (m, 2H), 6.45 (d, 1H, J = 2.7Hz), 7.21 to 8.04 (m, 8H), 16.0 (brs, 1H)

Production Example 5 ([R ¹ = t-butyl group, R ² = β-naphthyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3,5-di-tert -Butylphenyl)-(2-naphthyl) -methylene] -amino} -3-methyl-1-butanol)
Isolation yield of the final process: 78%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.69 to 0.92 (m, 6H), 1.05 (s, 9H), 1.40 (s, 9H), 1.79 to 1.92 (m, 1H), 3.18 to 3.30 ( m, 1H), 3.68 to 3.79 (m, 2H), 6.68 (d, 1H, J = 2.7Hz), 7.39 (d, 1H, J = 2.7Hz), 7.22 to 8.01 (m, 7H), 16.0 (brs) , 1H)

Comparative Production Example 2 ([R ¹ = hydrogen atom, R ² = hydrogen atom, R ³ = isopropyl group]; (S) -2- [N- (2-hydroxy-3′-tert-butylsalicylidene)- Synthesis of amino] -3-methyl-1-butanol
Isolated yield of the final process; 98%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.94 (d, 3H, J = 3.2 Hz), 0.96 (d, 3H, J = 3.2 Hz), 1.44 (s, 9H), 1.79 (brs, 1H ), 1.94 (m, 1H), 3.02 (m, 1H), 3.79 (m, 2H), 6.83 (m, 1H), 7.14 (m, 1H), 7.34 (m, 1H), 8.35 (s, 1H) , 13.8 (brs, 1H)

Production Example 6 ([R ¹ = hydrogen atom, R ² = phenyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butylphenyl) -phenyl-methylene Synthesis of] -amino} -3-methyl-1-butanol
Isolated yield of the final step; 94%

Production Example 7 ([R ¹ = hydrogen atom, R ² = 4-t-butylphenyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butylphenyl )-(4-tert-Butylphenyl) -methylene] -amino} -3-methyl-1-butanol)
Final process isolation yield; 76%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.87 (d, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 6.8 Hz), 1.38 (s, 9H), 1.48 (s, 9H ), 1.60 (brs, 1H), 1.89 to 1.94 (m, 1H), 3.29 to 3.34 (m, 1H), 3.74 to 3.80 (m, 2H), 6.55 (m, 1H), 6.66 (d, 1H, J = 7.1Hz), 7.05 to 7.21 (m, 2H), 7.27 (d, 1H, J = 9.8Hz), 7.45 (d, 1H, J = 8.1Hz), 16.3 (brs, 1H)

Production Example 8 ([R ¹ = hydrogen atom, R ² = α-naphthyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butylphenyl)-( Synthesis of 1-naphthyl) -methylene] -amino} -3-methyl-1-butanol
Isolated yield of the final process; 60%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.88 (m, 6H), 1.29 (m, 1H), 1.51 (s, 9H), 1.94 (s, 9H), 3.06 (m, 1H), 3.71 (m, 2H), 6.49 (m, 2H), 7.25-7.68 (m, 6H), 7.93 (m, 2H), 16.3 (s, 1H)

Production Example 9 ([R ¹ = hydrogen atom, R ² = β-naphthyl group, R ³ = isopropyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butylphenyl)-( Synthesis of 2-naphthyl) -methylene] -amino} -3-methyl-1-butanol
Isolation yield of final process; 82%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.92 (d, 9H, 7.59 Hz), 1.50 (s, 9H), 3.27 to 3.33 (m, 1H), 3.84 (s, 2H), 6.52 (dd , 1H, J = 7.99,7.99Hz), 6.63 (dd, 1H, J = 8.39,5.20Hz), 7.94-7.24 (m, 9H), 7.82 (s, 1H)

Production Example 10 ([R ¹ = hydrogen atom, R ² = methyl group, R ³ = isopropyl group]; (S) -2- {N- [1- (2-hydroxy-3-tert-butylphenyl) -ethylidene Synthesis of] -amino} -3-methyl-1-butanol
Final process isolation yield; 52%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.98 (m, 6H), 1.26 to 1.28 (m, 1H), 1.44 (s, 9H), 1.97 to 2.02 (m, 1H), 2.41 (s, 3H), 3.73 to 3.90 (m, 3H), 6.73 (dd, 1H, J = 6.8, 7.3Hz), 7.33 (d, 1H, J = 6.8Hz), 7.46 (d, 1H, J = 7.3 Hz), 16.8 (s, 1H)

Comparative Production Example 3 ([R ¹ = hydrogen atom, R ² = hydrogen atom, R ³ = t-butyl group]; (S) -2- [N- (2-hydroxy-3 ′, 5′-di-tert -Butylsalicylidene) -amino] -3,3-dimethyl-1-butanol)
Isolated yield of the final process; 99%
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.99 (s, 9H), 1.34 (d, 1H, J = 8.34, 4.00 Hz), 1.44 (s, 9H), 2.94 (dd, 1H, J = 9.19, 2.80), 3.77 (ddd, 1H, J = 10.79, 10.79, 4.00Hz), 3.94 (ddd, 1H, J = 8.39, 8.39, 2.80), 6.84 (dd, 1H, J = 7.99, 7.99Hz), 7.16 (dd, 1H, J = 7.59, 1.6Hz), 7.34 (dd, 1H, J = 7.59, 1.60Hz), 8.36 (s, 1H), 13.82 (s, 1H)

Production Example 11 ([R ¹ = hydrogen atom, R ² = β-naphthyl group, R ³ = t-butyl group]; (S) -2- {N-[(2-hydroxy-3-tert-butylphenyl) Synthesis of-(2-naphthyl) -methylene] -amino} -3,3-dimethyl-1-butanol
Final process isolation yield; 63%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.92 (s, 9H), 1.45 (s, 1H), 1.50 (s, 9H), 3.27 to 3.33 (m, 1H), 3.84 (m, 2H) 6.52 (dd, 1H, J = 7.99, 7.99Hz), 6.63 (dd, 1H, J = 8.4, 5.2 Hz), 7.24-7.94 (m, 9H), 16.27 (s, 1H)

Production Example 12 ([R ¹ = t-butyl group, R ² = α-naphthyl group, R ³ = t-butyl group]; (S) -2- {N-[(2-hydroxy-3,5-di- -tert-Butylphenyl)-(1-naphthyl) -methylene] -amino} -3,3-dimethyl-1-butanol)
Final process isolation yield; 63%
In addition, this compound is a novel compound.
¹ H-NMR (CDCl ₃ , δ (ppm)); 0.85 (s, 9H), 0.89 (s, 9H), 1.26 (m, 1H), 1.52 (s, 9H), 3.17 (m, 1H), 3.88 (m, 2H), 7.26-7.75 (m, 7H), 7.89-7.97 (m, 2H), 16.1 (br s, 1H), 0.91 (s, 9H), 1.00 (s, 9H), 1.27 (m, 1H), 1.52 (s, 9H), 3.04 (m, 1H), 3.72 (m, 2H), 6.44 (m, 2H), 7.26-7.75 (m, 5H), 7.89-7.97 (m, 2H), 16.1 (br s, 1H)

Example 1 ([R ¹ = hydrogen atom, R ² = phenyl group, R ³ = t-butyl group, R ⁴ = phenyl group, R ⁵ = ethyl group]; synthesis of optically active 1-phenyl-1-propanol )
An ampule tube with an internal volume of 25 ml equipped with a stirrer was added to (S) -2- {N-[(2-hydroxy-3-tert-butyl-phenyl) -phenyl-methylene] -amino} -3,3-dimethyl. 6.6 mg (0.019 mmol) of 1-butanol and 4 ml of hexane were added. While stirring the mixture at −40 ° C., 0.4 ml (3.9 mmol) of diethylzinc was added in an argon atmosphere and stirred at 0 ° C. for 30 minutes to form a zinc complex. Next, the mixture was cooled to −40 ° C., 200 mg (1.9 mmol) of benzaldehyde was added, and the mixture was reacted at 0 ° C. with stirring for 24 hours. After completion of the reaction, the resulting reaction mixture was dissolved in diethyl ether, added to 20 ml of 1 mol / l hydrochloric acid cooled with ice water, and extracted three times with 10 ml of diethyl ether. The obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developing solvent; n-hexane / ethyl acetate = 15/1 (volume ratio)). Then, the obtained liquid was distilled under reduced pressure to obtain 225.1 mg of optically active 1-phenyl-1-propanol as a colorless transparent liquid (isolation yield; 88%, optical yield; 96% ee ( R)).

Examples 2 to 25 and Comparative Examples 1 to 3 (Synthesis of optically active hydroxy compounds)
In Example 1, the reaction was performed in the same manner as in Example 1 except that the aldehyde compound, the ligand, and the ligand amount (relative to the aldehyde compound) were changed. The results are shown in Table 1.

Production Example 13 ([R ¹ = hydrogen atom, R ² = phenyl group, R ³ = t-butyl group]; synthesis of zinc complex (catalytically active species))
An ampule tube with an internal volume of 5 ml equipped with a stirrer was charged with (S) -2- {N-[(2-hydroxy-3-tert-butyl-phenyl) -phenyl-methylene] -amino} -3,3-dimethyl. 1-butanol 40 mg (0.115 mmol), diethylzinc 0.012 ml (0.117 mmol) and n-hexane 2 ml were mixed and reacted at 0 ° C. for 30 minutes with stirring in an argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a zinc complex as a yellow solid.
The zinc complex is a novel compound represented by the following physical property values.

¹ H-NMR (C ₆ D ₆ , δ (ppm)); 1.09 (s, 9H), 1.66 (s, 9H), 3.43 (d, 1H, J = 6.40 Hz), 4.13 (dd, 1H, J = 10.40, 6.40Hz), 4.32 (d, 1H, J = 10.40Hz), 6.50 (t, 1H, J = 7.60Hz), 6.73 (dd, 1H, J = 7.60Hz, 2.00Hz), 7.04 (t, 1H , J = 7.20Hz), 7.11 (t, 2H, J = 7.60Hz), 7.27 (dd, 1H, J = 7.60Hz, 2.00Hz), 7.37 (d, 2H, J = 7.60Hz)
In addition, peaks corresponding to the hydroxyl group of the optically active Schiff base, around 0.7 ppm (hydroxyl proton derived from amino alcohol) and 16 ppm (hydroxyl proton bonded to the benzene ring) completely disappeared.

  The present invention relates to a novel process for producing optically active hydroxy compounds. An optically active hydroxy compound is, for example, a compound useful as a raw material for pharmaceuticals and agricultural chemicals or a synthetic intermediate.

Claims (3)

General formula (1)

(In the formula, R ¹ represents a hydrogen atom or a hydrocarbon group, R ² and R ³ represent a hydrocarbon group, and * represents an asymmetric carbon atom.)
In the presence of an optically active Schiff base represented by the general formula (2)

(In the formula, R ⁴ represents a hydrocarbon group or a heterocyclic group which may have a substituent. The heterocyclic group may be condensed.)
An aldehyde compound represented by the general formula (3)

(In the formula, R ⁵ represents an alkyl group.)
The reaction mixture is treated with an acid after the reaction with the dialkylzinc represented by the general formula (4).

(In the formula, R ⁴ and R ⁵ are different and have the same meanings as above, and * represents an asymmetric carbon atom.)
The manufacturing method of the optically active hydroxy compound shown by these. General formula (1)

(Wherein R ¹ , R ² and R ³ are any of the following cases.
(1) R ¹ = hydrogen atom, R ² and R ³ are the same or different hydrocarbon groups,
(However, R ¹ = hydrogen atom, R ² = phenyl group, R ³ = except isopropyl group)
(2) R ¹ = t-butyl group, R ² = α-naphthyl group, R ³ = t-butyl group)
An optically active Schiff base represented by Generated by reaction of optically active Schiff base with dialkylzinc, general formula (5)

(Wherein R ¹ represents a hydrogen atom or a hydrocarbon group, R ² and R ³ represent a hydrocarbon group, * represents an asymmetric carbon atom, and n is 1 or 2. .)
A novel zinc complex having the optically active Schiff base represented by