JP2002255923A - Method for producing optically active phenyl carbinol compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an optically active phenyl carbinol compound useful as a medicine, an agrochemical and an intermediate therefor. SOLUTION: This method for producing the optically active phenyl carbinol compound represented by formula (3) [wherein, Ar means phenyl group; R means a 1-10C alkyl group or a 6-10C aromatic group; and the absolute configuration of sulfur atom and carbon atom represented by * means R or S] is characterized by reacting an optically active arylsulfinylbenzaldehyde compound represented by formula (1) [wherein, Ar is the same as described above; the absolute configuration of sulfur atom represented by * means R or S] with a Grignard compound represented by formula (2) R-MgX [wherein, R means a 1-10C alkyl group or a 6-10C aromatic group; and X means chlorine atom, bromine atom or iodine atom].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active phenylcarbinol compound by a stereoselective addition reaction of a Grignard compound using an optically active arylsulfinylbenzaldehyde compound as a substrate.

[0002]

2. Description of the Related Art Optically active phenylcarbinol compounds are important intermediates of various fine chemical derivatives including physiologically active substances such as medical and agricultural chemicals.

[0003] Conventionally, a method for producing an optically active carbinol compound by stereoselective addition reaction to an aldehyde compound has been proposed. Tetrahedron Lett., 2000, 41, 4157 discloses a method using an optically active arylsulfinyl naphthaldehyde as a substrate. A selective addition reaction has been reported, and an optically active naphthocarbinol compound can be obtained very selectively by selecting a substrate and a nucleophile.

[0004]

However, even with the above-mentioned production methods, satisfactory results in terms of yield and selectivity have not been obtained depending on the types of the substrate and the nucleophile. Further, at present, studies are actively being conducted with the aim of producing an efficient optically active carbinol compound.

[0005]

Means for Solving the Problems As a result of intensive studies on a method for producing an optically active phenylcarbinol compound, the present inventor has found that the use of an optically active arylsulfinylbenzaldehyde compound as a substrate makes it very selective. The present inventors have found a manufacturing method and completed the present invention.

That is, the present invention provides the following formula (1)

[0007]

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Wherein Ar represents a phenyl group (the phenyl group may be optionally substituted with a C _1-10 alkyl group, a C _1-10 alkoxy group or a halogen atom);
The absolute configuration of the sulfur atom represented by means R or S. The optically active arylsulfinylbenzaldehyde compound represented by the formula (2)

[0009]

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Wherein R is a C _1-10 alkyl group (the alkyl group is a C _1-10 alkyl group, a C _1-10 alkoxy group or a C _1-10 alkyl group;
_It may be optionally substituted with a _6-10 aromatic group. ) Or C
_6-10 aromatic group (the aromatic group is a C _1-10 alkyl group,
_It may be optionally substituted with a _1-10 alkoxy group, a halogen atom or a nitro group. X) represents a chlorine atom, a bromine atom or an iodine atom. Wherein the compound is reacted with a Grignard compound represented by the formula (3):

[0011]

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[Wherein, Ar and R are as defined above. The absolute configuration of sulfur and carbon atoms represented by * is R or S
Means ] The method for producing an optically active phenylcarbinol compound represented by the formula:

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

In the present specification, "n" means "i" for normal.
Is iso, "s" is secondary, "t" is tertiary, "p" is para, "m" is meta and "o" is ortho.

First, the substituents Ar and R will be described.

The C _1-10 alkyl group includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-butyl,
Pentyl group, 2-pentyl group, 3-pentyl group, i-pentyl group, neopentyl group, t-pentyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1-methyl-1-ethyl-n -Pentyl group, 1,1,2-trimethyl-n-propyl group, 1,2,2-trimethyl-n-propyl group, 3,3-dimethyl-n-butyl group, 1-heptyl group, 2-heptyl group , 1-ethyl-1,2-dimethyl-n-propyl group, 1-ethyl-2,2-dimethyl-
n-propyl group, 1-octyl group, 3-octyl group, 4
-Methyl-3-n-heptyl group, 6-methyl-2-n-
Heptyl group, 2-propyl-1-n-heptyl group, 2,
4,4-trimethyl-1-n-pentyl group, 1-nonyl group, 2-nonyl group, 2,6-dimethyl-4-n-heptyl group, 3-ethyl-2,2-dimethyl-3-n- A pentyl group, a 3,5,5-trimethyl-1-n-hexyl group,
1-decyl group, 2-decyl group, 4-decyl group, 3,7-
Dimethyl-1-n-octyl group and 3,7-dimethyl-
And a 3-n-octyl group.

Examples of the C _1-10 alkoxy group include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy and n-pentyloxy. , N-hexyloxy group,
Examples include an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy group, and an n-decyloxy group.

Examples of the C _6-10 aromatic group include phenyl, 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-
Indenyl group, 7-indenyl group, 1-naphthyl group, 2
-Naphthyl group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthyl group, 5-tetrahydronaphthyl group, 6-tetrahydronaphthyl group, and the like, preferably phenyl group, 1-naphthyl group, 2-naphthyl group,
-Tetrahydronaphthyl group and 2-tetrahydronaphthyl group.

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

Specific examples of Ar include a phenyl group, o-
Methylphenyl group, m-methylphenyl group, p-methylphenyl group, 3,5-dimethylphenyl group, 2,4,6
-Trimethylphenyl group, 2,4,6-triisopropylphenyl group, and preferably p-methylphenyl group, 2,4,6-trimethylphenyl group and 2,2
4,6-triisopropylphenyl group and the like.

Specific examples of R include methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl group,
m-methoxyphenyl group, p-methoxyphenyl group, o
-Chlorophenyl group, m-chlorophenyl group, p-chlorophenyl group, 1-naphthyl group, 2-naphthyl group and the like, and preferably methyl group, ethyl group and phenyl group.

Next, a specific method of the reaction will be described.

The optically active arylsulfinylbenzaldehyde compound represented by the formula (1) can be produced by the same method as described in Tetrahedron Lett., 2000, 41, 4157, as shown in Scheme 1. Scheme 1

[0024]

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That is, 2-bromobenzaldehyde dimethyl acetal is lithiated to give 1,1-diacetone-D-
It can be produced by reacting with glucosyl (DAG) sulfinate to introduce a sulfinyl group, and then hydrolyzing the acetal.

The DAG sulfinate used here is:
Tetrahedron: Asymmetry, 1999, 10, 737.

On the other hand, examples of the Grignard compound represented by the formula (2) include methyl Grignard reagent, ethyl Grignard reagent, n-butyl Grignard reagent and phenyl Grignard reagent.

The amount of the Grignard compound used is in the range of 1 molar equivalent to 10 molar equivalents, preferably in the range of 1 molar equivalent to 3 molar equivalents, based on the substrate.

The reaction solvent is not particularly limited as long as it does not participate in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene and o-dichlorobenzene, and n-hexane. ,
Aliphatic hydrocarbons such as cyclohexane, n-octane and n-decane; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether and dimethoxyethane And the like, preferably, tetrahydrofuran and toluene.

Further, these solvents can be used alone or in combination.

The reaction temperature is usually in the range of -100 ° C to 100 ° C, preferably in the range of -80 ° C to 20 ° C.

The reaction time depends on the reactivity of the substrate, but is usually 0.1 to 1000 hours.

After completion of the reaction, the reaction is stopped by acid treatment, followed by extraction with a suitable solvent, and concentration of the solvent under reduced pressure to isolate the desired optically active phenylcarbinol compound.

If necessary, a high-purity optically active phenylcarbinol compound can be isolated by purification by silica gel column chromatography or the like.

[0035]

The present invention will be described in more detail with reference to the following examples.
The present invention is not limited to these.

Reference Example 1 Production of (S) -2- (2,4,6-triisopropylphenyl) sulfinylbenzaldehyde dimethyl acetal

[0037]

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(In the formula, Tip means a 2,4,6-triisopropylphenyl group, and Me means a methyl group.)

To a solution of 2-bromobenzaldehyde dimethyl acetal (241 mg, 0.472 mmol) in ether (15 mL) was slowly added n-butyllithium (1.50 M, 0.30 mL, 0.450 mmol) at −78 ° C. Stir for 30 minutes. (-)-1,1-diacetone-D-glucosyl-2,4,6-triisopropylbenzenesulfinate (304 mg, 0.595 m
mol) in ether (5 mL). 1 hour 3
After stirring for 0 minutes, the reaction solution was quenched by adding a saturated aqueous solution of ammonium chloride, and the aqueous layer was further extracted with methylene chloride.
The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solution was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 30 g, hexane: ethyl acetate = 95: 5) to obtain 220 mg of the desired product (96% yield).

Liquid chromatography analysis (Chira)
lcel OD-H, hexane / isopropanol = 9
6/4, 0.3 mL / min), the optical purity is 97% e
e.

[Α]_D ^{twenty five} -68.3 (c0.436, C
HCl_Three)¹ H NMR (200 MHz, CDCl_Three) δ0.92 (d, 6H, J = 6.8Hz,-
iPr), 1.23 (d, 6H, J = 6.8Hz, -iPr), 1.24 (d, 6H, J =
6.8Hz, -iPr), 2.85 (hep, 1H, J = 6.7Hz, -iPr), 3.13
(s, 3H, -OMe), 3.17 (s, 3H, -OMe), 3.80 (hep, 2H,
J = 6.8Hz, -iPr), 5.13 (s, 1H, -CH-), 7.07 (s, 2H, Ti
p), 7.30-7.50 (m, 2H, Ar), 7.60-7.70 (m, 1H, Ar),
7.75-7.85 (m, 1H, Ar)¹³ C NMR δ23.8, 23.9, 24.3, 28.8, 34.4, 51.3, 54.
0, 98.9, 122.9, 126.0, 127.4, 128.7, 129.6, 136.4,
 143.4, 151.6, 153.3 IR (neat) 2980, 1600, 1480, 1360, 1260, 1200, 110
0, 1060, 1020, 740 cm ^-1

Reference Example 2 Production of (S) -2- (2,4,6-triisopropylphenyl) sulfinylbenzaldehyde

[0043]

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(In the formula, Tip means a 2,4,6-triisopropylphenyl group, and Me means a methyl group.)

To a suspension of silica gel (500 mg) in methylene chloride (4 mL) were added 2 drops of 15% sulfuric acid and the mixture was stirred for 5 minutes. The dimethyl acetal obtained in Reference Example 1 (1
28 mg, 0.315 mmol) of methylene chloride (1.
5 mL) solution was added. After stirring for 1 hour, a small amount of sodium bicarbonate was added to the reaction solution, and the mixture was further stirred for 4.5 hours. After filtering the reaction solution,
After washing with methylene chloride, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 30 g, hexane: ethyl acetate = 90: 10) to obtain 102 mg of the desired product (yield 91%).

Liquid chromatography analysis (Chira)
lcel OD-H, hexane / isopropanol = 9
6/4, 0.5 mL / min) and the optical purity is 97% e
e.

[Α] _D ²⁵ -87.4 (c 0.464, C
HCl ₃ ) ¹ H NMR (200 MHz, CDCl ₃ ) δ 0.90 (d, 6H, J = 6.8Hz,-
CH3), 1.24 (d, 6H, J = 6.8Hz, -CH ₃ ), 1.25 (d, 6H, J =
6.8Hz, -CH ₃ ), 2.90 (hep, 1H, J = 6.7Hz, -iPr), 3.80
(hep, 2H, J = 6.8Hz, -iPr), 7.06 (s, 2H, Tip), 7.55-
7.65 (m, 1H, Ar), 7.70-7.80 (m, 1H, Ar), 7.90-8.00
(m, 2H, Ar), 10.2 (s, 1H, CHO) ¹³ C NMR δ23.6, 23.9, 24.4, 29.1, 34.4, 123.3, 12
6.7, 130.0, 131.3, 133.6, 134.1, 148.7, 151.0, 15
3.6, 189.4 IR (neat) 2950, 1700, 1600, 1460, 1200, 1060, 1020
cm ^-1

Example 1 Preparation of 1- {2- {1-[(2,4,6-triisopropylphenyl) sulfinyl] phenyl} ethanol

[0049]

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(In the formula, Tip means a 2,4,6-triisopropylphenyl group, and Me means a methyl group.)

The (S) -2- (2,2) obtained in Reference Example 2
4,6-triisopropylphenyl) sulfinylbenzaldehyde (141.0 mg, 0.396 mmol)
Was cooled to −78 ° C., and methylmagnesium iodide (0.96 M ether solution, 0.70 mL, 0.672 mmol) was added dropwise.
After stirring for 90 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 15 g, hexane: ethyl acetate = 85: 15). 131.
6 mg (89% yield) was obtained.

The product obtained had a diastereomeric selectivity by NMR of> 98: 2.

¹ H NMR (200 MHz, CDCl ₃ ) δ1.00 (d, 6
H, J = 6.8Hz, -CH3) , 1.19 (d, 6H, J = 6.8Hz, -CH 3), 1.
26 (d, 12H, J = 6.8Hz, -CH ₃ ), 2.92 (hep, 1H, J = 6.7H
z, -iPr), 3.61 (hep, 2H, J = 6.8Hz, -iPr), 4.26 (br,
1H, -OH), 5.24 (q, 1H, J = 6.8Hz, -CH), 7.12 (s, 2H, T
ip), 7.20-7.68 (m, 4H, Ar), ^13C NMR δ21.5, 23.7, 24.0, 29.0, 34.3, 64.9, 67.
5, 123.4, 125.2, 126.9, 127.4, 130.6, 133.8, 141.
7, 145.1, 151.2, 153.8 IR (KBr) 3350, 2970, 2920, 2880, 1600, 1460, 1380,
1360, 1100, 1070, 1010, 770, 640 cm ^-1

Examples 2 to 5 The results of carrying out the reaction in the same manner as in Example 1 except that the optically active arylsulfinylbenzaldehyde compound and Grignard compound of Example 1 were changed are shown in the following table. Table 1

[0055]

[Table 1]

(Where Tip is 2,4,6-triisopropylphenyl group, Mes is 2,4,6-trimethylphenyl group, p-Tol is p-methylphenyl group, Ph is
Represents a phenyl group, and Me represents a methyl group. )

[0057]

According to the method of the present invention, an optically active phenylcarbinol compound can be efficiently produced.

Claims (3)

[Claims] (1) Formula (1) [Wherein, Ar represents a phenyl group (the phenyl group may be optionally substituted with a C _1-10 alkyl group, a C _1-10 alkoxy group or a halogen atom), and sulfur represented by * The absolute configuration of an atom means R or S. An optically active arylsulfinylbenzaldehyde compound represented by the formula (2): Wherein R is a C _1-10 alkyl group (the alkyl group is
_It may be optionally substituted with a _1-10 alkyl group, C _1-10 alkoxy group or C _6-10 aromatic group. ) Or a C _6-10 aromatic group (the aromatic group may be optionally substituted with a C _1-10 alkyl group, a C _1-10 alkoxy group, a halogen atom or a nitro group), X represents a chlorine atom, a bromine atom or an iodine atom. Wherein the compound is reacted with a Grignard compound represented by the formula: [Wherein, Ar and R are as defined above. The absolute configuration of a sulfur atom and a carbon atom represented by * means R or S. A method for producing an optically active phenylcarbinol compound represented by the formula: 2. The method according to claim 1, wherein Ar is a 2,4,6-trimethylphenyl group. 3. The method according to claim 1, wherein Ar is a 2,4,6-triisopropylphenyl group.