JP3196242B2 - Optically active aromatic-substituted alkanoic acid compounds, intermediates thereof and methods for producing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active aromatic-substituted alkanoic acid compound, an intermediate thereof and a process for producing the same.

[0002]

The Aromatic group substituted alkanoic acid or its derivative, an optically active compound represented by the following formula 9 [formula (a)], respectively, journal Of Medeishinaru Chemistry (J.Med.Chem. ) Volume 13, page 203 (1
As an anti-inflammatory agent to 970 years), of 10 optically active compound represented by [formula (b)] is, Agri cultivators Yura Le and Biological Chemistry (Agric.Biol.Che
m.) 39, p. 267 (1975), which is reported as a pyrethroid insecticide.

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Further, an intermediate of the above-mentioned optically active compound wherein the alkyl ester of the above (a) and the alcohol part of the above (b) is an alkanol is tetrahedron letter (T
etrahedron Lett.) 23, 5427 (1982)
Years) and Bulltin of Chemical Society of Japan (Bull. Chem. Soc. Jpn.)
-Sulfonyloxy compounds are reported to be synthesized by a rearrangement reaction.

[0004] If a functional group is previously introduced into the aromatic-substituted alkanoic acid or a derivative thereof as described above, a new and useful compound such as an optical recording material, a liquid crystal material, Pharmaceuticals such as anti-inflammatory analgesics and pyrethroid-based agricultural chemicals can be synthesized. However, any of the above-mentioned optically active aromatic group-substituted alkanoic acid compounds has an alkyl group or an alkoxy group as a substituent of an aromatic group (benzene ring or naphthalene ring). The introduction of a functional group such as a carboxyl group into an aromatic group has restrictions on synthesis and cannot be used for this purpose.

[0005]

The present invention provides an aromatic-substituted alkanoic acid compound having an aldehyde group and an acetal group which can be further converted into a carboxyl group or a hydroxyl group, an intermediate thereof, and a process for producing the same. is there.

[0006]

Means for Solving the Problems The present optically active aromatic group substituted alkanoic acid compound of the invention is represented by the following formula 11 [general formula (I)].

Embedded image However, in the general formula (I), R ¹ and R ² together represent an alkylene group which may have a substituent or an alkyl group which may have a substituent independently, and R ³ is an alkyl group R ⁴ represents an alkyl group which may have a functional group.

In the general formula (I), R ¹ and R ² together represent -CH ₂ -,-(CH ₂ )
_3- , -CH ₂ -C (CH ₃ ) ₂ -CH _2- , o-phenylene group, [Formula (c)]

Embedded image When R ¹ and R ² are each independently an alkyl group, any of methyl, ethyl, propyl, butyl, octyl, hexadecyl and the like having 3 or more carbon atoms is optional. It can be structural isomerism. R ³ is a methyl group, an ethyl group, a propyl group, a butyl group, an octyl group, a hexadecyl group and the like, and those having 3 or more carbon atoms can have any structural isomerism. R ⁴ represents a methyl group, an ethyl group, a propyl group, a butyl group,
Octyl group, shall apply in a hexadecyl group and the like can be those having 3 or more carbon atoms is any structural isomers, also, -C _{2
H 5 OH, - (CH 2} ) 3 -OH, -CH 2 -C (CH 3) 2 -C
It may be H ₂ —OH or an alkyl group having a hydroxyl group such as the formulas (d) and (e) in the following formula ( 13 ).

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[0008] Specific examples of the compound represented by formula (I), in the following formula 14, formula (I-1) ~ formula (I-6)
And the like.

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The compound represented by the general formula (I) is
Chemical formula 15 [General formula (II)]

Embedded image [However, in the general formula (II), R ¹ and R ² together represent an alkylene group which may have a substituent or an alkyl group which may each independently have a substituent, and R ³ represents R ⁵ represents an alkyl group or an aryl group which may have a functional group.) The optically active ketone acetal compound represented by the formula: is subjected to a thermal rearrangement reaction in the presence of water and under basic conditions. It can be manufactured by a method characterized by the above.

In the general formula (II), specific examples of the groups represented by R ¹ , R ² and R ³ are the same as those described above for the general formula (I), and R ⁵ is a methyl group , A trifluoromethyl group, a phenyl group, a parabromophenyl group, and a paramethylphenyl group.

[0011] Specific examples of the compound represented by the general formula (II) include compounds such as in the following formula 16 (II-1) ~ ( II-6).

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In the above reaction, water is preferably present in an amount of at least equimolar to the compound represented by the general formula (II). If the amount of water is too small, the yield decreases.

In the above reaction, a base such as sodium acetate, potassium acetate, sodium propionate, potassium propionate or the like is added in an amount of at least 1 equivalent to the compound represented by the general formula (II) to raise the pH of the reaction system to 7 It is adjusted so that it becomes above. In this case, a proton acceptor such as 1,8-diazabicyclo [5,4,0] -7-undecene or calcium carbonate is added in an amount of 1 equivalent or more to the compound represented by the general formula (II) to form during the reaction. It is preferred to remove the acid that forms.

The above reaction is preferably carried out in the presence of an organic solvent, such as a polar solvent such as dioxane, dimethylformamide and dimethylsulfoxide, an aromatic solvent such as toluene, benzene and xylene, methanol and ethanol. If the reaction is carried out at a high temperature, dioxane, ethanol or the like is preferable.

In the above reaction, the reaction temperature is preferably 70 ° C. or higher, and when the number of carbon atoms in the general formula (II) is large, the reaction is preferably performed at a higher temperature.

The ketone acetal compound represented by the general formula (II), of 17 [general formula (III)]

Embedded image [However, in the general formula (III), R ^1, R ² and R ³ are the same as in the general formula (I), and two R ¹ and R ² may be different from each other, but are the same. Is preferable], and the optically active hydroxyketone acetal compound represented by the formula (1) is treated with a sulfonic acid esterification reagent.

[0017] The hydroxyketone acetal compound represented by the formula (III), in the following formula 18, (III
-1) to (III-5).

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The sulfonic acid esterifying agent includes:
_{CH 3 SO 2 Cl, Ph-} SO 2 Cl ( provided that, Ph represents a phenyl _{group), CH 3 -Ph-SO 2} Cl ( provided that, Ph is p- _{phenylene), Br-Ph-SO 2} Cl ( provided that, Ph Is a p-phenylene group), a sulfonyl halide such as CF ₃ SO ₂ Cl, (CH ₃ SO ₂ ) ₂ O, (Ph-S
O ₂ ) ₂ O (where Ph is a phenyl group), (CH ₃ -P
h-SO ₂ ) ₂ O (where Ph is a p-phenylene group),
(CF ₃ SO ₂ ) ₂ O and other sulfonic anhydrides. These are preferably used in an amount of 1 equivalent or more based on the hydroxyketone acetal compound represented by the general formula (III). The sulfonic acid esterifying agent is preferably used together with a base such as pyridine and triethylamine, and the base is preferably used in an amount of 1 equivalent or more based on the sulfonic acid esterifying agent. Sulfene may be used as the sulfonic esterification reagent, in which case it is not necessary to use a base.

As the solvent for the above reaction, a basic solvent such as pyridine and an alkyl halide such as chloroform and methylene chloride are preferable. The reaction temperature is preferably in the range of 0 to 50 ° C.

The compounds represented by the general formula (III), of 19 [general formula (IV)]

Embedded image [However, in the general formula (IV), R ¹ and R ² together represent an alkylene group which may have a substituent or an alkyl group which may each independently have a substituent, and R ³ represents R ⁵ represents hydrogen, a trimethylsilyl group, a triethylsilyl group, a trialkylsilyl group, a 1-alkoxyalkyl group or an alkylthioalkyl group] in the presence of a reagent for acetalization of an optically active ketone compound represented by the formula: It can be produced by a method characterized by reacting with a dihydric alcohol.

[0021] As the compound represented by the general formula (IV), in the following Formula 20 include compounds such as (IV-1) ~ (IV -6).

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Examples of the acetalization reagent include trimethylsilane chloride, trimethylsilane iodide, trimethylsilyl p-toluenesulfonate, trimethylsilyltrifluoromethanesulfonate and the like.
Is preferably used in an amount of 2 equivalents or more based on the hydroxyketone compound represented by

Examples of the dihydric alcohol include 1,2-ethanediol, 1,3-propanediol, neopentyl glycol, 1,2-dihydroxybenzene, 1,2
-Di (hydroxymethyl) benzene and the like. These are preferably used in an amount of 1 equivalent or more based on the hydroxyketone compound represented by the general formula (IV).

The above reaction is carried out in a solvent such as an aromatic solvent such as benzene or toluene, an ether solvent such as diethyl ether or tetrahydrofuran, or a halogen solvent such as chloroform or methylene chloride. preferable.

The above reaction is preferably carried out at 0 ° C. to room temperature. If the reaction temperature is too high, side reactions tend to occur.

After the reaction, it is preferable to mix the reaction solution with an alcohol such as methanol or ethanol, and carry out stirring at 0 ° C. to room temperature in the presence of sodium carbonate and potassium carbonate. It is preferable that sodium carbonate and potassium carbonate are previously dissolved in alcohol.

The ketone compound represented by the general formula (III) can be obtained by converting the hydroxyketone compound represented by the general formula (IV) to a trialkyl orthoformate such as trimethyl orthoformate or triethyl orthoformate by using the above-described hydroxyketone. Use at least one equivalent to the compound,
It can also be synthesized by reacting an acid such as methanesulfonic acid or p-toluenesulfonic acid in a catalytic amount. The reaction solvent and the reaction temperature are the same as in the case of using the acetalization reagent described above, but the reaction solvent is preferably alcohol.

In the hydroxy ketone compound represented by the general formula (IV), those in which R ⁶ is other than hydrogen can be subjected to the above reaction after converting the compound in which R ⁶ is hydrogen. In the hydroxy ketone compound represented by the general formula (IV), when R ⁶ is other than hydrogen and R ⁶ is hydrogen, an acid such as p-toluenesulfonic acid, methanesulfonic acid, and pyridinium paratoluenesulfonate is used. There is a method of heating to room temperature to 40 ° C. in alcohol in the presence of a catalyst. When R ⁶ is a 1-ethoxyethyl group, the reaction can be carried out in the presence of an acid catalyst at a temperature of −20 ° C. or lower while distilling off the formed ethoxyvinyl ether.

The compounds represented by the general formula (IV), of 2
1 [General formula (V)]

Embedded image [However, in the general formula (V), R ¹ and R ² together represent an alkylene group which may have a substituent or an alkyl group which may have a substituent independently, and Z is M
g, a functional group containing a metal such as Zn or Li and capable of reacting with a carbonyl group (for example, MgBr, MgCl, Mg
I, Li, Zn _0.5 ), and that Z is Zn _0.5 means that two residues other than Z in the general formula (V) are bonded to Zn. Organometallic compound of 22 represented by] [Formula (VI)]

Embedded image [However, shown in the general formula (VI), Y is an optionally substituted amino group, R ³ represents an alkyl group, a R ⁵ is hydrogen or optionally substituted alkyl group ] It can be produced by a method characterized by reacting the represented amide compound.

[0030] The organometallic compound may, for example, a Grignard reagent, which is the following formula 23 [general formula (VII)]
Is synthesized by reacting the compound represented by the formula with Mg.

Embedded image [However, in the general formula (VII), R ¹ and R ² together represent an alkylene group which may have a substituent or an alkyl group which may independently have a substituent].

The Grignard reagent has the general formula (VII)
A compound represented by the formula and metal Mg in tetrahydrofuran,
In ether solvents such as dioxane and diethyl ether,
Preferably, it can be obtained by carrying out the reaction while keeping the temperature at 30 ° C. or lower. Compounds represented by the general formula (V) in which Z is Li can be similarly synthesized by using metal Li instead of metal Mg. A compound represented by the general formula (V) wherein Z is Zn _0.5 can be synthesized by reacting the above Grignard reagent with ZnCl ₂ or ZnBr ₂ . The compound represented by the general formula (V) is used in an ether solvent as a synthesis solvent.

The compound represented by the general formula (IV) can be obtained by mixing the compound represented by the general formula (V) and the compound represented by the general formula (VI), preferably at room temperature or lower. .

Examples of the compound represented by the general formula (VII), there are compounds such as in the following formula 24 (VII-1) ~ ( VII-5).

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The amide compound represented by the general formula (VI) includes (S) -2-O- (1-ethoxyethyl)
Lactic acid dimethylamide, (R) -2-O- (1-ethoxyethyl) lactic acid dimethylamide, (S) -2-O-methoxymethyllactic acid dimethylamide, (S) -2-O-methoxymethylbutyric dimethylamide , (R) -2-O-
And methoxymethyl lactic acid morpholinamide.

In each of the above synthesis methods, after completion of the reaction,
Purification of the desired product according to a conventional method, such as extraction with a solvent such as chloroform or ethyl acetate, recrystallization using hexane, etc., silica gel column chromatography, washing, drying, neutralization, and desalting using an ion exchange resin. be able to.

[0036]

Examples of the present invention will be described below.

Example 1 1.85 g (3 equivalents) of metallic magnesium was placed in a 100 ml three-necked flask equipped with a condenser, 70 ml of anhydrous tetrahydrofuran was added, and 4- (5,5-dimethyl-1,
3-Dioxan-2-yl) phenylbromide 6.88
g (1.3 equivalents) of a solution of 30 ml of tetrahydrofuran was added dropwise with stirring while maintaining the liquid temperature at 40 ° C. or lower. 3
After hours, the resulting reddish brown Grignard reagent solution
A solution of 4.00 g of -O- (1-ethoxyethyl) -L-lactic acid dimethylamide in 30 ml of tetrahydrofuran was added dropwise. After 15 hours, the reaction solution to which 4 ml of pyridine was added was poured into an aqueous sodium carbonate solution, and
Extracted in ml. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained was purified using silica gel column chromatography (hexane / ethyl acetate = 3/1) to give (S) -1- (1-ethoxyethoxy). ) Ethyl-4
-(5,5-dimethyl-1,3-dioxan-2-yl)
6.88 g (97%) of phenyl ketone were obtained as an oily residue.

The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Infrared absorption spectrum: ν (cm ⁻¹ ) 1700, ¹
Absorption at 690, 1620. (2) Nuclear magnetic resonance spectrum: δ (ppm) 0.82 (3H, s), 1.01.5.14 (3H, t × 2, J = 7.0 Hz), 1.28.2.34 ( 3H, d × 2, J = 5.3 Hz), 1.29 (3H, s), 1.39 · 1.45 (3H, d × 2, J = 7.0 Hz), 3.4 to 3.7 (2H, m), 3.65 / 3.79 (4H, d × 2, J = 11.1H
z), 4.70 · 4.83 (1H, q × 2, J = 5.3 Hz), 4.91 · 5.07 (1H, q × 2, J = 7.0 Hz), 5.44 (1H) , S), 7.61 (2H, d × 2, J = 8.4 Hz), 8.00 · 8.08 (2H, d × 2, J = 8.4 Hz) In the above nuclear magnetic resonance spectrum, In parentheses,
The integrated intensity ratio, peak type and coupling constant are shown, s means singlet, d means doublet, t means triplet, q means quartet, and the same applies to the following.

Example 2 158 mg (3 equivalents) of metallic magnesium was placed in a 100 ml three-necked flask equipped with a condenser, 10 ml of anhydrous tetrahydrofuran was added, and 4- (1,3-dioxane-
A solution of 520 mg (1.2 equivalents) of 2-yl) phenyl bromide in 10 ml of tetrahydrofuran was added dropwise with stirring while keeping the liquid temperature at 40 ° C. or lower. Four hours later, a solution of 340 mg of 2-O- (1-ethoxyethyl) -L-lactic acid dimethylamide in 5 ml of tetrahydrofuran was added dropwise to the obtained light brown Grignard reagent solution. After 18 hours, the reaction solution to which 4 ml of pyridine was added was neutralized by pouring into an aqueous solution of sodium carbonate. Neutralized solution is chloroform 100m
Extracted with l. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. This residue is subjected to silica gel column chromatography (hexane / ethyl acetate = 3/1).
The residue was purified using to obtain (S) -1- (1-ethoxyethoxy) ethyl-4- (1,3-dioxan-2-yl) phenyl ketone (387 mg, 69%) as an oily residue.

The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Infrared absorption spectrum: ν 1698 cm ⁻¹ , 168
4cm ^-1, there is absorption in 1616cm ^-1. (2) Nuclear magnetic resonance spectrum: δ (ppm) 1.05 (3H, t, J = 7.0 Hz), 1.28 (3H, m), 1.38 (3H, m), 1.2-1 2.6 (2H, m), 2.1 to 2.4 (2H, m), 3.3 to 3.7 (2H, m), 3.9 to 4.1. 4.1 to 4.3 ( 4H, m), 4.6 to 5.1 (2H, m), 5.55 (1H, s), 7.58 (2H, d, J = 8.3 Hz), 8.03.8.06 ( (2H, d × 2, J = 8.3 Hz) In the above nuclear magnetic resonance spectrum, m means a multiplet, and the same applies to the following.

Example 3 (S) -1- (1-ethoxyethoxy) ethyl-4-
1.00 g of (5,5-dimethyl-1,3-dioxan-2-yl) phenyl ketone was dissolved in 20 ml of methanol, and a catalytic amount of pyridinium paratoluenesulfonate was added. This mixture was subjected to a vacuum treatment at room temperature for 1 hour using a vacuum concentrator. 20 ml of saturated saline was added to the reaction solution, and extracted with 50 ml of chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give (S) -1-hydroxyethyl-4- (5.5). 0.51 g (70%) of -dimethyl-1,3-dioxan-2-yl) phenyl ketone were obtained as colorless crystals.

The melting point, specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Melting point: 78.6-80.2 ° C. (2) Specific rotation: as shown in Formula 1 (c 0.60, CHC
l ₃ ).

(Equation 1) (3) Infrared absorption spectrum: ν 3440 cm ⁻¹ , 167
6 cm ^-1 (4) Nuclear magnetic resonance spectrum: δ (ppm) 0.82 (3H, s), 1.29 (3H, s), 1.42 (3H, d × 2, J = 6.9 Hz), 3.4 to 3.7 (2H, m), 3.67.3.80 (4H, d × 2, J = 11.0H)
z), 3.78 (1H, d, J = 6.9 Hz), 5.16 (1H, q, J = 6.9 Hz), 5.45 (1H, s), 7.65 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 8.2 Hz)

Example 4 104.3 mg of (S) -1-hydroxyethyl-4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl ketone (8) and 1,3-propanediol 30
0 mg (10 equivalents) was dissolved in 4 ml of methylene chloride under an argon atmosphere. 0.22 ml (5 equivalents) of trimethylsilane chloride was added dropwise to the mixed solution under ice-cooling, and the mixture was allowed to stir to room temperature. Four hours later, 1.50 ml (35 equivalents) of trimethylsilane chloride was added dropwise. Eighteen hours later, 4 ml of pyridine was added under ice cooling, and a saturated aqueous solution of sodium hydrogen carbonate was further added, followed by vigorous stirring. The reaction solution was extracted with diethyl ether and dried over magnesium sulfate. A small amount of pyridine was added and the mixture was concentrated under reduced pressure.
A mixed solution of 0 ml and 10 ml of water was prepared, an excess amount of sodium carbonate was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 1/1) to give (S) -1-hydroxyethyl -4- (1,3-Dioxan-2-yl) phenylketone trimethylene acetal (9) 44.5 mg
(36.4%) was obtained as an oily residue.

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 2 (c 0.89, CHC
l ₃ ).

(Equation 2) (2) Infrared absorption spectrum: ν3512 cm ^-1 (3) Nuclear magnetic resonance spectrum: δ (ppm) 0.97 (3H, d, J = 6.5 Hz), 1.4 to 1.6 (2H, m) 2.0-2.4 (2H, m), 3.78 (1H, broads), 3.39 (1H, q, J = 6.5 Hz), 3.5-4.1 (6H, m) ), 4.28 (2H, dd, J = 5.0 Hz, J = 10.7 H)
z), 5.54 (1H, s), 7.42 (2H, d, J = 8.2)
Hz), 7.55 (2H, d, J = 8.2Hz)

Example 5 (S) -1- (1-ethoxyethoxy) ethyl-4-
(1,3-dioxan-2-yl) phenyl ketone 38
7 mg and 943 mg (10 equivalents) of trimethylene glycol were dissolved in 12 ml of methylene chloride. 0.78 ml (5 equivalents) of trimethylsilane chloride was added to the mixture under ice cooling, and the mixture was heated to room temperature and stirred for 19 hours. 2 ml of pyridine was added to the reaction solution under ice cooling, 1 g of sodium carbonate and 20 ml of methanol were added, and the mixture was stirred vigorously for 3 hours. The reaction solution was extracted with chloroform, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and azeotroped with toluene, and the oily residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) (S ) 1-Hydroxyethyl-4- (1,3-dioxan-2-yl) phenylketone trimethylene acetal (284 mg, 74%) was obtained as crystals.

The melting point, specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Melting point: 104-107 ° C. (2) Specific rotation: as shown in Formula 3 (c1.00, MeO
H).

(Equation 3) (3) Infrared absorption spectrum: absorption is at ν 3580 cm ^-1 . (4) Nuclear magnetic resonance spectrum: δ 0.97 (3H, d, J = 6.5 Hz), 1.2 to 1.6 (2H, m), 2.0 to 2.4 (2H, m), 2.62 (1H, broads), 3.68 (1H, q, J = 6.5 Hz), 3.7-4.1 (6H, m), 4.29 (2H, dd, J = 5. 0Hz, J = 10.7H
z), 5.55 (1H, s), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz)

Example 6 44.5 mg of (S) -1-hydroxyethyl-4- (1,3-dioxan-2-yl) phenylketone trimethylene acetal was dissolved in 4 ml of pyridine, and 50 mg (3 times) of methanesulfonyl chloride was dissolved. Was added and the mixture was heated and stirred at 50 ° C. After 4 hours, the reaction solution was poured into 30 ml of water.
The mixture was extracted with diethyl ether, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform / ethyl acetate = 4/1) to give (S) -1-methanesulfonyloxyethyl. -4
53.5 g (96.1%) of-(1,3-dioxan-2-yl) phenyl ketone trimethylene acetal were obtained as an oily residue.

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 4 (c1.07, CH
Cl ₃ )

(Equation 4) (2) Infrared absorption spectrum: absorption is at ν 1362 cm ^-1 . FIG. 1 shows the infrared absorption spectrum. (3) Nuclear magnetic resonance spectrum: δ (ppm) 1.23 (1H, d, J = 13.5 Hz), 1.30 (3H, d, J = 6.5 Hz), 1.47 (1H, d, J = 13.5 Hz), 2.0-2.4 (2H, m), 2.79 (3H, s, OSO2Me,), 3.76 (2H, t, J = 11.6 Hz), 3.8 ４4.0 (2H, m), 4.01 (2H, t, J = 11.6 Hz), 4.26 (2H, dd, J = 4.9 Hz, J = 11.8H)
z), 4.60 (1H, q, J = 6.5 Hz), 5.54 (1H, s,), 7.27 (2H, d, J = 7.
7.57 (2H, d, J = 7.2Hz)

Example 7 As in Example 2, 520 mg of 4- (1,3-dioxan-2-yl) phenyl bromide and 1 mg of metallic magnesium
58 mg of a Grignard reagent solution prepared from
From 340 mg of O- (1-ethoxyethyl) -D-lactic acid dimethylamide, 502 mg (89) of (R) -1- (1-ethoxyethoxy) ethyl-4- (1,3-dioxan-2-yl) phenyl ketone %) Was obtained as an oily residue.

The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Infrared absorption spectrum: ν 1698 cm ⁻¹ , 168
4cm ^-1, there is absorption in 1616cm ^-1. (2) Nuclear magnetic resonance spectrum: δ (ppm) 1.05 (3H, t, J = 7.0 Hz); .28 (3H, m), 1.38 (3H, m), 1.2 to 1.6 (2H, m), 2.1 to 2.4 (2H, m), 3.3 to 3.7 (2H, m), 3.9-4.1. 4.1-4.3 (4H, m), 4.6-5.1 (2H, m), 5.55 (1H, s, 7. 58 (2H, d, J = 8.3H
z), 8.03.8.06 (2H, d × 2, J = 8.3 Hz)

Example 8 As in Example 5, (R) -1- (1-ethoxyethoxy) ethyl-4- (1,3-dioxan-2-yl) phenyl ketone (252 mg) and trimethylene glycol 61
5 mg was dissolved in 16 ml of methylene chloride and treated with 0.44 ml of trimethylsilane chloride to obtain 224 mg (89) of (R) -1-hydroxyethyl-4- (1,3-dioxan-2-yl) phenylketone trimethyleneacetal.
%).

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 5 (c 1.00, Me
OH).

(Equation 5) (2) Infrared absorption spectrum: absorption is at ν 3580 cm ^-1 . (3) Nuclear magnetic resonance spectrum: δ (ppm) 0.97 (3H, d, J = 6.5 Hz), 1.2 to 1.6 (2H, m), 2.0 to 2.4 (2H, m), 2.62 (1H, broads), 3.68 (1H, q, J = 6.5 Hz), 3.7-4.1 (6H, m), 4.29 (2H, dd, J) = 5.0Hz, J = 10.7H
z), 5.55 (1H, s), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz)

Example 9 As in Example 5, (R) -1-hydroxyethyl-4
Treatment of 124 mg of-(1,3-dioxan-2-yl) phenyl ketone trimethylene acetal with 69 mg of methanesulfonyl chloride gives (R) -1-methanesulfonyloxyethyl-4- (1,3-dioxan-2- Ill)
126 g of phenyl ketone trimethylene acetal (81
%) As an oily residue.

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 6 (c 0.95, CH
Cl _3).

(Equation 6) (2) Infrared absorption spectrum: absorption is at ν 1362 cm ^-1 . (3) Nuclear magnetic resonance spectrum: δ (ppm) 0.97 (3H, d, J = 6.5 Hz), 1.2 to 1.6 (2H, m), 2.0 to 2.4 (2H, m), 2.62 (1H, broads), 3.68 (1H, q, J = 6.5 Hz), 3.7-4.1 (6H, m), 4.29 (2H, dd, J = 5.0Hz, J = 10.7H
z), 5.55 (1H, s), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz)

Example 10 (S) -1-Methanesulfonyloxyethyl-4-
186.1 mg of (1,3-dioxan-2-yl) phenyl ketone trimethylene acetal was prepared by adding dioxane / water =
Transfer to a 100 ml shield tube with 24 ml of the 3/1 mixed solution, and 59.0 mg of sodium acetate (1.5 equivalents).
And 1,8-diazabicyclo [5,4,0] -7-undecene (109.4 mg, 1.5 equivalents), sealed and sealed.
The mixture was heated and stirred at 30 ° C. After 28 hours, the reaction solution was poured into a phosphate buffer under ice cooling, and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in 5 ml of methanol, and an excess amount of sodium borohydride was added under ice cooling. One hour later, the reaction solution was added with 20 m of saturated saline.
l, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained is subjected to silica gel column chromatography (chloroform / ethyl acetate / methanol =
15/15/1), and purified by 3-hydroxypropyl (S) -2- [4- (1,3-dioxan-2-yl)
Phenyl] propionate 79.8 mg (59%, 87
% Ee) was obtained as an oily residue.

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 7 (c 0.90, CH
Cl _3).

(Equation 7) (2) Infrared absorption spectrum: ν 3404 cm ⁻¹ , 162
There is absorption at 0 cm ^-1 . FIG. 2 shows the infrared absorption spectrum. (3) Nuclear magnetic resonance spectrum: δ (ppm) 1.47 (3H, d, J = 7.1 Hz), 1.4 to 1.5 (1H, m), 1.6 to 1.9 (3H, m), 2.1-2.3 (1H, m), 3.51 (2H, t, J = 6.1 Hz), 3.71 (1H, q, J = 7.1 Hz), 3.9- 4.1 (2H, m), 4.1 to 4.4 (4H, m), 5.48 (1H, s), 7.30 (2H, d, J = 8.2 Hz), 7.44 ( 2H, d, J = 8.2Hz)

Example 11 (S) -1-Methanesulfonyloxyethyl-4-
12.5 mg of (1,3-dioxan-2-yl) phenylketone trimethylene acetal was added in dioxane / water = 3.
The mixture was transferred to a 10 ml shielded tube with 2 ml of the mixed solution of 1.0 / 1, 4.0 mg (1.5 equivalents) of sodium acetate and 6.4 mg (4 equivalents) of calcium carbonate were added, and the mixture was sealed.
The mixture was heated and stirred at 35 ° C. After 14 hours, the reaction solution was poured into a phosphate buffer and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (chloroform / ethyl acetate = 4 /
3-hydroxypropyl (S) -2-purified in 1)
4.0 mg (44%) of (1,3-dioxan-2-yl) phenylpropionate were obtained.

Example 12 (R) -1-methanesulfonyloxyethyl-4-
78.7 mg of (1,3-dioxan-2-yl) phenyl ketone trimethylene acetal was added in dioxane / water = 2.
The mixture was transferred to a 100 ml shield tube with 6 ml of a 1: 1 mixed solution, and 24.9 mg (1.5 equivalents) of sodium acetate and 46.3 mg (1.5 times) of 1,8-diazabicyclo [5,4,0] -7-undecene. Equivalent) and sealed at 130 ° C
And heated and stirred. After 28 hours, the reaction solution was poured into a phosphate buffer under ice cooling, and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure. The residue obtained was dissolved in 5 ml of methanol, and an excess amount of sodium borohydride was added under ice cooling. One hour later, 20 ml of saturated saline was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (chloroform / ethyl acetate / methanol = 15/15 / Purified in 1), 3-hydroxypropyl (R) -2- [4- (1,
4-Dioxan-2-yl) phenyl] propionate (41.9 mg, 73%, 87% ee) was obtained as an oily residue.

The specific rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained above are as follows. (1) Specific rotation: as shown in Equation 8 (c 0.20, CH
Cl _3).

(Equation 8) (2) Infrared absorption spectrum: ν 3404 cm ⁻¹ , 162
There is absorption at 0 cm ^-1 . (3) Nuclear magnetic resonance spectrum: δ (ppm) 1.47 (3H, d, J = 7.1 Hz), 1.4 to 1.5 (1H, m), 1.6 to 1.9 (3H, m), 2.1-2.3 (1H, m), 3.51 (2H, t, J = 6.1 Hz), 3.71 (1H, q, J = 7.1 Hz), 3.9- 4.1 (2H, m), 4.1 to 4.4 (4H, m), 5.48 (1H, s), 7.30 (2H, d, J = 8.2 Hz), 7.44 ( 2H, d, J = 8.2Hz)

[0060]

The aromatic-substituted alkanoic acid compound in claim 1 has an acetal group, and by utilizing this group, other functional groups such as an aldehyde group can be easily introduced.
The compounds in claims 2 to 4 are intermediates for the aromatic-substituted alkanoic acid compounds in claim 1. The compounds according to claims 1 to 4 can be easily produced by the methods according to claims 5 to 8, respectively.

[Brief description of the drawings]

FIG. 1 is an infrared absorption spectrum of (S) -1-methanesulfonyloxyethyl-4- (1,3-dioxan-2-yl) phenylketone trimethylene acetal obtained in Example 6.

FIG. 2 shows 3-hydroxypropyl (S) -2- [4- (1,3-dioxan-2-yl) obtained in Example 10.
1 is an infrared absorption spectrum of [phenyl] propionate.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07C 67/24 C07C 67/24 69/734 69/734 Z 303/28 303/28 309/65 309/65 309/72 309 / 72 319/20 319/20 323/12 323/12 C07F 7/18 C07F 7/18 A (58) Field surveyed (Int.Cl. ⁷ , DB name) C07C 43/315 C07C 41/54 C07C 45/45 C07C 49/84 C07C 67/24 C07C 69/734 C07C 303/28 C07C 309/65 C07C 309/72 C07C 319/20 C07C 323/12 C07F 7/18

Claims (8)

(57) [Claims] [Chemical formula 1] [Chemical formula 1] [However, in the general formula (I), R ¹ and R ² together carbon
An alkylene group of the formulas 1 to 5 , an o-phenylene group, a formula (c)
Or each independently represent an alkyl group having 1 to 16 carbon atoms, R ³ represents an alkyl group having 1 to 16 carbon atoms, R ⁴ is charcoal
Alkyl group prime _{1~16, -C 2 H 5 OH,} - (CH 2) 3
—OH, —CH ₂ —C (CH ₃ ) ₂ —CH ₂ —OH, formula (d)
And an alkyl group having a hydroxyl group of the formula (e) ]. Embedded image Embedded image 2. A formula 4 [formula (II)] embedded image [However, in the general formula (II), R ¹ and R ² together represent carbon
An alkylene group of the formulas 1 to 5 , an o-phenylene group, a formula (c)
Or an alkyl group having 1 to 16 carbon atoms, R ³ is the number of carbon atoms
Represents an alkyl group of 1 to 16 ; R ⁵ is a methyl group;
Fluoromethyl group, phenyl group, parabromophenyl group,
Optically active ketone acetal compound represented by showing a para-methylphenyl group]. 3. A reduction 5 [formula (III)] embedded image [However, in the general formula (III), R ¹ and R ² together charcoal
An alkylene group having 1 to 5 primes , an o-phenylene group, a formula
(C) or an alkyl group having 1 to 16 carbon atoms , wherein R ³ is
Which represents an alkyl group having 1 to 16 carbon atoms ]. 4. A reduction 6 [Formula (IV)] embedded image [However, in the general formula (IV), R ¹ and R ² together represent carbon
An alkylene group of the formulas 1 to 5 , an o-phenylene group, a formula (c)
Or an alkyl group having 1 to 16 carbon atoms, R ³ is the number of carbon atoms
It indicates 1 to 16 alkyl group, R ⁶ is hydrogen, trimethyl
Silyl group, triethyl Chirushiriru group, ethoxyethyl group, main
An optically active ketone compound represented by the following formula: 5. The method according to claim 1, wherein the optically active ketone acetal compound represented by the general formula (II) is subjected to a thermal rearrangement reaction in the presence of water and under basic conditions. A method for producing an optically active aromatic-substituted alkanoic acid compound represented by the general formula (I) described above. 6. A optically active hydroxy ketone acetal compound represented by the general formula of claim 3 (III) C
H ₃ SO ₂ Cl, Ph-SO ₂ Cl (where Ph is
Phenyl), CH ₃ —Ph—SO ₂ Cl (where Ph is p
-Phenylene group), Br-Ph-SO ₂ Cl (provided that
Ph is a p-phenylene group), CF ₃ SO ₂ Cl
_{Ruharaido, (CH 3 SO 2) 2} O, (Ph-SO 2) 2 O
(Where Ph is a phenyl group), (CH ₃ -Ph-S
O ₂ ) ₂ O (where Ph is a p-phenylene group), (CF
₃ SO _{2) 2} O sulfonic acid anhydride, an optically active represented by the general formula of claim 2, wherein the treatment with the scan <br/> sulfonic acid esterification reagent is sulfenic (II) A method for producing a ketone acetal compound. 7. trimethylsilane chloride optically active ketone compound represented by the general formula of claim 4 (IV), Yo
Trimethylsilane trioxide, trimethylsilyl p-toluene
Sulfonate, trimethylsilyl trifluoromethanes
4. The process for producing an optically active hydroxyketone acetal compound represented by the general formula (III) according to claim 3, wherein the reaction is carried out with a dihydric alcohol in the presence of an acetalization reagent which is a sulfonate. 8. Omitted [Formula (V)] embedded image [However, in the general formula (V), R ¹ and R ² together represent carbon
An alkylene group of the formulas 1 to 5 , an o-phenylene group, a formula (c)
Or an alkyl group having 1 to 16 carbon atoms, X is M gB
r, MgCl, MgI, Li, Zn 0.5 (X is in Zn _0.5
It means that the residue excluding X in the general formula (V) corresponds to Zn
It means that two are linked. ) Organometallic compounds represented by the indicating] and of 8 [formula (VI)] embedded image [However, in the general formula (VI), Y is amino group, R ³ is carbon
Indicates the number 1 to 16 alkyl group, R ⁵ is hydrogen or trimethyl
Tylsilyl group, triethylsilyl group, ethoxyethyl
A methoxymethyl group ). The method for producing an optically active hydroxyketone compound represented by the general formula (IV) according to claim 4, wherein