JPS63243058A - Production of optically active alpha-methylalkylcarboxylic acid - Google Patents

Abstract

PURPOSE:To easily produce the titled compound having high optical purity in high yield at a low cost, by using an optically active 1,2-epoxyalkane as a raw material which is easily available at a low cost, reacting the compound with trimethylaluminum and oxidizing the reaction product with potassium permanganate. CONSTITUTION:An optically active 1,2-epoxyalkane [e.g. (R)-1,2-epoxyoctane] is made to react with trimethylaluminum to obtain 2-methyl-1-alkanol, which is oxidized with potassium permanganate to produce the objective optically active alpha-methylalkylcarboxylic acid [e.g. (+)-alpha-methyloctanoic acid]. The optically active 1,2-epoxyalkane used as a starting raw material can be extremely easily produced by reacting an epoxy-producing microbial strain of Nocardia genus in a medium containing an alpha-olefin under aerobic condition. The obtained compound is useful as a synthetic intermediate for ferroelectric liquid crystal substance, physiologically active substance, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides optically active materials useful as synthetic intermediates for physiologically active substances such as ferroelectric liquid crystal substances that can take a chiral smectic phase and insect sex pheromones. The present invention relates to a method for producing an α-methylalkylcarboxylic acid having the following properties.

[Prior Art] Conventionally, as a method for synthesizing an optically active α-methylalkylcarboxylic acid, an optically active proline methyl ester is acylated to form an amide ester, and this is converted into a methyl ester in the presence of methylmagnesium iodide. A method [Li
n Guoqiang, et al., Acta Chemica 5candinavi
ca) 1338 P795-801), and a method of alkylating and then hydrolyzing 3-me-1-xy-2-phenyloxazoline having optical activity (Styrbj
oern Bystroem, et al., Tetrahedron (T
etrahedron) 37 p2249-2254
A method using tertiary asymmetric synthesis has been proposed.

[Problems to be Solved by the Invention] In the conventional method using the asymmetric synthesis described above, the optical purity of the obtained product is low at about 72% ee, and the reaction steps are long and the yield is low. There were drawbacks such as expensive reagents.

As a result of intensive studies in view of the current situation, the present inventors have discovered that α-methylalkylcarboxylic acid can be synthesized without racemization by reacting optically active 1,2-epoxy 1- in a certain method. I found it.

The present invention has been made based on this knowledge, and the object of the present invention is to provide an α- An object of the present invention is to provide a method for synthesizing methylalkylcarboxylic acid.

[Means for Solving the Problems] The present invention uses an optically active 1,2-epoxyalkane as a starting material, reacts it with trimethylaluminum to form 2-methyl-1-alkanol, and then converts this alcohol into 2-methyl-1-alkanol. This is a method for producing optically active α-methylalkylcarboxylic acid, which comprises oxidizing with potassium permanganate.

1 having the above optical activity used as a starting material of the present invention
, the 2-epoxyalkane has an optical purity of at least 70
%ee or more is preferable.

In addition, the alkane in this case is appropriately selected from various carbon numbers depending on the use, but the carbon number is 3 to 18.
Particularly preferred are those whose raw materials can be obtained at low cost.

Such 1,2-epoxy alkanes can be obtained by reacting a strain of Nocardia that has epoxy-producing ability in a medium containing α-olefin under aerobic conditions (Japanese Patent Publication No. 56 (Refer to Publication No. 40). 1,2- obtained by the method using this microorganism
It was subsequently confirmed that epoxy alkanes have optical activity, but since they can be produced extremely easily and inexpensively from α-olefins, their use as starting materials in the present invention is particularly advantageous. .

In the present invention, first, the 1,2-epoxyalkane is reacted with trimethylaluminum to open the ring and convert it into 2-methyl-1-alkanol. The above-mentioned 1,2-epoxyalkane is added dropwise to the organic solvent solution in a temperature range of -80°C to 150°C, but up to reflux temperature in the case of a low boiling point organic solvent, and reacted for 1 to 120 hours. After the reaction is completed, the reaction solution is poured into a dilute hydrochloric acid solution and hydrolyzed. In this reaction, it is preferable to use 0.5 to 3 moles of trimethylaluminum, particularly 1 to 2 moles of trimethylaluminum, per mole of 1,2-epoxyalkane.

The product 2-methyl-1-alkanol is obtained by extraction,
It can be isolated and purified by known means such as phase separation, distillation, and column chromatography.

Next, the 2-methyl-1-alkanol obtained by this operation is oxidized with potassium permanganate, but this oxidation reaction is preferably carried out under acidic conditions, and sulfuric acid is particularly preferably used as the acid. The reaction operation is to add 2-methyl-1-octatool to a 5-40% sulfuric acid aqueous solution, and add 1-3
Double the molar amount of potassium permanganate is slowly added and reacted while maintaining the temperature at 20-30°C.

-4= When the reaction mixture obtained as above is added to an aqueous solution of sodium bisulfite, unreacted potassium permanganate and manganese dioxide are dissolved in water, and α-methylalkylcarboxylic acid can be easily converted into an organic Can be extracted with a solvent.

Thereafter, the extraction is repeated, and the α-methylalkylcarboxylic acid can be isolated and purified by known means such as distillation and column chromatography.

The obtained α-methylalkylcarboxylic acid is first converted into an acid halide, reacted with phenol to obtain 4-alkanoylphenol, and then this 4-alkanoylphenol and 4'-alkoxybiphenyl-4-carboxylic acid are converted into an acid halide. By esterifying them, a ferroelectric liquid crystal material having a chiral smectic phase can be obtained.

On the other hand, the aforementioned literature (5tyrbjoern Bystr.
OEM, others, Tetrahedron
) 37 p. 2249-2254), insect sex pheromones can be synthesized.

[Example 1] [α]”+14..4° (neat) was added to a 1 molar hexane solution of 1-remethylaluminum under stirring.
(R)-1,2-epoxyoctane 85°8 g (
0.67 mol) was added dropwise over 30 minutes, and the mixture was refluxed for 2 hours.

After cooling, it was poured into an ice-cooled 12% aqueous hydrochloric acid solution, extracted with hexane, the hexane layer was washed with water, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off.
92°C) to obtain 78.2 g of 2-methyl-1-octatool with a purity of 90.4%. In addition, the purity is silicon 5E-
The measurement was carried out by gas chromatography using a 2 m column carrying 30. In addition, 2 with the above purity of 90.4%
-Purity 9 obtained by rectifying methyl-1-octatool
The specific optical rotation of 5.5% 2-methyl-1-octatool was [α) 25-9.6° (neat).

To 24.7 g (0.17 mol) of (-)2-methyl-1-octatool thus obtained was added 330 ml of water.
1. After adding 46.6 g of concentrated sulfuric acid, 63.4 g of potassium permanganate was slowly added while stirring while keeping the reaction temperature below 30°C.

Thereafter, the reaction mixture was transferred to 340 ml of ice water, 51.5 g of sodium bisulfite was added, and the pH was adjusted to 1 using hydrochloric acid.
After reducing the amount to below, it was extracted with ether.

α-Methyloctanoic acid was extracted from this ether layer with a 10% aqueous sodium hydroxide solution.

Next, 100 ml of ice water and 110 ml of concentrated hydrochloric acid were added to this aqueous layer to adjust the pH to below 1, and α-methyloctanoic acid was extracted with chloroform. The organic layer was washed with water and then dried over magnesium sulfate. After separation, vacuum distillation (0.28 field Hg, 9
(+)α-methyloctanoic acid at 15.
28g (0,097m01, yield 64%) was obtained.

■ 1H-NMR (CDCI, Medium, TMS! Semi+pp
m): 11.8 (b, LH), 2.5 (m, LH)
, 1.7-1.2 (m, 13H), 0.9 (t, 311
) ■ IR (cm-'): 2910.1700
■ [α)”: +14.O.

(Example 2) Using (R) -1,2-epoxydecane as a raw material, 2-methyl-1-1-decanol (83% ee) was produced by reacting it with trimethylaluminum in hexane in the same manner as in Example 1. By further oxidizing with potassium permanganate under sulfuric acid acidity, α was obtained without racemization.
-Methyldecanoic acid was obtained.

■ ”H-NMR (in CDCl2, TMS group 1.pp
m): 11.8 (b, LH), 2.5 (m, 11 (
), ], , 7~1.2 (m, 17H), 0.9 (t,
3H) ■ IR (cm-”): 2910.170
0.1460■ [α)”: +12.3° (Example 3) By using (R)-1,2-epoxyhexane as a raw material and reacting it with trimethylaluminum in hexane in the same manner as in Example 1. 2-Methyl-1-hexanol (67%ee) was obtained and further oxidized with potassium permanganate under sulfuric acid acidity to obtain α without racemization.
-Methylhexanoic acid was obtained.

■ 'H-NMR (CDC13IP, TM! Jl, p
pm): 11.8 (b, IH), 2.5 (m, IH
), 1.7-1.2 (m, 9H), 0.9 (t, 3) 1
) ■ IR (cm″i): 2910.1700.1
460■ [α]": +12.4"' (Reference example) Using the (+)α-methyldecanoic acid obtained in Example 2 above, (+)4-, which is a ferroelectric liquid crystal material, was prepared in the following manner. (
2-Methyl)decanoylphenyl, 4'-octyleoxybiphenyl-4-hydroxycarboxylic acid ester was synthesized.

4.9 g of the α-methylcarboxylic acid synthesized in Example 2 was placed in a flask, and 4.8 g of thionyl chloride was added dropwise from the dropping funnel over 6 minutes while stirring at room temperature. After reacting at room temperature for 40 minutes, the reaction is further stirred at 80° C. for 30 minutes.

Thionyl chloride was distilled off under reduced pressure to obtain 5.4 g of (+)α-methyldecanoic acid chloride.

Next, 2.3 ml of phenol was added to 2.5 ml of anhydrous methylene chloride.
2 g (25 mmol) of the above-obtained (+
) α-methyldecanoic acid chloride, 5639g (26m
mol) was added dropwise, and the mixture was stirred for 2 hours while cooling with brine and ice. This reaction mixture was placed in 300 ml of ice water,
After extraction with methylene chloride, washing with water, drying over magnesium sulfate, separation, and concentration, 4.3 g of phenyl-2-methyldecanoic acid ester was obtained. This phenyl-2-methyldecanoic acid ester was placed in 25 ml of methylene chloride and heated under nitrogen at a temperature of -10°C.
8m mol) and slowly return to room temperature,
The mixture was heated to reflux for an hour. The resulting reaction mixture was poured into 200ml of ice water.
1, extracted with chloroform, washed the organic layer with water, dried over magnesium sulfate, separated in a furnace, concentrated, isolated and purified by column chromatography using silica gel, and obtained a reddish brown liquid (+)4-(2- 1.77 g (9.6 mmol yield 40%) of methyl)decanoylphenol was obtained.

Next, 10 g of commercially available 4'-octyloxy-4-cyanobiphenyl (3
2m mol. ) was added thereto, and the mixture was reacted for 3 hours under heating and reflux. The reaction mixture was made acidic with hydrochloric acid, separated, and recrystallized from an ethanol-acetic acid solvent to obtain a solid. Infrared spectrum analysis of this product using the KBr method revealed that 34, O O cm-", 3200cn-", 2
950-2850 mark-1, 1650cm-”, 1600
Absorption was observed at 4'-octyloxybiphenyl-4-carboxylic acid.

450 μ (1.4 mmol) of 4'-octyloxybiphenyl-4-carboxylic acid in 5 ml of methylene chloride
, (+)4-(2-methyl)decanoylphenol 35
To a mixture containing 0 mg (1,4 mmol) and 4-dimethylaminopyridine IQmg was added 275 mg (1,4 m mol) of N,N'-dicyclohexylcarbodiimide.
mol) was added. After heating and refluxing this for 4 hours, it was filtered, and the filtrate was extracted with methylene chloride, washed with water, dried over magnesium sulfate, separated in a furnace, and concentrated. 4-(2-Methyl)decanoylphenyl as a solid.

4'-octyloxybiphenyl-4-carboxylic acid ester was obtained. The physicochemical properties of this compound are shown below.

■ ”H NMR (CDCI, Medium, TM!41,
ppm): 8.3-7.0 (12H), 4.0 (t,
2H), 3.4 (m, IH), 1.9-0.9 (m, 3
5H) ■ IR (KBr cm”): 2950-
2850, 1735, 1680, ■ Mass: 5
70 (M'') Observing the changes in the structure of the above compound using a polarizing microscope, it was found that during the heating process, it became a ferroelectric phase liquid crystal at 59.0℃ and became a smectic human phase liquid crystal at 124.0℃. It changed to an isotropic liquid at 1 5 2.0°C.In addition, during the cooling process, it changed to a smectic A phase liquid crystal state at 150.7°C, changed to a smectic C phase liquid crystal state at 125°C, It became a solid crystal at 58.0°C.

In addition, the above compound was sealed in a cell made of Nesa glass using a polyethylene terephthalate film with a thickness of 3 μm as a spacer, and the spontaneous polarization was measured by applying an alternating current of 100 Hz and using the triangular wave method.
It showed a very large spontaneous polarization with cJ.

[Effects of the Invention] The present invention has an extremely excellent effect in that α-methylalkylcarboxylic acid can be synthesized at low cost with good yield, high optical purity, and simple reaction steps.

Claims (1)

[Claims] An optically active 1,2-epoxyalkane is used as a starting material, and this is reacted with trimethylaluminum to produce 2-
1. A method for producing optically active α-methylalkylcarboxylic acid, which comprises preparing methyl-1-alkanol and then oxidizing this alcohol with potassium permanganate.