JP2001151724A - Method for producing optically active 2,2,4-trimethyl-3- cyclohexenecarboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply and efficiently producing optically active 2,2,4-trimethyl-3-cyclohexenecarboxylic acid. SOLUTION: This method for producing optically active 2,2,4-trimethyl-3- cyclohexenecarboxylic acid is to react a racemic form of 2,2,4-trimethyl-3- cyclohexenecarboxylic acid or optically impure 2,2,4-trimethyl-3- cyclohexenecarboxylic acid with an optically active 1-substituted ethylamine (e.g. 1-phenylethylamine) to generate a mixture of diastereomeric salts, separate the objective diastereomeric salt from the obtained mixture by crystallization, and treat the separated salt with an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active 2,2
The present invention relates to a method for producing 2,4-trimethyl-3-cyclohexenecarboxylic acid.

Optically active 2,2,4-trimethyl-3-
Among the cyclohexenecarboxylic acids, (R)-(+)-
2,2,4-trimethyl-3-cyclohexenecarboxylic acid is an antitumor substance represented by the following formula (3)

[0003]

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[0004] It is a compound that can be used as a raw material for synthesizing paclitaxel and analogs thereof.

[0005] Also, (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid is (S)-
(-)-2,2,4-trimethyl-3-cyclohexenemethanol is reduced to the following formula (2)
S, 6R)-(4)

[0006]

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(2S, 6R)-(-)-cis-α-iron represented by the following formula (2S, 6R)-(5)

[0008]

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[0009] It is possible to convert to (2S, 6R)-(-)-cis-γ-iron. Note that 2,
A method for synthesizing racemic cis-α-iron and cis-γ-iron from a racemic 2,4-trimethyl-3-cyclohexenecarboxylic acid has already been reported [J. O
rg. Chem. , 52, 2096 (1987)
And Helv. Chim. Acta, Volume 71, 619
1988).

[0010]

2. Description of the Related Art Conventionally, as a method for producing (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid, (-)-chrysantenone obtained by isomerizing (-)-verbenone is used. There is known a method of treating alkali with [J. Org. Chem. , 34, 2196
Pp. (1969)].

As a method for synthesizing a racemic 2,2,4-trimethyl-3-cyclohexenecarboxylic acid, a method of cyclizing acrylic acid and 2,4-dimethyl-1,2-pentadiene under heating is used. Are known [J. O
rg. Chem. 34, 2196 (1969)
reference].

[0012]

The above (S)-(-)
In the preparation of -2,2,4-trimethyl-3-cyclohexenecarboxylic acid, 4,6,6-trimethyl-3-
Cyclohexenecarboxylic acid is by-produced, and it is difficult to separate them. Also, (R)-(+)-2,2,4
A method for producing -trimethyl-3-cyclohexenecarboxylic acid is not known.

An object of the present invention is to provide a method for easily and efficiently producing optically active 2,2,4-trimethyl-3-cyclohexenecarboxylic acid.

[0014]

Means for Solving the Problems The present inventors have conducted intensive studies to develop a method for easily and efficiently producing optically active 2,2,4-trimethyl-3-cyclohexenecarboxylic acid. The racemic 2,2,4-trimethyl-3-cyclohexenecarboxylic acid is converted to an optically active salt of a 1-substituted ethylamine such as 1-phenylethylamine, and the resulting diastereomeric salt mixture is separated by fractional crystallization. By treating a diastereomer salt separated as a crystal with an acid, it has been found that optically active 2,2,4-trimethyl-3-cyclohexenecarboxylic acid can be easily and efficiently produced, and the present invention is completed. Reached.

That is, according to the present invention, the above-mentioned object is achieved by providing the following methods (A) and (B).

(A) The following equation (±)-(1)

[0017]

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2,2,4-trimethyl-3-
Racemic cyclohexenecarboxylic acid or optically impure 2,2,4-trimethyl-3-cyclohexenecarboxylic acid and the following general formula (R)-(+)-(2)

[0019]

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(X represents a hydrogen atom or a methyl group) to react with (R)-(+)-1-substituted ethylamine to form a diastereomer salt mixture, which is then obtained. (R)-(+)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid- (R)-(+)-1-substituted ethylamine salt was separated from the diastereomer salt mixture by crystallization, and separated. The following formula (R)-(+)-(1), wherein the salt is treated with an acid.

[0021]

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(R)-(+)-2,2,4-
A method for producing trimethyl-3-cyclohexenecarboxylic acid.

(B) The following equation (±)-(1)

[0024]

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2,2,4-trimethyl-3- represented by
Racemic cyclohexenecarboxylic acid or optically impure 2,2,4-trimethyl-3-cyclohexenecarboxylic acid and the following general formula (S)-(-)-(2)

[0026]

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(X represents a hydrogen atom or a methyl group) to form a diastereomer salt mixture by reacting with (S)-(-)-1-substituted ethylamine. (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid- (S)-(-)-1-substituted ethylamine salt was separated from the resulting diastereomer salt mixture by crystallization and separated. The following formula (S)-(-)-(1) characterized in that the salt obtained is treated with an acid.

[0028]

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(S)-(-)-2,2,4-
A method for producing trimethyl-3-cyclohexenecarboxylic acid.

[0030]

DETAILED DESCRIPTION OF THE INVENTION The above method (A) is illustrated by the following flow chart.

[0031]

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The above method (B) is shown by the following flow chart.

[0033]

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The diastereomer salt formation reaction is carried out by using 2,
Racemic 2,4-trimethyl-3-cyclohexenecarboxylic acid or optically active 1- and 2,2,4-trimethyl-3-cyclohexenecarboxylic acid
It is preferable to add the substituted ethylamine to the organic solvent with stirring and to heat the mixture to a temperature near the boiling point of the organic solvent, if necessary. Thereafter, the reaction solution is gradually cooled to a supersaturated state, and the desired hardly soluble diastereomer salt is precipitated. It is also possible to add a small amount of the desired hardly soluble diastereomer salt in a supersaturated state to precipitate the salt. The precipitated diastereomeric salt is
The fraction can be collected by ordinary separation means such as filtration, centrifugation and decantation.

The amount of the optically active 1-substituted ethylamine is not particularly limited, but is 2,2,4-trimethyl-3-.
It is preferred that the amount be about the same as the racemic cyclohexenecarboxylic acid or 2,2,4-trimethyl-3-cyclohexenecarboxylic acid which is not optically pure.

Examples of the organic solvent used include alcohols such as methanol, ethanol and 2-propanol (isopropyl alcohol); ethers such as diethyl ether, diisopropyl ether, dibutyl ether and t-butyl methyl ether; methyl acetate and ethyl acetate Esters such as dimethyl carbonate and diethyl carbonate; ketones such as acetone and methyl isopropyl ketone; amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; and 2-propanol is particularly preferred. These solvents are used alone or in combination of two or more. The amount of the solvent to be used is not particularly limited, but is usually preferably from 2 to 100 times by weight, more preferably from 5 to 20 times by weight, based on 2,2,4-trimethyl-3-cyclohexenecarboxylic acid.

The acid used in the acid treatment of the target diastereomer salt may be any acid having an acidity sufficient to neutralize the salt, for example, about 1 N hydrochloric acid or sulfuric acid. Is mentioned.

In the acid treatment, a solvent such as an ether such as diethyl ether or diisopropyl ether is mixed with an acid such as a 1N aqueous hydrochloric acid solution, and the desired diastereomer salt is added to the obtained mixed solution. This is performed by stirring.

The optically active 2,2,4-trimethyl-3-cyclohexenecarboxylic acid liberated by the above acid treatment, that is, (R)-(+)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid or (S)-(-)
-2,2,4-Trimethyl-3-cyclohexenecarboxylic acid can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, the reaction mixture is extracted with an organic solvent such as diethyl ether, the extract is concentrated, and the resulting crude product is purified, if necessary, by column chromatography, recrystallization, or the like.

The (±) -2,2,4-trimethyl-3-cyclohexenecarboxylic acid used as a raw material in the present invention is, for example, 2,2,4-trimethyl-3-cyclohexenecarbaldehyde, 2-methyl-cyclohexenecarbaldehyde. It can be produced by oxidation with sodium chlorite in the presence of 2-butene and sodium dihydrogen phosphate (see Reference Example 1). Also, 2,2,4-trimethyl-3
-Cyclohexenecarbaldehyde can be easily prepared by the Diels-Alder reaction of 2,4-dimethyl-1,3-pentadiene with acrolein [J.
Am. Chem. Soc. 63, 1979 (19
41)].

[0041]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples. The value of the specific rotation in Examples was measured as a chloroform solution, and ¹ H-NMR and ¹³ C-NMR in Examples and Reference Examples were
It is the value of the chemical shift based on tetramethylsilane (TMS) in deuterated chloroform (CDCl ₃ ).

Reference Example 1 Production of (±) -2,2,4-trimethyl-3-cyclohexenecarboxylic acid 5.0 g (33 mmol) of 2,2,4-trimethyl-3-cyclohexenecarbaldehyde and dihydrogen phosphate 3.9 g (33 mmol) of sodium and 2-methyl-2
-15.3 ml (144 mmol) of butene are suspended in a mixed solution of 235 ml of t-butyl alcohol and 62 ml of water, and 3.6 g of sodium chlorite are vigorously stirred.
(40 mmol) was added slowly over 1 hour. The mixture was stirred vigorously for another hour, then acidified with 1N aqueous hydrochloric acid and extracted three times with 100 ml of diethyl ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude carboxylic acid. This was recrystallized from acetonitrile and then subjected to silica gel column chromatography [hexane: ethyl acetate =
4: 1 (volume ratio)] to obtain 4.5 g (27 mmol, (27 mmol, 27 mg, 27 mmol) of a white plate-like crystal of (±) -2,2,4-trimethyl-3-cyclohexenecarboxylic acid having the following physical properties.
(Yield 82%).

Melting point: 84.5-88.0 ° C. IR (KBr): 2970, 1700, 1410, 13
00, 1225, 940, 835, 725 cm^{-1 1} H-NMR (500 MHz) δ: 0.98 (s, 3H,
-CH _Three ), 1.16 (s, 3H, -CH _Three ) 1.6
3 to 1.65 (br, 3H, -CH = C (CH _Three)
−) 1.7 to 2.0 (m, 4H), 2.34 (dd,
1H, J = 3.9, 11.2Hz, -CH(CO_Two H)
−), 5.08 (q, 1H, J = 1.5 Hz, −CH
=), 9-12 (br, 1H, -CO_Two H)¹³ C-NMR (125 MHz) δ: 22.2, 23.
4, 24.5, 29.1, 30.0, 34.3, 49.
9, 131.1, 131.8, 181.7 (-CO _Two 
H)

Example 1 (R)-(+)-2,2,4-
Production of trimethyl-3-cyclohexenecarboxylic acid and (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid (±) -2,2,4- obtained by the method of Reference Example 1. 12 g of trimethyl-3-cyclohexenecarboxylic acid (71 mm
ol) and 8.6 g (71 mmol) of (S)-(−)-1-phenylethylamine in 100 m of 2-propanol.
In addition, the mixture was dissolved while heating to 60 ° C., and then cooled to room temperature. The precipitated crystals are separated by filtration,
2.54 g (8.8 mmol, yield 12%) of crystals of (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid / (S)-(-)-1-phenylethylamine salt I got On the other hand, the filtrate was acidified with a 1N aqueous hydrochloric acid solution, extracted with diethyl ether, and the extract was concentrated to give 2,2,4-trimethyl-impurate.
11 g (65 mmol) of 3-cyclohexenecarboxylic acid
Was recovered. This optically impure 2,2,4-trimethyl-3-cyclohexenecarboxylic acid is converted to (R)-
7.9 g of (+)-1-phenylethylamine (65 mm
ol) together with 120 ml of 2-propanol and 6
After dissolving while heating to 0 ° C., the mixture was cooled to room temperature.
The precipitated crystals were separated by filtration, and (R)-(+)-
3.6 g (12 mmol, 18% yield) of 2,2,4-trimethyl-3-cyclohexenecarboxylic acid. (R)-(+)-1-phenylethylamine salt crystals were obtained.

(S)-(-)-2,2, obtained above.
4-trimethyl-3-cyclohexenecarboxylic acid
(S)-(-)-1-phenylethylamine salt 1.25
g was dissolved in diethyl ether, acidified with 1N aqueous hydrochloric acid, extracted with diethyl ether, and the extract was concentrated to give (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid. Acid ([α] _D ²⁷ = −
108 ° (c = 1.7, chloroform), optical purity 77
%) Was obtained. Similarly, (R)-(+)-
7. 2,2,4-trimethyl-3-cyclohexenecarboxylic acid (R)-(+)-1-phenylethylamine salt
From 49 g, (R)-(+)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid ([α] _D ²³ = + 14
4.91 g of 0% (c = 1.6, chloroform) was obtained. (Melting point: 58.9-59.0 ° C)

The obtained (R)-(+)-2,2,2
A part of 4-trimethyl-3-cyclohexenecarboxylic acid was sampled, converted into a sodium salt, and then refluxed with ethanol / aqueous solution together with parabromophenacyl bromide for 1 hour to obtain a parabromophenacyl ester. About this, an optically active column [Chiralcel OD (hexane: 2-propanol = 200: 1 (volume ratio), flow rate 0.5 ml /
Min)]] (HPL
C) Analysis showed that the product had an optical purity of 99%.
That was all. (Retention time 63.3 minutes)

Example 2 (R)-(+)-2,2,4-
Production of trimethyl-3-cyclohexenecarboxylic acid 4.0 g of (±) -2,2,4-trimethyl-3-cyclohexenecarboxylic acid obtained by the method of Reference Example 1 (24 m
mol) and 3.2 g (24 mmol) of (R)-(+)-1-paratolylethylamine in 20 m of 2-propanol.
In addition, the mixture was dissolved while heating to 60 ° C., and then cooled to room temperature. The precipitated crystals are separated by filtration,
0.61 g of crystals of (R)-(+)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid / (R)-(+)-1-paratolylethylamine salt (2.0 mmol, yield 8. 3%). This was dissolved in diethyl ether, acidified with 1N aqueous hydrochloric acid, extracted with diethyl ether, and the extract was concentrated to give (R)-
334 mg of (+)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid ([α] _D ²⁴ = + 76 ° (c = 1.2, chloroform), optical purity 54%) was obtained.

[0048]

According to the present invention, (R)-(+)-2,
2,4-Trimethyl-3-cyclohexenecarboxylic acid and (S)-(-)-2,2,4-trimethyl-3-cyclohexenecarboxylic acid can be easily and efficiently produced.

Claims (2)

[Claims] 1. The following formula (±)-(1) A racemic or optically pure 2,2,4-trimethyl-3-cyclohexenecarboxylic acid represented by
2,4-trimethyl-3-cyclohexenecarboxylic acid and the following general formula (R)-(+)-(2) (Wherein, X represents a hydrogen atom or a methyl group) to produce a diastereomer salt mixture by reacting with (R)-(+)-1-substituted ethylamine, (R)-(+)-
The following formula, wherein 2,2,4-trimethyl-3-cyclohexenecarboxylic acid. (R)-(+)-1-substituted ethylamine salt is separated by crystallization, and the separated salt is treated with an acid. (R)-(+)-(1) (R)-(+)-2,2,4-trimethyl-
A method for producing 3-cyclohexenecarboxylic acid. 2. The following formula (±)-(1) A racemic or optically pure 2,2,4-trimethyl-3-cyclohexenecarboxylic acid represented by
2,4-trimethyl-3-cyclohexenecarboxylic acid and the following general formula (S)-(-)-(2) (Wherein, X represents a hydrogen atom or a methyl group) to produce a diastereomer salt mixture by reacting with (S)-(-)-1-substituted ethylamine represented by the following formula: (S)-(-)-
The following formula, wherein 2,2,4-trimethyl-3-cyclohexenecarboxylic acid • (S)-(−)-1-substituted ethylamine salt is separated by crystallization, and the separated salt is subjected to an acid treatment. (S)-(-)-(1) (S)-(-)-2,2,4-trimethyl-
A method for producing 3-cyclohexenecarboxylic acid.