JP2877976B2 - Optically active 2,4,4-trimethyl-2-cyclohexen-1-ol and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel compounds (R)-(+)-2,4,4-trimethyl-2-cyclohexen-1-ol and (S)-(-)-2,4. , 4
-Trimethyl-2-cyclohexen-1-ols and their new processes. The optically active 2,4,4-trimethyl-2-cyclohexen-1-ol provided by the present invention is a very useful compound as a synthetic intermediate such as a fragrance compound and an agricultural chemical.

[0002]

2. Description of the Related Art Asymmetric hydrolysis using microorganisms or esterases is known. For example, optically active mevalonic acid is synthesized by asymmetric hydrolysis using pig liver esterase (hereinafter referred to as PLE). Methods have been reported [J. Am. Chem. Soc., 97 , 4144.
(1975)].

[0003]

SUMMARY OF THE INVENTION However, 2,
By asymmetrically hydrolyzing the racemate of 4,4-trimethyl-2-cyclohexenyl acetate using an esterase, high-purity optically active (R)-(+)-
It is completely known that 2,4,4-trimethyl-2-cyclohexen-1-ol and high-purity (S)-(-)-2,4,4-trimethyl-2-cyclohexen-1-ol can be obtained. Not been.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have developed optically active 2,4,4-trimethyl-2-cyclohexene-1-yl.
We have intensively studied a method for producing oars with high optical purity by simple means. As a result, the novel (R)-(+)-and () which are optically extremely pure by asymmetric hydrolysis of racemic 2,4,4-trimethyl-2-cyclohexenyl acetate with an esterase. S)-(-)-
It has been found that 2,4,4-trimethyl-2-cyclohexen-1-ol can be synthesized. That is, according to the present invention, both enantiomers of 2,4,4-trimethyl-2-cyclohexen-1-ol can be easily synthesized with high optical purity. Hereinafter, embodiments of the present invention will be specifically described.

[0005] The racemic 2,2 used in the present invention
4,4-Trimethyl-2-cyclohexenyl acetate [compound of formula (4) below] can be prepared by a method known per se, for example, from ethyl vinyl ketone and isobutyraldehyde by 2,4,4-trimethyl-2-cyclohexene-1.
It can be easily synthesized by synthesizing -one, reducing this to alcohol, and then esterifying with acetic acid. Hereinafter, the reaction steps will be described step by step.

To obtain 2,4,4-trimethyl-2-cyclohexen-1-one, for example, a mixture of 1 mol of ethyl vinyl ketone and about 1.5 mol of isobutyraldehyde, which is easily available on the market, is treated at about 50 ° C. or lower. While maintaining a temperature of about 0.1 to about 10
% By weight of a strong acid such as sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, etc., and the mixture is stirred at room temperature for about 1 to about 24 hours. Perform a time reaction. After completion of the reaction, the residue was distilled under reduced pressure to give 2,4,4-trimethyl-2.
-Cyclohexen-1-one can be obtained.

Next, the ketone compound obtained as described above is reduced by a method known per se, for example, using lithium aluminum hydride, sodium borohydride in the presence of cerium chloride, diisobutylaluminum hydride, aluminum hydride and the like. This leads to racemic 2,4,4-trimethyl-2-cyclohexen-1-ol.

[0008] The acetate of the racemic alcohol is
For example, by employing a conventionally known acetic acid esterification reaction such as a pyridine-acetic anhydride method, a 4-dimethylaminoviridine-acetic anhydride method, a phosphoric acid-acetic anhydride method, or a triethylamine-acetyl chloride method, the formula (4) is obtained. The compound (±) -2,4,4-trimethyl-2-cyclohexenyl acetate can be easily derived.

Also, (±) -2,4,4-trimethyl-2
The asymmetric hydrolysis of -cyclohexenyl acetate [compound of the formula (4)] can be carried out by the following reaction formula A.

[0010]

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One part by weight of the compound of the formula (4) is contained in a 0.1M phosphate buffer [containing about 5 to 50% by weight of a polar solvent such as methanol, ethanol and isopropanol (pH about 7 to 10%).
8)] Disperse in about 30 to about 50 parts by weight, add about 500 to about 5000 units of the esterase, and vigorously stir at a temperature of about −15 to about + 5 ° C. for about 5 to about 200 hours, for example. To carry out a hydrolysis reaction.

Examples of such esterases include enzymes such as pig liver esterase (hereinafter sometimes referred to as PEL) and pig pancreatic lipase (PPL). Pig liver esterase is preferred.

Then, the reaction solution is saturated with sodium chloride, ammonium chloride and the like, and extracted several times with ether and the like. The extract is washed by a conventional method, and a dehydrating agent such as sodium sulfate, magnesium sulfate, calcium chloride or the like is added and dried, and then the solvent is recovered and removed.

By this reaction, 100% ee (ena)
(r)-of nthio excess: optical yield
(+)-Alcohol [compound of formula (1)] and about 40%
e. e. (S)-(-)-acetate [compound of formula (3)] is produced in a ratio of about 1: 2 to about 4. This mixture can be easily separated and purified into the respective components by, for example, silica gel chromatography or the like.

Further, the compound of formula (3) (about 40% ee) to be separated is re-treated with an esterase in the same manner as described above, whereby (S)-having an optical purity of almost 100%.
(-)-.

The reaction for synthesizing the compound of the formula (2) from the compound of the formula (3) is represented by the following reaction formula B.

[0017]

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1 part by weight of the compound of the formula (3) is added in an amount of about 10 to about 2
0 parts by weight methanol, ethanol, dissolved in a solvent such as isopropanol, for example, potassium carbonate, sodium carbonate, potassium hydroxide, alkali such as sodium hydroxide, and stirred at room temperature for about 0.1 to about 10 hours, After completion of the reaction, the solvent is recovered and removed under reduced pressure, and the residue is diluted with water and extracted with ether or the like. The extract is washed by a conventional method, dried by adding a dehydrating agent, and then removing the solvent to obtain a crude compound of the formula (2).

Next, 1 part by weight of the crude compound of the formula (2) is mixed with about 1 part of a solvent such as pyridine, triethylamine or the like.
0 to about 20 parts by weight, and about 0.05 to 0.2 parts by weight of a catalyst such as DMAP (4-dimethylaminopyridine), to which 3,5-dinitrobenzoyl chloride,
3,5- such as 3,5-dinitrobenzoyl bromide
About 1 to about 2 parts by weight of dinitrobenzoyl halide are added in portions. After stirring at room temperature for about 1 to about 24 hours, the reaction solution is poured into ice water and extracted with ether or the like. After the extract is washed and dried by a conventional method, the solvent is recovered and removed to obtain a crude crystal of the compound of the formula (5). By recrystallizing the crude crystals from, for example, isopropyl ether or the like, a pure compound of the formula (5) can be obtained.

The compound of the formula (2) is dissolved in a solvent of, for example, methanol: dichloromethane = about 1: 1 and treated with an alkali such as potassium carbonate, potassium hydroxide, sodium hydroxide or the like. A compound can be obtained, which is further treated by silica gel chromatography or the like to give an optical purity of 100% e. e. (S)-(-)-2,4,4-trimethyl-2-cyclohexen-1-ol [compound of formula (2)] can be obtained. Hereinafter, embodiments of the present invention will be described more specifically with reference examples and examples.

[0021]

[Reference Example 1]2,4,4-trimethyl-2-cyclohex
Synthesis of sen-1-one  75.0 g (892 mmol) of ethyl vinyl ketone and iso
Mixture of 96.4 g (1.34 mol) of butyraldehyde
2.50m of concentrated sulfuric acid while stirring
1 was added little by little. Stir the mixture at room temperature for 5 hours
Then, a Dean-Stark trap was attached,
The reaction was carried out for 16 hours. The residue was distilled under reduced pressure, b.
2,4,4-trimethyl at p.
86.2 g of 2-cyclohexen-1-one was obtained.

[0022]

[Reference Example 2](±) -2,4,4-trimethyl-2-si
Synthesis of Clohexen-1-ol  Lithium aluminum hydride 1 in 800 ml of ether
Dissolve 8.5 g (486 mmol) and stir the solution
The ketone body 6 obtained in Reference Example 1 was cooled to 0 ° C.
Dissolve 7.1 g (486 mmol) in 300 ml of ether
The solution was added dropwise. After stirring at 0 ° C for 1 hour,
Then, the lithium aluminum hydride was decomposed.
After filtering and washing the solid, the filtrate is concentrated and the residue is distilled under reduced pressure.
And b. p. 89 ± 90 ° C./19 Torr (±) −2,
4,4-trimethyl-2-cyclohexen-1-ol
62.8 g were obtained.

[0023]

[Reference Example 3](±) -2,4,4-trimethyl-2-si
Synthesis of clohexenyl acetate [compound of formula (4)]  61.5 g of racemic alcohol obtained in Reference Example 2
(439 mmol), 67.3 g (659 mmol) of acetic anhydride and
And cooled to 0 ° C while stirring a mixture of 77 ml of pyridine
And put 4.3 g (35.2 mmol) of DMAP into it.
Added one by one. After further stirring at 0 ° C for 1 hour,
The liquid was poured into ice water and extracted with ether. Extract copper sulfate
Wash with aqueous solution, aqueous sodium carbonate solution and saline
After drying with magnesium acid, the ether is recovered and the residue is recovered.
Distillation under reduced pressure b. p. 82-84 ° C / 10.5 Torr
75.7 g of the compound (4) was obtained.

[0024]

Embodiment 1(±) -2,4,4-trimethyl-2-si
Asymmetric of clohexenyl acetate [compound of formula (4)]
Hydrolysis  26.3 g (145 mmol) of the compound of formula (4)
Molar phosphate buffer (ion exchange water: methanol = 8:
2; pH 7.5) Disperse in 1.1 l and stir vigorously
While cooling to −10 ° C.
Add 50250 units and perform enzymatic degradation for 65 hours
went. The reaction was saturated with salt and ammonium chloride,
Extracted three times with ether. Extract the sodium carbonate, diet
Wash with brine, dry with magnesium carbonate and recover ether.
27.5 g of the residue was subjected to silica gel chromatography.
And purified. As a result, the compound of formula (1) (R)-
(+)-2,4,4-trimethyl-2-cyclohexene
-1-ol 5.32 g [b. p. 63-64 ° C / 3To
rr; [α]_D= + 95.7 ° (21 ° C.) (C = 1.1
3, MeOH); 100% ee. And the formula (3)
Product (S)-(-)-2,4,4-trimethyl-2-cycl
17.7 g of rohexenyl acetate [b. p. 57-5
7.5 ° C / 2.5 Torr; [α]_D= −39.5 ° (21
° C); (C = 1.10, MeOH); 41% ee]
Obtained.

[0025]

Embodiment 2(S)-(-)-2,4,4-trimethyl
-2-cyclohexenyl acetate [compound of formula (3)
Of optical purity of  74 g (407 mmol) of the compound of formula (3)
Similarly treated with porcine liver esterase to obtain high optical purity
(S)-(-)-2,4,4-trimethyl-2-cyclo
Hexenyl acetate [compound of formula (3)] 49.3 g
[B. p. 57-58 ° C / 2 Torr; [α]_D= -97.9
° (21 ° C); (C = 1.07, MeOH); 96%
ee] and 18.0 g of the compound of formula (1).

[0026]

Embodiment 3(S)-(-)-2,4,4-trimethyl
-2-cyclohexen-1-ol [compound of the formula (2)
Synthesis of  49 g of the compound of the formula (3) obtained in Example 2 (270 g)
mmol, 96% ee) in 750 ml of methanol
And add 75.5 g (550 mmol) of potassium carbonate
After stirring at room temperature for 2 hours, recover methanol under reduced pressure.
The residue was diluted with water and extracted with ether. Wash the extract
After purification and drying, the ether is recovered and the crude compound of formula (2) is recovered.
42 g (96% ee) were obtained.

Then, 500 ml of pyridine and D
2.93 g (24 mmol) of MAP were added, and 83 g (360 g) of 3,5-dinitrobenzoyl chloride was added with stirring.
mmol) was added little by little. After stirring for 3 hours at room temperature, the reaction solution was poured into ice water and extracted several times with ether. Extract solution is diluted hydrochloric acid aqueous solution, sodium carbonate aqueous solution,
After washing with brine and drying over magnesium sulfate, the ether was recovered to give 87 g of crude crystals of the compound of formula (5). This was recrystallized from isopropyl ether to give pure formula (5)
77.5 g [mp 130-131 ° C, [α]
_D = -118.5 ° (21 ° C.), (C = 1.04; CHC
l ₃ )].

76.5 g (229) of the compound of formula (5)
mmol) in a mixed solvent of methanol and dichloromethane (1:
1) Dissolve in 1050 ml and add 59.5 g of potassium carbonate
(431 mmol) was added and the mixture was stirred at room temperature for 3 hours, the solvent was removed, and the residue was purified by silica gel column chromatography. As a result, a compound of (S)-(-)-2,4,4-trimethyl-2-cyclohexen-1-ol [formula 2] having an optical purity of 100% ee;
85 ° C./13.5 Torr; [α] _D = −95.9 ° (2
1 ° C.), (C = 1.02, MeOH)].

[0029]

According to the present invention, the racemic 2,4,4
-Asymmetric hydrolysis of trimethyl-2-cyclohexenyl acetate with an esterase to produce (R)-(+)-and (S)-(-)-with extremely high optical purity.
2,4,4-trimethyl-2-cyclohexen-1-ol can be easily synthesized. That is, according to the present invention, the novel compound 2,4,4-trimethyl-2
Both enantiomers of -cyclohexen-1-ol can be synthesized simply and with high purity, high yield, and high optical purity by an industrially extremely advantageous method. The optically active 2,4,4-trimethyl-2-cyclohexen-1-ol obtained by the method of the present invention is a very useful compound as a synthetic intermediate such as a fragrance compound and an agricultural chemical.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C12P 41/00 C07C 27/02 C07C 35/18 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] [Claim 1] The following formula (1) (R)-(+)-2,4,4-trimethyl- represented by
2-cyclohexen-1-ol. (2) The following formula (2): (S)-(-)-2,4,4-trimethyl- represented by
2-cyclohexen-1-ol. 3. The following formula (4): Wherein, Ac is asymmetric hydrolysis an acetyl group, in represented the (±)-2,4,4-trimethyl-2-cyclohexenyl acetate in esterase, then the following equation from the hydrolyzate ( 1) A method for producing (R)-(+)-2,4,4-trimethyl-2-cyclohexen-1-ol, which comprises separating and collecting a compound represented by the formula: 4. The following formula (3): In the formula, Ac represents an acetyl group.
(-)-2,4,4-Trimethyl-2-cyclohexenyl acetate is hydrolyzed and then reacted with 3,5-dinitrobenzoyl halide to give the following formula (5): In the formula, DNB represents a 3,5-dinitrobenzoyl group, and is derived into a dinitrobenzoyl derivative represented by the following formula: and the derivative is treated with an alkali. (S)-(-)-2,4,4-trimethyl- represented by
Production method of 2-cyclohexen-1-ol.