JP2642959B2 - Optically active fluorine-containing α-hydroxycyclopropane compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an optically active fluorinated .alpha.-olefin useful as a raw material for esters, ethers and carboxylic acids used as enzyme inhibitors, biologically active substances, anticancer agents and ferroelectric liquid crystals.
It relates to a hydroxycyclopropane compound.

[Problems to be solved by conventional technology and invention]

Conventionally, some compounds have been reported as optically active fluorinated alcohols (fluorinated hydroxy compounds) applied to liquid crystals and pharmaceuticals.

However, fluorine hydroxy compounds that are satisfactory with respect to optical purity have not yet been reported. Accordingly, an object of the present invention is to provide a novel optically active fluorinated hydroxy compound having high optical purity.

[Means for solving the problem]

The present inventors have particularly studied various optically active hydroxy compounds having a cyclopropane ring, and found that an optically active fluorinated hydroxy compound having high optical purity can be obtained by asymmetric hydrolysis using an enzyme. completed.

That is, the present invention relates to the general formula (In the formula, R ¹ and R ² are each a fluorine-substituted alkyl group having 1 to 2 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Wherein at least one of R ¹ and R ² represents a fluorine-substituted alkyl group having 1 to 2 carbon atoms.) An optically active fluorine-containing α-
A hydroxycyclopropane compound is provided.

The optically active fluorine-containing α- of the general formula (I) according to the present invention
There are various types of hydroxycyclopropane compounds depending on the types of the substituents R ¹ and R ² , and all are optically active compounds in which the carbon atom bonded to the hydroxyl group (OH) is an asymmetric center. trans-the arrangement of the substituents R ^2, may take the respective structures of the cis-form. R ¹ and R ² are a fluorine-substituted alkyl group having 1 to 2 carbon atoms (for example, a hydrogen atom such as a methyl group or an ethyl group in which part or all of hydrogen is substituted by fluorine), a carbon atom having 1 to 2 carbon atoms as described above. 10 alkyl groups (methyl group, ethyl group, propyl group, butyl group, isobutyl group, hexyl group, octyl group, nonyl group, etc.) and aralkyl groups having 7 to 10 carbon atoms (benzyl group,
A phenethyl group) or an aryl group having 6 to 10 carbon atoms (phenyl group, toluyl group, p-chlorophenyl group, m
-Chlorophenyl group). However, at least one of R ¹ and R ² needs to be the above-mentioned fluorine-substituted alkyl group having 1 to 2 carbon atoms.

Specific examples of such an optically active fluorinated α-hydroxycyclopropane compound of the present invention include various types, and in addition to those described in Examples described later, it is possible to produce various structures. It is possible.

Incidentally, this fluorine-containing α-hydroxycyclopropane compound can be produced by various methods, but can be generally produced by the following reaction formula.

In the above formula, COR 'represents an acyl group.

 Next, each manufacturing process will be described in detail.

Reduction Step The fluorine-containing hydroxy compound having a triple bond of the general formula (II) (a fluorine-containing alcohol derivative) is reduced to produce a fluorine-containing hydroxy compound having a double bond of the general formula (III). The reducing agent that can be used in this step may be any reducing agent that is commonly used for reducing a triple bond to a double bond, and depending on the type of the reducing agent, a bond on both sides of the double bond obtained after reduction. Causes differences in structure.

For example, when this bonding structure is of a trans type, sodium bis (2-methoxyethoxy) aluminum hydride; Na [AlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ ], lithium diisobutylmethylaluminum hydride; LiAlH [( CH ₃ ) ₂ CHC
H ₂ ] ₂ CH ₃ , tributyltin hydride; (C ₄ H ₉ ) ₃ SnH, and the like, with sodium bis (2-methoxyethoxy) aluminum hydride being particularly preferred.

This reduction reaction is preferably carried out in an organic solvent such as ether. The reaction temperature can be from low to high, but the range of -30 to -50C is particularly preferable.

When the bonding structure is cis-type, a Lindlar catalyst together with hydrogen; Pd / CaCO ₃ —Pd (OAc) ₂ or Pd / BaSO ₄
A method using a quinoline catalyst, a method using diisobutylaluminum hydride; AlH [(CH ₃ ) ₂ CHCH ₂ ) ₂ or the like as a reducing agent, and a combination using a Lindlar catalyst together with hydrogen is particularly preferable. This reaction is preferably performed in an organic solvent such as hexane.

Acylation step Acylation can be carried out by a conventional method. Examples of the acylating agent include acetyl chloride, propionyl chloride,
Butyryl chloride, benzoyl chloride, octyl chloride and the like.

Enzymatic hydrolysis step The compound obtained in the acylation step is asymmetrically hydrolyzed with an enzyme to give a compound of the general formula (V) having high optical purity.

As the enzyme, various enzymes can be used as long as they are so-called hydrolyzed oxygen. For example, lipase P, lipase MY, lipase M10, lipase OF, lipase P679, cellulase, PLE and the like can be used. In this case, the optical activity varies depending on the selected enzyme. For example, when lipase MY is used, a hydroxy compound (alcohol derivative) generated
When the acylated product (Va) is treated with an enzyme such as cellulase or a basic catalyst such as sodium hydroxide, a left-applied hydroxy compound may be obtained. When lipase P is used, a hydroxy compound having the opposite light-emitting property to that of lipase MY may be obtained.

Cyclopropanation Step The compound of the general formula (I) of the present invention is obtained by cyclopropanating the optically active compound obtained by oxygen hydrolysis.

Cyclopropanation is carried out using methylene iodide (CH ₂ I ₂ ) and Sm,
Zn-Cu or Zn (C ₂ H _{5) 2} or diazomethane (CH ₂ N
₂ ) and a ZnI ₂ catalyst in combination. Particularly, a combination of methylene iodide and Sm is desirable as a stereoselective reaction. This reaction is carried out in an organic solvent such as tetrahydrofuran, and the reaction temperature can be from low to high, but the optimum is about 0 ° C.

The reaction in each step is performed under optimal conditions, and the reaction time and temperature are appropriately selected depending on conditions such as the type of solvent and the amounts of various auxiliaries.

〔Example〕

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example 1A Synthesis of (1R)-(+)-1- (trans-2-phenylcyclopropyl) -2,2,2-trifluoroethanol (A) Reduction step Under a nitrogen atmosphere, 40 ml of ether was added to the three-necked flask, and the reaction vessel was kept at -30 ° C with a dry ice-acetone bath. After 4.5 ml (15.3 mmol) of sodium bis (2-methoxyethoxy) aluminum hydride was added, and the temperature of the dry ice-acetone bath was reduced to -50 ° C, 4,4,4-trifluoro-3-hydroxy-1-phenyl-phenyl- was added. 1-butyne 2.81
A solution of g (14.0 mmol) in ether (10 ml) was added dropwise over 10 minutes and allowed to react for 1 hour, followed by a further 1 hour at room temperature.

The reaction was quenched with 1N hydrochloric acid and extracted with ether. Next, the mixture was washed with a saturated sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After ether was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography.

(B) acylation step (E) -4,4,4-trifluoro-3- obtained in the reduction step
A solution of 3.75 g (17.7 mmol) of hydroxy-1-phenyl-1-butene and 1.6 ml (19.4 mmol) of pyridine in dichloromethane (20 ml) was stirred in an ice bath, and acetyl chloride 1.6 m
l (23.0 mmol) was added dropwise over 5 minutes and reacted at room temperature for 13 hours. The reaction was stopped by adding 1N hydrochloric acid thereto, and extracted with dichloromethane. Next, it was washed with water and dried over anhydrous magnesium sulfate. After distilling off dichloromethane under reduced pressure, the residue was separated and purified by silica gel column chromatography.

(C) hydrolysis step (E) -3-acetoxy-4,4,4 obtained in the acylation step
4.23 g of trifluoro-1-phenyl-1-butene (17.
5 mmol) was suspended in 70 ml of distilled water, and 40 to 41 in a thermostat.
C. 2.0 g of Lipase MY (manufactured by each sugar industry company) was added thereto and reacted for 6 hours 30 minutes. The reaction was terminated by adding 1N hydrochloric acid thereto, ethyl acetate was added thereto, and the mixture was subjected to suction filtration with Celite, followed by extraction with ethyl acetate. Next, the extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the ethyl acetate was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography to give (3R)-(-)-(E) -4,4,4,4.
-Trifluoro-3-hydroxy-1-phenyl-1-
Butene and (3S)-(E) -3-acetoxy-4,4,4-trifluoro-1-phenyl-1-butene were obtained.

(D) cyclopropanation step Under an argon atmosphere, samarium 1.60 was placed in a three-necked flask.
g (10.6 mmol) and 3 ml of tetrahydrofuran (THF) were added, and the reaction vessel was kept at 0 ° C. in an ice bath. To the solution, 3 ml of a THF solution containing 0.14 g (0.5 mmol) of mercuric chloride was added dropwise over 10 minutes, and (3R)-(-)-(E) obtained in the hydrolysis step.
A solution of 0.20 g (1.0 mmol) of -4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butene in 3 ml of THF was added to 10
And the mixture was stirred for 30 minutes. Next, methylene iodide 0.
3 ml of a 81 ml (10.0 mmol) THF solution was added dropwise over 1 hour,
The reaction was carried out at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of potassium carbonate and extracted with ether. Next, it was washed with saturated saline and dried over anhydrous magnesium sulfate. After ether was distilled off under reduced pressure, the residue was decomposed and purified by silica gel column chromatography.

The physical properties of the obtained (1R)-(+)-1- (trans-2-phenylcyclopropyl) -2,2,2-trifluoroethanol are shown below.

The proton nuclear magnetic resonance ( ¹ H-NMR) spectrum was measured using a carbon tetrachloride solvent, and the fluorine nuclear magnetic resonance ¹⁹ F-NM was used.
R) The spectrum was measured using a diethyl ether solvent.

Molecular weight 216.20 ¹ H-NMR δ (ppm) 0.93 to 1.50 (m, 3H), 1.88 to 2.31
(M, 2H), 3.67 (dq, J = 6.3, 12.6 Hz, 1H), 7.24 (m, 5H) ¹⁹ F-NMR + 0.82 (d, J = 6.8 Hz) IR (cm ⁻¹ ) 3400, 2940 , 1610, 1505, 1445 Example 1B Synthesis of (1S)-(-)-1- (trans-2-phenylcyclopropyl) -2,2,2-trifluoroethanol (C) hydrolysis step (3S)-obtained in the above Example 1A (c) hydrolysis step
(E) -3-acetoxy-4,4,4-trifluoro-1-
2.57 g (10.6 mmol) of phenyl-1-butene was added to distilled water 5
It was suspended in 0 ml and kept at 40-41 ° C. in a thermostat. Thereto, 1.2 g of cellulase (manufactured by Amano Pharmaceutical) was added and reacted for 30 hours. To this was added 1N hydrochloric acid to stop the reaction, ethyl acetate was added, and the mixture was extracted with ethyl acetate after suction filtration with celite. Next, it was washed with saturated saline and dried over anhydrous magnesium sulfate. After the ethyl acetate was distilled off under reduced pressure,
Separation and purification by silica gel column chromatography,
(3S)-(+)-(E) -4,4,4-trifluoro-3-
Hydroxy-1-phenyl-1-butene was obtained.

(D) cyclopropanation step The same operation as in the cyclopropanation step of Example 1A (d) was performed to obtain (1S)-(−)-1- (trans-2-phenylcyclopropyl) -2,2,2-trifluoroethanol. .

Example 2A Synthesis of (1R)-(+)-1- (cis-2-phenylcyclopropyl) -2,2,2-trifluoroethanol (A) Reduction step Under a hydrogen atmosphere, Lindlar catalyst 0.40 was placed in a three-necked flask.
g and hexane (35 ml) were added, and the reaction vessel was kept at -78 ° C in a dry ice-acetone bath. There, 4.52 g of 4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butyne
(20,1 mmol) was added dropwise over 5 minutes and reacted at room temperature for 14 hours.

The reaction solution was filtered, hexane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (Z) -4,
4,4-trifluoro-3-hydroxy-1-phenyl-
1-butene was obtained.

(B) acylation step The same operation as in Example 1A (b) was carried out to obtain (Z) -3-acetoxy-4,4,4-trifluoro-1-phenyl-1-phenyl.
I got butene.

(C) hydrolysis step The same operation as in Example 1A (c) was performed, and (3R)-(+)
-(Z) -4,4,4-trifluoro-3-hydroxy-1
-Phenyl-1-butene and (3S)-(Z) -3-acetoxy-4,4,4-trifluoro-1-phenyl-1-butene were obtained.

(D) cyclopropanation step In this step, the same operation as in Example 1A (d) was performed.

The physical properties of the obtained (1R)-(+)-1- (cis-2-phenylcyclopropyl) -2,2,2-trifluoroethanol are shown below.

Molecular weight 216.20 ¹ H-NMR δ (ppm) 0.94 to 1.29 (m, 2H), 1.46 (ddt, J =
6.5,8.9,8.9Hz, 1H), 2.12 (d, J = 6.5Hz, 1H), 2.37 (dt,
J = 6.5,8.7Hz, 1H), 3.19 (dq, J = 8.9,6.3Hz, 1H), 7.29
(M, 5H) ¹⁹ F-NMR + 1.08 (d, J = 6.8 Hz) IR (cm ⁻¹ ) 3400, 2945, 1605, 1500, 1450 Example 2B (1S)-(−)-1- (cis Synthesis of -2-phenylcyclopropyl) -2,2,2-trifluoroethanol (C) hydrolysis step (3S)-obtained in the hydrolysis step of Example 2A (c) above
(Z) -3-acetoxy-4,4,4-trifluoro-1-
2.61 g (17.4 mmol) of potassium carbonate was added to 1.41 g (5.8 mmol) of phenyl-1-butene, 15 ml of methanol and 1 ml of water, and reacted at room temperature for 3 hours. After distilling off the solvent under reduced pressure, 1N hydrochloric acid was added to stop the reaction, and the mixture was extracted with dichloromethane. Next, it was washed with water and dried over anhydrous magnesium sulfate. After distilling off dichloromethane under reduced pressure,
Separation and purification by silica gel column chromatography,
(3S)-(-)-(Z) -4,4,4-trifluoro-3-
Hydroxy-1-phenyl-1-butene was obtained.

(D) cyclopropanation step The same operation as in Example 1A (d) was performed, and cyclopropanation was performed to obtain (1S)-(−)-1- (cis-2-phenylcyclopropyl) -2,2,2-trifluoroethanol.

Example 3A Synthesis of (1R)-(+)-1- (trans-2-hexylcyclopropyl) -2,2,2-trifluoroethanol (A) Reduction step (E) -1,1,1-trifluoro-2-hydroxy-3-decene was obtained from 1,1,1-trifluoro-2-hydroxy-3-decyne in the same manner as in Example 1A (a). Was.

(B) acylation step The same operation as in Example 1A (b) was carried out to obtain (E) -2-acetoxy-1,1,1-trifluoro-3-decene.

(C) hydrolysis step By performing the same operation as in Example 1A (c), (2R)-(+)
-(E) -1,1,1-trifluoro-2-hydroxy-3
-Decyne and (2S)-(E) -2-acetoxy-1,1,1-
Trifluoro-3-decene was obtained.

(D) cyclopropanation step (2R)-(+)-(E) -1,1,1-trifluoro-2
-Hydroxy-3-decene was subjected to the same operation as in Example 1A (d).

The physical properties of the obtained (1R)-(+)-1- (trans-2-hexylcyclopropyl) -2,2,2-trifluoroethanol are shown below.

Molecular weight 224.27 ¹ H-NMR δ (ppm) 0.72 to 1.57 (m, 17H), 2.48 (bs, 1
H), 3.32 (dq, J = 11.9, 6.5 Hz, 1H) ¹⁹ F-NMR + 1.05 (d, J = 6.2 Hz) IR (cm ⁻¹ ) 3360, 2900 Example 3B (1S) − (−) Synthesis of -1- (trans-2-hexylcyclopropyl) -2,2,2-trifluoroethanol (C) hydrolysis step Example 2B (2S)-(E) -2-acetoxy-1,1,1-trifluoro-3-decene obtained in (c)
The same operation as in the hydrolysis step (c) was performed.

(D) cyclopropanation step The same operation as in Example 1A (d) was performed on the obtained (2R)-(-)-(E) -1,1,1-trifluoro-2-hydroxy-3-decene to obtain (1S)-( −)-1- (trans−
(2-hexylcyclopropyl) -2,2,2-trifluoroethanol was obtained.

Example 4A Synthesis of (1R)-(+)-1- (cis-2-hexylcyclopropyl) -2,2,2-trifluoroethanol (A) Reduction step The same operation as in Example 2A (a) was carried out to obtain (Z) -1,1,1-trifluoro-2-hydroxy-3-decene from 1,1,1-trifluoro-2-hydroxy-3-decyne. Was.

(B) acylation step The same operation as in Example 1A (b) was performed to obtain (Z) -2-acetoxy-1,1,1-trifluoro-3-decene.

(C) hydrolysis step By performing the same operation as in Example 1A (c), (2R)-(+)
-(Z) -1,1,1-trifluoro-2-hydroxy-3
-Dezen and (2S)-(Z) -2-acetoxy-1,1,1-
Trifluoro-3-decene was obtained.

(D) cyclopropanation step (2R)-(+)-(Z) -1,1,1-trifluoro-2
-Hydroxy-3-decene was subjected to the same operation as in Example 1A (d).

The physical properties of the obtained (1R)-(+)-1- (cis-2-hexylcyclopropyl) -2,2,2-trifluoroethanol are shown below.

Molecular weight 224.27 ¹ H-NMR δ (ppm) 0.70 to 1.89 (m, 17H), 2.28 (bd, 1
H), 3.52 (dq, J = 13.1, 6.3 Hz, 1H) ¹⁹ F-NMR + 1.07 (d, J = 6.2 Hz) IR (cm ^-1 ) 3370,2900 Example 4B (1S)-(-) Synthesis of -1- (cis-2-hexylcyclopropyl) -2,2,2-trifluoroethanol Example 4B The above Example 2B was applied to (2S)-(Z) -2-acetoxy-1,1,1-trifluoro-3-decene obtained in Example (c).
The same operation as in (c) was performed.

(D) cyclopropanation step (2S)-(-)-(Z) -1,1,1-trifluoro-2
-Hydroxy-3-decene was subjected to the same operation as in Example 1A (d) to give (1S)-(-)-1- (cis-2-hexylcyclopropyl) -2,2,2-trifluoroethanol. Obtained.

Example 5 Synthesis of (+)-(trans-2-trifluoromethylcyclopropyl) phenylmethanol (B) acylation step (E) -1,1,1-trifluoro-4-hydroxy-4
-Phenyl-2-butene 3.00 g (14.8 mmol) and pyridine 1.8 ml (22.2 mmol) in dichloromethane solution (10 m
l) was stirred in an ice bath and 2.3 ml of isobutyryl chloride (2
2.2 mmol) was added dropwise over 5 minutes and reacted at room temperature for 2 hours. The reaction was stopped by adding 1N hydrochloric acid thereto, and extracted with dichloromethane. Next, it was washed with water and dried over anhydrous magnesium sulfate. After distilling off dichloromethane under reduced pressure, the residue was separated and purified by silica gel column chromatography.

(C) hydrolysis step The same operation as in Example 1A (c) was performed, and (+)-(E)
-1,1,1-trifluoro-4-hydroxy-4-phenyl-2-butene and (E) -4-isobutyryloxy-1,
1,1-trifluoro-4-phenyl-2-butene was obtained.

(D) cyclopropanation step (+)-(E) -1,1,1-trifluoro-4-hydroxy-4-phenyl-2-butene was subjected to the same operation as in Example 1 (d).

The physical properties of the obtained (+)-(trans-2-trifluoromethylcyclopropyl) phenylmethanol are shown below.

Molecular weight 216.20 ¹ H-NMR δ (ppm) 0.78 to 1.09 (m, 2H), 1.36 to 1.77
(M, 2H), 1.92 (ds, 1H), 4.59 (d, J = 4.2Hz, 1H), 7.24
7.47.49 (m, 5H) ¹⁹ F-NMR -10.67 (d, J = 6.8 Hz) IR (cm ⁻¹ ) 3330 The optical purity [% ee], specific rotation [α] ] _D and the yield (%) are shown together.

[Effects of the Invention] As described above, the optically active fluorinated α-hydroxycyclopropane compound according to the present invention has a remarkably high optical purity, and various liquid medicines including liquid crystals, or as intermediates thereof. Broad and effective use is expected.

Claims (1)

(57) [Claims] (1) General formula (In the formula, R ¹ and R ² are each a fluorine-substituted alkyl group having 1 to 2 carbon atoms, an alkyl group having 1 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Wherein at least one of R ¹ and R ² represents a fluorine-substituted alkyl group having 1 to 2 carbon atoms.) An optically active fluorine-containing α-
Hydroxycyclopropane compounds.