JPH0249742A - Optically active fluorine-containing alpha-hydroxycyclopropane compound - Google Patents

Abstract

NEW MATERIAL:An optically active fluorine-containing alpha-hydroxycyclopropane compound expressed by formula I (R<1> and R<2> are 1-2C fluorine-substituted alkyl, 1-10C alkyl, 7-10C aralkyl or 6-10C aryl, provided that at least either of R<1> and R<2> is 1-2C fluorine-substituted alkyl). EXAMPLE:(1R)-(+)-1-(trans-2-Phenylcyclopropyl)-2,2,2-trifluoroethanol. USE:A raw material for esters, ethers and carboxylic acids used as an enzymic inhibitor, biologically active substance, anticancer agent and ferroelectric liquid crystal. PREPARATION:For example, a compound, having triple bond and expressed by formula II is reduced to provide a compound expressed by formula III, which is then acylated to afford a compound expressed by formula IV. The resultant compound expressed by formula IV is further subjected to asymmetric hydrolysis using an enzyme to provide compounds expressed by formulas V and Va. The obtained compound expressed by formula V is then converted into cyclopropane to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to esters used as enzyme inhibitors, biologically active substances, anticancer agents, and ferroelectric liquid crystals.

The present invention relates to an optically active fluorine-containing α-hydroxycyclopropane compound useful as a raw material for ethers and carboxylic acids.

[Prior Art and Problems to be Solved by the Invention] Several compounds have been reported so far as optically active fluorine-containing alcohols (fluorine-containing hydroxy compounds) that are applied to liquid crystals, pharmaceuticals, and the like.

However, a fluorine-containing hydroxy compound with satisfactory optical purity has not yet been reported.

Therefore, an object of the present invention is to provide a novel optically active fluorine-containing hydroxy compound with high optical purity.

[Means to solve the problem]

In particular, the present inventors investigated various optically active hydroxy compounds containing a cyclopropane ring and found that an optically active fluorine-containing hydroxy compound with high optical purity can be obtained by asymmetric hydrolysis using an enzyme. completed.

That is, the present invention is based on the general formula OH (where RI and R2 are each a fluorine-substituted alkyl group having 1 to 2 carbon atoms, an alkyl group having 1 to 10 carbon atoms,
Aralkyl group having 7 to 10 carbon atoms or 6 carbon atoms
~10 aryl groups are shown. However, at least one of R' and R2 represents a fluorine-substituted alkyl group having 1 to 2 carbon atoms. ) An optically active fluorine-containing α-
The present invention provides hydroxycyclopropane compounds.

The optically active fluorine-containing α-hydroxycyclopropane compound of the general formula (I) according to the present invention has various types depending on the type of substituents R' and R'', but all of them are bonded to hydroxyl l (OH). It is an optically active compound in which the carbon atom of
, Rz is a fluorine-substituted alkyl group having 1 to 2 carbon atoms (e.g., a methyl group, an ethyl group, etc. in which some or all of the hydrogen atoms are substituted with fluorine), a fluorine-substituted alkyl group 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.), aralkyl group having 7 to 10 carbon atoms (benzyl group, phenethyl group, etc.) or aryl group having 6 to 10 carbon atoms (phenyl group) , tolyl group, p-chlorophenyl group, 1m-chlorophenyl group, etc.). However, at least one of R1 and Rz needs to be the aforementioned fluorine-substituted alkyl group having 1 to 2 carbon atoms.

There are various specific examples of the optically active fluorine-containing α-hydroxycyclopropane compound of the present invention, and in addition to those described in the Examples below, compounds with various structures can be produced. Is possible.

By the way, this fluorine-containing α-hydroxycyclopropane compound can be produced by various methods, but for boat fishing, it can be produced by the following reaction formula.

OH * (V) * (I) In the above formula, COR' represents an acyl group.

Next, each manufacturing process will be explained in detail.

Reduction step A fluorinated hydroxy compound (fluorinated alcohol derivative) having a triple bond of general formula (II) is reduced to produce a fluorinated hydroxy compound having a double bond of general formula (II[). The reducing agent that can be used in this step may be any reducing agent commonly used to reduce triple bonds to double bonds, but depending on the type of reducing agent, the bond on both sides of the double bond obtained after reduction may be Causes differences in structure.

For example, when this bond structure is trans-type, sodium bis(2-methoxyethoxy)aluminum hydride;Na(A I!, Hz(OCH2CR20CH
z)z Lithium diisobutylmethylaluminum hydride; LiA E H ((CHs)zc HCHz] 2G
Hz, tributyltin hydride; (CaHJtSnH and the like may be mentioned, but sodium bis(2-methoxyethoxy)aluminum hydride is particularly optimal.

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

In addition, when the bond structure is cis-type, a method using Lindlar catalyst; Pd/CaCO3Pd(OAc)t or Pd/Ba5On-quinoline catalyst together with hydrogen, diisobutylaluminum hydride; AfH[(CH3)z
Although there are methods using cHcH2h etc. as a reducing agent, a combination using hydrogen and a Lindlar catalyst is particularly preferred. This reaction is preferably carried out in an organic solvent such as hexane.

Acylation Step Acylation can be carried out in a conventional manner. Examples of the acylating agent include acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, octyl chloride, and the like.

Enzymatic hydrolysis step By asymmetrically hydrolyzing the compound obtained in the acylation step with an enzyme, a compound of general formula (V) with high optical purity can be obtained.

As the enzyme, various so-called hydrolytic enzymes can be used, such as lipase P.

Lipase MY, Lipase M10. Lipase OF.

Lipase P679. Cellulase, PLE, etc. can be used. In this case, the optical activity varies depending on the enzyme selected. For example, when lipase MY is used, if the generated hydroxy compound (alcohol derivative) is dextrorotatory, the acylated product (V a ) can be used with cellulase, etc. When treated with an enzyme or a basic catalyst such as sodium hydroxide, it may become a left-handed hydroxy compound. Furthermore, when lipase P is used, a hydroxy compound having a decorative property opposite to that of lipase MY may be obtained.

Cyclopropanation step The compound of general formula (1) of the present invention is obtained by cyclopropanation of the optically active compound obtained by enzymatic hydrolysis.

Cyclopropanation can be carried out using a combination of methylene iodide (CH, I2) and Sm, Zn-Cu or Zn(CzHs)z, or diazomethane (CHzNz) and a Zn1z catalyst. Especially methylene iodide and Sm
A combination of these is desirable as a stereoselective reaction.

This reaction is carried out in an organic solvent such as tetrahydrofuran, and the reaction temperature can range from low to high temperatures, but is optimally around O'C.

The reactions in each step are carried out under optimal conditions, and are carried out by appropriately selecting the reaction time, temperature, etc. depending on conditions such as the type of solvent and the amount of various auxiliaries added.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to this.

Example IA Synthesis of (IR)-(+) nylcyclopropyl) ethanol CH (a) Reduction step CH 1-(trans-2-fe2.2.2-trifluoro+Na (Af H2(OCH2CH2OCHs)z)
Under a nitrogen atmosphere, add 40 d of ether to a three-necked flask, and place the reaction vessel in a dry ice-acetone bath.
It was kept at 0°C. 4.5 d (15.3 mmol) of sodium bis(2methoxyethoxy)aluminum hydride was added thereto, and the dry ice-acetone bath was heated to -50°C.
After that, 2.81 g (14,0
An ether solution (10d) of 1 mmol) was added dropwise over 10 minutes to react for 1 hour, and then for another 1 hour at room temperature.

The reaction was stopped by adding 1N hydrochloric acid thereto, and the mixture was extracted with ether. Then saturated sodium bicarbonate solution,
It was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the ether under reduced pressure, the residue was separated and purified using silica gel column chromatography.

(b) Acylation step H Ac (E)-4,4,4-trifluoro-3 obtained in the reduction step
-Hydroxy-1-phenyl-1-butene 3.75 g
(17,7 mmol) and pyridine 1.6R1 (19,
A dichloromethane solution (20d) of 4 mmol) was stirred in a water bath, 1.6 mmol of acetyl chloride (23.0 mmol) was added dropwise over 5 minutes, and the mixture was reacted at room temperature for 13 hours. 1 for this
The reaction was stopped by adding specified hydrochloric acid, and extracted with dichloromethane.

Next, it was washed with water and dried over anhydrous magnesium sulfate.

After dichloromethane was distilled off under reduced pressure, the residue was separated and purified using silica gel column chromatography.

(c) Hydrolysis step Ac -1-butene and (3S)-(E)-3-acetoxy-
4,4,4-)rifluoro-1-phenyl-1-butene.

(d) Cyclopropanation step H (E)-3-acetoxy obtained in the acylation step 4.4.4
-1-Lifluoro-1-phenyl-1-butene 4.23
g (17.5 mmol) was suspended in 70ml of distilled water and kept at 40-41°C in a constant temperature bath. There is lipase MY (
2.0 g (manufactured by Meito Sangyo Co., Ltd.) was added and reacted for 6 hours and 30 minutes. The reaction was stopped by adding 1N hydrochloric acid thereto, ethyl acetate was added thereto, the mixture was suction filtered through Celite, and then extracted with ethyl acetate. Next, it was washed with saturated brine, and anhydrous magnesium sulfate was dried. After distilling off ethyl acetate under reduced pressure, it was separated and purified by silica gel column chromatography to obtain (3
R)-(-)-(E)-4,4゜4- t+7 Fluoro-3-hydroxy-1-pheniH \,h 1.6 samarium in a three-necked flask under an argon atmosphere
0 g (10,6 mmol), tetrahydrofuran (
3d of THF) was added and the reaction vessel was kept at 0°C with a water bath. A THF solution 3d containing 0.14 g (0.5 mmol) of mercuric chloride was added dropwise thereto over 10 minutes, and the (3R)(-) -(E)-4,4,4- A THF solution of 0.20 g (1.0 mmol) of trifluoro-3-hydroxy-1-phenyl-1-butene was added to 10
The mixture was added dropwise over a period of minutes and stirred for 30 minutes. Next, a THF solution of 0.81 methylene iodide (10.0 mmol) was added to 1
The mixture was added dropwise at 0°C for 1 hour and reacted at room temperature for 2 hours. A saturated potassium carbonate aqueous solution was added to this to stop the reaction, and the mixture was extracted with ether. Next, it was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the ether under reduced pressure, the residue was separated and purified using silica gel column chromatography.

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

Note that the proton nuclear magnetic resonance ('H-NMR) spectrum uses a carbon tetrachloride solvent, and the fluorine nuclear magnetic resonance (I9
F-NMR) spectrum was measured using diethyl ether solvent.

Molecular weight 216.20'H-NMRδ (ppm) 0.93-1.50 (t
s, 3H).

1.88-2.31 (ra, 2H).

3.67 (dq, J=6.3.12.6Hz.

7.24 (rm, 5H) "F-NMR+0.82 (d, J-6,8Hz) I
R(am-') 3400.2940.1610
．． 1505.1445 Example IB Synthesis of (Is)-(-)-1-(trans-2-phenylcyclopropyl)-2,2,2-)rifluoroethanol H Ma (c) Hydrolysis step Ac Ma H Ma LH).

(3S)- obtained in the above Example IA (c) hydrolysis step
(E)-3-acetoxy-4,4゜4-trifluoro-
2.57 g (10.6 mmol) of 1-phenyl-1-butene was suspended in 50 d of distilled water and heated in a constant temperature bath for 40-40 g.
It was kept at 1°C. 1.2 g of cellulase (manufactured by Amano Pharmaceutical Co., Ltd.) was added thereto, and the mixture was allowed to react for 300 hours. The reaction was stopped by adding 1N hydrochloric acid thereto, ethyl acetate was added thereto, the mixture was suction filtered through Celite, and then extracted with ethyl acetate. Next, it was washed with saturated brine and dried over anhydrous magnesium sulfate.

After distilling off ethyl acetate under reduced pressure, it was separated and purified using silica gel column chromatography to obtain (3S)-(+)-(E).
-4°4.4-) Refluoro-3-hydroxy-1-phenyl-1-butene was obtained.

(d) Cyclopropanation step H The same operation as the cyclopropanation step of Example IA (d) was carried out, and (IS)-(=)-1-()trans-2-phenylcyclopropyl)- 2,2°2-trifluoroethanol was obtained.

Example 2A (IR) = (+) -1-(cis-2-phenylcyclopropyl)-2,2,2-) Synthesis of refluoroethanol ○H (a) Reduction step H H OAc Under hydrogen atmosphere, three Lindlar catalyst 0.4 in a two-flask
0g of hexane were added, and the reaction vessel was maintained at -78°C with a dry ice-acetone bath.

There, 4,4,4-trifluoro-3-hydroxy-
4.02 g (20.1 mmol) of 1-phenyl-1-butyne was added dropwise over 5 minutes, and the mixture was reacted at room temperature for 14 hours.

After filtering the reaction solution and distilling off hexane under reduced pressure, it 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 Example IA Perform the same operation as in (b) to obtain (Z) = 3-
Acetoxy-4,4,4-trifluoro-1-phenyl-1-butene was obtained.

(C) Hydrolysis step The same operation as in Example IA (c) was performed, and (3R)-(+
)-(Z)-4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butene and (33)-(Z)-3
-acetoxy-4,4,4-trifluoro-1-phenyl-1-butentra was obtained.

(d) Cyclopropanation step H H This step was also performed in the same manner as in Example IA (d).

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

Molecular weight 216.20'H-NMRδ (ppm) 0.94-1.29 (cm
, 2H).

1.46 (dat, J=6.5.8.9°8.9Hz
, IH).

2.12 (d, J=6.5Hz, 10).

2.37 (dt, J=6.5.8.7Hz.

3.19 (dq, J-8,9,6,3Hz.

7.29 (m, 5H) ”F-NM R+1.08 (d, J=6.8H2) IR
(Rho') 3400. 2945. 1605.
1500. 1450 Example 2B Synthesis of (IS)-(-)-1-(cis-2-phenylcyclopropyl)-2,2,2-trifluoroethanol H Ma(c) Hydrolysis step Ac MaH Ma Above example Obtained in the hydrolysis step of 2A (c) (3S)
-(Z)-3-acetoxy-4,4,41H).

-trifluoro-1-phenyl-1-butene 1.41
g (5.8 mmol) and methanol 15d.

2.61 g (17.4 mmol) of potassium carbonate was added to water 1-, and the mixture was reacted at room temperature for 3 hours. After evaporating the solvent under reduced pressure, 1N hydrochloric acid was added to stop the reaction, followed by extraction with dichloromethane. Next, it was washed with water and dried over anhydrous magnesium sulfate. After distilling off dichloromethane under reduced pressure, it was separated and purified using silica gel column chromatography to obtain (3S) -(-)-(Z)-4,4,4-)lifluoro-3-hydroxy-1-phenyl-1-butene. Obtained.

(d) Cyclopropanation step H Propanation was performed to obtain (IS)-(-)-1-(cis-2-phenylcyclopropyl)-2,2,2-trifluoroethanol.

Example 3A Synthesis H of (IR)-(+)-1-(1-lanse-2-hexylcyclopropyl)-2,2,2-trifluoroethanol H (a) Reduction step H Example IA (d) Perform the same operation as Cyclo H ＼. 6H13 Working as in Example IA(a), from 1,1,1-trifluoro-2-hydroxy-3-decyne to (E)-1,1
, 1-trifluoro-2-hydroxy-3-decene was obtained.

(b) Acylation step Ac The same operation as in Example LA(b) was performed to obtain (E) 2-acetoxy-1,1,1-)lifluoro-3-decene.

(C) Hydrolysis step The same operation as in Example IA (c) was performed, and (2R)-(+
)-(E)-1,1,1-1-lifluoro-2-hydroxy-3-decyne and (2S)-(E)-2-acetoxy-1,1,1-trifluoro-3-decene. Obtained.

(d) Cyclopropanation step H \. 6H13H0H Ma(2R)-(+)-(E)-1,1,1-)lifluoro-2-hydroxy-3-decene was subjected to the same operation as in Example IA (d).

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

Molecular weight 224.27'H-NMRδ (ppm) 0.72-1.57 (m
, 17H).

2.48 (BS, 18).

3.32 (dq, J=11.9.6.5Hz.

+1.05 (d, J=6.2Hz) 3360,
2900 -9F-NMR IR (cm-') Example 3B (IS) -(-) -1-(1-Lance-2-hexylcyclopropyl)-2,2,2-) Synthesis of refluoroethanol (c) Hydrolysis step AC Example 2B (c) to (2S)-(E)-2-acetoxy-1,1,1-trifluoro-3-decene obtained in Example 3A (C) The same operation as in the hydrolysis step was performed.

(d) Cyclopropanation step H (a) Reduction step H H To the obtained (23)-(-)-(E)-1,1゜1-trifluoro-2-hydroxy-3-decene Example IA
Perform the same operation as (d) and (1s)-(-)-1-(
) lance-2-hexylcyclopropyl)-2,2,2
-1-Refluoroethanol was obtained.

Example 4A Synthesis of (IR)-(+)-1-(cis-2-hexylcyclopropyl)-2,2,2-trifluoroethanol H Similar procedure to Example 2A(a), 1,1 .1-trifluoro-2-hydroxy-3-decyne to (Z)-1,1
, 1-trifluoro-2-hydroxy-3-decene was obtained.

Ac r3 = 1. ．． 11 r, u If-UN The same operation as in Example LA(b) was performed to obtain (Z)-2-acetoxy-1,1,1-trifluoro-3-decene.

(C) Hydrolysis step H Perform the same operation as in Example LA(c), and (2R)-(+
)-(Z)-1,1,1-trifluoro-2-hydroxy-3-decene and (2S)-(Z)-2-acetoxy-
1,1,1-)refluoro-3-decene was obtained.

(d) Cyclopropanation step (2R)-(+)-(z)-1,1,1-)Refluoro-2-hydroxy-3-decene in Example IA (cl)
The same operation was performed.

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

Molecular weight 224.27'H-NMRδ (ppm) 0.70-1.89 (m
, 17H).

2.28 (, bd, LH).

3.52 (dq, J=13.1.6.31 (z.

"F-NMR+1.07(d, J-6,2Hz
)IR (cm-') 3370. 29
00 Example 4B Synthesis of (LS)-(-)-1-, ccis-2-hexylcyclopropyl)-2,2,2-trifluoroethanol H Ma (C) Hydrolysis step H Ma Example 4A ( The same operation as in Example 2B (c) above was performed on the (2S)-(Z)-2-acetoxy-1,1,1-trifluoro-3-decene obtained in c).

(d) Cyclopropanation step H Ma(2S) -(-)-(Z)-1,1,1-4 refluoro-2-hydroxy-3-decene was subjected to the same operation as in Example IA(d). , (IS)-(-)-1-(cis-2
-hexylcyclopropyl)-2,2,2-trifluoroethanol was obtained.

Example 5 Synthesis of (+)-(1-lance-2-trifluoromethylcyclopropyl)phenylmethanol H (b) Acylation step 0COCH(CHsh (E)-1,1,1-trifluoro-4-hydroxy −
4-phenyl-2-butene3. A dichloromethane solution (10d) of OOg (14.8 mmol) and pyridine 1.8 m (22.2 mmol) was stirred in a water bath, and 2.3 d (22.2 mmol) of isobutyryl chloride was added dropwise over 5 minutes. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was stopped by adding 1N hydrochloric acid thereto, and the mixture was extracted with dichloromethane.

Next, it was washed with water and dried over anhydrous magnesium sulfate.

After dichloromethane was distilled off under reduced pressure, the residue was separated and purified using silica gel column chromatography.

(C) Hydrolysis step OCOCR(CH3)2 Perform the same operation as in Example IA(c), and (+)-(E)
-1,1,1-1-refluoro-4-hydroxy-4-
Phenyl-2-butene and (E)-4-isobutyryloxy-1,1,1-1-lifluoro-4-phenyl-2-
Obtained butene.

(d) Cyclopropanation step H H (+)-(E)-1,1,1-trifluoro-4-hydroxy-4-phenyl-2-butene in Example 1 (d
) was performed.

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

Molecular weight 216.20'H-NMR6 (ppm) 0.78-1.09 (m
, 28).

1.36-1.77 (m, 28).

1.92 (BS, IH).

4.59 (d, J=4.2Hz, IH).

7.24-7.49 (m, 5H)” F-NMR-10,67 (d, J=6.811
z)I R(C1l-') 3330 The following table shows the optical purity (%e, e) and specific optical rotation [α] of the products obtained in each example. Yields (%) are summarized.

〔Effect of the invention〕

As described above, the optically active fluorine-containing α according to the present invention
-Hydroxycyclopropane compounds have extremely high optical purity and are expected to be widely and effectively used as liquid crystals, various pharmaceuticals, and intermediates thereof.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 are respectively a fluorine-substituted alkyl group having 1 to 2 carbon atoms, an alkyl group having 1 to 10 carbon atoms, An aralkyl group having 7 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms.However, R^1 and R
At least one of ^2 represents a fluorine-substituted alkyl group having 1 to 2 carbon atoms. ) Optically active fluorine-containing α-
Hydroxycyclopropane compound.