JPH03128338A - Production of optically active diol compound - Google Patents

Abstract

PURPOSE:To obtain the subject compound as intermediate of antifungal agent having high optical purity in one process by reacting an optically active epoxy alcohol having aryl at 2-position and alkyl at 3-position with alkoxide, imidazole or triazole as the nucleophilic agent in the presence of a basic catalyst. CONSTITUTION:An optically active 2,3-epoxy alcohol compound expressed by formula I (R is lower alkyl; Ar is substitutable phenyl) is reacted with a compound expressed by formula II (Nu is alkoxy, imidazolyl or triazolyl) in a solvent in the presence of a basic catalyst to afford the objective optically active diol compound expressed by formula III having alkoxy, amidazole or triazole group at 1-position carbon and simultaneously having inverted stereospecific configuration of 2-position carbon. Said compound is useful as synthetic intermediate of antifungal agent. By this method, number of processing stages are reduced and product having high optical purity is obtained.

Description

Detailed Description of the Invention The present invention provides an optically active compound represented by the formula (wherein R represents a lower alkyl group and Ar represents a phenyl group which may have a substituent). H(2) [In the formula, Nu represents an alkoxy group, imidazolyl group or triazolyl group] By reacting with a compound represented by the formula [In the formula, R1^r, Nu represents the same meaning as above] This is a method for producing an optically active diol compound, which is characterized by obtaining the compound shown below.

In the above formula, R includes lower alkyl such as methyl, ethyl, propyl, and isopropyl.

Ar is 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 2-fluoro-
Examples include 4-(1-lifluoromethyl)phenyl, 2-10-4-fluorophenyl, and Matacha-4-2-fluorophenyl.

Examples of Nu include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, and p-methoxybenzyloxy, or imidazolyl and triazolyl.

This production method uses an optically active 2,3-epoxy alcohol compound (1
) is reacted with an alkali metal salt of alcohol or an alkali metal salt of igodazole or triazole to introduce an alkoxy group, imidazole group, or triazole group into the 1-position carbon of the starting compound (1), and at the same time introduce an alkoxy group, an imidazole group, or a triazole group into the 2-position carbon. The optically active diol compound (3) obtained by this method is a compound useful as an intermediate for antifungal agent synthesis.

It has been previously reported that the above optically active diol compound (3) (Nu:
986) ). Furthermore, a method for producing an optically active antifungal agent derived from the diol compound using lactic acid as a starting material is described in Japanese Patent Application No. 1-51336. The above-mentioned method using L-lactic acid as a starting material is a useful method because the starting material is inexpensive and easily available, but the reaction process is rather long, and racemization may occur in part, or the formation of stereoisomers may occur. This is not always a satisfactory method. Therefore, the present inventors developed a formula [wherein R and Ar have the same meanings as above] that can be obtained relatively easily starting from L-lactic acid without racemization or generation of stereoisomers. We investigated the reactions of the indicated compound under various conditions and found that the desired diol compound (3) could be obtained in one step.We succeeded in shortening the number of steps and at the same time obtaining a compound with high optical purity. and completed the present invention.

Generally, 2,3-epoxy alcohol (A) as shown in the following formula is produced under alkaline conditions, its isomer 1,2
-Epoxy-3-ol (B), and it is known that both exist as an equilibrium mixture (Payne rearrangement). When an appropriate nucleophile Nu is present in this reaction system, the nucleophile Nu selectively reacts only with highly reactive 1,2-epoxy-3-ol (B) to obtain diol (C). . Suitable nucleophiles in this reaction include mercaptans and (A) (B) H H (C) amines [C, tl, Behrens &
K.B.

5harpress, Aldrichimica
Acta 6. 67 (1983)).

The present inventors have determined that the epoxy alcohol corresponding to (A) is a compound of formula (1) having an aryl group at the 2-position, an alkoxide or imidazole as a nucleophile,
Using triazole, we investigated the above-mentioned Payne rearrangement-epoxide ring-opening reaction and found that the reaction proceeded regioselectively (ring-opening at C-1 position) and stereospecifically (inversion of steric configuration at C-3 position). It has been found that the target diol (3) can be obtained.

The method of the present invention will be specifically explained below.

In this method, when an optically active compound represented by the formula Ar is reacted with a compound represented by the formula in the presence of a solvent, an optically active diol compound (3) represented by the formula (2) is obtained. It will be done.

As the solvent used in the reaction, when Nu is an alkoxy group, the corresponding alcohol, ie, methanol, ethanol, propatool, isopropanol, benzyl alcohol, p-methoxybenzyl alcohol, is used, and usually the epoxidized metal (1 ) is suitable. Further, these alcohols may be used in combination with a solvent that does not participate in the reaction, such as ether, tetrahydrofuran, or ethers such as dioxane. When Nu is a dazolyl or triazolyl group, the reaction solvent is preferably a tertiary alcohol such as L-methanol or t-alcohol. The appropriate amount of imidazole and triazole to be used is 1 to 3 molar equivalents of the epoxy compound. The basic catalyst used in the reaction is the usual Pay
In addition to the sodium hydroxide used in the ne rearrangement reaction, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. can be used in the presence of water if necessary, but in order to suppress the by-formation of triol compounds. Preferably, when Nu is alkoxy, a metal alkoxide obtained by dissolving lithium, sodium or potassium metal in the corresponding alcohol, or when Nu is imidazolyl or triazolyl, a lithium, sodium or potassium salt of a tertiary alcohol used as a reaction solvent. is preferably used under anhydrous conditions. The amount of base catalyst used is N
If u is alkoxy, 0 for epoxy compound (1)
．． When Nu is imidazolyl or triazole, it is desirable to use 1 to 1.2 molar equivalents of the imidazole or triazole used. The reaction temperature is from room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent. Reaction time is 1 to 15 hours. The diol compound (3), which is a reaction product, can be isolated from the reaction solution by a conventional organic synthesis method. For example, after the completion of the reaction, the reaction solution is cooled, an appropriate amount of water is added, extracted with an appropriate organic solvent, the extract is dried, and the solvent is distilled off to obtain the target compound. If necessary, a pure product can be obtained by further performing column chromatography or recrystallization.

In addition, the optically active compound (1) which is the starting compound of the present invention
) is prepared according to a known method, for example, the method described in Japanese Patent Application No. 1-51336.
It can be produced by the following route using L-α-acetoxy lower fatty acid (4) derived from hydroxy lower fatty acid as a starting material.

(4) (5) (6) (7) (8) (9) 00) (II) (1) On the other hand, the diol compound (3) obtained by the method of the present invention can be used as an important intermediate in the synthesis of antifungal agents. Available.

For example, compound (3A) in which Nu is a benzyloxy group can be led to compounds 07) and 120 having strong antifungal activity by the following route.

(3A) 02) 8r (13) 04) 08) 09) Among the compounds represented by the general formula (3) of I2, the compound (3B) in which Nu is a triazolyl group is the same as described above in the route shown below. (3B) (21) In the above formula, R and Ar have the same meanings as above, THP represents a 2-tetrahydropyranyl group, and Ms represents a methanesulfonyl group. and R' represents a phenyl group which may have a substituent.

Examples and reference examples are given below to specifically demonstrate the present invention.
offi) was washed with hexane, dissolved in benzyl alcohol 20, and (23,3R)-2-(
2,4-difluorophenyl)-2,3-epoxy-1
- Add 2.50 g (12.5 mmole) of butanol. Heat at 100'C for 4 hours under nitrogen atmosphere.

After the reaction is complete, add ice water to the reaction solution and saturate it with salt.
Extract with ethyl acetate. After washing the extract with saturated brine and drying over anhydrous magnesium sulfate, the solvent and most of the benzyl alcohol were distilled off under reduced pressure to obtain (2R,3R)-
5.0 g of a mixture of 1-benzyloxy-2-(2,4-difluorophenyl)-2,3-butanediol and benzyl alcohol was obtained as an oil.

NMR spectrum (CDCI!, 3) δppm
: (Excluding absorption of benzyl alcohol) 0.
83(3H, d, J=6.5f(z); 3.65(il
l, dd, J=9.5, 1.5Hz); 4.07 (1
8, dd, J=9.5°1.511z); 4.42(
III, qd, J=6.5.3Hz); 4.50(2
8, s); 6.5-7.1 (2H, m), 7.27 (
5)1. s); 7.73 (1B, td, J=9°6.
5Hz).

4-1 (2S, 3R)-2-(2,4-difluorophenyl)
-2,3-epoxy-1-butanol 138ml (0
, 69 mmol) and triazole 134 mg (2,0
Dissolve 7mmoJ2) in L-butanol 4.1 Ini, and dissolve 256mg of potassium t-butoxide (2.28m
mof) for 15 h at 70 °C under nitrogen atmosphere.
A. Stir. After the reaction is completed, water is added, extracted with ethyl acetate, dried, and the solvent is distilled off. The resulting crude product was chromatographed on silica gel with ethyl acetate. The desired (2R,3R)2-(2,4-difluorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2,3-butanediolttOmg(
Yield: 59%) was obtained as a solid. Specific optical rotation [α]. -1
01° (c=0.95.cHclz). Recrystallization from acetone-benzene mixed solvent yields a melting point of 126-
82 mg of pure product with a temperature of 118°C was obtained.

Specific optical rotation (α) o 108° (c = 0.79. CI
ICL).

NMR spectrum (CDCf s) 6 ppm: 0
．． 95 (31Ld, J=6.5Hz); 2.8H11
1, d, J=9) 1z); 4.35 (IH, m),
4.75 (IH, s); 4.80 (28, s); 6
．． 7-7.0 (2H, m); 7.2-7.7 (IH,
m); 7.84 (18, s); 7.88 (LH, s
).

The method of Lochschen Lund-Cohen et al. (S. G., Cohen, J. Am.
Chem.

Soc, 85.1685 (1963)). (S)-2-acetoxypropionic acid 20
g (0.15 mole) of methylene chloride 100 trt
16.9 ml of oxalyl chloride (0,
197 mole) and dimethylformamide 1.0 i
ft and stirred at room temperature for 185 hours. After the reaction is complete,
25.9 g (0,227 mole) of m-difluorobenzene was added to the oil obtained by distilling off the solvent under reduced pressure, and then 50.5 g of aluminum chloride was added under stirring while cooling with water.
(0,379 mole) was added. After 1 hour, the temperature was returned to room temperature, and stirring was continued overnight. After adding 60-methylene chloride,
The reaction solution was added little by little to water. Ethyl acetate 400 m
The organic layer was separated, washed successively with water, aqueous sodium bicarbonate, and saturated brine, and the solvent was distilled off. 36 g of the obtained oil was dissolved in 180 ml of methanol, and while stirring while cooling with water, 15 ml of concentrated sulfuric acid diluted with water was added, and the mixture was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, 400% of ethyl acetate was added, and water and hydrogen carbonate were added.
The mixture was washed successively with Jum water and saturated brine, and the solvent was distilled off.

Distill the residual oil to a boiling point of 65-67°C (3mmHg)
18.65 g (yield 66.8%) of the target compound with
I got it.

Specific optical rotation [α) D 67.1° (c=1.17.C
HCJ23).

Infrared absorption spectrum ν. x (CIICf s) cm
Reference: 3500, 1680° NMR spectrum (CD (/!i + ozo ) δpp
m: 1.42 (311, dd, J=6.5.2Hz)
; 5.0 (IH, qd, J=6.5.2Hz); 6.
7-7.3 (2H, m); 7.8-8.2 (LH,
m).

-Herobinyloxy erent(S)-(2,4-difluorophenyl) 1-hydroxyethyl ketone 10.0 g (53.7 mmo
le) in 100 d of methylene chloride, and while stirring under water cooling, 5.87 g of 2,3-dihydrobilane (
69.8 mmole) and 945 mg of pyridinium P-toluenesulfonate were added. Return to room temperature 3,5
After standing for a period of time, ethyl acetate was added, and the mixture was washed with aqueous sodium hydrogen carbonate and saturated brine. After drying, the solvent was distilled off and the obtained oil was subjected to silica gel chromatography.
Elution was performed with a mixed solvent of benzene-hexane (4:1) to obtain 13.0 g of the target compound as an oil.

Specific optical rotation (α) o 56.3° (c=1.11.C
HCffi 3).

Infrared absorption spectrum! ' mix (CHCj! :+
) Cm-': 1695°NMR spectrum (CDC
j23) δppm: 1.42 (1.5H.

dd, J=6.5.3Hz); 1.45(1,5H
, dd, J=6.5.1.5Hz); 1.3-2.0(
6H, m): 3.1-4.02)1. m); 3
．． 6-3.8 (IH, m); 4.86 (0,511, q
d, J=6.5.2Hz); 5.10 (0.5H,
qd, J=6.5.211z); 6.7-7.2 (211, m); 7.7 8.2 (lft, m).

To 110 d of anhydrous tetrahydrofuran, 1.
60 g (66 mmole) and vinyl bromide 7,
4 ml (105 mmole) was added, and the mixture was heated and stirred at 45-50°C for 5 minutes under a nitrogen atmosphere. Once the reaction started, the temperature was returned to room temperature and stirred for 30 minutes. The reaction solution was cooled with dry ice-acetone, and (S)-(2,4-difluorophenyl)-1-(2-tetrahydropyranyloxyethyl ketone 7.10 g (26,3 mmole)
) in 70d of anhydrous tetrahydrofuran,
The mixture was added dropwise over 30 minutes while stirring. After raising the temperature to -30°C and stirring for 20 minutes, saturated ammonium chloride solution was added and extracted with ethyl acetate.

After washing the organic layer with saturated brine, the solvent was distilled off to obtain 7.85 g (yield: 100%) of the target compound as an oil.

NMR spectrum (CDCf:+) δppm:
0.92 (1,5H.

d, J = 6.5Hz); 1.01 (1,5H, d, J
=6.511z); 1.2-2.0(6H, m);
3.19 (Ill, d, J=4Hz); 3.3-4.
1 (3H, m); 4.1-4.6 (IH, m): 4.
6-4.9 (ill, m); 5.0-5.6 (211
, m); 6.2-7.0 (3H, m); 7.6-8.
0(IH, m).

Nyl-4-ben-so23-diolto(3R,43)-3-(2,4-difluorophenyl)
-4-(2-tetrahydropyranyloxy)-1-penten-3-ol 7.85 g (26,3 mmol
e) was poured into BOml of methanol, 500 mg (2.6 mmole) of P-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 20 minutes. After about half of the methanol was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed successively with aqueous sodium bicarbonate and saturated brine, and the solvent was distilled off. The obtained oil was subjected to column chromatography using 100 g of silica gel, and benzene-ethyl acetate (10:1
) Elution with a mixed solvent yielded 5.60 g of the target compound (yield: 99
%) was obtained as an oil.

Specific optical rotation (α) o +54.3° (cmo, 96.C
HC41! the law of nature.

N? II? Spectrum (CDCl!, z: DzO=
20:1) δppm: 0.98 (38, d, J=
6.511z); 4.38 (IH, qd, J=6.
5.3Hz); 5.23 (IH, br, d, J=11t
(z); 5.44 (LH, br, d, J=18Hz
); 6.50 (LH, ddd, J=18.11.311
z); 6.5-7.0 (211, m); 7.5-8
．． 0 (IH, m).

none-3-old (23,3R)-3-(2,4-difluorophenyl)
-4-pentene-2,3-diol 5.60 g (26
, 1 mmole) in 40 mf of pyridine and heated to 0°
3.65 m of methanesulfonyl chloride while stirring at C.
1 (47 mmole) was added. After 15 minutes, pyridine was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed successively with cold aqueous sodium hydrogen oxide and saturated brine. The solvent was distilled off and the desired product 8. Obtained OOg as an oil.

Infrared absorption spectrum ν,. (C) ICl z) cm-
': 3600, 1350.1180° NMR spectrum (cocL) δppm: 1
．． 25 (38, d.

J=6.511z); 3.03(311,s); 4
．． 30 (IH, q, J=6.5Hz); 5.2-5.7
(211, m); 6.54 (IH, ddd, J=17
．． 11.3Hz); 6.6-7.0211. m); 7
．． 4-8.0 (Ill, m).

Lu--Lu 2-vinyl oxirant 55% sodium hydride 1.80 g (41,3 mm
ole) was washed with dry hexane and then suspended in 80 ml of dimethylformamide. Dissolved in 40 ml of anhydrous tetrahydrofuran (3R245
)-3-(2,4-difluorophenyl)-4-(methanesulfonyloxy)-1-penten-3-ol8.
0 Og (26 mmole) was fully discharged in 5 minutes.

After returning to room temperature and stirring for 3 hours, ice water was added and extracted with hexane. The solvent was distilled off, and the obtained oil was subjected to column chromatography using 50 g of silica gel and eluted with a benzene-hexane (3:1) mixed solvent to obtain 4.23 g of the target compound (2-step yield: 83 %) was obtained as an oil.

Specific optical rotation C (X'J o +76.3° (cm0.95
．． CHCj! 3).

NMR spectrum (cocL) δppm: 1
．． 40 (38, d.

J=5.511z); 3.1? (IH, q, J=5.
5Hz); 5.15 (IH, dt, J=17.1.5
Hz); 5.30 (LH, dd, J=11, 1.5H
z); 6.03 (IH, ddd, J=17.11.1
．． 5Hz); 6.6-7.6 (3H, m).

-3-Eboxybut-(2R,3R)-2-(2,4-difluorophenyl)
-3-methyl-2-vinyloxirane 4.18g (2
1.3 mmole) was dissolved in methanol-water (5:2) mixed solvent 210-, and sodium mek periodate 13
．． 7 g (64 mmole) and 1 osmium tetroxide
25 ml was added and stirred at room temperature for 2.5 hours. After adding ethyl acetate and washing with saturated brine, the solvent was distilled off to obtain 4.20 g of the target compound as an oil.

NMR spectrum (COCl,) δppIl: 1.6
0 (311, d.

J=5.5Hz); 3.42(111,q, J=5.
511z); 6.7-7.0 (28, m); 7.1-
7.5(II(,m); 9.65(LH,d, J=2
Hz).

Ru--Epoxy--ru(2R,3R)-2-(2,4-difluorophenyl)
-2,3-epoxybutanal 4.20 g (21,2
mmole) and 80 ml of methanol. Ninjakashi,
Under water cooling and stirring, 0.80 g of sodium borohydride.
(21.2 mmole) was added and pressed at the same temperature for 30 minutes. After concentrating methanol to about half under reduced pressure,
Ethyl acetate was added, and the mixture was washed with saturated brine.

The oil obtained by distilling off the solvent was subjected to chromatography using 60 g of silica gel and eluted with a benzene-hexane (4:1) mixed solvent to obtain the target compound 3. OOg(
A two-step yield of 70%) was obtained as an oil.

Specific optical rotation (cr) o 21.8° (cm1.10.C
tlt,e:l).

Infrared absorption spectrum V IIIX (CHCj2:+
) Cm-': 3500.1100°NMR spectrum (CDCε3) δppm:
1.48 (3H, dJ=5.51!z); 2.02
(IH, s); 3.10 (III, q, J=5.5
Hz); 3.83 (111, d, J=12)1z);
4.17 (111, dd, J=12.0.511z)
; 6.6-7.1 (2H, m); 7.2-7.6 (
LH, m).

Unpurified (2R,3R)-1-benzyloxy-2-(2,4-difluorophenyl)-2,
3-Butanediol5. 100 ml of ethanol
1.0 g of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature under a hydrogen gas atmosphere at normal pressure for 25 hours. After the reaction is completed, the reaction solution is filtered using Celite. The residue obtained by concentrating the filtrate was subjected to column chromatography on silica gel and eluted with a mixed solvent of benzene-ethyl acetate (1:1) to obtain 2.26 g (yield 83% in two steps from epoxy alcohol) of (2R ,3R)-2-(2,4-difluorophenyl)-1,2,3-butanetriol was obtained as a solid. Specific optical rotation (α). +11.5° (cm
1.05. CHI, ), recrystallized from acetone-cyclohexane to obtain pure product 1 having a melting point of 81-82'C.
．． 99 g was obtained.

Specific optical rotation [αL+11.8° (cm0.97.CHC
l:l).

Infrared absorption spectrum ν□X (KBr) cm-':
3430(br,), 3370(br,).

NMR spectrum (CD: 1cOcD3) δppm
: 0.87 (311, d.

J=6.5Hz); 3.5-4.7 (6H, m);
6.7-7.2 (2H, s); 7.81 (III,
td, J・9,7H7,).

, 221] Shisagi Nijo (2R,3R)-2-(2,4-difluorophenyl)
-1,2,3-butanetriol 1.54 g (7
,06 mmole) to 6 mft of pyridine? 1.51 ml (19.5 mmole) of methanesulfonyl chloride was added to the flask while stirring at 0°C, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, pyridine was distilled off under reduced pressure, and 59 mfl of ethyl acetate was added to the obtained oil, which was washed successively with cold aqueous sodium hydrogen oxide solution and saturated brine.

The solvent was distilled off to obtain 2.64 g (yield 96%) of the target compound as an oil.

NMR spectrum (CDC13) δppm: 1.2
3 (3H, d.

J=6.5Hz); 2.95(3[(,s); 3.
10 (3H, s); 3.82 (LH.

s); 4.70 (2H, s); 5.32 (LH, q
, J=6.511z); 6.7-7.2(211,m
); 7.6-8.0 (LH, m).

Part 2, Section 11, 1.08 g (24.7 mm) of 55% sodium hydride
After washing the ole) with dry hexane, it was suspended in 30 rrdl of dimethylformamide and added to I with stirring at O'C.
H-12,4-triazole 1.95 g (28,2
mmole) was gradually added. When the generation of hydrogen gas has stopped, add 2.62 g (7,05 mmol) of (2R,3R)-2-(2',4-difluorophenyl)-1,3-bis(methanesulfonyloxy)2-butanol.
A solution of e) dissolved in dimethylformamide (5 mA) was added, and the mixture was stirred at 65-70"C for 2 hours. The solvent was distilled off under reduced pressure, cold water was added, and the mixture was extracted twice with 50% of benzene. The organic layer was saturated. After washing with brine, the solvent was distilled off and the resulting oil was subjected to column chromatography using 30 g of silica gel, eluted with a benzene-+lf-ethyl (2:1) mixed solvent, and the resulting crystals were Recrystallization from benzene-hexane gave 1.40 g (79% yield) of the target compound having a melting point of 88-89.5°C.

Specific optical rotation [α] o 7.55' (c=1.06
．． CHCj23) NI'IR spectrum (CDC no. 3)
δppm: 1.64<311. dJ=5.5
11z); 3.16 (11Lq, J=5.5tlz)
: 4.40 (It!, d, J=1511z); 4.
88 (ltl, d, J=15Hz); 6.5-7.2
(311, m); 7.79 (LH, s); 7.98 (
LH,s).

(2R,3S)-2-(2,4-difluorophenyl)
-3-Methyl-2-C(I H-1,2,4-triazol-1-yl)methyl]oxirane 30 g (119
mmole) in 400 ml of dimethylformamide, and 23.5 g (360 mmole) of sodium azide was dissolved in 400 ml of dimethylformamide.
) and ammonium chloride 10.6g (195mmole
) and stirred at 105°C for 4 hours. After cold welding, benzene was added to the reaction mixture, which was then washed with water and saturated brine, dried, and then the solvent was distilled off. 32.7 g of crystalline residue obtained
was recrystallized from benzene-hexane to give a melting point of 139.
-140'C target compound 25.8g (yield 73
%) was obtained.

Specific optical rotation Ca'J o 88' (c=1.12.
CI (C13).

Infrared absorption spectrum νwax (KBr) Cm-'
:3195(br,), 2120.2090.

NMR spectrum (CDCl2:+) δppm
: 1.16 (3H, d.

J=6.5Hz); 3.7B(LH, q, J=6.5
11z); 4.78 (2H, s); 4.95 (LH,
s); 6.5-7.0 (211, m); 7.2-7
．． 6 (LH, m); 7.76 (IH, s); 7.82
(LH,s).

Zol-1-yl-2-phenolt(2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(I H-1,2,4-triazol-l-yl)-2 -Butanol5. OOg to 100ml of ethanol? To the flask, 1.3 g of 10% palladium on carbon was added, and the mixture was stirred for 1 hour under a hydrogen gas atmosphere at normal pressure. After the reaction is complete, filter the reaction solution using Celite,
When the solvent is distilled off, the target compound 4.
56 g (yield 100%) was obtained.

Recrystallized from benzene, melting point 154-155°C
A pure product with .

Specific optical rotation (α), -73° (cm1.06. Cf1
Cffi3).

Infrared absorption spectrum ν. x (KBr) cm-':
3210, 1620.1600°NMR spectrum (CDC°C3) δppm:
0.84 (3H, dJ=6.51Lz); 1.04-
1.91(211,br,); 3.61(ill,q
, J=6.5Hz); 4.3-5.5(lft, br
); 4.68 (2H, s); 6.5-7.1 (2
H, m); 7.2-7.84 (iH, m); 7.8
1 (IH, s); 8.01 (18, s).

1.13 g (4 ,2
1 mmoA) is dissolved in 12 ml of pyridine, and while stirring at 0°C, 1.05 g (5.03 mmole) of 4-(trifluoromethyl)benzoyl chloride is added. After 1 hour, 0.5 mQ of methanol was added at the same temperature, and the mixture was stirred for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, and then the solvent is distilled off. The resulting residue was chromatographed on silica gel and eluted with benzene-ethyl acetate (2:IHm mixed solvent) to obtain 1.80 g of the title compound as an oil.

Specific optical rotation [α] D”-101° (C・1.10.C
HCl:l).

tJMR spectrum (cDcL) δI)pm:
1.05 (3H, d.

J=7Hz); 4.46(18,d, J=14Hz
); 4.95 (LH, m); 5.08 (IH, d, J
=14t(z); 5.40(III, s); 6.6
-7.0 (2H.

m); 7.2-7.6 (Ill, m); 7.7
2 (2H, d, J=8Hz); 7.82 (2H, s
); 8.00 (2H, d, J=8!Iz).

1.65 g of this amide compound was added to 10 ml of ethyl acetate.
Dissolve in 1.03ml of 4N hydrogen chloride-dioxane solution.
1 was added and crystallized to obtain 1.44 g of hydrochloride having a melting point of 132-140°C.

Specific optical rotation [α) o 72.3' (c・0.97.
EtOH) Infrared absorption spectrum ν□x (KBr)
cm-': 3360, 3240.1655°-55% sodium hydride 35mg (0,80mmof
After washing f) with hexane, dimethylformamide 2m
122 mg of thioacetic acid (1,
60 mmof). After stirring at the same temperature for 5 minutes (2R
35)-2-(2,4-difluorophenyl)-3-methyl-2-((I H-L2,4-)lyazole-1
-yl)methyl]oxirane 100 mg (0,31
0 mmof) and stirred at 70°C for 4 hours. After the reaction is completed, ethyl acetate is added to the reaction mixture, and the mixture is washed with dilute deuterium chloride water and saturated saline in this order. The oil obtained by distilling off the solvent was purified by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (1:3) mixed solvent] to obtain the title compound 91■ (yield 70%). was obtained as an oil.

Specific optical rotation (α) o 1.42° (cml, 07.C
lICE:l).

Infrared absorption spectrum I' max (CIICj2 i
)Cm-' :3440,168O NMI? Spectrum (CD13) δppm:
1.11 (3H.

d, J=7! Iz); 2.40 (3H, s); 4.
33 (IH, q, J = 711z); 4.62 (III,
d, J=1511z); 4.94(IH, d, J=1
511z); 5.25 (ill, br,); 6.5-
7.0 (211, m); 7.1-7.6 (IH, m)
; 7.74 (LH, s); 7.82 (III, s).

Azol-1-yl-2-benolt 21 mg (0.92 mmole) of sodium was added to 7 ml of methanol under a nitrogen atmosphere. At night, -10
'C at (2R,3R)-3-(acetylthio)-2-(
2,4-difluorophenyl)-1-(IH-1,2,
4-) Riazol-1-yl)-2-butanol 300
mg (0.92 mmole) and stirred at the same temperature for 1 hour. After the reaction is complete, 60 mg of acetic acid is added, diluted with ethyl acetate, and washed with saturated saline. The crude product obtained by distilling off the solvent is purified by column chromatography on silica gel.

Elution with a benzene-ethyl acetate (2:1=I:1) mixed solvent gave 195 mg (yield 74%) of the title compound as crystals. Recrystallization was performed from a mixed solvent of ethyl acetate and hexane to obtain a pure product having a melting point of 175-178°C.

Specific optical rotation [α]o 53.3° (c=0.52.H
e'll).

NMR spectrum (CDCf,) δppm 71
．． 13 (311, d.

J=7Hz); 1.91(IH, dd, J=10.0
．． 5t (z); 3.46 (IH, m); 4.76 (1
8, d, J=1511z); 5.04 (Ill, d,
J=151(z); 6.5-7.0(211,m);
7.41 (11, td, J=9.6.511z);
7.80 (211°S).

Reference 111L Eruto(2R,3R)-2-(2,4-difluorophenyl)
-3-Mercapto-1-(L H-1,2,4triazol-1-yl)-2-butanol 165 mg (0,
58 mmon) in 2 ml of pyridine and cooled in water.
A While stirring, 263 μm (1,16 mmoffi) of 2-fluoro-4-(trifluoromethyl)benzoyl chloride was added and stirred for 30 minutes. Add 1 mf of methanol to the reaction solution.
After stirring for 15 minutes, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed successively with water and saturated brine, and the solvent was distilled off. The crude product obtained is purified by chromatography on silica gel. Elution with benzene-ethyl acetate (1:1) mixed solvent yielded the title compound 205■
was obtained as an oil.

NMR spectrum (CDCl2:l) δppm
: 1.22 (3H, d.

J=IHz"): 4.66 (111,q, J=711
z): 4.71 (IH, d, J=14Hz); 5.0
8 (18, d, J=1411z); 5.35 (IH,
d, J=1.5Hz); 6.7-7.0 (2H, m)
; 7.2-8.2 (411, m); 7.80 (It
(,s).

7.85 (IH, s).

200μ of this thioester is dissolved in ethyl acetate, oxalic acid 39Id is added and cooled to precipitate oxalate 1-2-2-1<2R,3R)-2-(2,4-difluorophenyl).
-1-(I H-1,2,4-1-riazol-1yl) -2,3-butanediol 240 mg (0,8
Dissolve 9 mmof) in 6 ml of pyridine and stir on ice for 1↑
Bottom, methanesulfonyl chloride 163 mg (1,4
2 mmole). After returning to room temperature and stirring for 2 hours,
Dilute aqueous sodium bicarbonate is added to the residue obtained by distilling off pyridine under reduced pressure, and the mixture is extracted with ethyl acetate. After washing with saturated brine, the solvent was distilled off to give 31.0 mg of the title compound (yield 100
%) was obtained as an oil.

Specific optical rotation (α) o 97° (c=1.11.CHC
E3).

NMR spectrum (CDC1x) δppm
: 1.27 (311, d.

J=6.511z); 3.1l (311,s); 4
．． 69 (IH, d, J = 1411z); 5.04 (LH
, d, J=14Hz); 5.33(ltl, q, J=
6.5Hz); 5.38(ill,s); 6.6-
7.0 (211, m); 7.2-7.7 (III,
m); 7.75 (18, s); 8.03 (LH, s
).

Pouryl methyl oxynto 55% sodium hydride 35mg (0.80mmof
) with hexane, then add 2 m of dimethylformamide.
(2R, 3 shaku)-2(2,
4-difluorophenyl)-1-(LH-C2,4-1
250 mg (0,72 mmo)-3-(methanesulfonyloxy)-2-butanol
f! ,) to 2 ml of tetrahedral o-))? Add the solution dropwise to the container. The reaction was brought to room temperature and stirred for 1 hour. Add ethyl acetate, wash with saturated brine, dry, and then evaporate the solvent. The obtained solid crude product was recrystallized from a benzene-hexane mixed solvent to give a melting point of 88-89.5.
157.degree. C. of the title compound (yield 87%) was obtained.

Specific optical rotation [α) o 7.5' (c=0.93.
CHCj23) NMR spectrum matched that of the compound of Reference Example 11.

Claims (1)

[Claims] Optical activity represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R represents a lower alkyl group, and Ar represents a phenyl group which may have a substituent] By reacting a compound represented by the formula Nu-H with a compound represented by the formula Nu-H [wherein, Nu represents an alkoxy group, imidazolyl group, or triazolyl group], the formula ▲ is a mathematical formula, a chemical formula, a table, etc. ▼ [where R , Ar, and Nu have the same meanings as above.