JPH0570439A - Production of optically active azole derivative - Google Patents

Abstract

PURPOSE:To easily provide in high yield the title derivative having excellent antibacterial activity. CONSTITUTION:The racemic compound of an alcohol derivative of formula l (X is CH or N; Y is H or halogen; n is 1 or 2) is condensed at 10-100 (pref. 10-50) deg.C with an optically active o-acetylmandelic acid in the presence of a dehydrating agent (pref. dicyclohexylcarbodiimide) to produce o-acetylmandelic acid derivatives of formula II, which are then separated into the respectively corresponding diastereomers followed by hydrolysis with an acid or base to obtain optically active alcohol derivatives of formula III in high yield. Thence, each of these derivatives is reacted at -78 to 200 (pref. -20 to 100 deg.C with an alkene halide of formula IV (Z is halogen; m is 1 or 2; wavy line denotes that either cis-or trans-comformation is possible), thus efficiently obtaining the objective optically active azole derivative of formula V.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active azole derivative, and more particularly to a method for producing an optically active azole derivative having an excellent antifungal activity.

[0002]

2. Description of the Related Art Conventionally, it is known that some azole derivatives have antifungal activity, and for example, clotrimazole, miconazole, sulconazole, ketoconazole, fluconazole and the like have been reported.

By the way, fungal infections are often caused by fungi that normally do not cause infectious diseases, as seen in bacterial replacement phenomenon, opportunistic infections, etc., and once infected, such as deep infections, severe infections occur. It is said that it is preferable to use a drug having a broadest antifungal spectrum and having a systemic action for the treatment because it may cause a serious medical condition.

On the other hand, physiologically active substances that interact with enzymes and receptor proteins in the living body are
It is expected that there will be differences in physiological activity. Therefore,
Optically active substances have also attracted attention in the fields of pharmaceuticals and the like. Therefore, there is a strong demand for a method of obtaining these optically active substances in a simple and high yield, and many methods have been studied so far. For example, Japanese Patent Publication Sho 55-396641
Japanese Patent Publication No. 2 discloses a method for producing an alcohol derivative which is an important intermediate for the synthesis of an optically active compound having an antifungal action.

[0005]

However, since the yield of the (-) form among the alcohol derivatives obtained by the above method is as low as 1.3%, there is a problem in putting the above method into practical use. Therefore, it has been desired to develop a method by which an optically active compound having an antifungal effect can be simply obtained in a high yield.

[0006]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of the above-mentioned circumstances, and as a result, optically active o-acetylmandelic acid was reacted with a racemic compound of alcohols to obtain an ester form, which was diastereomeric. It was found that the optically active alcohols can be obtained in a high yield when separated into mers and then hydrolyzed, and that optically active azole derivatives having antifungal activity can be efficiently obtained by using these optically active alcohols as raw materials. The present invention has been completed.

The present invention is represented by the following reaction formula.

[Chemical 7]

(In the formula, X represents --CH or a nitrogen atom,
Y represents a hydrogen atom or a halogen atom, n represents 1 or 2, Z represents a halogen atom, m represents 1 or 2, and
The wavy line indicates that either the cis or trans configuration can be adopted. )

That is, the present invention is represented by the general formula (5), which is obtained by condensing a racemic compound of an alcohol derivative represented by the general formula (4) and an optically active o-acetylmandelic acid in the presence of a dehydrating agent. -Providing a method for producing an optically active alcohol derivative represented by the general formula (2), characterized in that an acetylmandelic acid derivative is separated into respective diastereomers and then hydrolyzed.

The present invention is also characterized by reacting an optically active alcohol derivative represented by the general formula (2) with a halogenated alkene represented by the general formula (3). It also provides a method for producing an azole derivative.

Each step of the above reaction formula will be described below. First, the reaction of the racemic compound (4) of the alcohol derivative with the optically active o-acetylmandelic acid is carried out, for example, by adding 1.0 to 2.0 mol of o-acetyl to 1 mol of the racemic compound (4) of the alcohol derivative. With mandelic acid
It is carried out by stirring at a temperature of 10 to 100 ° C, more preferably 10 to 50 ° C for several hours. Examples of the solvent include ethyl acetate, methylene chloride, chloroform and the like, but any solvent that is inert to the above reaction can be used.

As the dehydrating agent, dicyclohexylcarbodiimide, phenyldichlorophosphate, chlorosulfonyl isocyanate, methanesulfonyl chloride / triethylamine, N, N'-carbonyldiimidazole and the like can be used. Of these, dicyclohexylcarbodiimide is particularly preferable. After completion of the reaction, the solvent is distilled off, and the obtained mixture of diastereomers is separated by means such as chromatography and recrystallization, and purified if necessary, whereby the diastereomeric compound (5) can be isolated. .

Hydrolysis of the isolated diastereomer (5) is carried out by acting with an acid or base. For example, 1.0 to 1 with respect to 1 mol of the compound (5)
It is carried out by stirring with 0.0 mol of base at a temperature of 0 to 80 ° C. for several minutes to several hours. Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like. Examples of the solvent include water, methanol, ethanol, dimethyl sulfoxide, N, N-dimethylformamide and the like, but any solvent can be used as long as it is inert to the reaction. After completion of the reaction, the solvent is distilled off and the optically active alcohol derivative (2) can be isolated by means of chromatography, recrystallization or the like.

Next, the reaction between the optically active alcohol derivative (2) and the halogenated alkene (3) is carried out by, for example, 1.0 to 3.
Using 0 mol of halogenated alkene (3), -78 to 20
It is carried out by stirring at 0 ° C., preferably −20 to 100 ° C. for several hours. Any base can be used as long as it does not adversely affect the reaction.
For example, sodium hydride, sodium amide, potassium carbonate, sodium carbonate, potassium hydroxide and the like are preferably used. Any solvent can be used as long as it is inert to the reaction. For example, N,
N-dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether, tetrahydrofuran, ethanol, methanol and the like are preferably used. After completion of the reaction, the solvent is distilled off and the optically active azole derivative (1) of the present invention is isolated by purification by means such as chromatography.

The optically active azole derivative (1) of the present invention thus obtained is further subjected to inorganic salts such as nitrates and hydrochlorides, or fumaric acid, maleic acid, tartaric acid and citric acid by a conventional method, if necessary. It can be an organic acid salt such as an acid.

[0016]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Example 1 (+) and (-)-1- (2,
4-dichlorophenyl) -2- (1H-imidazole-
Preparation of 1-yl) ethanol (±) -1- (2,4-dichlorophenyl) -2- (1
H-imidazol-1-yl) ethanol 33.10
g, (S)-(+)-o-acetylmandelic acid 25.0
g was dissolved in 1200 ml of ethyl acetate, and 26.6 g of dicyclohexylcarbodiimide was added. After stirring for 1.5 hours, the precipitate was collected by filtration, and the organic layer was washed with 1000 ml of saturated sodium hydrogen carbonate aqueous solution and 1000 ml of saturated saline solution and dried with sodium sulfate. 63.42 g of an oily substance obtained by concentration was separated by flash column chromatography to obtain 16.42 g of a low polar component (yield 29.4).
%) And 22.60 g of a highly polar component (yield 40.4%). The low polar component was recrystallized from chloroform / ether / hexane.

The shape, mp, Rf value, and
The data relating to NMR, IR and the like are shown below. White needle crystals mp 101.6-102.9 ℃ Rf value (Merck Art.5715, MeOH / CHCl ₃ = 1/30) 0.51 ¹ H NMR (CDCl ₃ , δ, ppm) 2.18 (s, 3H), 4.17 (dd, 1H , J = 14.9,5.9Hz), 4.19 (dd, 1H, J = 1
4.9,3.6Hz), 5.97 (s, 1H), 6.25 (m, 1H), 6.32 (s, 1H), 6.81
(s, 1H), 6.93 (s, 1H) 7.03 (d, 1H, J = 8.4Hz), 7.22 (dd, 1H, J = 8.4,1.5Hz), 7.42 (d,
1H, J = 1.5Hz), 7.47 (s, 5H) IR (KBr, cm ^-1 ) 3132,3116,2944,1762,1744,1592,1510,1476,1446,1387,
1352,1334,1286,1283,1204,1182,1142,1106,1088,1072,
1062,1040,1002,880,834,820,788,748,694,664,622,56
2,530

The highly polar component is chloroform / ether /
Recrystallization was performed with hexane. Shape below, mp,
Data relating to Rf value, NMR, IR, etc. are shown. White powdery crystal mp110.2-111.1 ℃ Rf value (Merck Art.5715, MeOH / CHCl ₃ = 1/30) 0.38 ¹ H NMR (CDCl ₃ , δ, ppm) 2.22 (s, 3H), 4.26 (dd, 1H , J = 15.0,4.7Hz), 4.42 (dd, 1H, J = 1
5.0,3.2Hz), 5.97 (s, 1H), 6.19 (d, 1H, J = 8.4Hz), 6.28 (m, 1
H), 6.74 (s, 1H), 6.85 (d, 1H, J = 8.4Hz), 6.96 (s, 1H), 7.23
(s, 1H) 7.30 ~ 7.35 (m, 1H) 7.40 (s, 5H) IR (KBr, cm ^-1 ) 3124,2956,1768,1594,1504,1476,1442,1384,1370,1272,
1228,1184,1170,1146,1104,1080,1060,1022,1006,926,9
08,896,822,810,764,740,706,696,660,630,594,500

Next, 12.0 g of crystals of a highly polar component was dissolved in 30 ml of methanol, and 60 ml of methanolic KOH was added. After stirring for 30 minutes at room temperature, 10 ml of water was added and methanol was distilled off. 100 ml of water was added and extracted with chloroform. The crude product obtained by drying over sodium sulfate and concentrating was recrystallized from chloroform / hexane to obtain 6.29 g of white needle crystals.

The yield from the racemate was 35.5%, and the yield of the reaction was 88%. Below mp, specific rotation, NM
Data concerning R, IR, etc. are shown. mp109.6-110.6 ° C [α] _D ²⁰ -98 ° (C; 0.354, methanol) ¹ H NMR (CDCl ₃ , δ, ppm) 3.84 (dd, 1H, J = 14.1,8.3Hz), 4.19 (dd, 1H , J = 14.1,2.1Hz),
5.21 (dd, 1H, J = 8.3,2.1Hz), 6.80 (s, 1H), 6.88 (s, 1H), 7.23
~ 7.32 (m, 1H), 7.35 (s, 1H), 7.39 (d, 1H, J = 2.0Hz) 7.60 (d, 1H, J = 8.4Hz) IR (KBr, cm ^-1 ) 3120,2940,2852 , 2756,1588,1562,1516,1478,1448,1386,
1284,1238,1108,1078,1052,1028,924,896,862,830,818,
792,744,660,628,484

In the case of the low-polarity component as well, in the same manner as in the case of the high-polarity component, 6.23 g of white needle crystals were obtained from 12.0 g of the low-polarity component crystal. The yield from the racemate is 25.8%,
The reaction yield was 88%. The data on mp and specific rotation are shown below. mp109.4 to 111.1 ° C. [α] _D ²⁰ 99 ° (C; 0.320, methanol) As is clear from the above, the optically active alcohol derivative of the present invention can be obtained only in a simple process and in high yield. did it.

Example 2 (+) and (-)-1- [2-
(2,4-dichlorophenyl) -2-{(E) -3,7
-Dimethylocta-2,6-dienyloxy} ethyl]-
Production of 1H-Imidazole ((-) Compound 1 and (+) Compound 2) (-)-1- (2,4-dichlorophenyl) -2- (1
H-imidazol-1-yl) ethanol 2.5 g D
The MF solution was added dropwise to a DMF suspension of 0.42 g of NaH at room temperature. After stirring at 40 ° C for 10 minutes, -1 in an ice-salt bath
After cooling to 0 ° C., a DMF solution of 2.32 g of geranyl bromide was added dropwise. After stirring for 20 minutes as it was, the temperature was raised to room temperature, and the mixture was stirred at room temperature for 2.5 hours. DMF is distilled off and water is added 1
50 ml was added and the mixture was extracted 3 times with 100 ml of ethyl acetate. 3. Crude product obtained by drying and concentrating with sodium sulfate
33 g was column-separated, and a pale yellow oily substance (Compound 1) 2.
83 g (yield 74%) was obtained.

The data relating to the specific optical rotation, NMR and IR are shown below. [α] _D ²⁰ -88 ° (C; 0.402, Methanol) ¹ HNMR (CDCl ₃ , δ, ppm) 1.50 (s, 3H), 1.60 (s, 3H), 1.69 (s, 3H), 1.87 (m, 4H), 3.79 (d
d, 1H, J = 11.7,7.3Hz), 3.91 (dd, 1H, J = 11.7,6.6Hz), 3.99 (d
d, 1H, J = 14.3,7.3Hz), 4.15 (dd, 1H, J = 14.3,2.7Hz), 4.92 (d
d, 1H, J = 7.3,2.7Hz), 5.03 to 5.12 (m, 1H), 5.17 to 5.24 (m, 1
H), 6.93 (s, 1H), 7.02 (s, 1H), 7.22 ~ 7.38 (m, 2H), 7.38 ~
7.43 (m, 1H), 7.48 (s, 1H) IR (neat, cm ^-1 ) 2968,2932,2860,1590,1506,1473,1440,1386,1287,1233,
1218,1107,1095,1077,1044,1005,909,867,825,789,756,
663,627

This oily substance was dissolved in ethanol and a solution of 1.25 g of fumaric acid in ethanol was added. After ethanol was distilled off, acetone was added and hexane was added to obtain 3.18 g of white powdery crystals. Specific rotation is [α] _D ²⁰ -57 °
(C; 0.268, methanol). Then (+)-1-
2.85 g of a pale yellow oily substance (compound 2) having (+) optical rotation in the same manner as above, starting from 2.5 g of (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethanol. (Yield 75%) was obtained. The specific rotation is
It was [α] _D ²⁰ 87 ° (C; 0.504, methanol). Also,
Fumaric acid was added in the same manner as in the production of compound 1 to obtain 3.04 g of white powdery crystals (compound 2). Specific rotation is [α] _D
^{It was 20} 56 ° (C; 0.342, methanol). As is clear from the above, according to the present invention, an optically active azole derivative can be obtained by a simple process and in high yield.

The compounds 1 and 2 thus obtained were tested for antifungal activity. Sabouraud agar medium (glucose 2%, peptone 1%, agar 1.5%) was used to aseptically prepare dilution series plates of the test substance. To this, 1 μl of a test bacterial solution was inoculated with a fixed amount of platinum or the like, the yeast was cultured at 37 ° C., and after 2 days, the growth state was determined to determine the minimum inhibitory concentration (M
IC, μg / ml) was determined. The results are shown in Table 1.

[0027]

[Table 1]

Example 3 (+) and (-)-1- [2-
(2,4-Dichlorophenyl) -2-{(E, E)-
3,7,11-Trimethyldodeca-2,6,10-trienyloxy} -ethyl] -1H-imidazole ((-)
(-)-1- (2,4-dichlorophenyl) -2- (1)
0.08 g of NaH was added to a DMF solution of 0.50 g of H-imidazol-1-yl) ethanol. After stirring at room temperature for 2 hours, farnesyl chloride 0.607 g DMF
The solution was added dropwise at room temperature. After stirring for 15 minutes at room temperature, D
MF was distilled off, 100 ml of water was added, and 70 ml of ethyl acetate was added for 3 times.
Extracted twice. Dried over sodium sulfate, concentrated to 10
0 g of crude product was obtained. This crude product was subjected to flash column chromatography to obtain 0.54 g of a pale yellow oily substance (Compound 3).

Data relating to specific optical rotation, NMR, IR, etc. are shown below. [α] _D ²⁰ -72 ° (C; 0.250, Methanol) ¹ HNMR (CDCl ₃ , δ, ppm) 1.50 (s, 3H), 1.60 (s, 6H), 1.68 (s, 3H), 1.84 (m, 8H), 3.78 (d
d, 1H, J = 11.6,7.5Hz), 3.90 (dd, 1H, J = 11.6,6.5Hz), 3.98 (d
d, 1H, J = 14.4,7.3Hz), 4.16 (dd, 1H, J = 14.4,2.8Hz), 4.91 (d
d, 1H, J = 7.3,2.8Hz), 5.01 to 5.29 (m, 3H), 6.93 (s, 1H), 7.02
(s, 1H), 7.26 to 7.32 (m, 2H), 7.38 to 7.42 (m, 1H), 7.45 (s, 1
H) IR (neat, cm ^-1 ) 2928,2860,1592,1506,1472,1442,1386,1232,1108,1092,
1044,824,790,662

A pale yellow oil (Compound 4) 0 was prepared in the same manner as in the production of Compound 3 using 0.5 g of (+)-1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethanol. 0.45 g (yield 52%) was obtained. The specific optical rotation was [α] _D ²⁰ 72 ° (C; 0.234, methanol).

[0031]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active azole derivative having an excellent antifungal activity and an optically active alcohol derivative which is a production intermediate thereof can be easily produced in a high yield.

Claims (3)

[Claims] 1. The following general formula (2): (Wherein, X represents —CH or a nitrogen atom, Y represents a hydrogen atom or a halogen atom, and n represents 1 or 2), and an optically active alcohol derivative represented by the following general formula (3): 2] (In the formula, Z represents a halogen atom, m represents 1 or 2, and the wavy line represents that it can have either a cis or trans configuration.) The following is characterized by reacting with a halogenated alkene. General formula (1) (In the formula, X represents —CH or a nitrogen atom, Y represents a hydrogen atom or a halogen atom, and m and n are 1 or 2 respectively.
And the wavy line indicates that either the cis or trans configuration can be adopted. The manufacturing method of the optically active azole derivative represented by these. 2. The following general formula (4): (In the formula, X represents —CH or a nitrogen atom, Y represents a hydrogen atom or a halogen atom, and n represents 1 or 2.) and a racemic compound of an alcohol derivative and an optically active compound o.
-Acetylmandelic acid is condensed with a dehydrating agent in the following general formula (5): (In the formula, X represents —CH or a nitrogen atom, Y represents a hydrogen atom or a halogen atom, and n represents 1 or 2.), and the o-acetyl mandelic acid derivative is separated into respective diastereomers. The following general formula (2) is characterized by post-hydrolysis. (In the formula, X represents —CH or a nitrogen atom, Y represents a hydrogen atom or a halogen atom, and n represents 1 or 2.). 3. The method for producing an optically active alcohol according to claim 2, wherein the dehydrating agent is dicyclohexylcarbodiimide.