JPH06271531A - Butene derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a butene derivative usable as an intermediate for medicines, agrichemicals, etc., such as utilizability for producing the skeleton of carbapenem-based antibiotic substances. CONSTITUTION:This optically active butene derivative is expressed by formula I (R<2> is 1-4C alkyl, aralkyl or 6-10C aryl in which the aryl can be substituted with halogen, alkyl, OH or alkoxy; * indicates asymmetric carbon), e.g. (E)-(R)-4-benzoylthio-3-buten-2-ol. The compound is obtained by reacting an esterase having the ability to preferentially hydrolyze either of butene derivatives expressed by formula II (R<1> is 1-6C alkyl or 6-16C aryl in which the acyl can be substituted with halogen, alkyl, OH or alkoxy) with the butene derivatives. The compounds expressed by formula II are obtained by reacting butenols expressed by formula III with an acylating agent expressed by formula IV (X is OH, Cl, Br or R<1>COO) in the presence of a base or an acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a butene derivative which can be used as an intermediate for medicines and agricultural chemicals, and a process for producing the same.

[0002]

BACKGROUND OF THE INVENTION The racemic or optically active butene derivative of the present invention is disclosed in Japanese Patent Application Laid-Open No.
The present invention is a compound that can be an intermediate of the drug or the like described in JP-A 1-207373, and an object of the present invention is to provide the compound and an industrially advantageous production method thereof.

[0003]

Means for Solving the Problems The inventors of the present invention have achieved the present invention as a result of extensive studies to solve the above problems. That is, the present invention is represented by the general formula [II]

[Chemical 9] (In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms, an aralkyl group, or an aryl group having 6 to 10 carbon atoms, and the aryl group is substituted with a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group. The optically active butene derivative represented by the symbol * represents an asymmetric carbon.), A method for producing the same, an intermediate and a method for producing the intermediate.

The optically active butene derivative of the present invention [II]
Can be easily used for producing a skeleton of a carbapenem antibiotic as shown below.

[Chemical 10]

The present invention will be described in detail below. The optically active butene derivative [II] of the present invention can be produced, for example, by the following route. [Manufacturing route]

[Chemical 11] First, the reaction of the butenone derivative represented by the general formula [VI] with the thiolcarboxylic acid represented by the general formula [VII] in the first step is carried out in the absence of a solvent or in an organic solvent inert to the reaction in the presence of an acid catalyst. Done in. Examples of the organic solvent used include aliphatic or aromatic hydrocarbons such as heptane, hexane, cyclohexane, toluene, xylene, benzene, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, chlorobenzene, dichloromethane and dichloroethane, ethers and esters. , Halogenated hydrocarbons and the like, and preferably benzene or toluene. Examples of the acid catalyst used in this reaction include inorganic acids or organic acids such as sulfuric acid, paratoluenesulfonic acid, camphorsulfonic acid, etc., and usually a catalytic amount to about 1 equivalent is used. The reaction temperature is usually 20 to 20.
The temperature is in the range of 100 ° C, preferably 30 to 80 ° C. The amount of thiolcarboxylic acid [VII] used is usually 2 to 3 equivalents relative to 1 equivalent of butenone derivative [VI]. When the amount of thiolcarboxylic acid [VII] is as small as about 1 equivalent, some butene derivative [IV] is produced. After the reaction, the butanone derivative [V] can be obtained by the usual post-treatment.

Next, the reaction for obtaining the butene derivative [IV] in the second step is carried out by reacting the butanone derivative [V] with an organic base or a metal salt. Examples of such organic bases include triethylamine, diisopropylethylamine, diazabicycloundecene, and the like, and examples of metal salts include copper salts, zinc salts, and the like. The above reaction is usually performed in the presence of an organic solvent, and as the organic solvent, heptane, hexane, cyclohexane, toluene, xylene, benzene, dioxane, tetrahydrofuran, diethyl ether, dichloromethane,
Examples of solvents that are inert to the reaction, such as chloroform, are:
Tetrahydrofuran, toluene, dichloromethane and the like are preferable. The reaction temperature is usually in the range of -50 to 50 ° C, preferably -15 to 20 ° C. After completion of the reaction, a butene derivative [IV] can be obtained by performing a usual post-treatment.
Is obtained. The butene derivative [IV] obtained in the unreacted state is mainly in the trans form.

Next, the third step is a reaction for reducing butene derivative [IV] obtained above to obtain butenols represented by the general formula [III]. The reducing agent used in the above reaction is preferably sodium borohydride, zinc borohydride, or the like. In the above reaction, an organic solvent inert to the reaction is usually used, and examples of the organic solvent to be used include aromatic hydrocarbons such as toluene and benzene, halogenated hydrocarbons such as chloroform and dichloromethane, tetrahydrofuran, and diethyl. Examples thereof include ethers such as ether, alcohols such as isopropanol, ethanol and methanol, and alcohols or ethers are preferably used.
The reaction temperature is generally -78 to 30 ° C, preferably -20.
It is in the range of -10 ° C. After the completion of the reaction, a butenols [III] can be obtained by a usual post-treatment operation.
In general, reduction of enones may be accompanied by reduction of double bond, but in this reaction, only butenols [III] can be obtained.

In the fourth step, the butene derivative [III] obtained above is reacted with an acid halide or acid anhydride in the presence of a base or an acid to obtain a butene derivative represented by the general formula [I]. It is a reaction. Preferable examples of the base used in the above reaction include organic bases such as pyridine, triethylamine, imidazole, dimethylaminopyridine and picoline. In this reaction, the butene derivative [I] can also be obtained by using an acid such as sulfuric acid or p-toluenesulfonic acid in place of the base and reacting it with an acid anhydride. The above reaction can be carried out in the presence or absence of an organic solvent. Examples of the solvent used include aromatic hydrocarbons such as toluene and benzene, halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrahydrofuran and diethyl ether, and solvents inert to the reaction such as ethyl acetate. And preferably halogenated hydrocarbons or ethers are used. The reaction temperature is -30 to 100.
C., preferably in the range of -10 to 50.degree. After completion of the reaction, the butene derivative [I] can be obtained by a usual post-treatment operation.

In the fifth step, the butene derivative [I] obtained above is subjected to asymmetric hydrolysis using an esterase having the ability to preferentially hydrolyze only one of the compounds [I]. ] It is a reaction which gives the optically active butene derivative shown by these. The esterase in the present invention is not particularly limited as long as it is an enzyme (for example, lipase) that converts an acyloxy group into a hydroxy group. As the hydrolase used, esterase in a broad sense including lipase can be used, and lipase is preferably used. The origin of the lipase to be used is not particularly limited, but lipase derived from microorganisms is inexpensive and easy to obtain in large quantities, and thus is easy to use. Examples of microorganisms having a lipase include Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus. Genus,
Lactobacillus, Trichoderma, Candida,
Saccharomyces, Rhodotorula, Cryptococcus, Tolulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureopasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Acro Examples include microorganisms belonging to the genus Mobacter.

[0010] These microorganisms have lipase in their cells and may be used in the reaction as they are.
It may be used as a crude enzyme solution by a usual method such as ultrasonic crushing, or may be a purified enzyme purified according to a usual purification method. In addition, some microbial-derived lipases are commercially available, and these commercially available enzymes may be used as they are or after performing a simple purification operation. Asymmetric hydrolysis using these enzymes is usually achieved by vigorously stirring the butene derivative [I] in a buffer solution. Of these enzymes, Pseudomonas or Arthrobacter lipases give particularly good results. The preferable pH and concentration of the buffer solution, the reaction time, and the reaction temperature vary depending on the enzyme used and the characteristics of the butene derivative [I]. Preferably, the pH of the buffer solution is 4 to 10, the concentration of the buffer solution is 0.05 to 2 M, the reaction temperature is 10 to 70 ° C., and the reaction time is 10 to 100 hours, but it is particularly limited to these reaction conditions. Not a thing. In addition, in the case of this asymmetric hydrolysis, in addition to the buffer solution, an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, acetone, ethyl ether can be used, and these can be used. Asymmetric hydrolysis can also be advantageously carried out by means of

By the above-mentioned asymmetric hydrolysis reaction, only one of the starting butene derivative [I] is preferentially hydrolyzed to produce the optically active butene derivative [II] represented by the general formula [II]. On the other hand, of the starting butene derivative [I], the other optically active butene derivative [I], which is an optically active substance, remains without being hydrolyzed. After completion of the asymmetric hydrolysis, for example, the reaction solution is subjected to extraction treatment with an organic solvent such as ethyl acetate, chloroform, and ethyl ether, the solvent is distilled off from the organic layer, and the residue is treated with column chromatography or the like. An optically active butene derivative [II] which is an asymmetric hydrolysis product and an optically active butene derivative [I] which is an asymmetric hydrolysis residue can be isolated.

[0012]

The optically active butene derivative of the present invention [II]
Is an important compound as an intermediate for medical and agricultural chemicals, and the intermediate can be advantageously obtained by the production method of the present invention.

[0013]

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

Example 1 Synthesis of 4,4- (dibenzoylthio) butan-2-one (E) -4-Methoxy-3-buten-2-one (20.4 ml)
, 0.2 mol) was dissolved in toluene (300 ml), thiobenzoic acid (52 ml, 0.44 mol) and paratoluenesulfonic acid (700 mg) were added, and the mixture was stirred at 50 to 60 ° C. for 16 hr. After cooling, the reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The concentrated residue is crystallized from ethanol,
58.13 g (84.4%) of the title compound was obtained as fine needle crystals. Melting point: 74-75 ° C NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.41 (2H, d, J = 5.60
Hz), 5.95 (1H, t, J = 5.60Hz), 7.38 ~ 7.96 (5H, m)

Example 2 Synthesis of (E) -4-benzoylthio-3-buten-2-one 4,4- (dibenzoylthio) butan-2-one (17.22)
g, 50 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0 ° C. Under stirring, 1,8-diazabicyclo [5,4,0] -7-undecene (7.5 ml, 50 mmol) was added dropwise over 10 minutes, and the mixture was stirred at 0-5 ° C for 4 hours. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain 5.36 g (52.0%) of the title compound as microplate crystals, and the starting material was 7.64 g (44.4%).
%) Recovered. Melting point: 87-88 ° C NMR (CDCl ₃ ) δ: 2.37 (3H, s), 6.50 (1H, d, J = 16.5)
Hz), 7.47 to 8.05 (5H, m), 8.27 (1H, d, J = 16.5Hz)

Example 3 Synthesis of (E) -4-benzoylthio-3-buten-2-ol (E) -4-Benzoylthio-3-buten-2-one (3.83 g, 18.6 mmol) Suspended in methanol (30 ml) and stirred at 0 ° C with sodium borohydride (281
mg, 7.43 mmol) was added. After about 5 minutes, the reaction solution became a homogeneous solution. After stirring at the same temperature for 30 minutes, the reaction mixture was diluted with ether (100 ml), washed with water (100 ml), saturated brine (100 ml), dried over anhydrous magnesium sulfate and concentrated. The obtained residue (3.70 g) was subjected to the next reaction without isolation and purification.

Example 4 Synthesis of (E) -2-acetoxy-4-benzoylthio-3-butene The syrup (3.70 g) obtained in Example 3 was dissolved in dichloromethane (50 ml) and stirred at 0 ° C. Pyridine (2.3 ml,
28.4 mmol) and acetyl chloride (1.6 ml, 22.5 mmol) were slowly added dropwise. The reaction solution was stirred at room temperature for 1.5 hours. The reaction mixture was 1N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml), saturated saline (50 ml).
The extract was washed successively with, dried over anhydrous magnesium sulfate, and concentrated. The resulting syrupy residue was purified by silica gel column chromatography to give the title compound (3.42 g, 73.5
%) As a colorless syrup. NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 6.60Hz), 2.08 (3
H, s), 5.45 ~ 5.58 (1H, m), 6.02 (1H, dd, J = 16.2, 6.27H
z), 7.03 (1H, d, J = 16.2Hz), 7.36 ~ 8.00 (5H, m)

Example 5 (E)-(R) -4-benzoylthio-3-butene-2
-Ol and (E)-(S) -2-acetoxy-4-benzoylthio-3-butene in 0.1M phosphate buffer (pH 7.0, 150 ml) with amanolipase PS (Amano Pharmaceutical Co., Ltd.) (347 ml) ) Was added and the mixture was stirred at 25 ° C. for 30 minutes. (E)-(RS) -2-acetoxy-4-benzoylthio-3-butene (3.47 g, 1
3.9 mmol) was added, and the mixture was vigorously stirred at 30 ° C. for 30 hours. The reaction mixture was extracted with ethyl acetate (80 ml × 2), washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulfate and concentrated. The obtained concentrated residue is purified by silica gel column chromatography to obtain (E)-(R) -4.
-Benzoylthio-3-buten-2-ol (1.30 g,
45.0%) and (E)-(S) -2-acetoxy-4-
Benzoylthio-3-butene (1.81 g, 52.2%) was obtained. ◎ (E)-(S) -2-acetoxy-4-benzoylthio-3-butene NMR is the same as the compound of Example 4 Specific rotation [α] _D ²⁰ -65.9 ° (c, 1.68, CHCl
₃ ) ・ Optical purity 95.1% ee ◎ (E)-(R) -4-benzoylthio-3-butene-
2-ol NMR (CDCl ₃ ) δ: 1.34 (3H, d, J = 6.60Hz), 2.35
~ 2.90 (1H, broad), 4.39 ~ 4.55 (1H, m), 6.08 (1H, dd, J = 1
5.8, 5.94Hz), 6.91 (1H, d, J = 15.8Hz), 7.36 ~ 7.94 (5H,
m) ・ Specific rotation [α] _D ²⁰ −8.5 ° (c, 1.95, CHCl
₃ ) Optical purity 98.1% ee Optical purity was measured by liquid chromatography under the following conditions.・ Column: Chiralcel OD (manufactured by Daicel Chemical Industries) ・ Carrier: n-hexane / isopropanol = 95 /
5 (V / V) ・ Detection wavelength: UV254 nm

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Claims (11)

[Claims] 1. A general formula [II]: (In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms, an aralkyl group, or an aryl group having 6 to 10 carbon atoms, and the aryl group is substituted with a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group. The optically active butene derivative represented by * represents an asymmetric carbon. 2. A general formula [I]: (In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, and 6 to 6 carbon atoms.
10 represents an aryl group, which may be substituted with a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group. R ² has the same meaning as described above. ) A method for producing an optically active butene derivative represented by the above general formula [II], which comprises causing an esterase having the ability to preferentially hydrolyze one of the butene derivatives represented by the formula (II). 3. A compound represented by the general formula [III]: (In the formula, R ² has the same meaning as described above.) And the butenols represented by the general formula [VIII] (In the formula, X represents a hydroxy group, a chlorine atom, a bromine atom, or represents a group R ¹ CO0, and R ¹ has the same meaning as described above.) In the presence of a base or an acid. The method for producing the butene derivative represented by the general formula [I], wherein 4. A general formula [IV]: (In the formula, R ² has the same meaning as described above.) A butene derivative represented by the above general formula [III] is reduced, wherein the butene derivative represented by the above general formula [III] is reduced. 5. A general formula [V]: (In the formula, R ² has the same meaning as described above.) A method for producing a butene derivative represented by the above general formula [IV], which comprises reacting a butanone derivative represented by the above with a base or a metal salt. 6. A compound represented by the general formula [VI]: (In the formula, R ³ represents an alkyl group having 1 to ³ carbon atoms.)
A butenone derivative represented by the general formula [VII] (In the formula, R ² has the same meaning as described above.) A thiolcarboxylic acid represented by the formula is reacted in the presence of an acid catalyst to produce a butanone derivative represented by the general formula [V]. 7. A butenone derivative represented by the general formula [VI] is reacted with a thiolcarboxylic acid represented by the general formula [VII] in the presence of an acid catalyst to obtain a butanone derivative represented by the general formula [V]. Then, this is reacted with a base or a metal salt to obtain a butene derivative represented by the general formula [IV], which is then reduced to obtain a butenol represented by the general formula [III]. The reaction is performed with an acylating agent represented by the general formula [VIII] in the presence of a base or an acid to obtain a butene derivative represented by the general formula [I]. A process for producing an optically active butene derivative represented by the general formula [II], which comprises reacting an esterase having the ability to decompose. 8. A butene derivative represented by the general formula [I]. 9. A butenol represented by the general formula [III]. 10. A butene derivative represented by the general formula [IV]. 11. A butanone derivative represented by the general formula [V].