JP2962402B2 - Method for producing 2-pyrrolidinone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active 2-pyrrolidinone derivative useful as a synthetic intermediate of a pharmaceutical antibacterial agent.

[0002]

2. Description of the Related Art For optically active 4-hydroxy-2-pyrrolidinone, a method is known in which an optically active S- or R-coordinated 4-amino-3-hydroxybutyric acid is used as a raw material. It is necessary to use an expensive condensing agent such as hexamethyldisilazane (Synthesi
s, 1978, 614). Also, low optical purity (S)-
A method for producing (S) -4-hydroxy-2-pyrrolidinone by heating 4-chloro-3-hydroxybutyric acid with 25% aqueous ammonia (J. Chem. Research)
(S), 1984, 132), but they have problems such as a low yield and a high optical purity cannot be obtained, and all of them are unsuitable for an industrial production method.

[0003]

The inventor of the present invention has made intensive studies to solve these problems and obtain a large amount of high quality optically active 2-pyrrolidinone derivatives. By introducing the compound having the formula (1) having the formula (1) into the compound having the formula (2) having an azide group, and then obtaining the compound having the formula (3) having an amino group, The inventors have found that the formula (4) having an R configuration or an S configuration was efficiently obtained, and completed the invention.

[0004]

The present invention relates to a compound having an R configuration or an S configuration.

[0005]

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Wherein X is a halogen atom, R ¹ is a hydrogen atom or a hydroxyl-protecting group, and R ² is a carboxyl-protecting group.

[0007]

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(Wherein R ¹ and R ² have the same meanings as described above), and by reducing this compound,

[0009]

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(Wherein R ¹ and R ² have the same meanings as described above), and the compound is subjected to a ring closure reaction to give a compound of the formula

[0011]

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(Wherein R ¹ has the same meaning as described above.) This is a method for producing an optically active 2-pyrrolidinone derivative represented by the formula:

In the formula (1), X represents a halogen atom such as chlorine, bromine or iodine, and the protecting group for the hydroxyl group of R ¹ is, for example, a silyl group such as trimethylsilyl or triethylsilyl; benzyl, 4-nitro Aralkyl groups such as benzyl, 2-nitrobenzyl and 4-methoxybenzyl; acyl groups such as acetyl, propionyl and benzoyl; substituted oxycarbonyl groups such as methoxycarbonyl and allyloxycarbonyl or tetrahydropyranyl, methoxymethyl and 1-ethoxyethyl And ether groups. The protecting group for the carboxyl group of R ² is
Alkyl groups such as methyl, ethyl or tert-butyl; benzyl, diphenylmethyl, 4-
Aralkyl groups such as nitrobenzyl or 2-nitrobenzyl; alkenyl groups such as allyl, 2-chloroallyl, 2-methylallyl or 3,3-dimethylallyl; trimethylsilyl groups; pivaloyloxymethyl;
Alkanoyloxyalkyl groups such as acetoxymethyl; 1- (ethoxycarbonyloxy) ethyl, 1-
Alkoxycarbonyloxyalkyl groups such as (isopropoxycarbonyloxy) ethyl; phthalidyl, indanyl and methoxymethyl groups.

In the definitions of formulas (2) and (3), R ¹ , R
² has the same meaning as described above.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION A compound having formula (1) having R or S coordination is reacted with an alkali metal azide such as lithium azide, potassium azide or sodium azide to form a compound having R coordination. From (1), a compound having the R-coordinated formula (2) can be obtained, and from S-coordinated (1), S-coordinated (2) can be obtained.

The amount of the alkali metal azide used is 1 to 5 times, preferably 1.2 to 5 times the molar ratio of the compound (1).
It is twice. Examples of the organic solvent used in this reaction include hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride and 2,4-dichloroethane;
Examples thereof include ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide, and preferably amides. The reaction temperature is 40 to 120 ° C., particularly preferably 80.
１１０110 ° C. The reaction time varies depending on the reaction temperature, but is usually 3 to 10 hours, preferably 4 to 7 hours. In addition, depending on the solvent used, the reaction is carried out in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide or the like in order to make the reaction proceed smoothly. Is particularly preferable, and tetra-n-butylammonium bromide and tetra-n-butylammonium iodide are particularly preferable.

The target compound can be purified by chromatography or distillation.

In the definition of the formula (3), R ¹ and R ² have the same meanings as described above.

Compounds having formula (2) having R or S coordination include hydrogenation reactions, reduction reactions using metals and acids, reduction reactions using metals and alcohols, reduction reactions using metal hydrides, phosphorus compounds. The compound of formula (3) having R coordination can be obtained from (2) having R coordination by a reduction reaction or the like, and the S coordination can be obtained from (2) having S coordination ( 3) can be obtained. Preferably, it is a reduction reaction by hydrogenation.

In the hydrogenation reaction, 5% to 10% as a catalyst
Palladium carbon, 5% platinum carbon, Raney nickel, Lindlar catalyst and the like can be used. The amount of the catalyst used is 0.02 to 1.0 times by weight the compound (2),
Preferably it is 0.05 to 0.5 times. This reaction is usually performed in an organic solvent, and examples of the organic solvent include hydrocarbons such as benzene, toluene, and xylene, tetrahydrofuran,
Examples thereof include ethers such as dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol and isopropyl alcohol, and amides such as dimethylformamide and dimethylacetamide, and preferably alcohols. The reaction temperature is 0 to 40 ° C, particularly preferably 10 to 30 ° C. The pressure of hydrogen is preferably 1 to 4 atm. The reaction time varies depending on the reaction temperature and the pressure of hydrogen, but is preferably 0.5 to 2.0 hours.

In the reduction reaction using a metal and an acid, zinc or chromium chloride in the form of particles or powder can be used as the metal to be used. The amount of the metal used is 5 to 15 by weight, preferably 8 to 10 times, the weight ratio of the compound (2). The acids used are mineral acids such as hydrochloric acid and organic acids such as acetic acid. The amount of the acid to be used is 5 to 15 times by volume, preferably 8 to 10 times, based on the weight of the compound (2).
It is twice. As a reaction solvent, acetone and a mixed solvent of acetone and water are preferable.

In the reduction reaction using a metal and an alcohol, examples of the metal used include granular or powdered magnesium, granular or powdered calcium, and tin tetrachloride. The amount of the metal used is 0.1 to 5.0 times, preferably 0.2 to 3.0 times, the weight ratio of the compound (2). The alcohols used are methanol, ethanol, isopropanol, etc.
Ethanol.

In the reduction reaction using a metal hydride, examples of the metal hydride used include sodium borohydride and lithium aluminum hydride. The amount of the metal hydride used is 2.0 to 5.0 times, preferably 2.5 to 3.5 times, the molar ratio of the compound (2). Examples of the organic solvent used include ethers such as ether and tetrahydrofuran, and alcohols such as methanol and ethanol. The reaction temperature is in the range of room temperature to the reflux temperature of the solvent used, and the reaction time is 3 to 15 hours, depending on the reaction temperature.

In the reduction reaction using a phosphorus compound, trialkylphosphines such as triphenylphosphine and trialkylphosphites such as triester phosphite are used. The amount of the phosphorus compound used is 1.0 to 3.0 times, preferably 1.0 to 1.5 times, the molar ratio of the compound (2). The reaction is performed in a mixed solution of an organic solvent and water, and examples of the organic solvent include ethers such as diethyl ether, tetrahydrofuran, and dioxane;
Alcohols such as methanol, ethanol and isopropyl alcohol are used. The reaction temperature is room temperature, and the reaction time is 15 to 20 hours.

The compound (3) obtained by the above various reduction reactions can be purified by a conventional method (for example, chromatography or hydrochloride).

In the definition of formula (4), R ¹ has the same meaning as described above.

The compound having the formula (3) having the R or S configuration is left at room temperature or closed by heating to convert the compound having the R configuration to the compound having the formula (4). And S-coordinated (4) can be obtained from S-coordinated (3).

The ring closure reaction is carried out without a solvent or in an organic solvent. Examples of the organic solvent used include hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol and isopropyl alcohol, dimethylformamide and dimethylacetamide. And the like, preferably esters and alcohols. The reaction temperature is from room temperature to the reflux temperature of the organic solvent used, preferably from 50 to 70 ° C.
It is. The reaction time varies depending on the reaction temperature, but is preferably 4.0 to 6.0 hours.

After completion of the reaction, the compound (4) can be isolated by concentrating the solvent, crystallizing it from alcohols, esters and the like or a mixture thereof.

This reaction is carried out by a continuous operation of heating the reaction solvent or the extraction solvent without isolating the compound of the formula (3) depending on the method and the solvent used in the reduction reaction of the compound of the formula (2). Compound (4) can be obtained.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0032]

According to the present invention, a 2-pyrrolidinone derivative can be obtained efficiently and in large quantities. The 2-pyrrolidinone derivative obtained here can be led to a carbapenem derivative which is an excellent antibacterial agent by the method described in JP-A-2-49783.

[0033]

【Example】

Example 1 Ethyl (S) -4 -azido-3-hydroxybutyrate Ethyl (S) -4-chloro-3-hydroxybutyrate (10
0g) was dissolved in dimethylformamide (11) and sodium azide (78.0 g) was added.
Heat for 3 hours. After cooling the reaction solution to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer is
After washing with 0% saline and saturated saline and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain oily (S) -4.
-Ethyl-azido-3-hydroxybutyrate (94.7 g) was obtained (yield 91%).

Infrared absorption spectrum (NaCl) 2102 cm ⁻¹ , 1725 cm ⁻¹ nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δppm: 1.28 (3H, t, J = 7.20 Hz), 2.54 (2H, d, J = 6.39Hz), 3.35
(2H, d, J = 5.31Hz), 3.20-3.45 (1H, m), 4.19 (2H, q, J = 7.20H
z).

Example 2 Ethyl (S) -4 -hydroxy-2-pyrrolidinone (S) -4-azido-3-hydroxybutyrate (9
0.0g) was dissolved in methanol (450 ml), and 5
A palladium-carbon powder (palladium content, 75% by weight, 180 g) having a water content of 0.1% was added, and the mixture was added under hydrogen pressure (3.
0kg Weight / cm ²⁾ 20 ℃, it was carried out for 1.5 hours.
Thereafter, the reaction solution was filtered, washed with methanol (450 ml), and heated as it was at 60 ° C. for 5.0 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized with a mixed solvent of ethanol and ethyl acetate to give white crystals of (S) -4-hydroxy-2-pyrrolidinone (38.0 g). I got

Melting point: 158 to 161 ° C. Light intensity [α] _D ²⁴ −55.24 ° (C = 1.0, H ₂ O) Infrared absorption spectrum (KBr) ν _max cm ⁻¹ : 3247,3145,16
. 72,1483,1446,1416 Nuclear magnetic resonance spectrum (400MHz, D ₂ O, trimethylsilyl propionic acid sodium -d ₄ internal standard) δppm: 2.28 (1H, dd , J = 17.72,1.64Hz), 2.77 (1H, dd , J = 17.7
2,6.72Hz), 3.34 (1H, dd, J = 11.75,1.03Hz), 3.72 (1H, dd, J =
11.75,5.21Hz), 4.60-4.64 (1H, m). Example 3 Ethyl (S) -4 -hydroxy-2-pyridinone (S) -4-amino-3-hydroxybutyrate (1.
85 g) in methanol (19 ml),
The reaction was performed for 5.0 hours. Hereinafter, processing is performed in the same manner as in Example 2,
Purification gave crystalline (S) -4-hydroxy-2-pyrrolidinone (0.67 g). This was in agreement with that obtained in Example 2 in melting point and light intensity nuclear spectrum.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Isao Kawamoto 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-A-4-95067 (JP, A) JP-A-48 -62721 (JP, A) JP-A-63-27477 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 207/00-207/50 C07B 53/00 C07C 229/22 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound having an R configuration or an S configuration. (Wherein X represents a halogen atom, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, and R ² represents a carboxyl-protecting group). The compound represented by the formula is reacted with an alkali metal azide to give a compound of the formula ] (Wherein, R ¹ and R ² have the same meanings as described above.)
By reducing this compound, a compound represented by the formula: (Wherein, R ¹ and R ² have the same meanings as described above.)
This compound is subjected to a ring closure reaction to give a compound of the formula (Wherein, R ¹ has the same meaning as described above.) A method for producing an optically active 2-pyrrolidinone derivative represented by the formula: