JPH07252248A - Beta-lactam-based compound and its sterically selective production - Google Patents

Abstract

PURPOSE:To obtain new derivative derivable into an important synthetic intermediate for a carbapenem-based antibiotic. CONSTITUTION:This derivative is expressed by formula I (Q is phenyl or an aralkyl which may be substituted with a 1-6C alkyl or alkoxy, respectively; R is H or a 1-6C alkyl; Z is H or phenyl which may be substituted with a 1-6C alkyl, a halogen, etc.) such as 3-(p-methoxyphenylamino)-3-(4,5- dimethoxymethyl-1,3-dioxolan-2-yl)propionic acid t-butyl ester. The derivative is obtained by reacting an optically active imine of formula II with a metal enolate of an acetic ester of formula III (Met is a metal).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel β-lactam derivative which can be converted into an important synthetic intermediate of carbapenem antibiotics and a stereoselective process for producing an optical isomer thereof.

[0002]

BACKGROUND ART β having antibacterial activity such as thienamycin
-Many studies have been conducted on lactam compounds and methods for producing the same, but simple and highly stereoselective synthetic reactions have been desired due to their usefulness.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel β-lactam derivative and a stereoselective production method thereof.

[0004]

The present invention has the general formula [I]

[Chemical 6] [Q is phenyl (which may be substituted with C1 to C6 alkyl, C1 to C6 alkoxy) phenyl or (C1 to C6 alkyl, which may be substituted with C1 to C6 alkoxy)
Represents aralkyl, R represents hydrogen, C1 to C6 alkyl, Z represents hydrogen, C1 to C6 alkyl, (C1 to C6)
Alkyl, C1 -C6 alkoxy, optionally substituted by halogen) phenyl, C1 -C6 alkoxy or C1 -C6 alkylthio. ] The β-amino acid derivative represented by the general formula [II]

[Chemical 7] [Q and Z represent the same meaning as described above. ] A β-lactam derivative represented by the general formula [III]

[Chemical 8] (Q and Z have the same meanings as described above.) And an optically active imine represented by the general formula [IV]

[Chemical 9] (Met represents a metal and R represents the same meaning as described above.)
By reacting a metal enolate of an acetic acid ester represented by
A method for producing a stereoselective β-lactam, which comprises cyclizing.

[0005] well where the metal in the metal enolate of acetic acid ester anything that forms the enolate, _{specifically, Li, ZnX, AlR '3} · Li, Ti (OR') 3, SnR '3 ·
Li, etc. [X represents halogen such as Br, Cl, F and I, and R'represents C1 to C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl. ]
Is.

The following optical isomers exist in the general formula [I], and they can be stereoselectively produced by selecting the reaction conditions such as the metal species of the enolate, the ester moiety and the reaction solvent. it can.

[Chemical 10]

The general formula [I] obtained by cyclizing the general formula [I]
I] has the following optical isomers, but the stereochemistry of [I] is not impaired under the condition of cyclization.

[Chemical 11]

Next, the manufacturing method will be specifically described. Lithium enolate is formed by acetic ester derivative and lithium diisopropylamide (LDA) in a solvent at room temperature or lower. This solution is slowly added dropwise to the solution containing the imine. After that, the temperature is gradually raised to room temperature and stirred for several to several tens of hours. After completion of the reaction, extraction and purification are carried out to obtain the target compound.

Here, the solvent is tetrahydrofuran (TH
F), diethyl ether, dimethoxyethane (DM
E), dimethylformamide (DMF), methylene chloride, toluene, hexamethylphosphoric triamide (HMPA), and the like, and mixed solvents thereof can be used. The reaction temperature is room temperature or lower, preferably from -150 ° C.
It is 0 ° C. Further, titanium enolate or zinc enolate can be produced by adding chlorotitanium triisopropoxide, zinc chloride or the like to lithium enolate and performing metal exchange.

The optically active imine as a raw material can be synthesized by the following formula.

[Chemical 12]

The obtained compound of the present invention can be converted into 2-azetidinone useful as an intermediate for carbapenem and penem antibacterial substances, for example, by the following formula.

[Chemical 13]

[0012]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. The compound was identified by NMR, IR and MS, and the ratio of stereoisomers was determined by capillary GLC and HPLC.

Example 1 Synthesis of 3- (p-methoxyphenylamino) -3- (4,5-dimethoxymethyl-1,3-dioxolan-2-yl) propionic acid t-butyl ester

[Chemical 14] Diisopropylamine 308 mg (3.1 mmol) TH in a 30 ml two-necked eggplant flask under argon atmosphere.
F 3 ml solution was added and cooled to -78 ° C. 1.56
2.0 ml of a hexane solution of n-butyllithium of N (3.
1 mmol) was added and the mixture was stirred at -78 ° C for 15 minutes. 360 mg (3.1 mmol) of t-butyl acetate was added to the solution.
THF solution (3 ml) was slowly added dropwise at -78 ° C for 15 minutes.
Stir for minutes. 3.1 ml (3.1 mmol) of a hexane solution of 1.0 N triisopropoxytitanium chloride was slowly added, and the mixture was stirred at -78 ° C for 15 minutes. The solution -1
After cooling to 10 ° C., imine [III ′] 150 mg (0.
A solution of 51 mmol) in THF (3 ml) was slowly added dropwise, and the mixture was stirred for 3 hours while allowing the temperature to naturally rise to -95 ° C. The reaction was stopped by adding a phosphate buffer solution, the mixture was filtered through Celite, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel thin layer chromatography (hexane: ether = 1: 3) to obtain the indicated β-amino ester. Yield 63 mg (yield 30%) Rf 0.4 (hexane: ether = 1: 3) (S: R) = 20: 80 (HPLC hexane: ethyl acetate = 5: 1) Rt 63.52 min 68.11 min 1H-NMR (CDCl ₃ ) δ 1.40 (S, 9H), 2.36-2.59 (m, 2H), 3.37-
3.57 (m, 11H), 3.73 (s, 3H), 3.96-4.04 (m, 3H), 5.21 (d, J = 1.
98,1H), 6.64 (d, J = 9.07,2H), 6.75 (d, J = 9.07,2H) IR (neat) cm ^-1 3360,2900,1730,1510,1240,1150

Example 2 Synthesis of 3- (p-methoxyphenylamino) -3- (4,5-dimethoxymethyl-1,3-dioxolan-2-yl) propionic acid t-butyl ester

[Chemical 15] THF in a 30 ml 2-neck eggplant flask under argon atmosphere
0.5 ml of 3 ml and potassium hexamethyldisilazide
1.08 ml (0.54 mmol) of a toluene solution was added and the mixture was cooled to -78 ° C and stirred. T-Butyl acetate 62.7
A solution of mg (0.54 mmol) in 3 ml of THF was slowly added, and the mixture was stirred at -78 ° C for 15 minutes. 73.6 mg (0.54 mmol) of zinc chloride was added to the solution, and the temperature was 0 ° C.
The temperature was raised to and stirred for 1 hour. The reaction solution was cooled to −80 ° C. again, and imine [III ′] 40 mg (0.14 mmo
A solution of 1) in THF (3 ml) was slowly added, and the mixture was stirred for 48 hours while allowing the temperature to rise naturally to room temperature. Then, the same treatment as in Example 1 was performed. Yield 20.1 mg (yield 36%) (S: R) = 8: 92

Example 3 Synthesis of 3- (p-methoxyphenylamino) -3- (4,5-dimethoxymethyl-1,3-dioxolan-2-yl) propionic acid t-butyl ester

[Chemical 16] Diisopropylamine 41 mg (0.41 mmol) TH was added to a 30 ml 2-necked eggplant flask under an argon atmosphere.
A 3 ml F solution was added and the mixture was cooled to -78 ° C and stirred.
1.48 N n-butyllithium hexane solution 0.2
7 ml (0.41 mmol) was added and it stirred at -78 degreeC for 15 minutes. To the solution, 48 mg of t-butyl acetate (0.
41 mmol) in 3 ml of THF was slowly added-
The mixture was stirred at 78 ° C for 15 minutes. 0.29 ml of 1.4N toluene solution of trimethylaluminum (0.41 mmo
1) was added and stirred for 30 minutes. The reaction solution was cooled to −110 ° C., and imine [III ′] 40 mg (0.14 mm
solution) in THF (3 ml) was slowly added dropwise at -95 ° C.
The mixture was stirred for 3 hours while allowing the temperature to rise naturally. Example 1 below
The same process was performed. Yield 14 mg (24% yield) (S: R) = 89: 11

Production examples are shown in Table 1 including the compounds of Examples 1 to 3.

[0017]

[Table 1]

Example 8 Synthesis of 3- (p-methoxyphenylamino) -3- (4,5-dimethoxymethyl-1,3-dioxolan-2-yl) propionic acid

[Chemical 17] Under argon atmosphere, a solution of β-amino ester [I′-S] 39 mg (0.095 mmol) in methylene chloride 9 ml was put in a 50 ml eggplant flask, cooled to 0 ° C. and stirred. 0.73 ml of trifluoroacetic acid (9.
(5 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and purified by silica gel thin layer chromatography (hexane: ether = 1: 3) to obtain the indicated β-amino acid. Yield 34 mg (yield 100%) Rf 0.1 (hexane: ether = 1: 3) 1H-NMR (CDCl ₃ ) δ 2.60 (broad, 2H), 3.35-3.61 (m, 11H),
3.74 (s, 3H), 3.99 (broad, 3H), 5.18 (broad, 1H), 6.76 (broa
d, 4H) IR (neat) cm ^-1 3400,2900,1700,1510,1200,830

Example 9 4-[(4S, 5S) -4,5
-Dimethoxymethyl-1,3-dioxolan-2-yl] -1-p-methoxyphenyl-2-azetidinone

[Chemical 18] N-methyl-2-chloropyridinium iodide 18 mg (0.
(076 mmol) in 1 ml of methylene chloride,
It was cooled to 0 ° C. and stirred. A solution of 18 mg (0.051 mmol) of β-amino acid obtained in Example 8 in 1 ml of methylene chloride was slowly added dropwise to the solution. Triethylamine (0.04 ml, 0.26 mmol) was slowly added, and the mixture was stirred for 12 hours while naturally warming to room temperature.
The reaction was stopped by adding saturated saline and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, silica gel thin layer chromatography (hexane: ether = 1: 1)
Purification was performed according to 3) to obtain the indicated β-lactam. Yield 0.4 mg (yield 4%) S: R = 8: 92 Rf 0.2 (hexane: ether = 1: 3) Rt 61.923 min, 65.056 min (GC
SE30 50 m 230 ° C. constant) 1H-NMR (CDCl ₃ ) δ 2.98-3.11 (m, 2H), 3.32-3.51 (m, 10
H), 3.79 (s, 3H), 3.84-3.90 (m, 1H), 4.04-4.09 (m, 1H), 4.17
-4.21 (m, 1H), 5.33 (d, J = 3.63,1H), 6.84 (d, J = 8.91,2H), 7.
49 (d, J = 8.91,1H) IR (neat) cm ^-1 2900,1760,1510,1380,1100

Example 10 4-[(4S, 5S) -4,
Synthesis of 5-dimethoxymethyl-1,3-dioxolan-2-yl] -1-p-methoxyphenyl-2-azetidinone

[Chemical 19] Under argon atmosphere, a solution of 7 mg (0.020 mmol) of β-amino acid obtained in Example 8 in 2 ml of acetonitrile was placed in a 50 ml eggplant-shaped flask and stirred. An acetonitrile solution of triphenylphosphine was added, an acetonitrile solution of dipyridyl disulfide was added, and the mixture was heated to 45 ° C. and stirred for 13 hours. The reaction was stopped with saturated saline, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The same operation as in Example 9 was performed below. Yield 3.3 mg (yield 49%) S: R = 28: 72

[0021]

The β-lactam derivative can be stereoselectively obtained.

Claims (4)

[Claims] 1. A compound represented by the general formula [I]: [Q is phenyl (which may be substituted with C1 to C6 alkyl, C1 to C6 alkoxy) phenyl or (C1 to C6 alkyl, which may be substituted with C1 to C6 alkoxy)
Represents aralkyl, R represents hydrogen, C1 to C6 alkyl, Z represents hydrogen, C1 to C6 alkyl, (C1 to C6)
Alkyl, C1 -C6 alkoxy, optionally substituted by halogen) phenyl, C1 -C6 alkoxy or C1 -C6 alkylthio. ] The beta-amino acid derivative represented by these. 2. A compound represented by the general formula [II]: [Q and Z represent the same meaning as described above. ] The beta-lactam derivative represented by these. 3. A compound represented by the general formula [III]: (Q and Z have the same meanings as described above.) And an optically active imine represented by the general formula [IV] (Met represents a metal and R represents the same meaning as described above.)
The method for producing a stereoselective β-amino acid derivative according to claim 1, which comprises reacting a metal enolate of an acetic acid ester represented by: 4. A compound represented by the general formula [I]: [Q, R and Z have the same meanings as described above. ] Represented by
-Cyclization of the amino acid derivative.
Process for producing the stereoselective β-lactam described.