JPH08283267A - Carbapenem-based compound and its production - Google Patents

Abstract

PURPOSE: To obtain the subject compound having a carbonate group, easily synthesized, stable and useful as an intermediate for carbapenem as an antimicrobial agent. CONSTITUTION: This carbapenem-based compound is a compound of formula I [R<1> is a (protected) hydroxy-substituted lower alkyl; R<2> is H or a lower alkyl; R<3> is a protecting group for carboxyl; R<4> is an alkyl, an alkenyl, an alkynyl or an aryl which may have a substituting group], e.g. 4-nitrobenzyl(4R,5R,6S)-3- methoxycarbonyloxy-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3,2,0]hepto-2-ene-2-carboxylate. Further, the compound of formula II is reacted with the compound of the formula XC(=0)OR<4> (X is a halogen) of 1-5 fold mol in the presence of a base (e.g.; diethylamine) of 1-10 fold mol in a solvent such as toluene, at (-)30-50 deg.C reaction temperature for 10min to several days to obtain the objective compound.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a compound of formula (I) useful as a carbapenem intermediate which is an excellent antibacterial agent

[Chemical 6] (In the formula, R ¹ represents an optionally protected hydroxy-substituted lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a protecting group for a carboxy group, and R ⁴ represents a substituent. An alkyl group which may have, an alkenyl group,
An alkynyl group or an aryl group is shown. ) Relates to a compound represented by

[0002]

2. Description of the Related Art As an effective method for synthesizing a carbapenem derivative, a leaving group is introduced into a compound represented by the formula (II) to form a compound (VI), and the leaving group is converted to a compound having a thiol residue. There is a method of substituting it to obtain a compound represented by formula (V). (JP-A-4-217985)

[Chemical 7]

However, the leaving group represented by OL is only exemplified by a phosphoric acid group, a sulfonic acid group, a carboxylic acid residue such as halogen, acetyl or benzoyl, and a pyridinium oxy derivative residue. Only in the case of diphenyl phosphate group. Further, the compound (VI) having the diphenyl phosphate group introduced therein is stable in a crystal, but unstable in an amorphous form, and it is reported that it is difficult to trade as a bulk raw material other than the crystal (Japanese Patent Laid-Open Publication No. SHO 4- 330
085). In terms of production, it is necessary to take out the crystals as crystals or to use them without isolating them before decomposing them, and there is a problem in stability.

On the other hand, Oda et al.

Embedded image The phenyl sulfoxide or phenyl sulfone moiety of was removed using a metal salt or a complex of a metal salt, and thiol substitution was performed to obtain the compound represented by the formula (V). (JP-A-6
-293765, JP-A-6-220058) It can be said that the possibility of using even a group which has been difficult to be eliminated or substituted with thiol has been suggested.

However, the phenyl sulfoxide or phenyl sulfone moiety of the compound (VIII) had a good yield only when it had a substituent capable of coordinating with a metal at the ortho position.
Such a unique compound (VIII) is not practical because it requires more multistep reactions in synthesis.

[0006]

The present inventors have found a novel carbapenem intermediate having a carbonate group, which has not been used as a leaving group for a carbapenem intermediate, and which is easy to synthesize and stable, and further has a metal salt or a metal. The inventors have found a method of utilizing elimination and thiol substitution using a salt complex, and completed the present invention.

[0007]

The present invention is a carbapenem intermediate represented by formula (I), a method for producing the same, and a method for using the compound.

[Chemical 9]

In the above formula, R ¹ represents an optionally protected hydroxy-substituted lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a protecting group for a carboxy group, and R ⁴ represents An alkyl group which may have a substituent,
An alkenyl group, an alkynyl group or an aryl group is shown.

The protecting group for the optionally substituted hydroxy-substituted lower alkyl group for R ¹ is a protecting group commonly used as a protecting group for a hydroxyl group, preferably t-butyldimethylsilyl group, t-butyldiphenylsilyl group. , Substituted silyl groups such as triethylsilyl group and trimethylsilyl group, aralkyloxycarbonyl groups such as benzyloxycarbonyl group and 4-nitrobenzyloxycarbonyl group, and optionally substituted acetyl groups such as acetyl, chloroacetyl and methoxyacetyl. can give.

The lower alkyl group of the optionally substituted hydroxy-substituted lower alkyl group for R ¹ is a linear or branched alkyl group having 1 to 3 carbon atoms, preferably an ethyl group.

The substitution position of the optionally substituted hydroxy-substituted lower alkyl group for R ¹ is 1 to 3 position, preferably 1 position.

The lower alkyl group for R ² is a linear or branched alkyl group having 1 to 3 carbon atoms, preferably a methyl group.

The protecting group for the carboxy group of R ³ is a protecting group for the carboxy group commonly used in the synthesis of carbapenem derivatives, preferably a lower alkyl group such as methyl, ethyl or t-butyl, 2-chloroallyl or crotyl. A substituted or unsubstituted allyl group such as cinnamyl, 4-nitrobenzyl,
Examples of the substituted or unsubstituted benzyl group include 2-nitrobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, diphenylmethyl and the like.

Examples of the substituent of the alkyl group, alkenyl group or alkynyl group which may have a substituent of R ⁴ include alkoxy groups such as methoxy group and ethoxy group, alkylthio groups such as methylthio group and ethylthio group, acetoxy group. Group, acyloxy group such as benzoyloxy group, phenoxy group, phenylthio group, halogen group, nitro group, phenyl group, 4-nitrophenyl group, dimethylamino group, diethylamino group, cyano group, acetyl group, benzoyl group,
Examples thereof include a dimethylcarbamoyl group, a diethylcarbamoyl group, a dimethylsulfamoyl group and a diethylsulfamoyl group.

The alkyl group (which may have a substituent) of R ⁴ includes methyl, ethyl, n-propyl and is.
Examples thereof include C1-8 linear, branched or cyclic alkyl groups such as o-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-octyl, cyclopentyl or cyclohexyl.

Examples of the alkenyl group (which may have a substituent) of R ⁴ include C1-8 linear or cyclic alkyl groups such as an allyl group and a cyclohexenyl group.

Examples of the alkynyl group (which may have a substituent) of R ⁴ include linear alkynyl groups such as 2-propynyl group.

The substitution position of the alkyl group, alkenyl group or alkynyl group which may have a substituent of R ⁴ is 1
~ 3rd place is given.

The substituent of the aryl group which may have a substituent of R ⁴ is methyl, ethyl, n-propyl or i.
C1-4 linear or branched alkyl group such as so-propyl, n-butyl or tert-butyl, alkoxy group such as methoxy group and ethoxy group, phenoxy group, halogen group,
Nitro group, phenyl group, dimethylamino group, diethylamino group, cyano group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, benzoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, etc. Can be given.

The aryl group of R ⁴ (which may have a substituent) is an aromatic ring group such as a phenyl group and a naphthyl group, a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyrazoyl group, an imidazolyl group and a thiazolyl group. And a heterocyclic group such as a benzothiazolyl group or a benzimidazolyl group.

As a method for producing the compound represented by the formula (I), the formula (II)

[Chemical 10] And a compound represented by the formula (III) XC (═O) OR ⁴ (III) in a 1- to 5-fold molar amount in the presence of a 1- to 10-fold molar amount of a base. The reaction temperature range is -70.
C to 70 ° C, preferably -30 to -50 ° C. The reaction time is 10 minutes to several days.

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

In the above formula (III), X represents a halogen group such as chlorine and bromine, and R ⁴ has the same meaning as described above.

Examples of the base used in the method for producing the compound represented by the formula (I) are diethylamine, cyclohexylisopropylamine, diisopropylamine, dicyclohexylamine, dibenzylamine, triethylamine, tri-n-propylamine and tri-n-butylamine. ,
Secondary or tertiary amines such as diisopropylethylamine and tribenzylamine, secondary or tertiary anilines such as N-methylaniline, N-ethylaniline, N, N-dimethylaniline, N, N-diethylaniline and diphenylmethylamine. Alternatively, pyrrole, imidazole, pyridine, 4-dimethylaminopyridine, picoline, lutidine, morpholine, piperidine, piperazine, 1-methylpiperidine, 4-methylmorpholine, 1-methylpiperidine, quinoline, quinoxaline, 1,8-diazabicyclo [5. 4.0] Examples include heterocyclic bases such as undecene, which may be mixed and used.

The reaction solvent used in the method for producing the compound represented by the formula (I) is not particularly limited as long as it does not participate in the reaction, and aromatic solvents such as toluene, xylene and chlorobenzene, methyl acetate, ethyl acetate, Ester solvents such as n-propyl acetate and ethyl propionate, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone, hydrocarbon solvents such as cyclohexane, hexane and heptane, nitrile solvents such as acetonitrile and benzonitrile. Solvent, diisopropyl ether,
Ether solvents such as dioxane and tetrahydrofuran,
Examples thereof include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, methylene chloride, chloroform and the like, and these may be mixed and used.

The compound represented by the formula (II) used as a starting material is known and can be easily obtained according to the method described in JP-A-4-217985.

The compound represented by the formula (I) is obtained by reacting a thiol compound represented by the formula (IV) HSR ⁵ (IV) with a metal salt or a complex of a metal salt in the presence or absence of a base, Formula (V)

[Chemical 11] It is possible to induce the compound represented by The reaction temperature range is -70 ° C to 70 ° C, preferably -30 ° C.
C to -50 ° C. The reaction time is 10 minutes to several days. The molar ratio of the reaction is Compound 1 represented by the formula (I)
The amount is 1 to 3 mol of the compound represented by the formula (IV), 1 to 20 mol of a metal salt or metal salt, and 1 to 40 mol when a base is used. Thereafter, the compound represented by the formula (V) can be deprotected and modified to give a corresponding carbapenem derivative.

In the above formula, R ⁵ represents a chain-like or current alkyl group or heterocycle which may have a substituent.

Examples of the substituent of the chain or cyclic alkyl group or heterocyclic ring which may have a substituent of R ⁵ include amino group, acetylamino group, dimethylamino group, diethylamino group, methoxyamino group and ethoxy group. Examples thereof include an amino group, a hydroxyl group, a methoxy group, an ethoxy group, a dimethylcarbamoyl group, a diethylcarbamoyl group, a dimethylsulfamoyl group, a diethylsulfamoyl group, and a heterocyclic group having a substituent.

R ⁵ is a portion called a pendant of the carbapenem derivative.
It has been synthetically developed to reduce central nervous system toxicity and improve antibacterial activity. Usage of the present invention spans the R ⁵ to their corresponding, not to be further limiting. Hereinafter, as an example, R ⁵ described in literatures such as pharmaceuticals and pharmaceutical manufacturers will be shown together with the literatures.

[Chemical 12]

[Chemical 13]

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[Chemical 15]

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[Chemical 17]

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The metal salt or the complex of the metal salt used in the production of the compound represented by the formula (V) from the compound represented by the formula (I) includes magnesium chloride, magnesium bromide, magnesium iodide and odor. Magnesium ether complex, methyl magnesium bromide, phenyl magnesium bromide, magnesium methoxide, magnesium ethoxide, calcium bromide, bromomagnesium cyclohexyl isopropylamide, bromomagnesium diisopropylamide, bromomagnesium diethylamide, bromomagnesium hexamethyldisilazide, bromo Examples thereof include those containing Group II or Group III metals such as magnesium t-butoxide and diethylaluminum chloride, and these may be used as a mixture.

As the base used for producing the compound represented by the formula (V) from the compound represented by the formula (I), diethylamine, cyclohexylisopropylamine, diisopropylamine, dicyclohexylamine, dibenzylamine, triethylamine, Secondary or tertiary amines such as tri-n-propylamine, tri-n-butylamine, diisopropylethylamine and tribenzylamine, N
-Secondary or tertiary aniline or pyrrole such as methylaniline, N-ethylaniline, N, N-dimethylaniline, N, N-diethylaniline and diphenylmethylamine, imidazole, pyridine, 4-dimethylaminopyridine, picoline, lutidine , Morpholine, piperidine,
Heterocyclic bases such as piperazine, 1-methylpiperidine, 4-methylmorpholine, 1-methylpiperidine, quinoline, quinoxaline, and 1,8-diazabicyclo [5.4.0] undecene can be mentioned. You may use.

The reaction solvent used for producing the compound represented by the formula (V) from the compound represented by the formula (I) is not particularly limited as long as it does not participate in the reaction, and may be toluene, xylene, chlorobenzene or the like. Aromatic solvents, ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate and ethyl propionate, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone, hydrocarbons such as cyclohexane, hexane and heptane. Examples thereof include system solvents, nitrile solvents such as acetonitrile and benzonitrile, ether solvents such as diisopropyl ether, dioxane and tetrahydrofuran, dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, methylene chloride and chloroform.

The reaction temperature range is -70 ° C to 70 ° C, preferably -30 ° C to -50 ° C. The reaction time is 10 minutes to several days.

[0035]

EXAMPLES Next, the present invention will be described more specifically with reference to examples. Example 1 4-Nitrobenzyl (4R, 5R, 6S) -3-methoxycarbonyloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylate (Compound A):

[Chemical 19] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (18.12 g) in methyl isobutyl ketone (100 ml) was cooled to -7 ° C.
4-Dimethylaminopyridine (0.09g) and methyl chlorocarbonate (7.09g) were added. At the same temperature, diisopropylethylamine (9.69 g) was added dropwise over 16 minutes, and the mixture was aged for 2 hours. After the reaction was completed, a saturated aqueous solution of sodium dihydrogen phosphate was added so as to have a pH of 7.3, the solution was washed and then separated, and the obtained organic layer was further washed with water (50 ml) and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (17.61 g). Melting point 108-110 ° C. ¹ H NMR (270 MHz. CDCl ₃ ) δ ppm:
1.25 (3H, d), 1.35 (3H, d), 3.3
0 to 3.45 (2H, m), 3.83 (3H, s),
4.22 to 4.35 (2H, m), 5.35 (2H, d
d, J = 13.8, 51.0 Hz), 7.61 (2H,
d), 8.24 (2H, d)

Example 2 4-nitrobenzyl (4R, 5R, 6S) -3-ethoxycarbonyloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3 .2.0] hept-2-ene-2-carboxylate (Compound B):

Embedded image 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (3.62 g) in methyl isobutyl ketone (25 ml) was cooled to 5 ° C. and 4-dimethylaminopyridine (0.02 g). And ethyl chlorocarbonate (1.63 g) were added. Diisopropylethylamine (1.94 g) was added dropwise at the same temperature over 20 minutes, and 3
Aged for hours. After completion of the reaction, a saturated aqueous solution of sodium dihydrogen phosphate was added so as to have a pH of 7.0, washed and then separated, and the obtained organic layer was further washed with water (40 ml) and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (2.36 g). ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.23-1.36 (9H, m), 3.30-3.42
(2H, m), 4.21 to 4.33 (4H, m), 5.
36 (2H, dd, J = 13.8, 51.0Hz),
7.62 (2H, d), 8.23 (2H, d)

Example 3 4-nitrobenzyl (4R, 5R, 6S) -3-isopropyloxycarbonyloxy-6-[(R) -1-
Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (Compound C):

[Chemical 21] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (7.25 g) in methyl isobutyl ketone (50 ml) was cooled to -10 ° C and 4
-Dimethylaminopyridine (0.04g) and isopropyl chlorocarbonate (3.68g) were added. Diisopropylethylamine (3.88 g) was added dropwise at the same temperature over 20 minutes, and the mixture was aged for 4 hours. After the reaction was completed, a saturated aqueous solution of sodium dihydrogenphosphate was added to adjust the pH to 7.3, the mixture was washed and then separated, and the obtained organic layer was added to water (40 ml).
It was washed with and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (2.51 g). ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.23-1.37 (12H, m), 3.30-3.4
2 (2H, m), 4.25 to 4.32 (2H, m),
4.91 (1H, dq), 5.36 (2H, dd, J =
13.8, 51.0 Hz), 7.62 (2H, d),
8.22 (2H, d)

Example 4 4-nitrobenzyl (4R, 5R, 6S) -3-allyloxycarbonyloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [ 3.2.0] Hept-2-ene-2-carboxylate (Compound D):

[Chemical formula 22] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (7.25 g) in methyl isobutyl ketone (40 ml) was cooled to −10 ° C. and 4
-Dimethylaminopyridine (0.04g) and allyl chlorocarbonate (3.62g) were added. Diisopropylethylamine (3.88 g) was added dropwise at the same temperature over 30 minutes, and the mixture was aged for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 ml) was added, and the mixture was washed and separated, and the obtained organic layer was further washed with water (50 ml) and separated. The obtained organic layer was concentrated, the residue was purified by silica gel column chromatography, and the title compound (7.6
6 g) was obtained. ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.25 (3H, d), 1.36 (3H, d), 3.3
4 to 3.41 (2H, m), 4.25 to 4.33 (2
H, m), 4.66 (2H, dd), 4.91 (1H,
dq), 5.35 (2H, dd, J = 13.8, 51.
3 Hz), 5.34 to 5.42 (2H, m), 5.84
~ 5.96 (1H, m), 7.61 (2H, d), 8.
22 (2H, d)

Example 5 4-Nitrobenzyl (4R, 5R, 6S) -3-benzyloxycarbonyloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [ 3.2.0] Hept-2-ene-2-carboxylate (Compound E):

[Chemical formula 23] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (7.25 g) in methyl isobutyl ketone (40 ml) was cooled to -5 ° C and 4-
Dimethylaminopyridine (0.04g) and benzyl chlorocarbonate (4.09g) were added. At the same temperature, diisopropylethylamine (3.10 g) was added dropwise over 2 hours,
Aged for 1.5 hours. After completion of the reaction, a saturated aqueous solution of sodium dihydrogen phosphate was added so as to have a pH of 7.8, and after washing, the layers were separated, and the obtained organic layer was washed with water (50 ml) to separate the layers. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (7.43 g). Melting point 111-114 ° C. ¹ H NMR (270 MHz. CDCl ₃ ) δ ppm:
1.23 (3H, d), 1.34 (3H, d), 3.3
3 to 3.40 (2H, m), 4.27 to 4.32 (2
H, m), 5.15 to 5.39 (4H, m), 7.36
(5H, s), 7.55 (2H, d), 8.15 (2
H, d)

Example 6 4-Nitrobenzyl (4R, 5R, 6S) -3- (4
-Nitrobenzyloxycarbonyloxy) -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
En-2-carboxylate (Compound F):

[Chemical formula 24] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (7.25 g) in methyl isobutyl ketone (50 ml) was cooled to −5 ° C., and 4-
Dimethylaminopyridine (0.04g) and chlorocarbonic acid 4
-Nitrobenzyl (6.47g) was added. At the same temperature, diisopropylethylamine (6.47 g) was added to 30
The mixture was added dropwise for 1 minute and aged for 30 hours. After the reaction was completed, a saturated aqueous solution of sodium dihydrogen phosphate was added to adjust the pH to 7.8, the mixture was washed, and the layers were separated.
It was washed with 0 ml) and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (5.03 g). Melting point 57-6
1 ° C. ¹ H NMR (270 MHz. CDCl ₃ ) δ ppm:
1.25 (3H, d), 1.36 (3H, d), 3.2
9 to 3.41 (2H, m), 4.23 to 4.34 (2
H, m), 5.30 (2H, s), 5.33 (2H, d
d), 7.55 (2H, d), 7.59 (2H, d),
8.19 (2H, d), 8.22 (2H, d)

Example 7 4-Nitrobenzyl (4R, 5R, 6S) -3-phenoxycarbonyloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3 .2.0] hept-2-ene-2-carboxylate (Compound G):

[Chemical 25] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (7.25 g) in methyl isobutyl ketone (45 ml) was cooled to -5 ° C and 4-
Dimethylaminopyridine (0.04g) and phenyl chlorocarbonate (3.45g) were added. At the same temperature, diisopropylethylamine (2.84 g) was added dropwise over 1 hour,
Aged for 4 hours. After completion of the reaction, the mixture was washed with saturated aqueous sodium dihydrogenphosphate and then separated, and the obtained organic layer was washed with water and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (9.65 g). ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.31 (3H, d), 1.35 (3H, d), 3.3
6 to 3.44 (2H, m), 4.29 to 4.37 (2
H, m), 5.39 (2H, dd, J = 13.8, 5
2.9 Hz), 7.14 to 7.40 (5 H, m), 7.
62 (2H, d), 8.17 (2H, d)

Example 8 4-Nitrobenzyl (4R, 5R, 6S) -3- (2
-Chloroethoxycarbonyloxy) -6-[(R)-
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Carboxylate (Compound H):

[Chemical formula 26] 4-Nitrobenzyl (4R, 5R, 6S) -6-
[(R) -1-hydroxyethyl] -4-methyl-3,
A solution of 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate (3.25 g) in methyl isobutyl ketone (40 ml) was cooled to -7 ° C, and 4-
Dimethylaminopyridine (0.04 g) and 2-chloroethyl chlorocarbonate (4.30 g) were added. At the same temperature, diisopropylethylamine (3.88 g) was added to 30
The solution was added dropwise over a period of 30 minutes and aged for 30 minutes. After completion of the reaction, saturated aqueous ammonium chloride solution (10 ml) was added, and the mixture was washed and then separated, and the obtained organic layer was further washed with water (40 ml) and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (8.38 g). ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.26 (3H, d), 1.35 (3H, d), 3.3
0-3.44 (2H, m), 3.71 (2H, t),
4.23 to 4.33 (2H, m), 4.44 (2H,
t), 5.36 (2H, dd), 7.62 (2H,
d), 8.23 (2H, d)

Example 9 4-Nitrobenzyl (4R, 5R, 6S) -3- (2
-Acetylaminoethylthio) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (compound Method I)

[Chemical 27] To a solution of the compound A (0.63 g) prepared in Example 1 in methylene chloride (10 ml) was added N-acetylcysteamine (0.18 g) and magnesium bromide ether complex (1.55 g). After cooling to -10 ° C, diisopropylethylamine (0.39g) was added dropwise over 10 minutes. After aging at −10 ° C. for 3 hours, diisopropylethylamine (0.39 g) was added, and the mixture was further heated at the same temperature for 18 hours.
Aged for hours. After completion of the reaction, saturated aqueous ammonium chloride solution (10 ml) was added, and the mixture was washed and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain compound I (0.38 g).

Example 10 Method for producing compound I: N-
A solution of acetylcysteamine (0.22 g) in tetrahydrofuran (10 ml) was cooled to -10 ° C, and 1.0N bromomagnesium cyclohexylisopropylamide.
Tetrahydrofuran solution (2.5 ml) and compound A prepared in Example 1 (0.63 g) were added. 1 at room temperature
The mixture was aged for 6 hours, ethyl acetate (20 ml) and saturated aqueous ammonium chloride solution (10 ml) were added, and the mixture was washed and separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to give compound I (0.18
g) was obtained.

Example 11 Method for producing compound I: N-
A solution of acetylcysteamine (0.18 g) in tetrahydrofuran (10 ml) was cooled to -10 ° C, and 1.0N bromomagnesium cyclohexylisopropylamide.
Tetrahydrofuran solution (2.5 ml) and compound A
(0.84 g) was added. The mixture was aged at −10 ° C. for 22 hours, ethyl acetate (20 ml) and saturated aqueous ammonium chloride solution (10 ml) were added, and the mixture was washed and then separated. The obtained organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain compound I (0.13 g).

Reference Example 1 Method for producing compound I:

[Chemical 28] 4-Nitrobenzyl (4R, 5R, 6S) -3-diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept N-acetylcysteamine (0.20 g) was dissolved in a solution of 2-ene-2-carboxylate (1.02 g) in acetonitrile (10 ml),
After cooling to -10 ° C, diisopropylethylamine (0.22g) was added dropwise. The reaction solution was aged at −10 ° C. for 2 hours and further at 10 ° C. for 70 hours, then N-acetylcysteamine (0.03 g) and diisopropylethylamine (0.04 g) were added and aged for 24 hours. Saturated ammonium chloride (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml). The obtained organic layer is concentrated,
The residue was purified by silica gel column chromatography to obtain the title compound (0.58 g). ¹ H NMR (270 MHz.CDCl ₃ ) δppm:
1.26 (3H, d), 1.37 (3H, d), 1.9
9 (3H, s), 2.79 to 2.89 (1H, m),
3.10 to 3.17 (1H, m), 3.26 to 3.39
(2H, m), 3.52 to 3.63 (2H, m), 4.
22-4.29 (2H, m), 5.36 (2H, dd,
J = 13.8, 78.0 Hz), 5.92 (1H,
m), 7.66 (2H, d), 8.22 (2H, d)

[0047]

The compound represented by the formula (I) obtained by the production method of the present invention is converted into the compound represented by the formula (III) by reacting with the compound represented by the formula (IV). I can guide you.

The compound represented by the formula (I) obtained by the production method of the present invention is more stable than the conventional carbapenem intermediate compound (VI).

The compound represented by the formula (III) exhibits excellent antibacterial activity by removing a hydroxyl-protecting group in R ¹ by a conventional method and further removing a carboxy-protecting group R ^3. It can lead to carbapenem derivatives. Therefore, the compound of the present invention is a useful intermediate in the synthesis of carbapenem antibiotics, and the utilization method and production method thereof contribute to the synthesis of carbapenem derivatives.

Claims (7)

[Claims] 1. Formula (I): (In the formula, R ¹ represents an optionally protected hydroxy-substituted lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a protecting group for a carboxy group, and R ⁴ represents a substituent. A compound represented by an alkyl group, an alkenyl group, an alkynyl group or an aryl group which may be present. 2. The compound according to claim 1, wherein R ¹ is an optionally protected 1-hydroxyethyl group. 3. The compound according to claim 1 or ^{2, wherein} R ² is a methyl group. 4. R ⁴ is an alkoxy group, an alkylthio group,
An acyloxy group, a halogen group, a nitro group, a dialkylcarbamoyl group, a dialkylsulfamoyl group, a dialkylamino group, a cyano group, an acyl group, or a linear group which may be substituted with a phenyl group which may have a substituent, A branched or cyclic alkyl group, an allyl group, a 2-propynyl group,
The compound according to claim 1, 2 or 3, which is a phenyl group, a naphthyl group, a pyridyl group, a pyrazyl group, a pyrimidyl group, a pyrazoyl group, an imidazolyl group, a thiazolyl group, a benzothiazolyl group or a benzimidazolyl group. 5. Formula (II): (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) And the formula (III) XC (═O) OR ⁴ (III) (wherein, X represents a halogen group. R ⁴ has the same meaning as described above.), And the compound represented by the formula (I): is reacted in the presence of a base. (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). 6. Formula (I): (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.) And the formula (IV) HSR ⁵ (IV) (wherein R ⁵ has a substituent. A chain or cyclic alkyl group or heterocycle which may be present) is reacted with a metal salt or a complex of a metal salt in the presence or absence of a base. (V) (Wherein R ¹ , R ² , R ³ and R ⁵ have the same meanings as described above). 7. The metal of a metal salt or a complex of a metal salt is II.
The method according to claim 6, wherein the metal is a group III or group III metal.