JPH01163188A - Alkenylsilylazetidinone intermediate - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R represents H or (substituted)alkyl; R<1> represents eliminating group; R<2> and R<3> represent H, (substituted)alkyl or aryl; R<4> represents H, (substituted)alkyl or nucleophilic group; R<5> and R<6> represent H, (substituted)alkyl, aryl or (protected)carboxy; R<1> and R<8> represent H, halogen, (substituted)alkyl or aryl]. EXAMPLE:1-(Z)-Crotyldimethylsilyl-3alpha-(1-(R)-t-butyldimethylsilylox yethyl)-4beta- acetoxyazetidin-2-one. USE:A raw material for producing 1-alkylcarbopenem compound, etc., useful for antimicrobial agents. PREPARATION:A 4-eliminating group-substituted azetidinone compound expressed by formula II is reacted with a (substituted or non-substituted allyl) halosilane compound expressed by formula III in the presence of an acid receptor under mild condition.

Description

Detailed Description of the Invention This invention can be produced from a 4-leaving group-substituted azetidinone compound (1) and a (substituted or unsubstituted allyl) halosilane compound (n) by the new reaction (1) in the reaction formula on the next page. New intermediate (4), 4-leaving group substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (I
The present invention relates to a method for stereoselectively producing 4-(2-alkenyl)-2-azetidinone compound (IV), which is an intermediate for beta-lactam compound synthesis, by subjecting II) to new reaction (2).

That is, this invention consists of the following reactions and compounds.

(1) 4-Leaving group substituted azetidinone compound (I) +: (
The corresponding 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (II) is reacted with the substituted or unsubstituted allyl)halosilane compound (II).
Method of manufacturing [).

(4-Leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (m)) Corresponding 4-(2-alkenyl)-2-azetidinone compound (IV) by reacting with diacid How to manufacture.

(3) 4-Leaving group-substituted azetidinone compound (I) is reacted with a (substituted or unsubstituted allyl)halosilane compound (n) to produce a corresponding 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl - A method for producing a 2-azetidinone compound (IN) and treating it with an acid to produce a corresponding 4-(2-alkenyl)-2-azetidinone compound (IV).

(4) 4-Leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (■).

(In the formula, R is hydrogen or an alkyl group that may have a substituent, R1 is a leaving group, and RI and R3 are the same or different hydrogen or an alkyl or aryl group that may have a substituent. , R6 is hydrogen, an alkyl group or a nucleophilic group that may have a substituent, R' and R@ are the same or different, hydrogen, an alkyl or aryl group that may have a substituent, or a protected (R2 and R1 are the same or different and are hydrogen, a halogen or an alkyl or aryl group which may have a substituent, and Hal represents a halogen, respectively) [Industrial Application Fields] This invention The present invention relates to an industrial method for producing raw materials for producing 1-alkylcarbapenem compounds useful as antibacterial agents.

[Problems of the prior art solved by the present invention] 1-Alkylcarbapenem compounds have been attracting attention in the field of antibacterial agents for the past few years, and 4-(2-alkenyl)-
Since the synthesis method of 2-azetidinone compound (IV) is an intermolecular reaction, it is stereo-nonspecific (e.g., The Journal of Organic Chemistry, Vol. 50, No. 34).
38, 1985), the configuration of the 1-alkyl group could not be synthetically controlled, resulting in low yields and low operability, making it impractical.

The present inventor has developed a method for producing a 4-(2-alkenyl)-2-azetidinone compound (■), which is a raw material for producing a 1-alkylcarbapenem compound having a 1β configuration that is advantageous for antibacterial action, by a stereoselective rearrangement reaction. By developing this, the problems of the conventional technology were solved.

[Summary of the Invention] According to the present invention, a 4-leaving group-substituted azetidinone compound (1) and a (substituted or unsubstituted allyl) halosilane compound (It) are reacted under mild conditions in the presence of an acid scavenger. A new compound unknown in the literature, a 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (
III) Manufacture.

This product is a 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (■°)
When treated with an acid, a 4-(2-alkenyl)-2-azetidinone compound CN) is obtained. This product, 4-
(2-Alkenyl)-2-azetidinone compound (IV)
is a raw material for synthesis of 1-alkylcarbapenem compounds and the like.

Although this carbon-carbon bond forming reaction is a new reaction, the intermolecular reaction does not proceed under the same conditions as this intramolecular reaction.

That is, a 4-leaving group-substituted azetidinone compound (I) and a (substituted or unsubstituted allyl) halosilane compound (I) are reacted in the presence of zinc bromide, which is a Lewis acid that can be used in the rearrangement reaction of the present invention. Even if the 4-(2-alkenyl)-2-azetidinone compound (V) is not produced.

4-Leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (II[) has an intramolecular alkenylation with acid that is opposite to the 3-position side chain regardless of the coordination of the leaving group. occurs stereoselectively from the aspect of As a result, the 4-(2-alkenyl)-2-azetidinone compound (I
V) 95% or more is 3.4-trans isomer.

[Effect of the invention] This 4-leaving group substitution-1- (substituted or unsubstituted allyl)
Silyl-2-azetidinone compound (■) to 4-(2-
The intramolecular reaction to the (alkenyl)-2-azetidinone compound (IV) is a sterically controlled sigmatropic reaction, resulting in a high stereochemical purity of the product. As a result, when compared with known techniques based on intermolecular reactions, the production of the target carbapenem compound was improved in terms of reaction mixture treatment, isomer separation, purification operations, amount of reagents, etc.

In particular, the production method of the present invention is suitable for producing 1β-methylcarbapenem. For example, highly pure (Z)-2-butenyldimethylchlorosilane compound (II) is produced from butadiene and dimethylchlorosilane by the method described in Izvestia Academia Nauka USSR (Chemistry Edition), 1980, p. 2. This product (It) and 4
-React with leaving group-substituted azetidinone compound (I) to produce 4-leaving group-substituted-1-(2-butenyl)silyl-2-azetidinone compound (II[). This product (
II[) is treated with an acid such as zinc bromide to give 4-(2-buten-2-yl)-2-azetidinone compound (IV). This product (IV) can be manufactured using known methods (patent application 1986-
260731, etc.), carbapenem compounds with high steric purity can be produced.

[Description of 6 units] The six groups in the above formula will be explained below.

R is hydrogen or an alkyl group which may have a substituent. Typical examples include hydrogen, alkyl groups having 1 to 8 carbon atoms (e.g. methyl, ethyl, propyl), hydroxyalkyl groups having 1 to 8 carbon atoms (e.g. hydroxyalkyl 1 −
hydroxyethyl, 1-hydroxypropyl, 2-hydroxyisopropyl) group, haloalkyl group having 1 to 8 carbon atoms (for example, fluoromethyl, chloromethyl, 1-fluoroethyl, 2-fluoroisopropyl, trifluoromethyl) group, carbon dioxoryl of numbers 4 to 8 (for example, 2
-oxo-4-alkyl (eg, methyl, ethyl, propyl) dioxolyl) group, and the like.

The hydroxy group of the hydroxyalkyl group may be protected, for example, with a hydroxy protecting group as described below. Acyl group having 1 to 8 carbon atoms, substituted (for example, alkyl having 2 to 10 carbon atoms, chloroalkyl, benzyl,
p-nitrobenzyl, p-methoxybenzyl, 0-nitrobenzyl, allyl-substituted) oxycarbonyl group, ether-forming group having 2 to 8 carbon atoms (e.g., methoxymethyl, methoxyethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl) ), silyl having 3 to 18 carbon atoms (
For example, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, diphenyl-t-butylsilyl, triphenylsilyl, dimethyl-t-pentylsilyl) groups, and active aralkyl groups having 7 to 19 carbon atoms (eg, triphenylmethyl) groups.

R1 is a leaving group. Typical examples include a hydroxy group, an alkanoyloxy group having 1 to 8 carbon atoms which may have a substituent, an aroyloxy group having 7 to 15 carbon atoms, and 1 carbon number.
~8 alkylsulfinyl groups, arylsulfinyloxy groups having 6 to 10 carbon atoms, alkylsulfonyloxy groups having 1 to 8 carbon atoms, arylsulfonyloxy groups having 6 to 1.0 carbon atoms, halogens (e.g. chlorine, fluorine, bromine) atoms, etc.

R1 and Rj each represent hydrogen or an alkyl group or aryl group which may have a substituent.

Typical examples include, for example, oxygen functional groups as described below,
Alkyl having 1 to 8 carbon atoms (for example,
Examples include methinoethyl, propyl) groups, and aryl groups having 6 to 8 carbon atoms (eg, phenyl, tolyl) groups.

R1 is hydrogen, an alkyl group which may have a substituent, or a nucleophilic group. A typical example is a hydrogen atom, with 1 or more carbon atoms.
8 alkyl group, and an alkyl group having 1 to 8 carbon atoms substituted with a nucleophilic group. Here, as a representative nucleophilic group, the nucleophilic group at the 3-position of cephalosporin has 1 to 18 carbon atoms.
contains nucleophilic groups. For example, halogen atom - halogen (e.g. fluoro, chloro,
Bromo, iodo)yX, oxygen group, hydroxyl group, alkoxy group having 1 to 8 carbon atoms,
Aryloxy group having 6 to 10 carbon atoms, acyl having 1 to 10 carbon atoms (e.g., alkanoyl, substituted alkanoyl, aroyl, carbamoyl, substituted carbamoyl, mono- or dialkylcarbamoyl (e.g., p-methoxybenzyloxy, benzhydryl) Sulfur group - C6-C10 aryl (e.g. phenyl, naphthyl, indenyl) thio L, oxacyly L, thiazolyl, imidazolyl, oxacyly Ju
, Chiasiasiri &.

triazolyl, theatriazolyl, tetrazolyl, pyridyl, virani) indolinobenzofuri4, penzocheninobenzimidazolyl, benzothiazolyl, penzovirazininoquinolyl, pyridopyridyl) thio group,
Alkyl (for example, ethyl, fluoroethyl, fluorovinyl) thio group having 1 to 8 carbon atoms, nitrogen group-amino group, mono- or di(alkyl)amine group having 1 to 8 carbon atoms, tetrazol-1-yl group, triazol-1-yl group, monocyclic or polycyclic nitrogen rings having 1 to 10 carbon atoms (e.g. pyridinio, carboxypyridinio, carbamoylpyridinio, picolinio, cyclopentenopyridinio, cyclohexeno) Pyridinio, quinolinio, 1-lower alkyl imidazolidinio, cycloalkanopyridinio, 1-lower alkyl triacylinio,
carbon groups - alkyl having 1 to 8 carbon atoms (e.g. methyl, methoxymethyl, ethyl, ethoxymethyl, iodoethyl, propyl, isopropyl, butyl, isobutyl, ethoxyethyl, methylthioethyl, methane), such as piperidinio, pyrrolidinio, quinuclidinio) groups; Sulfonylethyl, trichloroethyl, t-butyl) group, carbon number 3-1
2 alkenyl (e.g., propenyl, allyl, prenyl, hexenyl, phenylpropenyl, dimethylhexenyl, 2-xo-1,3-dioxolylmethyl) group,
Aralkyl having 7 to 19 carbon atoms (e.g., benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenylethyl, trityl, di-t-
butylhydroxybenzyl, phthalidyl, phenacyl)
group, an aryl group having 6 to 12 carbon atoms (e.g., phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl) group,
Carboxy group, alkyl having 1 to 8 carbon atoms (e.g., methyl, methoxymethyl, ethyl, ethoxymethyl, iodoethyl, propyl, isopropyl, butyl, isobutyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, trichloroethyl, t-butyl) Oxycarbonyl group, alkenyl having 3 to 12 carbon atoms (e.g. propenyl, allyl, pre-hexenyl, phenylpropenyl, dimethylhexenyl, 2-oxo-1,3-
dioxolylmethyl)oxycarbonyl group, carbon number 8~
20 aralkyl (e.g. benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenylethyl, trityl, di-t-butylhydroxybenzyl, phthalidyl, phenacyl)oxycarbonyl group, Aryl groups having 6 to 12 carbon atoms (e.g. phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl) oxycarbonyl groups, aminooxycarbonyl groups having 1 to 12 carbon atoms (e.g. acetone oxime, acetophenone oxime, aceto ester with aldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide) group, silyl group having 3 to 12 carbon atoms (e.g., trimethylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl), oxycarbonyl group having 3 to 12 carbon atoms 12 stannyl (e.g. trimethylstannyl)oxycarbonyl groups,
1-oxygenated alkyloxycarbonyl having 2 to 15 carbon atoms, such as straight-chain, branched, cyclic or partially cyclic alkanoyloxyalkyl (for example, acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl) , cyclohexanecarbonyloxyethylnyl group, 1-alfkydicarbonyloxyalkyl having 3 to 15 carbon atoms (for example, ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, t-butoxycarbonyloxyethyl, isopentyloxycarbonyl group) Oxybropyl, cyclohexylmethoxycarbonyloxy ether, bornyloxycarbonyloxymethyl)oxycarbonyl group, alkoxyalkyl group having 2 to 8 carbon atoms (e.g. methoxymethy&, methoxyethyl)oxycarbonyl group, carbon i number 4 to 8 Examples include 2-oxacydichloroalkyl (eg, tetrahydrofuranyl, tetrahydropyranyl) oxycarbonyl group.

R8 and R1 are the same or different and represent hydrogen, an alkyl or aryl group which may have a substituent, or a carboxy group which may be protected. Typical examples include alkyl having 1 to 10 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, cyclopropyl butyl, isobutyl, tertiary butyl, cyclopropyl, pentyl, impentyl, neopentyl,
cyclopentyl, cyclopropylethyl, hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cyclohebutyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl, dodecyl) group, carboxy group, protected carboxy (e.g. Methyl, ethyl, propyl, isopropyl, cyclopropyl, ester group with alkyl having 2 to 10 carbon atoms such as isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethyl, pentyl, 2 to 10 carbon atoms such as chloroethyl, methanesulfonyl ethyl, etc. Ester groups with 10 substituted alkyls, ester groups with aralkyls having 7 to 19 carbon atoms such as benzyl, benzhydryl, p-nitrobenzyl, p-methoxybenzyl, and 0-nitrobenzyl, and alkenyl groups having 2 to 10 carbon atoms such as prenyl and allyl. (forming ester groups, etc.) groups.

R7 and R" are the same or different and are hydrogen, halogen, alkyl or aryl groups which may have substituents. Representative examples include alkyl having 1 to B carbon atoms (e.g. methyl, ethyl, propyl) , isopropyl, cyclopropyl, butyl, isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, neopentyl, cyclopentyl, cyclopropylethyl, hexyl, cyclohexyl) group, jt2 prime number 1 to 8
substituted alkyl (e.g., chloroethyl, methanesulfonylethyl) groups, carbon & t~10 5- to 6-membered monocyclic or bicyclic carbocyclic or heterocyclic aryl groups (e.g.
Phenino muttering naphthyl, indenyl, frill, thienyl,
pyrrolyl, oxacylyl, thiazolyl, imidazolyl,
Oxadiazolyl, thiadiazolyl, triazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyranyl,
indolyl, benzif, benzothienyl, benzimidazolyl, benzothiazolyl, benzopyrazinyl,
quinolyl, pyridopyridyl) groups, halogen (eg, fluorine, chlorine, bromine, iodine, pseudohalogen) atoms, and the like.

Hat is a halogen. Typical examples include chlorine, bromine, etc., as well as equivalent groups such as pseudohalogen (eg, lower alkanesulfonyloxy, benzenesulfonyloxy which may have a substituent) group.

Any of the R1, R''%R', R6, and R' may be bonded to each other with or without a hetero atom to form a part of a ring structure with or without a substituent.

Sarani, Mki R, R', R1, R1, R4, R6, R6
, R7, and R8 are one or more of the same or different substituents. Each substituent may be a nucleophilic group as described above, or may be, for example, a substituent as described below.

The six alkyl moieties are straight chain, branched or cyclic alkyl. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethypentyl, impentyl, neopentyl, cyclopentyl, cyclopropylethyl, hexyl,
Examples include cyclohexyl, cyclopentylmethyl, heptyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl, and dodecyl. Any of these may have a substituent as described below.

The aralkyl moiety is a combination of an alkyl moiety and an aryl moiety. Representative aralkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, naphthylmethyl, furylmethyl, thienylpropyl, oxacylylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, pyridylmethyl,
Examples include indolylmethyl, penzimidazolylethyl, benzothiazolylmethyl, and quinolylmethyl.

Any of these may have a substituent as described below.

The acyl moiety is a straight-chain, branched or cyclic alkanoyl, monocyclic or bicyclic, optionally heteroatom-containing alloy, aralkayl, arylalkenoyl, alkylsulfonyl, arylsulfonyl, carbamoyl, carbalkoxy, carboyl Acyl groups such as alkoxy and sulfo.

Any of these acyl groups may have a substituent as described below.

The aryl moiety is a monocyclic or bicyclic, 5- to 6-membered carbocyclic or heterocyclic aryl group. This heterocyclic group may have oxygen, nitrogen, sulfur as heteroatoms. Typical aryl groups include phenyl, naphthinol, indenyl, pyrrolyl, oxazolinol, and oxazolinol.
, ImidazoliJ oxadiazolino thiadiazolyl,
Examples include triazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyranyl, indolyl, benzofurinobenzothienyl, penzimidazolinobenzothiazolyl, benzopyrazinyl, quinolyl, and pyridopyridyl ring groups. Any of these may have a substituent as described below.

Representative examples of substituents that can be bonded to the above six groups include carbon functional groups (e.g., straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic groups,
acyl carboxylates, carboxy, protected carboxy, cyanide, etc.), nitrogen functional groups (e.g. amino, acylamino, guanidine, ureido, alkylamino, dialkylamino, inthiocyano, isocyano, nitro, nitroso, etc.), oxygen functional groups (e.g. , hydroxy, alkoxy, aryloxy, heterocyclic oxy, cyanato, oxo, carboxylic acid acyloxy, sulfonic acid acyloxy, phosphoric acid acyloxy, etc.), sulfur functional groups (e.g., mercapto, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, heterocyclic ring thio, heterocyclic sulfonyl, acylthio, thioxo, sulfo, sulfamoyl, etc.), halogen (e.g. fluorine,
Examples thereof include chlorine, bromine, iodo, etc.), silyl groups (eg, trialkylsilyl, dialkylalkoxysilyl, etc.), and stannyl groups (eg, trialkylstannyl, etc.).

The number of carbon atoms in the six groups is the number excluding the protecting group carbon.

[Embodiment of the invention] The reactions of the invention are carried out as described below.

■ N-silylation reaction 4-Leaving group-substituted azetidinone compound (I) is mixed with an inert solvent (e.g., hydrocarbon, halogenated hydrocarbon, ether,
ester) in the presence of a condensing agent with a (substituted or unsubstituted allyl) halosilane compound ([) to form the corresponding 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone. Compound (III) can be produced.

Usually, 4-leaving group-substituted azetidinone compound (I) is combined with (substituted or unsubstituted allyl) halosilane compound (■) 1 to 2
When reacted with an equivalent amount at -20 to 20°C, it will take 30 minutes to 25 minutes.
The reaction completes in time. Yield is about 80-95%.

Examples of condensing agents include tertiary amines (e.g., triethylamine, tri(2-hydroxyethyl)amine, Triton B, N, N-dimethylaniline), aromatic amines (
For example, pyridine, bifrin, lutidine, nicotine),
Weakly basic anion exchange resins (e.g. Amberlite I
R-45, IR-4B, Duolite A-4), metal oxides, aliphatic or aromatic carboxylic acids (e.g. formic acid,
1 to 5 equivalents of a base such as acetic acid, phenylacetic acid, benzoic acid) salts can be used as long as it promotes the reaction.

(211 Rearrangement Reaction 4-Leaving group substitution-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (III)
When an acid is applied to the ester), the corresponding 4-(2-alkenyl)-2-azetidinone compound (IV) is produced.Usually, the reaction is completed in 1 to 24 hours at -40 to 40°C. Yield is approximately 80-90%.

Here, acids include mineral acids (e.g., hydrochloric acid, phosphoric acid, sulfuric acid,
nitric acid, perchloric acid), carboxylic acids (e.g. formic acid, acetic acid,
malic acid, trifluoroacetic acid), sulfonic acid (e.g.
methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid trimethylsilyl ester), Lewis acids (e.g. aluminum chloride, zinc chloride, zinc bromide,
titanium chloride, tin chloride, antimony chloride, vinegar @ copper)
and the like are used in an amount of about 0.1 to 5.0 equivalents.

As mentioned above, the carbon-carbon bond formation by this acid is 4
-Leaving group substitution-1-(Substituted or unsubstituted allyl)silyl-2-azetidinone compound (II[,) This is a new reaction specific to the intramolecular reaction, and does not proceed as an intermolecular reaction.

[Reaction conditions: -30 to 100'' C5, especially -20
The reaction is often carried out at a temperature of ~50°C for 10 minutes to 10 hours. These are carried out in a solvent, optionally under anhydrous conditions. Stirring, isolation from outside air with inert gas, etc.
Other conventional methods may also be applied if necessary.

Reaction solvents include hydrocarbons (e.g., pentane, hexane, octane, benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (e.g., diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran), ketones (e.g. acetone, methyl ethyl ketone, cyclohexanone), esters (e.g. ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrohydrocarbons (e.g. nitromethane, nitrobenzene), Nitriles (e.g. acetonitrile, benzonitrile), amides (e.g. formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide), sulfoxides (e.g. formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide),
(e.g., dimethyl sulfoxide), carboxylic acids (e.g., formic acid, acetic acid, propionic acid), organic bases (e.g.,
Examples include industrial solvents belonging to the series such as diethylamine, triethylamine, pyridine, pilin, furizine, quinoline), alcohols (e.g., methanol, ethanol, propatool, hexanol, octatool, benzyl alcohol), water, and other series of industrial solvents or mixtures thereof. .

The desired product is obtained after removing impurities (e.g., unreacted raw materials, by-products, solvent) from the reaction solution by conventional methods (e.g., extraction, evaporation, washing, concentration, precipitation, filtration, drying). It can be isolated by a combination of conventional post-treatments (eg, adsorption, elution, distillation, precipitation, precipitation, chromatography).

[Application example The co-product 4-(2-alkenyl)-2-azetidinone compound (mV) can be produced by the method of reaction formula on the next page.
It can be efficiently converted into a β-methyl-2-nucleophilic group-substituted methylcarbapenem compound (■), and can also be used as a raw material for known antibacterial agents.

That is, 4-(2-buten-2-yl)-2-azetidinone compound (■) was treated with 1.5 equivalents of p-nitrobenzylglyoxylate in the presence of triethylamine in tetrahydrofuran at about 50°C for 3 hours. Glycolate (V) is obtained. This was epoxidized by reacting with 2 equivalents of p-chloroperbenzoin #2 and 2 equivalents of sodium hydrogen carbonate in tetrahydrofuran, and then reacted with 1.2 equivalents of thionyl chloride and 3 equivalents of lutidine at -20°C for 1.5 hours. , ylide (VI
). Tetrahydro (for example, Het is 1.
2.4-thiadiazolyl, Rゝ is 1-tertiary butyldimethylsilyloxyethyl, R'. represents p-nitrobenzyl) in furan, 1.2.4-thiadiazolyl-5-
Thiolate (■) is obtained by reacting 3 equivalents of thiol with 0.5 equivalents of butyllithium. This is oxidized in dichloromethane with 3 equivalents of dimethyl sulfoxide, 2 equivalents of triple oroacetic anhydride, and 4.5 equivalents of triethylamine to form a ketone, and then the mixture is closed by heating in toluene to synthesize a carbapenem ring. If this is deesterified by the action of aluminum chloride in cold methylene chloride, 1β-methyl-2-
(1゜2.4-thiadiazolyl-5-f)methyl-1
-Calper 2-benem-4-carboxylic acid (■) can be produced.

The 1β-methyl isomer has stronger antibacterial activity than the 1α-methyl isomer.

Also, 4-(2-alk Ru2-Nucleophile Substituted Cal It can also be converted to bapenem compound (IX).

The present invention will be explained in detail below by way of examples.

In NMR of a compound that has multiple groups with the same structure and each group's hydrogen has a different chemical shift, the corresponding signals are split, the area intensity ratio corresponds to the number ratio of the groups, and the total corresponds to the number of hydrogens in the group. In this case, each chemical shift is written together, separated by ",", and the number of separations and the symbol "1x" are added in front of the signal type symbol.

(Abbreviation) ACaI Acetyl. tBu m t-butyl*Bz
-benzoyl e Dioxolon wa 2-year-old xo-4-methyl-1,3-dioxo-4-yl a
Et■Ethyl, Me play Methyl, Ms■Mesyl.

PMB-9-methoxybenzyl, PNB p-nitrobenzyl, Ph-phenyl, pf Ha
Propyl* Tat -1-methyltetrazolyl,
Tdz-thiadiazolyl, THP-tetrahydropyranyl, Trityl, Ts-Tosyl.

(Left below) Example 1 [4β-acetoxyazededinone compound (Ia
) Example IA 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxyazetidin-2-one (
Ia) 10.01 g (34,83 mmol) and (Z)-
5.71 g of crotyldimethylchlorosilane (IIa) (
1.1 equivalent) was dissolved in 30n+1 dichloromethane, and 5.6ml (1 equivalent) of triethylamine was added to this while cooling with water and stirring.
, 15 equivalents) was added dropwise.

After stirring for 30 minutes and leaving it at room temperature overnight, hexane 3
00011 is added, and the precipitated triethylamine hydrochloride is filtered off. When the filtrate is concentrated under reduced pressure, 1-(Z)-crotyldimethylsilyl-3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxyazetidin-2-one (IIIa) 14. Obtain Og.

NMR (EM-390, CDC1,') δ: 0.0?
, 0.13.0.25 (3xs, 12H), 0.
89 (s, 9H), 1.23 (d, J: 6.5
Hz.

3H), 1.57 (d, J=4.5Hz, 3H
), 1.75 (d, J=7Hz, 3H), 2
．． 07 (s, 3)1), 3.15 (d 1ik
e, IH).

4.21 (m, LH), 5.23-5.57 (
m, 2H), 6.15 (s.

IH) ppm.

IR(Nujol)ν: 1756.1750.16
54.1260°1236, 840 cm-'.

NMR (VR-200, CDC1,) l: 0.
06.0.08.0.24゜0.27 (4xs,
12H), 0.88 (s, 9H), 1.
24 (d, J=6.4Hz, 3H), 1
．． 58 (d, J=5Hz, 3H), 1.
75 (d.

J=7.2Hz, 2H), 2.09 (s,
3H), 3.14 (dd-1ike.

LH), 4.19 (m, IH), 5.3
1-5.53 (m, 2H), 6.14 (s,
IH) pi)m- Example IB 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxy-1-(Z)-(crotyldimethylsilyl)azetidin-2-one ( Illa)
5.24 g (13.1 mmol) was dissolved in 18 ml of dichloromethane, and while stirring at -20°C, 1 ml of trifluoromethanesulfonic acid trimethylsilyl ester was dissolved.
．． 26 ml (0.5 eq.) are added dropwise and after 10 minutes the mixture is brought to room temperature and allowed to react for 1.5 hours. The reaction solution is poured into cold aqueous sodium bicarbonate, and the organic layer is separated, dried, and concentrated under reduced pressure. If the remaining crystals are recrystallized from n-hexane, 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-((R)-1-
buten-3-yl)azetidin-2-one (R-IVa
) Obtain 2.81 g. mp142-142.5℃
, yield near 5.7%.

Silica gel chromatography (Rover B:
The polar fraction was purified using toluene/ethyl acetate (2:1) to give 130 mg of crystals of the (R) isomer (yield: 3.
5%), and from the non-polar fraction, the (R) isomer crystals and the (S) isomer 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-(( S)-1-
buten-3-yl)azetidine,-2-one (S-IV
a) 206 mg of 1:1 mixture with crystals (yield: 5.6%
). This crystal mixture can be separated into each isomeric crystal by repeating silica gel chromatography separation.

NMR (VR-200, CDCl5) 8: 0.0
7 (s, 6H), 0.88 (s, 9H),
1.09 (d, J=6.8Hz, 3H),
1.18 (d, J=6.2Hz, 3H)
, 2.33 (m, LH>, 2.81 (brs
, LH).

3.50 (dd, J=7.5Hz, ,C2,(3
)1z, LH), 4.17 (m.

LH), 5.05-5.15 (n+, 2H)
, 5.69-5.86 (m, LH).

5.97 (brs, LH) ppm.

IR (Nujol) L/: 1758. 1712
．． 1642. 1051. 830cm-'.

Example IC 1-stage reaction (1) 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxyazetidin-2-one (
Ia) 900n+g (3.13 mmol) and (2)-
Crotyldimethylchlorosilane (IIa) 560mg
(1,2 equivalents) was dissolved in 45 ml of dichloromethane, and 0.53 ml (1,2 equivalents) of triethylamine was added thereto under stirring while cooling with water.
Add 740n of zinc bromide (1.05 equivalents) to the reaction solution and leave it overnight at room temperature.
Stir for 4 hours. The reaction solution is poured into cold aqueous sodium bicarbonate, the organic layer is separated, dried, and concentrated under reduced pressure. If the remaining crystals are recrystallized from acetonitrile, 3α-(1-(
R)-tert-butyldimethylsilyloxyethyl)-4
β-((R)-1-buten-3-yl)azetidine-2
-one (IVa) 355 mg is obtained. mp140~L
42°C, yield: 40.0%.

Example 2 [Production of intermediate (IVa) for synthesis of 1β-methylcarbapenem compound from 4β-benzoyloxyazetidinone compound (Ib)] One-stage reaction (re3α-(1-
(R,)-tert-butyldimethylsilyloxyethyl)
-4β-penzoyloxyavitidin-2-one (Ib
) and 185 mg (1°2 equivalents) of (Z)-crotyldimethylchlorosilane (IIa) in chloroform-
Dissolve the benzene (3:1) mixture to 1.5 ml, add 0.18 ml of triethylamine (1.2
Add 243 ffIg of zinc bromide to the reaction solution and stir for 24 hours at room temperature.Pour the reaction solution into cold sodium bicarbonate water.Separate the organic layer. After drying, concentrate under reduced pressure. If the remaining crystals are recrystallized from acetonitrile, 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-((R)-
1-buten-3-yl)azetidin-2-one (IVa
) Obtain 178 mg. mp140-142°C, yield: 61.2%.

Example 3 [4β-acetoxyazetidinone compound (Ia
) is an intermediate for the synthesis of 1β-unsubstituted cibapenem compound (
IVb)] Example 3A 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxyazetidin-2-one (
Ia) 287 mg (1 mmol), 190 mg (1°4 equivalents) of allyldimethylchlorosilane (IIb) and 0.2 ml of triethylamine in 2 ml of dichloromethane.
Dilute the reaction solution with dichloromethane, wash with sodium bicarbonate water, and dry.
Concentration under reduced pressure yields 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxy-1-(
Allyldimethylsilyl)azetidine-2-sun (mb)
Get 4so■.

NMR (VR-200, CDCl,) S: 0.0
6.0.07.0.26゜0.28 (4xs, 12
H), 0.87 (s, 9H), 1.23 (d
, J-6,5Hz, 3H), 1.77 (d,
7Hz, 2H), 2.09 (s.

3H), 3.15 (dd, J=3Hz, J=1
．． 3Hz, IH), 4.18(m, LH), 4
．． 82-4.98 (m, 2H), 5.66-5.
88 (m.

1t(), 6. L3 (d, J=1.3H
z, 1) Ri ppm.

IR (film) V: 1740-1780.16
36.1230.840am-'.

Example 3B 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-acetoxy-1-(allyldimethylsilyl)azetidin-2-one (nib) 450 mg
was dissolved in 2+nl of dichlorothane, 60 μm of trifluorometasulfonic acid trimethylsilyl ester was added under water cooling, and the mixture was stirred at room temperature for 1 hour. When the reaction solution is diluted with dichloromethane, washed with sodium bicarbonate water, dried, and concentrated, 3α-(1-(R)-tert-butyldimethylsilyloxyethyl)-4β-allyl azetidine exhibits the same constant as the literature value. -2-one (IVb>240 mg is obtained. Yield:
90%.

Example 4 From the 4-leaving group substituted azetidinone compound (I) under the same conditions as Examples 1 to 3, Table 1 (1) to (
4-Leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (II[) and 4-(2-alkenyl)-2-azetidinone compound (IV ) can be manufactured.

(Margin below)

Claims (4)

[Claims] (1) 4-Leaving group-substituted azetidinone compound (I) (
The corresponding 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (III) is treated with a substituted or unsubstituted allyl)halosilane compound (II).
How to manufacture. (2) A corresponding 4-(2-alkenyl)-2-azetidinone compound (IV ). (3) 4-Leaving group-substituted azetidinone compound (I) (
The corresponding 4-leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (III) is treated with a substituted or unsubstituted allyl)halosilane compound (II).
A method for producing the corresponding 4-(2-alkenyl)-2-azetidinone compound (IV) by reacting it with an acid. (4) 4-Leaving group-substituted-1-(substituted or unsubstituted allyl)silyl-2-azetidinone compound (III). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I ▲There are mathematical formulas, chemical formulas, tables, etc.▼II ▲There are mathematical formulas, chemical formulas, tables, etc.▼III ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, R is an alkyl group which may have hydrogen or a substituent, R^1 is a leaving group, R^2 and R^3 are the same or different, and an alkyl or aryl group which may have hydrogen or a substituent; R^4 is hydrogen, an alkyl group or nucleophilic group that may have a substituent, R^5 and R^6 are the same or different hydrogen, an alkyl or aryl group that may have a substituent, or a carboxyl group which may be protected, R^7 and R^8 are the same or different alkyl or aryl groups which may have hydrogen, halogen or a substituent, Hal represents a halogen, respectively)