JPH0657692B2 - Novel β-lactam compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) [In the formula, R represents a hydrogen atom or a lower alkyl group, or a hydroxyl group represents a protected or unprotected 1-hydroxy lower alkyl group. R'represents a hydrogen atom or a nitrogen atom-protecting group, and R "represents a halogenomethyl group, a hydroxymethyl group, a hydroxymethyl group having a protected hydroxyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group or aralkyl. An oxycarbonyl group, or R ′ and R ″ represent an alkylene chain which is bonded to each other through an oxygen atom, and a 6-membered cyclic aminoacetal group together with an adjacent nitrogen atom, that is, a partial formula (In the formula, ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ represent the same or different lower alkyl groups, or represent an alkylene chain bonded to each other and represent a 5- to 7-membered cycloalkyl group). Show. ] It is related with the novel (beta) -lactam compound represented by these, and its manufacturing method.

Thienamycin having useful activity as an antibacterial agent [US Pat. No. 3,950,357; J. Am. Chem. Soc., 100 , 313 (197
Since 8)] was discovered in nature and reported, methods for obtaining various carbapenem compounds by pure synthesis have been reported.

Recently, compounds in which the methylene group at the 1-position of the carbapenem skeleton has been substituted with various alkyl groups have been synthesized. Particularly, the 1-methylcarbapenem compound is superior to the conventional 1-position unsubstituted carbapenem compound in terms of in vivo stability and the like. It is reported that they are extremely useful as antibacterial agents. However, the synthetic method has a long number of reaction steps and is complicated, and a method for stereoselectively introducing a 1-methyl group has not yet been known.

The present inventors have found that a novel β-lactam compound represented by the general formula (I) is an excellent synthetic intermediate which enables stereoselective introduction of a 1-methyl group particularly in the production of the above-mentioned 1-methylcarbapenem compound. Therefore, the present invention has been completed.

As the lower alkyl group for R in the general formula (I),
For example, methyl, ethyl, n-propyl, isopropyl,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as n-butyl and sec-butyl, and preferable examples thereof include methyl and ethyl.

Examples of the 1-hydroxy lower alkyl group include the straight-chain or branched 1-hydroxyalkyl groups having 1 to 4 carbon atoms as described above, and preferable examples thereof include hydroxymethyl and 1-hydroxyethyl. be able to.

The protecting group for the nitrogen atom of R'may be any one commonly used, but is preferably trimethylsilyl, t
-Trialkylsilyl group such as butyldimethylsilyl, p
-Substituted phenyl groups such as -methoxyphenyl and 2,4-dimethoxyphenyl, benzyl, p-methoxybenzyl,
2,4-dimethoxybenzyl, diphenylmethyl, di-
Examples thereof include mono- or diarylmethyl groups such as p-anisylmethyl, substituted methyl groups such as methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl and the like.

Examples of R ″ include, for example, a methyl group; a halogenomethyl group substituted with a halogen atom such as chlorine, bromine or iodine; a hydroxymethyl group; a hydroxymethyl group protected by a general hydroxyl-protecting group; a formyl group, a carboxyl group; Lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group; benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group , Aralkyloxycarbonyl groups such as o-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group and diphenylmethyloxycarbonyl group.

As the protective group for the hydroxyl group, those commonly used can be used, but preferably, a lower alkoxycarbonyl group such as t-butyloxycarbonyl group, for example, 2-ethyl iodide carbonyl group, 2,2,2. A halogenoalkoxycarbonyl group such as a 2-trichloroethyloxycarbonyl group, for example, a benzyloxycarbonyl group,
Aralkyloxycarbonyl groups such as o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, for example, trialkylsilyl groups such as trimethylsilyl group, t-butyldimethylsilyl group, Examples thereof include a methoxymethyl group, a 2-methoxyethoxymethyl group, a methylthiomethyl group, and a substituted methyl group such as a tetrahydropyranyl group.

The object compound of the present invention represented by the general formula (I) is a novel compound group in which a 1-substituted ethenyl group is bonded to the 4-position of the β-lactam skeleton, and is the first compound synthesized by the present inventors.

The method for producing the compound of the present invention is described in detail below.

(1) General formula (II) [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group or a 1-hydroxy lower alkyl group in which a hydroxyl group is protected, and R ′ has the same meaning as described above. ] The β-lactam compound represented by the general formula (I-1) [Wherein, R ₁ and R ′ have the same meanings as described above. ] The compound represented by these can be obtained.

This dehydration reaction can be carried out in various forms in the presence or absence of a base with a dehydrating reagent, and preferred dehydrating reagents include thionyl chloride, halogenating agents such as phosphorus oxychloride, methanesulfonyl chloride, and chloride. Examples thereof include sulfonating agents such as tosyl and dehydrating agents such as dicyclohexylcarbodiimide. Examples of suitable bases include triethylamine, pyridine, lutidine, N-dimethylaminopyridine and the like.

This can be achieved by reacting the β-lactam compound represented by the general formula (II) with the dehydrating agent as it is or in the presence of an inert solvent in the presence or absence of these bases.

Examples of the inert solvent include benzene, toluene, tetrahydrofuran, dioxane, diethyl ether, methylene chloride, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphorylamide and the like.

It is desirable to use the dehydrating agent and the base in amounts sufficient for the reaction to proceed sufficiently, and the reaction temperature can be appropriately cooled or heated to suppress or accelerate the reaction.

(2) General formula (I-1) [In the formula, R ₁ and R ′ have the same meanings as described above. ] The β-lactam compound represented by the formula (I-2) by reacting with a halogenating agent in an inert solvent [In the formula, R ₁ and R ′ have the same meanings as described above, and X represents a halogen atom. ] The beta-lactam compound represented by these can be obtained.

In this reaction, it is possible to use various halogenating agents generally used for halogenating an allylmethyl group,
Suitable halogenating agents include, for example, molecular halogen such as chlorine and bromine, hypochlorous acid such as hypochlorous acid and hypobromite, N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccin. Examples thereof include N-halogen succinimide such as imide, chlorin monoxide, and t-butyl hypochlorite.

As an inert solvent, chloroform, methylene chloride, 1,
2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, dimethylformamide and the like, and these solvents. A single solvent or 2
It can be used as a mixed solvent of two or more species.

Among the halogenating agents, those existing in gaseous form at room temperature, such as chlorine and chlorin monoxide, can be blown as they are for the reaction, but it is preferable to use them as a solution of a halogenated hydrocarbon.

It is desirable to use the halogenating agent in an amount sufficient for the reaction to proceed sufficiently, but it is usually preferable to use 1 to 1.5 equivalents relative to compound (I-1). The reaction temperature may be appropriately cooled or heated to suppress or accelerate the reaction.

The halogen atom of the compound of the general formula (I-2) can be exchanged for another halogen atom by treating it with another alkali metal salt of a different halogen atom in an inert solvent.

Suitable alkali metal salts of halogen atoms include sodium iodide, potassium iodide, sodium bromide and the like, and inert solvents include acetone, acetonitrile, dimethylformamide and the like.

(3) General formula (I-2) [In the formula, R ₁ , R ′ and X have the same meanings as described above. ] The β-lactam compound represented by the general formula (I-
3) [In the formula, R ₁ and R ′ have the same meanings as described above. ] The beta-lactam compound represented by these can be obtained.

This reaction converts allyl halide to allyl alcohol
Use of low-valent ionic salts of various heavy metals used in
Cu is possible but is preferable⁺, Ag⁺, Hg⁺, T⁺，
Cd And the like. Forming a salt
Inorganic acid or organic
The acid anion may be mentioned.

This reaction is achieved by reacting a salt of these heavy metals with low valence ions in the presence of water in an inert solvent.

As the inert solvent, dimethylformamide, dimethylsulfoxide, ethyl acetate, acetone, acetonitrile,
Examples thereof include methylene chloride, chloroform tetrahydrofuran, dioxane, benzene, toluene, and the like, with preference given to dimethyl sulfoxide, dimethylformamide, and ethyl acetate.

Preferable examples of the acid used to form the salt include organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid, and inorganic acids such as sulfuric acid and pyrophosphoric acid.

It is desirable to use the heavy metal and the organic acid or the inorganic acid in such an amount that the reaction proceeds sufficiently, and the reaction temperature can be suppressed or promoted by appropriately cooling or heating, but preferably from room temperature. It can be said to be 100 ° C.

(4) General formula [In the formula, R ₁ and R ′ have the same meanings as described above. ] The β-lactam compound represented by the general formula (I-4) [Wherein R ₁ and R ′ have the same meanings as described above, and R ″
₁ represents a formyl group or a carboxyl group. ] The β-lactam compound represented by

This reaction can be carried out in various oxidation reaction modes generally used for converting a primary alcohol to an aldehyde or a carboxylic acid, and various oxidizing agents can be used, but a preferable oxidizing agent is chromium oxide (VI). -Sulfuric acid, chromium oxide (VI)
-Acetic acid, chromium (VI) oxide-pyridine complex, chromic acid oxidizing agents such as pyridinium chromamochromate, pyridinium dichromate, oxalyl chloride, sulfur trioxide, dimethyl sulfoxide used with acetic anhydride, chlorite, etc. However, various oxidizing agents such as permanganate, manganese dioxide, and silver compounds such as silver oxide can also be used.

This reaction is performed in an inert solvent with the above-mentioned oxidizing agent and compound (I-3).
It is achieved by reacting with and, but as the inert solvent, chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride, acetone, acetonitrile, acetic acid, isopropanol, t-butanol, water and a mixed solvent thereof are preferable. However, benzene, toluene, diethyl ether, tetrahydrofuran and the like can also be used.

The oxidation reaction of compound (I-3) to carboxylic acid can be directly obtained by a single type of oxidizing agent, but it is also possible to obtain aldehyde once and then induce it to carboxylic acid by another oxidizing agent. .

The oxidizing agent used is preferably used in an amount sufficient for the reaction to proceed, and the reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature.

(5) General formula (I-4 ′) [In the formula, R and R'have the same meanings as described above. ] The β-lactam compound represented by the general formula (I-5) [Wherein R and R'have the same meanings as described above, and R " ₂
Represents a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ] The beta-lactam compound represented by these can be obtained.

This reaction can be carried out in various modes in which an ester is generally obtained from a carboxylic acid. For example, a method of reacting with a corresponding alcohol derivative in the presence of an acid, in the presence of a base, in an inert solvent, various lower alkyl halides or aralkyl It is achieved by a method of reacting with a halide, a method of treating with a corresponding alcohol derivative and a dehydrating agent, a method of treating with a diazo lower alkane or diazoallyl alkane in an insoluble solvent.

Suitable acids when reacted with an alcohol derivative in the presence of an acid include, for example, mineral acids such as sulfuric acid and hydrochloric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and Lewis acids such as boron trifluoride etherate. Can be mentioned. Suitable bases when reacted with various halides in the presence of a base include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide or triethylamine,
Examples thereof include organic bases such as diisopropylethylamine, pyridine, 2,6-lutidine, and 1,8-diazabicyclo [5,4,0] -7-undecene (DBU).

Suitable examples of the dehydrating agent include dicyclohexylcarbodiimide (DCC) and the like.

These esterification reactions can be achieved by reacting with various reagents as they are or in an inert solvent if necessary.

As an inert solvent, chloroform, methylene chloride, 1,
2-dichloromethane, carbon tetrachloride, dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, acetonitrile, benzene, toluene and the like can be used.

It is desirable to use various reagents such as an acid, a base and a dehydrating agent in such amounts that the reaction proceeds sufficiently, and it is possible to appropriately cool or heat the reaction temperature.

(6) General formula (III) [In the formula, R has the same meaning as described above, and Z represents a leaving group. And a general formula (IV) PhS—CHR ″ ₂ —CH ₃ (IV) [wherein R ″ ₂ has the same meaning as described above and Ph represents a phenyl group]. ] The silyl ketene acetal derivative of the compound represented by the following is reacted in the presence of an acid, and then, after oxidation of the thiophenyl group,
General formula (I-5 ′) by subjecting to heating reaction [Wherein R and R ″ ₂ have the same meanings as described above], and a β-lactam compound represented by the following formula can be obtained.

Preferable examples of the leaving group Z of the raw material compound represented by the general formula (III) include a halogen atom such as chlorine, bromine and iodine, an acetoxy group, a mesyloxy group and a p-tosyloxy group.

As the acid that can be used in this reaction, various Lewis acids can be used, but preferably boron trifluoride etherate,
Examples thereof include silver borofluoride and zinc iodide, and it is also possible to use trimethylsilyl triflate.

This reaction is carried out in the presence of the above-mentioned acid, compound (III) and compound (IV)
It is achieved by reacting the silyl ketene acetal derivative of the above in an inert solvent, and as the inert solvent, halogenated hydrocarbon such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride, diethyl ether, Examples thereof include ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene and toluene.

It is desirable to use an acid and a silylketene acetal derivative used in this reaction in such amounts that the reaction proceeds sufficiently.
It is preferable to use 1 to 4 equivalents based on the raw material compound (III), and the reaction temperature can be appropriately suppressed or accelerated by cooling or heating, but preferably 0 to 50 ° C. be able to.

(7) General formula (I-3) [In the formula, R has the same meaning as described above. ] The β-lactam compound represented by
(V) ▲ R ⁰ ₁ ▼ -CO- ▲ R ⁰ ₂ ▼ (V) [wherein, ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ represent the same or different lower alkyl groups or are bonded to each other. It represents an alkylene chain and represents a 5- to 7-membered cycloalkyl group. ] In the presence of an acid with a carbonyl compound represented by the general formula (I-7) by subjecting to a dehydration reaction or an amino acetal reaction with a di-lower alkyl acetal derivative of the compound of the general formula (V) [Wherein R, ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ have the same meanings as described above. ] The beta-lactam compound represented by these can be obtained.

In general, this reaction can be carried out in various modes in which an amino acetal is obtained from an amino alcohol.

Suitable acids used in this reaction include sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, sulfuric acid,
Mineral acids such as hydrochloric acid, zinc chloride, boron trifluoride etherate,
Lewis acids such as boron tribromide can be mentioned.

In the presence of these acids, β-represented by the general formula (I-3)
This can be achieved by reacting the lactam compound with the carbonyl compound represented by the general formula (V) or a di-lower alkyl acetal derivative thereof as it is or in an inert solvent if necessary.

Examples of the inert solvent include benzene, toluene, tetrahydrofuran, dioxane, diethyl ether, methylene chloride, chloroform, 1,2-dichloroethane, dimethylformamide, dimethyl sulfoxide and the like.

Examples of ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ of the carbonyl compound represented by the general formula (V) used in this reaction include 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-butyl. A lower alkyl group or a 5- to 7-membered cycloalkyl group which represents an alkylene chain which can be bonded to each other is exemplified.

It is desirable to use the acid and the carbonyl compound (V) or its di-lower alkyl acetal derivative used in an amount sufficient for the reaction to proceed, and the reaction temperature may be appropriately cooled or heated to suppress or accelerate the reaction. be able to.

After completion of the reaction, the product can be taken out by a usual organic chemical method.

(8) General formula [In the formula, R ₁ and R ′ have the same meanings as described above. ] The β-lactam compound represented by the general formula (I-6) [In the formula, R ₁ and R ′ have the same meanings as described above, and Y represents a hydroxyl-protecting group. ] The beta-lactam compound represented by these can be obtained.

The reaction for protecting the hydroxyl group can be carried out in various modes generally carried out, for example, in the presence of a base, in an inert solvent, with various halides or in the presence of an acid, with an unsaturated cyclic ether such as dihydropyran. It can be achieved by reaction.

Examples of the halide used in this reaction include ethyl chloroformate, isopropyl chloroformate, se
Lower alkoxycarbonyl halides such as c-butyl chloroformate, halogenoalkoxycarbonyl halides such as 2,2,2, -trichloroethyl chloroformate and 2-iodoethyl chloroformate, benzyl chloroformate, p-nitrobenzyl Aralkyloxycarbonyl halides such as chloroformates, lower alkylcarbonyl halides such as acetyl chloride and propionyl chloride, arylcarbonyl halides such as benzoyl chloride, tri-lower alkylsilyl halides such as trimethylchlorosilane and t-butyldimethylchlorosilane,
Substituted methyl halides such as chloromethyl methyl ether and chloromethyl methyl thioether can be mentioned.

The compound represented by the general formula (II), which is the starting material compound of the present invention, can be produced by various methods. For example, it can be produced by the method shown below.

[Wherein R ₁ and R ′ have the same meanings as described above, R ₂ represents a hydrogen atom, a lower alkyl group or a 1-hydroxy lower alkyl group, and R ₃ represents a lower alkyl group. Step A The compound represented by the general formula 2 is usually obtained by various known methods for obtaining an ester from a carboxylic acid, for example, in the presence of a base, by the method described in JP-A-58-96060. It can be obtained by reacting acid 1 with various alkyl halides or by dehydration reaction with a lower alcohol.

Step B The compound represented by the general formula (II) is prepared by reacting compound 2 with an organometallic compound such as alkylmagnesium halide or alkyllithium in an inert solvent, and when R ₂ is a 1-hydroxy lower alkyl group, It can be obtained by subjecting a hydroxyl group used conventionally to protection reaction.

Further, the compound represented by the general formula (III) which is a raw material compound can be produced by various methods, for example, the method or the chemical method described in JP-A-58-96060.
And Pharmaceutical Bulletin (Chem.Phar
m.Bull) Vol. 29, pages 2899 to 2909 (1981).

The compound represented by the general formula (I) of the present invention produced as described above can be derived to a synthetic intermediate (VI) of a 1-methylcarbapenem derivative having excellent antibacterial activity, for example, by the method shown below. You can (JP-A-58-268
(Gazette No. 87) [In the formula, R and R'have the same meanings as described above. The compound (I-1) is subjected to a hydroboration reaction with ciborane or a dialkylborane such as 9-BBN, and the alcohol 3 having 5S coordination is preferentially treated by an oxidative treatment with hydrogen peroxide-sodium hydroxide or the like. Then, the carboxylic acid can be obtained by an oxidation reaction such as chromic acid oxidation and, if necessary, subjected to a reaction for removing the amino-protecting group to obtain the 5S coordination compound of the intermediate (VI) preferentially. it can.

[In the formula, R ₁ , R ′ and Y have the same meanings as described above. The compound (I-6) is subjected to a hydrogenation reaction such as catalytic reduction to preferentially obtain the 5R form of the compound 4 , and then a reaction for removing the hydroxyl-protecting group Y and the amino-protecting group is carried out simultaneously. Alternatively, they can be sequentially carried out to give compound 3, and the 5R coordination complex of intermediate (VI) can be preferentially obtained by the oxidation reaction as described in (1) above.

[In the formula, R, R ′ and R ″ ₂ have the same meanings as described above.] The compound (I-5) is subjected to hydrogenation reaction such as catalytic reduction to give preference to 5R coordinated compound 5. Then, the ester is hydrolyzed to remove the carboxylic acid and, if necessary, the amino-protecting group to remove 5R of the intermediate (VI).
Coordinators can be obtained preferentially.

[Wherein R, ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ have the same meanings as described above. By subjecting compound (I-7) to a hydrogenation reaction such as catalytic reduction, the 5R form of compound 6 is preferentially obtained, and then subjected to an oxidation reaction under acidic conditions such as chromic anhydride-sulfuric acid. The 5R coordinate of the intermediate (VI) can be obtained preferentially.

In the method according to (1), (2), (3), (4) above, the compound 3 ,
The step of obtaining 4 , 5 and 6 can proceed the reaction stereoselectively, and thus the compound (VI) which is a starting material intermediate of the 1-methylcarbapenem compound can be stereoselectively obtained.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

The abbreviations used in the following examples and reference examples have the following meanings.

Z: benzyloxycarbonyl group DAM: di- (p-anisyl) -methyl group Me: methyl group Et: ethyl group Ph: phenyl group TCC: 2,2,2, -trichloroethyloxycarbonyl group PNZ: p-nitrobenzyl Oxycarbonyl group Example 1-1 4- (1-hydroxy-1-methylethyl) -3- (1
-Benzyloxycarbonyloxyethyl) -1-di-
30 g of (p-anisyl) methyl-2-azetidinone was dissolved in 350 m of toluene, 10 m of pyridine was added,
Next, 9.0 g of thionyl chloride was added dropwise at 20 to 30 ° C, and the mixture was stirred for 5 hours as it was. 100 m of water was added, the layers were separated, the organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off.
Crystallized from ethyl acetate to 4- (1-methylethenyl)
-3- (1-benzyloxycarbonyloxyethyl)
-1-Di- (p-anisyl) methyl-2-azetidinone was obtained.

mp 117-118 ° C Example 1-2 4- (1-methylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl)
Methyl-2-azetidinone (200g, 0.388M) was dissolved in ethyl acetate 3 and chlorine-carbon tetrachloride solution (3.85
%, 870 g) was added dropwise over 15 minutes and then stirred for 1 hour. Next, water 1, 10% sodium thiosulfate aqueous solution 50
After adding m and stirring, the organic layer was separated. After washing successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, the extract is dried over sodium sulfate and the solvent is distilled off to give 4-
(1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

mp 84-85 ° C Example 1-3 4- (1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone (20 g) was dissolved in dimethyl sulfoxide (160 m), and water was stirred while stirring (40 m).
Then, 6.76 g of cuprous oxide and 7.6 g of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred at 50 to 55 ° C for 2 hours.
After cooling to room temperature, 90% of a 1% aqueous phosphoric acid solution was added, and the mixture was diluted with 200 m of ethyl acetate. The insoluble matter was washed 3 times with 20 m of ethyl acetate, and the washing liquid was separated. The aqueous layer was extracted with 200 m of ethyl acetate, the above organic layers were combined, washed with saturated saline and dried over sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from toluene-n-hexane (1: 1) to give 4- (1-hydroxymethylethenyl) -3-.
(1-Benzyloxycarbonyloxyethyl) -1-
Di- (p-anisyl) methyl-2-azetidinone was obtained.

mp 118-120 ° C Example 1-4 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p
20 g of (anisyl) methyl-2-azetidinone was dissolved in 45 m of dimethylformamide, 5.6 g of imidazole,
Then, 6.77 g of t-butyldimethylchlorosilane was added at room temperature, and the mixture was stirred as it was for 2 hours. 200m of cold water and then 150m of ethyl acetate were added for liquid separation. Water layer is ethyl acetate 150m
Extracted with, combined with the previous organic layer, 5% hydrochloric acid water 80m
2 times, and then washed with 80% of 5% saline solution 3 times each, and dried with Glauber's salt. The solvent was evaporated and the residue was recrystallized from isopropyl alcohol to give 4- (1-t-butyldimethylsilyloxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl). Methyl-2-azetidinone was obtained.

mp 90-92 ° C Examples 1-5 Oxalyl chloride 8.5m dry methylene chloride 212m
Comb cooled to -50 ° C or lower. Next, dry dimethylsulfoxide 14.5m dry methylene chloride 42.5m solution -50
After dropwise addition at 0 ° C or lower and stirring for 10 minutes, 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl)
Methyl 2-azetidinone 45 g, dry methylene chloride 400
The m solution was added dropwise over 15 minutes and the mixture was stirred for additional 15 minutes. 64 m of triethylamine was added dropwise at -50 ° C or lower, and the temperature was gradually raised to room temperature. Dilute with cold water 480m, 6N
-Add 65 m of hydrochloric acid to make it acidic, and make the organic layer a saturated saline solution.
Wash 3 times at 200m with 200m 2% sodium bicarbonate solution, again with 200m saturated sodium chloride solution, dry with sodium sulfate, distill off and then 4- (1-
Formylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

Example 1-6 4.5 g of 4- (1-formylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was added to t-butanol 3
After combing 80m to 42.5m of 2-methyl-2-butene, 7.15g of sodium chlorite and sodium phosphate
7.15 g was dissolved in 72.3 m of water and added dropwise at room temperature. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure at 40 ° C or lower. Ethyl acetate (150 m) and water (75 m) were added to the concentrated liquid for liquid separation, the aqueous layer was re-extracted with 80 m of ethyl acetate, the organic layers were combined and washed with saturated saline (150 m). Then, extract with 150 m of saturated aqueous sodium hydrogen carbonate, cool with ice, acidify with concentrated hydrochloric acid, and then extract with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and evaporated to give 4- (1-carboxyethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone. .

Example 1-7 3.7 g of 4- (1-carboxyethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was added to 60 m of acetone.
After melting, 1.88 g of anhydrous potassium carbonate and 1.4 g of benzyl bromide were added, and the mixture was refluxed for 2 hours. Cool to room temperature, remove insoluble material on Celite and concentrate the solution. Dilute the concentrate with ethyl acetate and wash with water. After mirabilite drying, it was distilled off and 4- (1-
Benzyloxycarbonylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was obtained.

Example 1-8 4- (1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone (2.24 g) in acetone 25
Dissolve in m, add 1.2 g of sodium iodide, stir at room temperature for 5 hours, concentrate under reduced pressure to about 10 m, and dilute with 50 m of benzene and 50 m of diethyl ether. Sequentially wash with 5% sodium sulfite water and water, and dry with Glauber's salt. The solvent was distilled off, and 4- (1-iodomethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-
Anisyl) methyl-2-azetidinone was obtained.

Example 2-1 4- (1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone
100 g of dimethylsulfoxide-water (4: 1) solution 1 was dissolved, 57.6 g of cuprous oxide and 10 parts of p-toluenesulfonic acid were added.
7 g was added, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction solution was ice-cooled, saturated saline solution 3, 2N-hydrochloric acid 1, ethyl acetate 2
, Ethyl ether 2 were added, and the mixture was stirred. After separation, the aqueous layer was re-extracted with ethyl acetate 1 and ethyl ether 1, and the organic layers were combined and washed successively with saturated saline solution 2, 5% aqueous sodium bicarbonate solution 2 and saturated saline solution 2, dried over sodium sulfate and evaporated to 4 -(1
-Hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Example 2-2 3.7 g of 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was dissolved in 26 m of dry methylene chloride,
After adding 1.45 g of 2-dimethoxypropane and then 0.14 m of boron trifluoride etherate and stirring at room temperature for 1.5 hours,
15m of saturated saturated sodium bicarbonate water was added for washing and 20m of cold water
After washing twice with, dried with Glauber's salt. The solvent was distilled off, the residue was purified by silica gel chromatography, and 8-oxo-2,2-dimethyl-5-methylidene-
7- (1-benzyloxycarbonyloxyethyl)-
Obtained 3-oxa-1-azabicyclo [4,2,0] octane.

Example 2-3 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone (6.1 g) and 1,1-dimethoxycyclohexane (3.4 g) were used in the same manner as in Example 2-2 to produce spiro. [Cyclohexane-2,2- (8-oxo-5-methylidene-7-
(1-benzyloxycarbonyloxyethyl) -3-
Oxa-1-azabicyclo [4,2,0] -octane]
Got

Example 2-4 4- (1-Hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained from 63 g by the same method as in Example 1-5.
(1-Formylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidine was obtained.

Example 2-5 (1) 4- (1-formylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone 55-g 4- (1-
Carboxyethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

(2) 37 g of the carboxylic acid obtained in (1) above was dissolved in methanol, diluted with diethyl ether, a solution of diazomethane in diethyl ether was added dropwise under ice-cooling, excess diazomethane was removed, and the mixture was concentrated to 4- (1 -Methoxycarbonylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidine was obtained.

Example 2-6 4- (1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone
From 3.2 g, by the same method as in Example 1-8, 4- (1-
Iodomethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Example-3 2.0 g of 4- (1-phenylthio-1-ethoxycarbonylethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-azetidinone was dissolved in 50 m of dry methylene chloride, and metachloroperbenzoic acid was cooled with ice.
0.69 g was added and the mixture was stirred as it was for 3 hours. Saturated sodium hydrogen carbonate solution was added for liquid separation, the organic layer was washed with saturated brine, and dried over sodium sulfate. After distilling off the solvent, the residue was dissolved in 18 m of toluene and refluxed for 1 hour, then the solvent was distilled off and the residue was subjected to silica gel chromatography to give 4- (1-ethoxycarbonylethenyl) -3- (1-p-nitro). Benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Example 4-1 4- (1-hydroxy-1-methylethyl) -3- [1
-(2,2,2-Trichloroethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-
From azetidinone in the same manner as in Example 1-1, 4
-(1-Methylethenyl) -3- [1- (2,2,2-
Trichloroethyloxycarbonyloxy) ethyl]-
1-Di (p-anisyl) methyl-2-azetidinone was obtained.

Example 4-2 4- (1-methylethenyl) -3- [1- (2,2,2
-Trichloroethyloxycarbonyloxy) ethyl]
4- (1-chloromethylethenyl) -3- [1- (2,2,2-trichloro) was prepared from -1-di (p-anisyl) methyl-2-azetidinone in the same manner as in Example 1-2. Ethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-azetidinone was obtained.

Example 4-3 4- (1-chloromethylethenyl) -3- [1- (2,
2,2-Trichloroethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-azetidinone was treated in the same manner as in Example 1-3 to 4- (1-hydroxymethylethenyl) -3-. [1- (2,2,2-
Trichloroethyloxycarbonyloxy) ethyl]-
1-Di (p-anisyl) methyl-2-azetidinone was obtained.

Example 4-4 4- (1-hydroxymethylethenyl) -3- [1-
2.20 g of (2,2,2-trichloroethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-azetidinone was dissolved in 10 m of dry methylene chloride,
Pyridinium chromochromate 1.64 g of methylene chloride 5
m solution was added, the mixture was stirred at room temperature for 1 hour, diluted with 15 m of diethyl ether, passed over Celite, the excess residue was washed with 10 m of diethyl ether-ethyl acetate (1: 1), the solution was concentrated, and the residue was subjected to silica gel chromatography. Attached to 4- (1-formylethenyl-3- [1- (2,
2,2-Trichloroethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-azetidinone was obtained.

Example 4-5 4- (1-chloromethylethenyl) -3- [1- (2,
2,2-Trichloroethyloxycarbonyloxy) ethyl] -1-di (p-anisyl) methyl-2-azetidinone was prepared in the same manner as in Example 1-8 to give 4- (1-
Iodomethylethenyl) -3- [1- (2,2,2-trichloroethyloxycarbonyloxy) ethyl] -1
-Di (p-anisyl) methyl-2-azetidinone was obtained.

Example-5 4- (1-hydroxy-1-methylethyl) -3- (1
-P-nitrobenzyloxycarbonyloxyethyl)
4- (1-Methylethenyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- from 1-di (p-anisyl) methyl-2-azetidinone in the same manner as in Example 1-1. Di (p-anisyl) methyl-
2-azetidinone was obtained.

▲ IR ^neat _max ▼ (cm ^-1 ): 1750,1610,1510,1378,1345,
1300,1250,1175,1028,845,750 NMR δ (CDC ₃ ): 1.40 (3H, d, J = 6.5Hz), 1.52 (3H, b
s), 3.08 (1H, dd, J = 2 and 6Hz), 3.74 (6H, s), 4.09 (1H,
d, J = 2Hz), 5.20 (2H, s), 5.49 (1H, s) Example 6 By the same method as in Example 3, 4- (1-phenylthio-1-ethoxycarbonylethyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone to 4- (1-ethoxycarbonylethenyl)- 3-
(1-benzyloxycarbonyloxyethyl) -2-
Azetidinone can be obtained.

NMR δ (CDC ₃ ): 1.27 (3H, t, J = 7Hz), 1.45 (3H, d, J
= 6Hz), 3.18 (1H, dd, J = 2.5 and 7Hz), 4.20 (2H, q, J = 7H
z), 4.53 (1H, br, s), 5.17 (2H, s), 5.22 (1H, m), 5.86 (1H, s),
6.31 (1H, s), 6.53 (1H, br.s), 7.39 (5H, s) Further, the above compound is 4- (1-carboxyethenyl)-
3- (1-benzyloxycarbonyloxyethyl)-
It can be obtained from 2-azetidinone and ethyl iodide by the same method as in Example 1-7.

Example 7-1 12.12 g of 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was dissolved in 120 m of dimethylformamide, and 22.26 m of triethylamine and 18.1 g of t-butyldimethylchlorosilane were sequentially added, By the same treatment as in Example 1-4, 4- (1-t-butyldimethylsilyloxyethenyl) -3- (1-benzyloxycarbonyloxyethyl-1-t-butyldimethylsilyl-2-azetidinone was obtained. .

Example 7 ₂ 4- (1-Hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone (30.5 mg) was dissolved in chloroform (5.2 m), dimethoxymethane (5.2 m) was added at room temperature, and phosphorus pentoxide (2.68) was added. g
Was added in portions and the mixture was stirred as it was for 3 hours. The mixture was diluted with 80 m of methylene chloride, washed with 10% aqueous sodium hydrogen carbonate, washed with water repeatedly, dried over sodium sulfate, and the solvent was distilled off. The obtained oily residue was purified by silica gel thin layer chromatography, and 4- (1
-Methoxymethoxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-methoxymethyl-2-azetidinone was obtained.

NMR δ (CDC ₃ ): 1.43 (3H, d, J = 6.5Hz), 3.32 (3H,
s), 3.33 (3H, s), 4.04 (2H, s), 4.58 (2H, s), 5.15 (2H, s), 5.2
3 (1H, s), 5.29 (1H, s), 7.34 (5H, s) Example _7-3 4- (1-hydroxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-
Anisyl) methyl-2-azetidinone (106 mg) was dissolved in methylene chloride (1 m), and dihydropyran (25 mg, p) was added at room temperature.
-Toluenesulfonic acid 1 mg was added and the mixture was stirred for 50 minutes as it was.

Dilute with ethyl acetate, repeat washing with 10% brine, dry with sodium sulfate, evaporate the solvent, and purify the resulting residue by silica gel thin layer chromatography. 4- (1-tetrahydropyranyloxymethylethenyl) ) -3- (1-Benzyloxycarbonyloxyethyl) -1-di (p-
Anisyl) methyl-2-azetidinone was obtained.

NMR δ (CDC ₃ ): 1.39 (3H, d, J = 6.2Hz), 1.575 (6H, 6H,
m), 3.72 (3H, s), 3.73 (3H, s), 5.18 (2H, s), 5.53 (1H, br.s),
7.39 (5H, s) Example 1-1 4-carboxy-3- (1-hydroxyethyl) -1-
34 g of di- (p-anisyl) methyl-2-azetidinone
Was dissolved in 310 m of methanol, 2.9 g of concentrated sulfuric acid was added, and the mixture was stirred at 65 ° C for 3 hours, cooled to 40 ° C and cooled to 8 ° C.
Neutralize with 15% aqueous sodium hydroxide solution. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 105 m of 1,2-dichloroethane and washed with water. The aqueous layer was again 1,2-dichloroethane 105
Extract with m, combine organic layers and wash with water. After drying with sodium sulfate, the solvent was distilled off to obtain 4-methoxycarbonyl-3- (1-hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone.

mp 102-104 ℃ Reference example 1-2 3-Methoxycarbonyl-3- (1-hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone (32.5 g) was dissolved in dry tetrahydrofuran (310 m) and cooled with ice. Under a nitrogen stream, 370 g of 1M-methylmagnesium bromide-tetrahydrofuran solution was added dropwise at 5 ° C or lower, and after stirring for 1 hour, 350 m of 20% hydrochloric acid water was added to 20-25.
The mixture was added dropwise at 0 ° C. and stirred for 1 hour as it was. Then ethyl acetate
Extract by adding 110m. The aqueous layer was re-extracted with 110 m of ethyl acetate, the organic layers were combined, washed with saturated saline solution, saturated sodium bicarbonate solution and water in that order, and dried over sodium sulfate. The solvent was distilled off to obtain 4- (1-hydroxy-1-methylethyl) -3- (1-hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone.

mp 154-156 ℃ Reference Example 1-3 4- (1-hydroxy-1-methylethyl) -3- (1
-Hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone (26 g) was dried with methylene chloride (200 m).
Then, 16 g of N-dimethylaminopyridine was added, and the mixture was ice-cooled. Benzyl chloroformate 2 under nitrogen stream
0 g was added dropwise over 1 hour, and the mixture was stirred as it was for 2 hours and then at room temperature for 10 hours, then ice-cooled and 5% hydrochloric acid water 100m.
Was added and stirred for 30 minutes for liquid separation. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over sodium sulfate. Evaporate the solvent,
4- (1-hydroxy-1-methylethyl) -3- (1
-Benzyloxycarbonyloxyethyl) -1-di-
(P-anisyl) methyl-2-azetidinone was obtained.

Reference example-2 320 g of 4- (1-chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisylmethyl) -2-azetidinone was added to acetonitrile-water (9: 1) mixed solution 3.8. However, a solution of cerium ammonium nitrate (CAN) 702 g of acetonitrile-water (9: 1) mixed solution 2.0 was added dropwise at 5 ° C. or lower.
Ethyl acetate 3.4 and water 5.2 were added to the reaction solution, extraction and separation were performed, and the aqueous layer was separated with ethyl acetate 1.7, ethyl ether 1.7,
Re-extract with a mixture of benzene 1.7, combine the organic layers,
After washing successively with saturated saline, 5% aqueous sodium hydrogen carbonate and saturated saline, the extract was dried over sodium sulfate and evaporated. Methanol 1.5 was added to the residue, and the mixture was heated and cooled, and the resulting crystals were separated and the solution was concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography,
4- (1-Chloromethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Reference example-3 1.76 g of 4-acetoxy-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-azetidinone was dissolved in 30 m of dry methylene chloride under a nitrogen stream, and 5.64 g of ethyl α-phenylthiopropionate-trimethylsilylketene acetal was added. , Then zinc iodide at room temperature 1.
After adding 6 g and stirring at 35 ° C for 2 hours, methylene chloride 2
The mixture was diluted with 00 m, 100 m of saturated aqueous sodium hydrogen carbonate was added, and the insoluble material was removed. The organic layer was washed with saturated brine, dried over sodium sulfate, evaporated to remove the solvent, and the residue was purified by silica gel chromatography to give 4- (1-phenylthio-1-ethoxycarbonylethyl) -3- (1-p-nitro). Benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Reference Example 4-1 4- (1-hydroxy-1-methylethyl) -3- (1
From 4-hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone (7.98 g) and 2,2,2-trichloroethyl chloroformate (7.63 g), a 4- () was prepared in the same manner as in Reference Example 1-3. 1-Hydroxy-1-methylethyl) -3- [1- (2,2,2-trichloroethyloxycarbonyloxy) ethyl] -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

Reference Example 4-2 4- (1-hydroxy-1-methylethyl) -3- (1
By the same method as in Reference Example 1-3, from 5.35 g of -hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone and 5.2 g of p-nitrobenzyl chloroformate, 4- (1-hydroxy- 1-methylethyl) -3-
(1-p-Nitrobenzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

Reference example 5 4- (1-phenylthio-1-ethoxycarbonylethyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone is 4-acetoxy-3- (1-
Obtained from benzyloxycarbonyloxyethyl) -2-azetidinone in the same manner as in Reference Example 3.

Reference Example 6 ₁ Under a nitrogen stream, sodium borohydride (0.32 g) was dissolved in dry tetrahydrofuran (40 m), and boron trifluoride etherate (1.81 g) was added dropwise at 10 to 20 ° C. As it is 1
After stirring for 1 hour, 1.21 g of 1,5-octadiene was added to 10-20
The mixture was added dropwise at 0 ° C, and stirring was continued for 1 hour. A solution of 2.63 g of 4- (1-methylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone in dry tetrahydrofuran (10 m) was added thereto at 20 to 25 ° C. After dropping for 1 hour, continue stirring for 3 hours, add 7 m of water,
After stirring at 10 to 30 ° C for 1 hour, 5.3% 4% aqueous sodium hydroxide solution was added and heated to 40 to 45 ° C.

Next, 5.3m of 35% hydrogen peroxide was added dropwise at 40 to 45 ° C, and after cooling to room temperature, 0.2g of sodium sulfite was added,
Further, 6 m of toluene was added to separate the layers, and the aqueous layer was mixed with 12
m again and washed the oil layer with 20% saline,
Glauber's salt dried. The solvent was evaporated, the residue was purified by silica gel chromatography, and 4- (1- (S) -hydroxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) was obtained. 0.51 g of (1- (R) -hydroxymethylethyl) corresponding to 1.88 g of methyl-2-azetidinone was obtained.

IR ν max (cm ^-1 ): 3450,1745,1615,1515,1460,1385,1260,
1180,1035, NMR δ (CDC ₃ ) [S-form] 0.73 (3H, d, J = 6.8Hz), 1.41 (3H, d, J = 6.4Hz), 2.
93 (1H, dd, J = 2.2 and 6Hz), 3.73 (3H, s), 3.75 (3H, s), 5.
11 (2H, s), 5.55 (1H, s), 7.37 (5H, s) (R body) 0.89 (3H, d, J = 6.8Hz), 1.41 (3H, d, J = 6.4Hz), 3.
17 (1H, dd, J = 2.2 and 7.5Hz), 3.73 (3H, s), 3.75 (3H, s),
5.16 (2H, s), 5.60 (1H, s), 7.37 (5H, s) Reference Example _6-2 Jones reagent prepared by dissolving 0.67 g of chromium trioxide and 1.05 g of 98% sulfuric acid in 2.5 m of water was used as 4- (1-hydroxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di A solution of 2.45 g of-(p-anisyl) methyl-2-azetidinone in acetone (25 m) was added dropwise at 0 to 10 ° C, and the mixture was stirred at 20 ° C or lower for 1 hour.

0.5m of isopropyl alcohol was added, and after stirring for 15 minutes, 100m of ethyl acetate and 100m of cold water were added for liquid separation, the water layer was re-extracted with 50m of ethyl acetate, and the oil layers were combined and combined.
Wash with 0% saline and dry with Glauber's salt. The solvent was distilled off, and 4- (1
-Carboxyethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

Reference Example 7-₁ 4- (1-t-butyldimethylsilyloxymethyl ete
Nyl) -3- (1-benzyloxycarbonyloxye
Cyl) -1-di (p-anisyl) methyl-2-azetidi
20g of non-solvent was dissolved in 200m of acetonitrile and nitrogen gas was added.
At the room temperature, 4.0g of 5% platinum carbon catalyst and 4m of water were added.
After substituting with hydrogen at 10.degree. C., hydrogenation was performed at 10.degree. Catalyst removed
After washing the excess with ethyl acetate, concentrate the washings,
4- (1-t-butyldimethylsilyloxymethylethyl)
L) -3- (1-benzyloxycarbonyloxyethyl)
Le) -1-di (p-anisyl) methyl-2-azetidino
I got it. This product is a liquid chromatography [Lichrosorb
RP-18, acetonitrile-water (85:15), flow rate
1 m / min] and NMR measurement, 4- (1- (R)-
(t-butyldimethylsilyloxymethylethyl) form
It is a mixture of (S) isomers, the ratio of which is R / S = 7.7
Met. For this mixture ethyl acetate-n-hex
Crystallized from a mixed solvent of sun (1:10) to give 4- (1-
(R) -t-butyldimethylsilyloxymethylethyl
L) -3- (1-benzyloxycarbonyloxyethyl)
Le) -1-di (p-anisyl) methyl-2-azetidino
You can get only mp.78-81 ° C NMR δ (CDC_Three): 0.01 (6H, s), 0.87 (9H, s), 1.40 (3
H, d, J = 6Hz), 3.31 (1H, dd, J = 2.2 and 7.0Hz), 3.44 (2H,
d, J = 5.3Hz), 3.73 (3H, s), 3.76 (3H, s), 5.07 (1H, m), 5.17
(2H, s), 7.38 (5H, s) Reference Example 7-₁The reaction described in 1.
, The target compound (R) can be obtained with priority.
You can

Reference Example 7 ₂ 20 g of 4- (1- (R) -t-butyldimethylsilyloxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was added to 200 m of methylene chloride. Melt,
Add 7.8 g of 1,3-dimethoxybenzene, then 10
After adding 23 g of boron trifluoride etherate at -20 ° C, the mixture was stirred at room temperature for 3 hours, heated to 45 ° C, and refluxed for 3-5 hours. After cooling to 10-15 ℃, 5% saline solution 200
m twice, then 200m 2.5% sodium bicarbonate water, 5% again
Wash with brine 200m, dry with sodium sulfate, evaporate the solvent and purify the residue by silica gel chromatography.
-(R) -Hydroxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

Reference Example _7-3 Chromium trioxide 2.78 g, 98% sulfuric acid 4.4 g and water 8.1 m
The Jones reagent prepared from was added dropwise to a solution of 4- (1- (R) -hydroxymethylethyl) 3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone (6.1 g) in acetone (60 m) at 10 to 20 ° C. , Stir for 1 hour. Next, 0.5 m of isopropyl alcohol was added, and after stirring for 15 minutes, 135 m of water and 122 m of ethyl acetate were added for liquid separation, the aqueous layer was re-extracted with 61 m of ethyl acetate, and the oil layers were combined and washed twice with 100 m of 5% saline. . Then 5
% Sodium bicarbonate water (61 m) was added for liquid separation, and the oil layer was re-extracted with 5% sodium bicarbonate water (30 m) again. The aqueous layer was washed with 60 m of methylene chloride and acidified by adding 20 m of 10% hydrochloric acid water under ice cooling.
It is extracted twice with 60 m of methylene chloride, washed with 10% saline solution, and dried with Glauber's salt. The solvent was distilled off to obtain 4- (1- (R) -carboxyethyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone.

Reference Example _7-4 0.40 g of 4- (1- (R) -t-butyldimethylsilyloxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was added to 40 m of methanol. After melting, 10 m of 6N hydrochloric acid was added dropwise under ice cooling, and the mixture was stirred for 20 minutes as it was. 200m of ethyl acetate and 200m of 10% saline are added,
Separation. The oil layer was washed with 10% saline, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, 4
-(1- (R) -hydroxymethylethyl) -3- (1
-Benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was obtained.

The product, obtained in Reference Example 6- ₁ (1- (R) - hydroxymethyl-ethyl) body and NMR, IR data match.

Reference Example _8-1 8-oxo-2,2-dimethyl-5-methylidene-7-
(1-benzyloxycarbonyloxyethyl) -3-
Oxo-1-azabicyclo [4,2,0] octane 18
g was dissolved in 180 m of ethanol, 3.6 g of 10% palladium carbon catalyst was added, and the mixture was stirred in a hydrogen atmosphere under ice cooling for 1 hour, then the catalyst was removed, washed with ethanol, and the washing solution was concentrated to give oily 8-oxo-2 oil. .2-dimethyl-5-methyl-
7- (1-Hydroxyethyl) -3-oxo-1-azabicyclo [4,2,0] octane was obtained. This product is NMR
As a result of the measurement, the content ratio of the 5 (R) body and the 5 (S) body is 5 (R)
/ 5 (S) was 2.2 / 1.

NMR δ (CDC ₃ ): 5 (R) methyl form: 1.11 (3H, d, 7.0Hz), 1.30 (3H, d, J = 6.
5Hz), 1.41 (3H, s), 1.72 (3H, s), 3.04 (1H, dd, J = 2.0 and
6.0Hz) 5 (S) methyl form: 0.91 (3H, d, J = 6.5Hz), 1.30 (3H, d, J
= 6.5Hz), 1.41 (3H, s), 1.72 (3H, s), 2.81 (1H, dd, J = 1.5 and 5.5 Hz) Reference Example 8 ₂ Spiro [cyclohexane-2,2- (8-oxo-5-
Methylidene-7- (1-benzyloxycarbonyloxyethyl) -3-oxo-1-azabicyclo [4,2,2]
0] spiro [cyclohexane in the same manner octane] Reference Example _8-1 2,2 (8-oxo-5-methyl-7- (1-hydroxyethyl) -3-oxo-1
-Azabicyclo [4,2,0] octane] was obtained. As a result of NMR measurement, this product was a mixture of 5 (R) -methyl form and 5 (S) methyl form, and the ratio was 5 (R) / 5 (S).
NMR δ (CDC ₃ ), which was 1.7 / 1: 5 (R) methyl form: 1.11 (3H, d, J = 7.2Hz), 1.28 (3H, d, J
= 6.5Hz), 3.01 (1H, dd, J = 2.0 and 5.7Hz) 5 (S) methyl form: 0.90 (3H, d, J = 6.5Hz), 1.28 (3H, d, J
= 6.5Hz), 2.77 (1H, dd, J = 1.5 and 5.5 Hz) Reference Example 9- ₁ 4- (1-ethoxycarbonylethenyl) -3- (1-
Benzyloxycarbonyloxyethyl) -2-azetidinone (1.00 g) was dissolved in dry dimethylformamide (12 m), triethylamine (0.88 g) and t-butyldimethylchlorosilane (0.96 g) were added, and the mixture was stirred at room temperature for 15 hr. Ethyl acetate (50 m) was added, the mixture was washed with 10% brine, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography, and 4- (1-ethoxycarbonylethenyl) -3- (1-benzyloxycarbonyl) was obtained. Oxyethyl) -1-t-butyldimethylsilyl-2-azetidinone was obtained.

NMR δ (CDC ₃ ): 0.04 (3H, s), 0.26 (3H, s), 0.95 (9
H, s), 1.30 (3H, t, J = 7.25Hz), 1.41 (3H, d, J = 6.5Hz), 3.23
(1H, dd, J = 2.5 and 6.5Hz), 4.23 (2H, q, J = 7.25Hz), 5.1
6 (2H, s), 5.16 (1H, m), 5.86 (1H, s), 6.30 (1H, s), 7.35 (5H,
s) Reference Example 9 ₂ (1) 4- (1-ethoxycarbonylethenyl) -3-
(1-Benzyloxycarbonyloxyethyl) -1-
14.6 g of t-butyldimethylsilyl-2-azetidinone was dissolved in 146 m of a mixed solution (19: 1) of ethanol and a phosphate buffer (0.01 M, pH 5.7), and 2.92 g of 10% palladium-carbon catalyst was added, followed by hydrogenation. Under an atmosphere, the mixture was stirred at room temperature for 2 hours. The catalyst was removed, washed with 100 m of ethyl acetate,
The washing solution was diluted with 500 m of ethyl acetate, washed with 10% saline solution, dried with Glauber's salt, and the solvent was distilled off.

(2) The obtained residue was dissolved in 100 m of dry benzene, evaporated under reduced pressure, dried sufficiently, and then dried with dimethylformamide.
After melting to 195 m, 4.3 g of imidazole and 7.0 g of t-butyldimethylchlorosilane were added, and the mixture was stirred at room temperature for 15 hours. 600m ethyl acetate, 600m ethyl ether
Diluted with water, washed with 10% brine, dried over sodium sulfate, evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give 4- (1-ethoxycarbonylethyl) -3- (1
-T-butyldimethylsilyloxyethyl) -1-t-
Butyldimethylsilyl-2-azetidinone was obtained.

Reference Example 9 ₃ 4- (1-ethoxycarbonylethyl) -3- (1-t
-Butyldimethylsilyloxyethyl) -1-t-butyldimethylsilyl-2-azetidinone (4.63 g) was dissolved in dry tetrahydrofuran (60 m), and tetra-n was added at 20 ° C.
96m of a solution of -butylammonium fluoride in tetrahydrofuran (1M) was added dropwise, the mixture was stirred at room temperature for 45 minutes, diluted with 250m of ethyl acetate and 60m of 10% saline, and separated.

The water layer was re-extracted with 50 m of ethyl acetate and the oil layers were combined and
The extract was washed with 0% saline solution, dried with Glauber's salt, and the solvent was distilled off. Remove the residue
Subjected to lica gel column chromatography, 4- (1-
Ethoxycarbonylethyl) -3- (1-t-butyldi
Methylsilyloxyethyl) -2-azetidinone is obtained.
It was This product is a liquid chromatography [Lichrosorb SI-
60, n-hexane-isopropyl alcohol (19:
1), flow rate 1 m / min] 4- (1- (R) -etoki
Cycarbonylethyl) form and 4- (1- (S) -ethoxy
A mixture of (carbonylethyl) forms with R / S = 3.7.
It was. This mixture was recrystallized twice from n-hexane.
Increase R / S ratio by returning to R / S = 10.3
I was able to.

NMR δ (CDC ₃ ): R-form: 0.08 (6H, s), 0.88 (9H, s), 1.17 (3H, d, J = 6Hz), 1.23
(3H, d, J = 7Hz), 1.28 (3H, t, J = 7Hz), 2.97 (1H, dd, J = 2.2
And 4Hz), 3.88 (1H, dd, J = 2.2 and 6Hz), 4.17 (2H, q, J
= 7Hz) S body: 0.08 (6H, s), 0.88 (9H, s), 1.23 (3H, d, J = 6Hz), 1.24
(3H, d, J = 7Hz), 1.28 (3H, t, J = 7Hz), 2.76 (1H, m), 3.69 (1
H, dd, J = 2.2 and 10Hz), 4.16 (2H, q , J = 7Hz) Reference Example 9 ₄ 4- (1-ethoxycarbonylethyl) -3- (1-t
-Butyldimethylsilyloxyethyl) -2-azetidinone (5.79 g) was dissolved in ethanol (57 m), and 1N-sodium hydroxide aqueous solution (18.4 m) was added.
According to the method described in 6887, 4- (1-carboxyethyl) -3- (1-t-butyldimethylsilyloxyethyl) -2-azetidinone was obtained.

To give the compounds shown in the table below in the same manner as in Reference Example 10 Reference Example _7-1.

To give the compounds shown in the table below in the same manner as in Reference Example 11 Reference Example _7-1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location 8415-4C C07D 498/04 112 (72) Inventor Shinji Takada 3 Kasuga, Kasuga, Osaka, Osaka No. 1-98 Sumitomo Pharmaceutical Co., Ltd. Examiner Norihiro Sano (56) References JP-A-60-54358 (JP, A)

Claims (3)

[Claims] 1. A general formula [In the formula, R represents a hydrogen atom or a lower alkyl group, or a hydroxyl group represents a protected or unprotected 1-hydroxy lower alkyl group. R'represents a hydrogen atom or a nitrogen atom-protecting group, and R "represents a halogenomethyl group, a hydroxymethyl group, a hydroxymethyl group having a protected hydroxyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group or an aralkyloxy group. A carbonyl group, or R ′ and R ″ represent an alkylene chain which is bonded to each other through an oxygen atom, and together with an adjacent nitrogen atom, a 6-membered cyclic aminoacetal group, that is, a partial formula (In the formula, ▲ R ⁰ ₁ ▼ and ▲ R ⁰ ₂ ▼ represent the same or different lower alkyl groups, or represent an alkylene chain bonded to each other and represent a 5- to 7-membered cycloalkyl group). Show. ] The beta-lactam compound represented by these. 2. The compound according to claim 1, wherein R is a 1-hydroxy lower alkyl group in which a hydroxyl group is protected. 3. The compound according to claim 2, wherein R ″ is a hydroxymethyl group.