JP2654753B2 - Method for producing β-lactam compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing a carbapenem compound. More specifically, the present invention provides a compound of the general formula

Embedded image Wherein it may be R ₁ and R ₂ have also, or different in the same, represent a hydrogen atom or a lower alkyl group, R ⁰ ₃
Represents a hydrogen atom or a lower alkyl group; R " ₄ represents a carboxyl group or a thiol carboxyl group-protecting group; X 'represents a hydrogen atom or a protected hydroxyl group;
Represents an oxygen atom or a sulfur atom, and COZ ′ represents an active ester of a carboxyl group or an active acid anhydride, a thiol carboxyl group protected by a thiol carboxyl protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group. Is shown. A compound represented by the formula:

[0002] Formula Z in the reaction solution ^'- (wherein, Z' is as defined above.) Thiol residues residues or protected thiol carboxyl group of an active ester or active acid anhydride represented by Is trapped with an alkylating agent or an acylating agent, and subsequently treated with an active esterifying agent for a hydroxyl group in the same reaction vessel to obtain a compound of the general formula (IX)

Embedded image _{Wherein, R 1, R 2, R} 0 3, R "4, X ' and Y are the same as defined above, L is shown an active ester group for a hydroxyl group.] To produce a compound represented by,

Further, in the presence of a base, the compound is reacted with a mercaptan compound represented by the general formula (X) R ₀ -SH (X) (where R ₀ represents an organic group), or X) is reacted with a salt of a base to form a compound of the general formula (VII)

Embedded image _{Wherein, R 1, R 2, R} 0 3, R "4, R 0, X ' and Y have. The same meanings as described above] to a method for producing a carbapenem compound represented by the.

[0004]

BACKGROUND OF THE INVENTION Thienamycin having activity useful as an antibacterial agent [US Pat. No. 3,950,357; J. Am. Che
m. Soc., 100 , 313 (1978)] was discovered in nature, and since it was reported, methods for obtaining various carbapenem compounds purely have been reported.

More recently, the methylene group at the 1-position of the carbapenem skeleton (according to conventional numbering (see formula A below; corresponding to the 4-position in the numbering of the present invention)) is substituted with an alkyl group. In particular, 1-methylcarbapenem compounds are superior to conventional 1-position unsubstituted carbapenem compounds in terms of, for example, in vivo stability, and are reported to be extremely useful as antibacterial agents. Accordingly, there has been much interest in developing an effective method for producing a 1-alkylcarbapenem compound.

[0006]

Embedded image

[0007]

The present inventors have studied a method for producing a carbapenem compound or a 1-alkylcarbapenem compound. As a result, the present invention is advantageous as a method for producing a carbapenem compound, particularly a 1-alkylcarbapenem compound. And completed the present invention.

Here, the substituents in the above formula will be mentioned. The lower alkyl group in R _1, R _2, such as methyl, ethyl, include lower alkyl groups having 1 to 4 carbon atoms such as n- propyl group, examples of the lower alkyl group R ⁰ _3, for example, methyl, ethyl And a lower alkyl group having 1 to 4 carbon atoms such as n-propyl group.

The protecting group for the hydroxyl group in X 'is not particularly limited as long as it is a commonly used protecting group. For example, a lower alkoxycarbonyl group having 1 to 4 carbon atoms such as a t-butyloxycarbonyl group; A halogenated alkyloxycarbonyl group having 1 to 3 carbon atoms such as an ethyloxycarbonyl iodide group or a 2,2,2-trichloroethyloxycarbonyl group; for example, a benzyloxycarbonyl group, an o-nitrobenzyloxycarbonyl group,
An aralkyloxycarbonyl group such as -nitrobenzyloxycarbonyl group or p-methoxybenzyloxycarbonyl group; an alkylsilyl group having 1 to 4 carbon atoms such as trimethylsilyl group or t-butyldimethylsilyl group; And a substituted methyl group such as a 2-methoxyethoxymethyl group and a methylthiomethyl group; and a tetrahydropyranyl group.

As a protecting group for a carboxyl group or a thiol carboxyl group in R " _{4, a} commonly used protecting group can be used, and preferably, for example, methyl, ethyl,
A linear or branched lower alkyl group having 1 to 4 carbon atoms such as isopropyl and tert-butyl; for example, 1 to 3 carbon atoms such as 2-ethyl iodide and 2,2,2-trichloroethyl; A lower alkoxyalkyl group having 1 to 4 carbon atoms such as methoxymethyl, ethoxymethyl and isobutoxymethyl; such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl Carbon number 1
5 lower aliphatic acyloxymethyl groups; for example, lower alkoxycarbonyloxyethyl groups having 1 to 4 carbon atoms such as 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl; for example, allyl, 2-methylallyl, 3-methylallyl, Substituted or unsubstituted 2-lower alkenyl groups having 3 to 10 carbon atoms such as 3-phenylallyl; benzyl, p-methoxybenzyl, 2,4
Substituted or unsubstituted monoarylalkyl groups such as dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl; substituted or unsubstituted diarylalkyl groups such as diphenylmethyl, di-p-anisylmethyl Groups; for example, phenyl, p-chlorophenyl, 2,4,5-trichlorophenyl, p-
Substituted or unsubstituted aryl groups such as nitrophenyl, o-nitrophenyl, p-methoxyphenyl; for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2- (4,6-dimethyl) pyrimidyl And a phthalidyl group.

When COZ ′ is an active ester or an acid anhydride of a carboxyl group, examples of the Z ′ group include halogen atoms such as chlorine, bromine and iodine; for example, ethoxycarbonyloxy, isopropyloxycarbonyloxy, sec. Lower alkyloxycarbonyloxy group having 1 to 5 carbon atoms such as -butyloxycarbonyloxy; 1 carbon atom such as methanesulfonyloxy
-4 lower alkane sulfonyloxy groups; for example, arylsulfonyloxy groups such as p-toluenesulfonyloxy; di (lower alkyl having 1 to 4 carbon atoms) phosphoryloxy groups such as dimethylphosphoryloxy and diethylphosphoryloxy; Diarylphosphoryloxy groups such as di (phenyl) phosphoryloxy; cyclic imidooxy groups such as N-succinimideoxy and N-phthalimidooxy; heteroaryl groups such as imidazole and triazole; e.g. 3- (2-thioxo) And heterocycloalkyl groups such as -thiazolidinyl. When COZ ′ is a protected carboxyl group or thiol carboxyl group, the same carboxyl-protecting group and thiol-carboxyl-protecting group as those described above can be suitably used. Further preferred examples of the substituted aryloxy group include p-nitrophenyloxy, o-nitrophenyloxy, and 2,4,5-trichlorophenyloxy. Examples of the heteroaryloxy group include o-pyridyloxy, p-pyridyloxy and the like can be mentioned.

The production method of the present invention will be described in more detail according to the following reaction formula.

Embedded image _{Wherein, R 1, R 2, R} 0 3, R "4, X ', Y, Z' and L
Represents the same meaning as described above, B represents an alkali metal atom, and RA represents an alkylating agent or an acylating agent. ]

[0013] Formula inert solvent a compound represented by (I-8 ^0), after treatment with a base, the compound (VI-2) without removing the active ester or active acid anhydride in the reaction solution remaining A thiol residue (Z ′ ⁻ ) of a group or a protected thiol carboxyl group with an alkylating agent such as iodomethane, iodopropane, allyl bromide, benzyl bromide, p-toluenesulfonic acid methyl ester, p-toluenesulfonyl chloride, After capturing with an acylating agent such as methanesulfonyl chloride, the compound is treated with an active esterifying agent for a hydroxyl group, whereby a carbapenem compound represented by the general formula (IX) can be derived.

The active ester of a hydroxyl group represented by L is, for example, a substituted or unsubstituted arylsulfonic acid ester group (substituted or unsubstituted arylsulfonyloxy group), a lower alkanesulfonic acid ester group (lower alkanesulfonyloxy group) , A halogeno lower alkanesulfonic acid ester group (halogeno lower alkanesulfonyloxy group) or a diarylphosphonic acid ester group (diarylphosphoryloxy group), or a halide atom which is an ester with hydrogen halide. Therefore, the active esterifying agent of the hydroxyl group,
This is an agent that reacts with the compound (VI-2) to produce an active ester as described above. Further, as the substituted or unsubstituted arylsulfonic acid ester, for example, benzenesulfonic acid ester, p-toluenesulfonic acid ester,
p-nitrobenzenesulfonic acid ester, p-bromobenzenesulfonic acid ester and the like; lower alkanesulfonic acid ester such as methanesulfonic acid ester and ethanesulfonic acid ester; halogeno lower alkanesulfonic acid ester such as trifluoromethane Sulfonates and the like, diarylphosphonic acid esters, for example, diphenylphosphoric acid esters, and halides, for example, chlorine, bromine, iodide, and the like can be mentioned. Preferable examples of such an alcohol active ester include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphonic acid ester.

Among the above-mentioned active esterifying agents for hydroxyl groups, there are those which are themselves acylating agents as described in Examples 4, 6 and 7, for example. These course Z 'is ^- can also serve to trap. In the case of such active esterifying agent, by adding more than 2 equivalents, Z ^'- the capture, hydroxyl groups can be used as serving also as an acylating agent and an active esterifying agent to be esterified.

The alkali metal atom in B is exemplified by lithium, sodium, potassium and the like.

The inert solvent is not particularly limited as long as it is inert. Preferred examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether; and aromatic solvents such as benzene and toluene. Hydrocarbon solvents, acetonitrile, dimethylformamide, dimethylsulfoxide,
Hexamethylphosphoric triamide (HMPT), t
-Butanol and a mixed solvent thereof.

[0018] Formula Suitable bases lithium diisopropylamide in processing (I-8 ⁰⁾ compounds represented by lithium bis (trimethylsilyl) amide,
Metal salts of amines such as sodium amide, potassium t-
Examples thereof include metal salts of alcohols such as butoxide, alkali metal hydrides such as sodium hydride and potassium hydride, and sodium methylsulfinyl methide.

The base is desirably used in such an amount that the reaction proceeds sufficiently, and an appropriate amount can be said to be 1.5 to 3 equivalents. Further, the reaction can be suppressed or promoted by appropriately cooling or heating, but a preferable reaction temperature can be -75 ° C to 50 ° C.

After completion of the reaction, the product can be taken out by ordinary organic chemical means.

[0021] When R ⁰ ₃ is a lower alkyl group, the general formula (I-8 ⁰⁾ compound in an inert solvent represented by the salts of enolates obtained by treatment with a base (VI-2) is the starting compound (I-8 ⁰⁾ is directly retention of configuration based on an asymmetric carbon (C5 position) of, is obtained which after induction the compound (IX) also retaining the steric alkyl group R ⁰ ₃ of the starting compound This reaction gives the carbapenem derivative (IX) without epimerization.

In this case, the enolate (VI-2) generated in the reaction system may have a chelate structure as shown in the following formula.

Embedded image

The active esterification agent of the hydroxyl groups are needed amount sufficient reaction proceeds sufficiently, with respect to the general formula (I-8 ⁰⁾ the compound represented by can be carried out using 1 to 1.5 equivalents. The reaction temperature is in the range of -78C to 60C, preferably in the range of -40C to 10C.

[0024] When further it is desired to obtain carbapenem compound (VII) directly from the compound represented by the general formula (I-8 ⁰⁾ is the carbapenem by the method described compound (I-8 ⁰⁾ above Without deriving the compound (IX) after the derivation to the derivative (IX), the mercaptan compound (X) R ₀ -SH (X) wherein R ₀ has the same meaning as described above. ] And a base to give a carbapenem compound represented by the general formula (VII). This is shown in the following reaction formula.

[0025]

Embedded image _{Wherein, R 1, R 2, R} 0 3, R "4, R 0, R-A, B,
X ', Y and Z' have the same meaning as described above. ]

In this case, in the treatment with the mercaptan compound (X), the base added is the first treatment (ring closing reaction).
The reaction may be the same as or different from that used in the above, and the reaction can be promoted by adding another inert solvent.

As the base in this case, in addition to those used in the above-mentioned conversion into the compound (VI-2), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.
4.0] -undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] -non-5-ene (DB
N) and organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO). Further, as the inert solvent added for further promoting the reaction, preferably, acetonitrile, dimethylformamide,
Dimethyl sulfoxide and the like can be mentioned.

The base added together with the mercaptan compound (X) must be in an amount sufficient for the reaction to proceed sufficiently.
It can be carried out usually using 1 to 1.5 equivalents to mercaptan (X). Mercaptan (X) is required amount sufficient reaction sufficiently proceeds, can be can be used in large excess conducted using 1-2 equivalents relative to compound (I-8 ^0). The mercaptan compound (X) and the base may be added individually as described above, or alternatively, a salt of the mercaptan compound (X) and the base may be added.

When the carbapenem derivative represented by the general formula (IX) is isolated, the derivative is reacted with the mercaptan compound (X) in the same manner as described above to obtain the compound represented by the general formula (VII) Can be produced.

As described above, a carbapenem derivative represented by the general formula (IX) or, if necessary, a carbapenem compound represented by the general formula (VII) is produced from the β-lactam compound (I-8 ⁰ ). Can be.

The carbapenem compound (VII) thus obtained can be easily prepared as follows.

Embedded image _{Wherein, R 1, R 2, R} 0 3 , and R ₀ is the same as defined above, X ⁰ represents a hydrogen atom or a hydroxyl group. ].

(A) When Y is an oxygen atom in the general formula (VII), the compound, that is, the general formula (VI)
I ')

Embedded image _{Wherein, R 1, R 2, R} 0 3, R 0 and X 'are the same as defined above, R' ₄ represents a protecting group of carboxyl group. From the compound represented by the general formula (VIII) having antibacterial activity by appropriately performing a reaction for removing a protecting group for a hydroxyl group, a reaction for removing a protecting group for a carboxyl group, or a reaction for removing an amino group. The carbapenem compound represented can be obtained.

The removal of the protecting group varies depending on the type thereof, but can be performed by a generally known method. For example, in the above general formula (VII '), a compound in which a protecting group for a hydroxyl group and a protecting group for a nitrogen atom are a halogenoalkoxycarbonyl group and an aralkyloxycarbonyl group, and a protecting group for a carboxyl group is a halogenoalkyl group, an aralkyl group or a benzhydryl group. Certain compounds may have their protective groups removed by subjecting them to an appropriate reduction reaction.

In the case where the protecting group is a halogenoalkoxycarbonyl group or a halogenoalkyl group, reduction with an organic solvent such as acetic acid, tetrahydrofuran, methanol or the like and zinc is preferable, and the protecting group is aralkyloxy. In the case of a carbonyl group, an aralkyl group or a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium-carbon is preferred.

Solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers and acetic acid such as tetrahydrofuran and dioxane, and organic solvents thereof and water or phosphoric acid, morpholinopropane sulfone. A mixed solvent with a buffer such as an acid is suitable. The reaction is carried out at a temperature in the range of 0 ° C to 100 ° C, preferably in the range of 0 ° C to 40 ° C.
The hydrogen pressure can be set at normal pressure or under pressure. When the protecting group is an o-nitrobenzyloxycarbonyl group or an o-nitrobenzyl group, the protecting group can be removed by a photoreaction.

(B) When Y in the general formula (VII) is a sulfur atom, a carbapenem compound (VIII) can be produced from the compound (VII ") as follows.

Embedded image _{Wherein, R 1, R 2, R} 0 3, R '4, R 0, X' and X ⁰ are the same as defined above, R ⁰ ₄ represents a protecting group of a thiol carboxyl group. ]

That is, the compound (VII ") is subjected to a reaction for removing various protecting groups as described above as necessary, and the thioester group is represented by the general formula (VIII) by hydrolysis in various known modes. Carbapenem compound, for example, by treating with an alcohol in the presence of a silver salt such as silver trifluoroacetate, etc.
After the conversion into I ′), the same treatment as in the above (A) can also give the carbapenem compound (VIII). Further, carbapenem (VIII) can be directly obtained by treatment with a silyl compound such as silanol.

The carbapenem compounds (VII ') and (VI
R ₀ of the 3-position substituent SR ₀ in I ″) may be any of those used in carbapenem compounds known so far, and examples thereof include the following examples. Substituted or unsubstituted alkyl or alkenyl group having 1 to 10 carbon atoms; cycloalkyl group having 3 to 6 carbon atoms in the ring, alkylcycloalkyl group, cycloalkyl-alkyl group; aryl such as phenyl Group, the aryl part is phenyl,
Alkyl is an arylalkyl group having 1 to 6 carbon atoms; a heteroaryl group, a heteroarylalkyl group, a heterocycloalkyl group;
And trialkylamino group, hydroxyl group, alkoxy group, mercapto group, alkylthio group, arylthio group such as phenylthio, sulfamoyl group, amidine group,
It may have at least one substituent selected from the group consisting of a halogeno group such as a guanidino group, a nitro group, a chloro, a bromo, and a fluoro group, a cyano group, and a carboxyl group; Selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms; the alkyl portion of the above substituents has 1 to 6 carbon atoms.

Although not necessarily limited to those shown below, the production method of the present invention will be described below with reference to the production method of 1-β-methylcarbapenem compound as an example.

Embedded image _{Wherein, R "4, Y, Z} ', B, R-A, L and R ₀ is the same as defined above, R' ₁₀ represents a protecting group for a hydroxyl group.]

The general formula (I-8 ^*) β- lactam compound of the following sequence represented by, 1) in an inert solvent, treated with a base; 2) Z ^'- trapping with an alkylating agent or an acylating agent 3) treatment with an active esterifying agent for a hydroxyl group; and, if necessary, 4) mercaptan derivative (X) R ₀ -SH (X) wherein R ₀ has the same meaning as described above. ] And is reacted in the presence of a base, or reacting the salt with a base of a mercaptan derivative (X); the general formula by sequentially reacting in the same vessel with (IX ^*) or (VI
The carbapenem compound represented by I ^* ) can be produced.

The reaction of the above 1), 2), 3) is not carried out in the same vessel, but the compound (I-8 ^* ) is subjected to the reaction shown in 1), followed by post-reaction treatment. Expression (VI
^* )

Embedded image [Wherein, R ″ ₄ , R ′ ₁₀ and Y have the same meaning as described above] under various conditions, for example, post-reaction treatment in the presence of a base, storage in a high-concentration solution, acetonitrile Depending on its presence in solution with polar solvents such as
Epimerization of the β-methyl group at the position tends to proceed. From this fact, there is a problem when the compound represented by the general formula (VI ^* ) is taken out and then the compound represented by the general formula (IX ^* ) is stereoselectively mass-produced from the compound (VI ^* ). Conceivable. In contrast, the compound (VI ^* ) in the reaction system
The method of deriving the compound (IX ^* ) in the form of the compound (VI-2 ^* ) instead of the carbapenem compound (IX ^* ) or (VII ^* ) without causing epimerization of the 1-β-methyl group
This is advantageous because it can lead to

[0042] In the compounds of the formula (I-8 ^0), the starting compound R ⁰ ₃ is a hydrogen atom can be produced by a known method or a similar method, R ⁰ ₃ is a lower alkyl group A certain starting compound can be produced, for example, as follows.

[A]

Embedded image [Wherein R ₁ , R ₂ and R ₄ ′ have the same meaning as described above;
X represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group,
Y ′ represents an oxygen atom or a sulfur atom, R ₃ represents a lower alkyl group, and R ₅ ′ represents a carboxyl protecting group or a thiol carboxyl protecting group. M represents an active ester of a hydroxyl group. ]

The compound represented by the general formula (I-1) is reacted with a compound represented by the general formula (II) and an acetic acid derivative represented by the general formula (III) in an inert solvent in the presence of a base.
A β-lactam compound represented by the following formula can be obtained.

In this reaction, a phase transfer catalyst can be used if necessary.

Examples of the inert solvent used in the present N-alkylation reaction include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diethyl ether, and halogenated solvents such as methylene chloride, dichloroethane and chloroform. Preferred examples include single or mixed solvents such as hydrocarbons, ketones such as acetone and methyl isobutyl ketone, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide (HMPT), t-butanol, and water. be able to. Suitable bases include 1,8-
Organic bases such as diazabicyclo [5.4.0] -undec-7-ene (DBU), alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like And various bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and potassium t-butoxide.

Further, as the phase transfer catalyst, for example, benzyltriethylammonium chloride, tetra-n-butylammonium bromide, tetraethylammonium bromide and the like can be used as required.

It is desirable that the amount of the base and the amount of the catalyst used in the case of using a phase transfer catalyst are such that the reaction proceeds sufficiently, and the reaction is suppressed or promoted by cooling or heating as appropriate. Can be.

Suitable examples of M which is an active ester of a hydroxyl group include sulfonyl esters such as mesylate and tosylate, and halogen atoms such as chlorine atom, bromine atom and iodine atom.

[B-1] When Y 'is a sulfur atom in the above formula (I-1), the compound is subjected to a selective hydrolysis reaction to give a compound of the formula (I-2)

Embedded image [Wherein, R ₁ , R ₂ , R ₃ , R ′ ₄ and X have the same meaning as described above. ] Can be obtained.

The selective hydrolysis reaction can be carried out according to a conventional method, for example, a hydrolysis method under basic conditions.

[B-2] When Y ′ is an oxygen atom in the general formula (I-1), the protective group R ′ ₄
And the general formula by removing one or both of R _'5 (I-3)

Embedded image Wherein, R _1, R _2, R ₃ and X have the same meanings as described above, "a protecting group for a hydrogen atom or a carboxyl group ₅ and R ₄ independently. However, R" R ₅ and R _At least one of ₄ is a hydrogen atom. A compound represented by the formula:

Further, (A) when R " ₅ and R ₄ are both hydrogen atoms in the general formula (I-3), a protecting group R ' ₄ is introduced into the compound; (I-3) R _"5 is a protecting group, if R ₄ is a hydrogen atom, R After introducing a new protecting group R _'4 in the compound" in selecting the protecting group represented by ₅ To remove,
Thereby, the β-lactam compound represented by the general formula (I-2) can be obtained.

[0054] Although methods for the removal of protecting group R _'4 and / or R' ₅ is different depending on the kind of protecting group, per se known general procedures, such as hydrolysis, catalytic reduction, treatment or reduction with an acid or a base such as It can be carried out by a technical method or the like. If the selective removal of one of R _'4 and R' ₅ may if first select an R _'4 and R' ₅ a combination of so as to allow such selective reactions.

[0055] carried out in accordance with the general method of introduction of ₄ 'protecting group R in the process of introduction of the ₄ and (ii)' protecting group R in the process, any removal of the protecting group R _"5 normal (a) above be able to.

[C] Further, the compound represented by the general formula (I-2) is converted into an active ester, an active acid anhydride, a thiol ester, an aryl ester or a heteroaryl ester of a carboxylic acid derivative by various known methods. The general formula (I-4)

Embedded image [Wherein R ₁ , R ₂ , R ₃ , R ′ ₄ , X ′ and COZ ′ have the same meaning as described above. ] Can be produced.

This reaction can be carried out, for example, as follows. (A) An acid halide can be produced by reacting a halogenating agent such as oxalyl chloride or thionyl chloride as it is or in the presence of a base. (B) For example, a mixed acid anhydride can be produced by using a chloroformate ester such as ethyl chloroformate in the presence of a base. (C) An acylimidazole derivative can be produced by treating with N, N'-carbonyldiimidazole. (D) An thiazolidine-2-thione derivative can be produced by reacting thiazolidine-2-thione in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC). (E) substituted or unsubstituted thiophenols, 4,6-
Dimethyl-2-mercaptopyrimidine, 2-mercaptopyridine and the like are condensed using a dehydrating agent such as DCC or reacted with an active ester such as the above-mentioned acid halide, mixed acid anhydride or acylimidazole derivative. A thiol ester can be produced by subjecting the mercaptan to an acylation reaction. (F) N-hydroxysuccinimide, N-hydroxyphthalimide, substituted or unsubstituted phenols, 2-
An active ester can be produced by subjecting a pyridone and a thiol ester to the same treatment as in the production of the above-mentioned thiol ester.

[D]

Embedded image _{Wherein, R 1, R 2, R} 3, R '5, X and Y' are as defined above, R ⁰ ₄ represents a protecting group of a thiol carboxyl group. ]

[0059] The general formula (I-1) selectively removing the protecting group R _'4 in the compound represented by to the general formula obtained (I-
5) A carboxylic acid derivative represented by the general formula HSR
⁰ ₄ wherein, R ⁰ ₄ are the same as defined above. To produce a β-lactam compound represented by the general formula (I-6). This reaction can be carried out according to a general mercaptan group acylation method.

[E] Further, general formula (I-7)

Embedded image _{Wherein, R 1, R 2, R} 3, R 0 4, X and Z 'are as defined above. ] -Lactam compound represented by the formula:
It can be produced from the compound represented by the general formula (I-6) according to the method described in the above [B] and [C].

[F]

Embedded image [Wherein, R ₁ , R ₂ , R ₃ , R ′ ₄ , X ′ and M have the same meaning as described above. ]

By reacting the alcohol derivative represented by the general formula (IV) with the acetic acid derivative represented by the general formula (III) in an inert solvent in the presence of a base, the β-form represented by the general formula (V) is obtained. After obtaining a lactam compound, this compound (V) is treated with an oxidizing agent to give a compound of the general formula (I)
Can be obtained represented by β- lactam compound at -2 ^0). This N-alkylation reaction can be carried out in the same manner as in the method described in the above [A]. In the subsequent oxidation reaction, various modes of oxidation reaction generally used for converting a primary alcohol into a carboxylic acid can be used, and various oxidizing agents can be used. For example, chromium (VI) oxide-sulfuric acid can be used. And chromium oxide-pyridine.

As described above, the general formula (I)

Embedded image [Wherein R ₁ , R ₂ , R ₃ , R ₄ and Y have the same meanings as described above, and COZ is a carboxyl group, an active ester of a carboxyl group, an active acid anhydride of a carboxyl group, a protecting group for a carboxyl group. It represents a protected carboxyl group or a thiol carboxyl group protected by a thiol carboxyl protecting group. ] Can be produced.

In the β-lactam compound represented by formula (I-4) or (I-7), when X is a hydroxyl group, the hydroxyl group of the compound is further protected by a conventional method to form a compound of the general formula (I-8)

Embedded image _{Wherein, R 1, R 2, R} 3, R "4, X ', Y and Z' are as defined above.] Beta-lactam compound represented by, i.e. the formula (I-8 ⁰ can be prepared a compound R ⁰ ₃ is a lower alkyl group in).

The compound represented by the general formula (VII) can also be produced by the following method.

Embedded image _{Wherein, R 1, R 2, R} 0 3, R "4, X ', Y and Z' are as defined above.]

The compound represented by formula (VI) can be obtained by treating the β-lactam compound (I-8 ⁰ ) with a base in an inert solvent. In this reaction, R ⁰ ₃
If it is a lower alkyl group, the starting compound (I-8 ⁰⁾
Asymmetric carbon bonded to 4-position β-lactam ring of (C5 position)
(VI), which retains the three-dimensional structure based on the above, can be obtained as the main product. In this reaction, the compound (I-8 ⁰ ) is reacted under the same conditions as in the above-mentioned method to give the compound (VI-2) by ring closure, and after the reaction is completed, a product is taken out by ordinary organic chemical means. Can be implemented.

However, for example, general formula (VI-1)

Embedded image The alkyl group at the 1-position of the compound represented by the formula (1) may form an epimer during post-treatment such as treatment with a base or concentration, and care must be taken in its handling.

Next, the compound represented by the general formula (VI) can be derived into the carbapenem compound (VII) by a method described in JP-A-57-123182 or a similar method.

The raw material compound (II) is disclosed in JP-A-57-1
Produced according to a known method described in, for example, Japanese Patent No. 23182, or when a starting material compound in which Y is a sulfur atom is desired, a compound represented by the aforementioned general formula (I-6) is further added. Similarly to the production method, -SR ₄
It can be produced by introducing a group.

The starting compound (IV) can be produced according to a known method described in JP-A-55-89285, but can also be produced, for example, by the following method.

Embedded image [In the formula, R ₁ , R ₂ , X ⁰ and X ′ have the same meaning as described above, R ′ is a protecting group for a nitrogen atom, A ′ is a halogen atom, and P is a protecting group for a hydroxyl 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. The resulting carboxylic acid 1 can be reacted with various alkyl halides or can be obtained by a dehydration reaction with a lower alcohol.

Step B : The compound represented by the general formula 3 is obtained by reacting the compound 2 with an organometallic compound such as methylmagnesium halide or methyllithium in an inert solvent,
When X ⁰ is a hydroxyl group, it can be obtained by subjecting a commonly used hydroxyl group protection reaction.

Step C : The compound represented by the general formula 4 is obtained by subjecting the compound 3 to a dehydration reaction performed with a dehydrating reagent such as thionyl chloride or tosyl chloride in the presence or absence of a base. Can be obtained by

Step D : The compound represented by the general formula 5 can be obtained by reacting compound 4 in an inert solvent with various halogenating agents used for halogenating an allylmethyl group, for example, molecular halogen, It can be obtained by reacting with N-halogenosuccinimide or the like.

Step E : The compound represented by the general formula 6 can be obtained by hydrolyzing the compound 5 in the presence of a low valent ionic salt of a heavy metal such as copper or silver.

Step F : The compound represented by the general formula 7 can be obtained by subjecting the compound 6 to a general hydroxyl group protection reaction.

Step G : The compound represented by the general formula 8 can be obtained by subjecting the compound 7 to hydrogenation such as catalytic reduction.

Step H : The compound represented by the general formula (IVa) can be obtained by simultaneously or sequentially carrying out the reaction of removing Compound 8 from the protecting group P for the hydroxyl group and the protecting group R ′ for the amino group.

Compound 3 represented by the above general formula (I)
Carbon atom at the 4-position, the carbon atom bonded to the β-lactam ring in the 4-position substituent, or R ₁ = methyl, R ₂
In the case where R ₁ , R ₂ , and X are different from each other, the carbon atom bonded to the β-lactam ring in the 3-position substituent is an asymmetric carbon, as in the case of = hydrogen atom and X = hydroxyl group. Therefore, the compound represented by the general formula (I) has optical isomers and stereoisomers based on asymmetric carbon, and these isomers are all represented by a single formula. The described range is not limited. However, preference is given to compounds of the following formula in which the carbon atom at position 4 is co-ordinated with thienamycin.

[0080]

Embedded image

[0081]

Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is of course not limited thereto. The meanings of the abbreviations are as follows. TBDMS: t-butyldimethylsilyl group Me: methyl group Ph: phenyl group Z: benzyloxycarbonyl group t-Bu: t-butyl group PNB: p-nitrobenzyl group PMB: p-methoxybenzyl group Im: 1-imidazolyl group Bt: 1-benzotriazolyl group Ac: acetyl group PNZ: p-nitrobenzyloxycarbonyl group DAM: di- (p-anisyl) methyl group

Reference Example 17-1

Embedded image

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidinone (70 mg) was dissolved in dry toluene (0.6 ml), and sodium hydride (50% oily) (12.5 m
g) was added dropwise to a suspension of dry tetrahydrofuran (0.1 ml) and stirred for 30 minutes. p-Toluenesulfonic acid 1
57 mg of hydrate was added, and the mixture was further stirred for 10 minutes, diluted with 20 ml of cooled ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and evaporated to remove the solvent (4R, 5R, 6
S, 8R) -4-Methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.
0] Hept-3,7-dione-2-carboxylic acid p-nitrobenzyl ester was obtained.

IR ^neat (cm ^-1 ): 1760, 1605, 1520, 146
0, 1350, 1250, 1220, 1110, 1045, 835, 780, 738; NMR δ (CDCl ₃ ): 1.21 (3H, d, J = 7.6 Hz), 1.29 (3H, d, J =
6.3Hz), 2.80 (1H, m), 3.22 (1H, dd, J = 2.3 and 6.3Hz), 4.18
(1H, dd, J = 2.3 and 1.9Hz), 4.29 (1H, m), 4.72 (1H, s), 5.30
(2H, ABq, J = 13.2Hz), 7.54 (2H, d, J = 8.9Hz), 8.24 (2H, d, J
= 8.9Hz).

Reference Example 17-2 (3S, 4S) -3-[(1R) -1-tert-butyldimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-p -Nitrobenzyloxycarbonylmethyl-2-azetidinone (60 m
g) was dissolved in 0.6 ml of a mixed solvent of heavy benzene and heavy tetrahydrofuran (4: 1), 11 mg of sodium hydride (50% oil) was added under ice cooling, and the mixture was stirred for 1 hour, and the reaction mixture was directly subjected to NMR measurement.

Reference Example 17-3 The reaction described in Reference Example 17-2 was carried out in a mixed solvent of heavy benzene and heavy dimethyl sulfoxide (9: 1), and the reaction solution was directly subjected to NMR measurement.

[0087]

[Table 1]

The compound is a 4-α-methyl compound (4S, 5
R, 6S, 8R) -4-Methyl-6- [1-t-butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic acid p-nitro When the benzyl ester was treated in the same manner as in Reference Example 17-2, the reaction solution showed an NMR spectrum different from that of Reference Example 17-2. NMR δ [C ₆ D ₆ -THFd ₈ (4: 1)]: 2.93 (1H, d, J = 6 Hz, 5-H),
3.52 (1H, d, J = 9Hz, 6-H).

Further, (4R, 5R,
6S, 8R) -4-methyl-6- [1-tert-butyldimethylsilyloxyethyl] -1-azabicyclo [3.
2.0] Hept-3,7-dione-2-carboxylic acid p-
The nitrobenzyl ester was subjected to the same treatment as in Reference Example 17-2, and the reaction solution was subjected to NMR measurement. Five minutes after the completion of the reaction, it was shown that the β-methyl form and the α-methyl form were present at almost 1: 1. After 5 hours at room temperature, all
-Methyl form. The NMR spectrum of the reaction solution obtained in Reference Example 17-2 after standing at room temperature for 5 hours showed that the β-methyl form remained.

Embodiment 1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidinone (117 mg, 0.2 mM) was dissolved in a dry tetrahydrofuran-toluene (1: 1) mixture (1.2 ml) and sodium hydride (50% oily) (22 mg, 0.46
mM) and dry tetrahydrofuran-toluene (1: 1)
Was added dropwise at −20 ° C. to a suspension with a mixture (0.2 ml) of
After stirring for 1 hour, a 2M solution of iodomethane in tetrahydrofuran (0.1 ml) was added, and the mixture was further stirred for 30 minutes. Next, 56 mg (0.21 mM) of diphenylchlorophosphate
Was dissolved in 0.1 ml of dry toluene and added dropwise, followed by stirring for 1.5 hours. The reaction mixture was diluted with 20 ml of ethyl acetate, washed several times with brine, dried over a mixed desiccant of magnesium sulfate-potassium carbonate (10: 1), and the solvent was distilled off.
The residue was purified by silica gel thin-layer chromatography, and (4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3 .2.
0] Hept-2-en-7-one-2-carboxylic acid p-
The nitrobenzyl ester (115 mg) was obtained.

IR ^neat (cm ^-1 ): 1775, 1725, 1630, 158
5,1518,1482,1340,1285,1185,1160,938,825,7
70; NMR δ (CDCl ₃ ): 0.06 (3H, s), 0.07 (3H, s), 0.86 (9H,
s), 1.20 (3H, d, J = 7.9 Hz), 1.23 (3H, d, J = 6.3 Hz), 3.29 (1
H, dd, J = 3.0 and 6.0Hz), 3.43 (1H, m), 4.22 (2H, m), 5.28 (2
H, ABq, J = 13.5Hz), 7.56 (2H, d, J = 8.9Hz), 8.14 (2H, d, J =
8.9Hz).

Embodiment 2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidinone (415 mg, 0.708 mM) was dissolved in a dry toluene-tetrahydrofuran (4: 1) mixture (4 ml), and sodium hydride (50% oily) (75 mg, 1.56
mM) and dry toluene-tetrahydrofuran (4: 1)
Was added dropwise at −20 ° C. to a suspension of
After stirring for 1 hour, a 0.5 M solution of iodomethane in tetrahydrofuran (1.49 ml, 0.745 mM) was added dropwise, and the mixture was further stirred for 30 minutes. Next, at the same temperature, diphenylchlorophosphate (218.5 mg, 0.814 mM) in dry toluene (2.2 m
l) The solution was added dropwise and stirred for 2 hours. Then, [2S,
4S] -1-p-nitrobenzyloxycarbonyl-2
-Dimethylaminocarbonyl-4-mercaptopyrrolidine (237.5 mg, 0.67 mM) and then sodium hydride (50% oily) (32.3 mg, 0.67 mM) were added and stirred for 2 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, washed several times with cold saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, and (4R, 5S, 6S, 8R, 2'S, 4'S)
-3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [ 3.2.0] Hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester (3.29 mg) was obtained.

IR ^neat (cm ^-1 ): 1775, 1715, 1660, 161
0, 1525, 1400, 1345, 1210, 1140, 1110, 835, 755.

Embodiment 3

Embedded image

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-p-
Nitrobenzyloxycarbonylmethyl-2-azetidinone (69 mg, 0.12 mM) in dry toluene (0.6 m
l) Transfer the solution to sodium hydride (50% oily) (12.5m
g, 0.26 mM) and dry tetrahydrofuran (0.1 ml)
Was added dropwise to the suspension under ice-cooling, and after stirring for 30 minutes, diphenylchlorophosphate (67 mg, 0.25 mM) was added, and the mixture was stirred for 1 hour. The reaction mixture was diluted with 10 ml of ethyl acetate, washed several times with brine, dried over a mixed desiccant of magnesium sulfate-potassium carbonate (10: 1), and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to give (4R, 5S, 6S, 8R) -3-phenylthio-
4-methyl-6- [1-t-butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylic acid p-nitrobenzyl ester (37 mg) and (4R, 5R, 6S, 8R)
-3-Diphenylphosphoryloxy-4-methyl-6-
(1-t-butyldimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester (34
mg).

(4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2 And NMR of -en-7-one-2-carboxylic acid p-nitrobenzyl ester
Was the same as that obtained in Example 1.

(4R, 5S, 6S, 8R) -3-phenylthio-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester IR ^neat (cm ^-1 ): 1765, 1707, 1522, 1378, 1350, 134
0, 1140; NMR δ (CDCl ₃ ): 0.06 (6H, s), 0.84 (9H, s), 0.95 (3H,
d, J = 7.3Hz), 1.17 (3H, d, J = 6.3Hz), 3.06 (1H, m), 3.19 (1
H, dd, J = 2.9 and 5.0Hz), 4.22 (2H, m), 5.40 (2H, ABq, J = 13.9
Hz), 7.3 to 7.6 (5H, m), 7.69 (2H, d, J = 8.9Hz), 8.23 (2H,
d, J = 8.9Hz).

Embodiment 4

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(3S, 4R) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1- (1-Imidazolylcarbonyl) ethyl]-
1-p-nitrobenzyloxycarbonylmethyl-2-
Azetidinone (52 mg, 0.096 mM) in dry toluene-tetrahydrofuran (4: 1) mixture (0.5 ml)
Sodium hydride (50% oil) under ice-cooling
After adding 0 mg, dry N, N-dimethylformamide
0.05 ml was added. Next, diphenylchlorophosphate (60 mg, 0.22 mM) was added, and the mixture was stirred for 2 hours.
[S, 4S] -1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (35.3 mg, 0.1 mM), and sodium hydride (50% oily) (5 mg). The mixture was stirred for 1.5 hours, diluted with 10 ml of ethyl acetate, washed several times with cold saline, dried over magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel thin layer chromatography, and (4R, 5S, 6S, 8R, 2'S, 4'S)-
3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio]
-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester was obtained. Was. IR and N of the compound obtained here
The MR was the same as the compound obtained in Example 2.

Embodiment 5

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(3S, 4S) -3-[(1R) -1-trimethylsilyloxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone (10
9 mg, 0.2 mM) in the same manner as in Example 2 (4
R, 5S, 6S, 8R, 2'S, 4'S) -3- [4-
(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-trimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester was obtained.

IR ^neat (cm ^-1 ): 1765, 1705, 1650, 160
0, 1512, 1395, 1335, 1200, 1130, 1100, 840, 740.

Reference Example 18

Embedded image

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-phenylthiocarbonylmethyl-2-azetidinone 20 mg
2.6 mg of sodium hydride was added to a dry N, N-dimethylformamide solution (0.2 ml), and the mixture was stirred at room temperature for 20 minutes. After the reaction solution was diluted with diethyl ether, a pH 6.86 phosphate buffer was added, and the mixture was separated. The aqueous layer was further extracted twice with diethyl ether, and the organic layers were combined and washed with water (three times) and brine (twice). After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (4R, 5R, 6S, 8R) -4-methyl-6.
-(1-t-butyldimethylsilyloxyethyl) -1
-Azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic acid phenylthioester was obtained.

IR ^neat (cm ^-1 ): 1780 (sh), 1760, 1750 (s
h), 1710, 1250, 1140, 1062, 830, 775, 742.

Embodiment 6

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-phenylthiocarbonylethyl] -1-phenylthiocarbonylmethyl-2-azetidinone (60 m
g, 0.107 mM) in dry acetonitrile (1 ml), and after cooling with ice, sodium hydride (50% oily) (13 m
g, 0.27 mM) and stirred for 15 minutes. Next, a solution of diphenylchlorophosphate (57.5 mg, 0.21 mM) in dry acetonitrile (0.3 ml) was added dropwise, and the mixture was stirred for 1.5 hours. After dilution with 10 ml of ethyl acetate and washing several times with saline, magnesium sulfate-potassium carbonate (10:
It dried with the mixed desiccant of 1), and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography (4R, 5
R, 6S, 8R) -3-diphenylphosphoryloxy-
4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-
2-ene-7-one-2-carboxylic acid phenylthioester (55 mg) was obtained. The IR and NMR of the compound obtained here were the same as the compound obtained in Reference Example 3-1.

Reference Example 19

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Phenylthiocarbonylethyl] -1- (1
-Phenylthiocarbonylmethyl) -2-azetidinone 20 mg in dry hexamethylphosphoric triamide-
Dissolve in 0.2 ml of a mixed solvent of tetrahydrofuran (1: 100), and add lithium bis (trimethylsilyl) at -30 ° C.
0.3 ml of a 0.5 M solution of amide in tetrahydrofuran was added dropwise. After the temperature was raised to 0 to 5 ° C. and stirred for 25 minutes, the reaction solution was diluted with diethyl ether, and a pH 6.86 phosphate buffer was added to separate the solution. The aqueous layer was further extracted twice with diethyl ether, combined with the previous organic layer, washed three times with brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel chromatography (4S, 5R, 6S, 8R) -4.
-Methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] -hept-
3,7-dione-2-carboxylic acid phenylthioester was obtained.

IR ^neat (cm ^-1 ): 1760, 1700, 1435, 136
7, 1247, 827, 765, 740, 680.

Reference Example 20

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-phenylthiocarbonylethyl] -1- (1
65 mg of -t-butyloxycarbonylmethyl) -2-azetidinone was dissolved in 1.0 ml of dry tetrahydrofuran, and 3.84 ml of a 0.1 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added dropwise at -70 ° C. After the temperature was raised to 0 to 5 ° C., the reaction was stopped by adding a pH 8.0 phosphate buffer, and the mixture was extracted twice with diethyl ether. The organic layer was washed with a pH 8.0 phosphate buffer (twice) and then dried over sodium sulfate. The solvent is distilled off (4R, 5R, 6S,
8R) -4-Methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0]
Hept-3,7-dione-2-carboxylic acid t-butyl ester was obtained.

NMR δ (CDCl ₃ ): 0.10 (6H, s), 0.89 (9H,
s), 1.18 (3H, d, J = 7.9 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.46 (9
H, s), 2.76 (1H, m), 3.18 (1H, dd, J = 2.5 and 5.8Hz), 4.22 (1H
H, dd, J = 2.5 and 8.1Hz), 4.58 (1H, s).

Embodiment 7

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(3S, 4S) -4-[(1R) -1-phenylthiocarbonylethyl] -3-[(1R) -1-
t-butyldimethylsilyloxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 101 mg
Was dissolved in 2 ml of dry tetrahydrofuran and cooled to -50 ° C under a nitrogen stream. 5 ml of a tetrahydrofuran solution of lithium diisopropylamide (0.1 M) was added dropwise thereto, and the temperature was raised to 0 ° C. in 2 hours. Subsequently, 120 mg of diphenylchlorophosphate was added to 7 ml of dry acetonitrile.
, And added dropwise under ice-cooling. After stirring for 2 hours,
The reaction solution was poured into a cooled mixture of 20 ml of diethyl ether and 20 ml of a pH 6.86 phosphate buffer, and the mixture was separated.
The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained oily residue was purified by silica gel thin-layer chromatography (4R, 5R, 6S, 8).
R) -3-Diphenylphosphoryloxy-4-methyl-
6- (1-t-butyldimethylsilyloxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylic acid t-butyl ester (83.5m
g) was obtained.

IR ^neat (cm ^-1 ): 1780, 1718, 1635, 158
5,1482,1360,1285,1185,1158,960,940,830,76
5; NMR δ (CDCl ₃ ): 1.17 (3H, d, J = 7.6 Hz), 1.21 (3H, d, J =
6.3Hz), 3.22 (1H, dd, J = 3.0 and 6.0Hz), 3.42 (1H, m), 4.12
(1H, dd, J = 3.0 and 10.0Hz), 4.21 (1H, m).

Reference Example 21

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Using the starting compounds shown in the following table and in the same manner as in Reference Example 20, (5R, 6S, 8R) -4-methyl-6- (1-tert-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] Hept-3,7
-Dione-2-carboxylic acid t-butyl ester was obtained as a mixture of 4R form and 4S form.

[0121]

[Table 2]

The NMR of the compound obtained here was the same as the compounds obtained in Reference Examples 20 and 22-2.

Reference Example 22-1- (1)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1-methoxycarbonylmethyl-2-azetidinone (50 mg) was dissolved in dry hexamethylphosphoric triamide-tetrahydrofuran (1: 100) mixed solvent (0.6 ml), and lithium bis (trimethylsilyl) amide was dissolved at -30 ° C. 0.44 ml of a 1M tetrahydrofuran solution was added dropwise. The reaction solution was heated to room temperature, and after the raw materials disappeared, the reaction solution was ice-cooled. After adding a pH 6.86 phosphate buffer to the reaction mixture, the mixture was diluted with diethyl ether. After separation, the aqueous layer was further extracted twice with diethyl ether, combined with the previous organic layer, and washed five times with a saline solution.
Glauber's salt was dried. The solvent is distilled off, and the residue is purified by silica gel chromatography (4S, 5R, 6S, 8R)-
4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-
3,7-dione-2-carboxylic acid methyl ester was obtained.

IR ^CHCl 3 (cm ^-1 ): 1770, 1760, 1740, 143
5, 1245, 1120, 825; NMR δ (CDCl ₃ ): 0.10 (6H, s), 0.90 (9H, s), 1.27 (8H,
d, J = 7.0Hz), 1.30 (3H, d, J = 6.2Hz), 2.29 (1H, m), 3.14 (1
H, dd, J = 1.5 and 5.7Hz), 3.77 (3H, s), 4.31 (1H, m), 4.71 (1
H, s).

Reference Example 22-1- (2)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1- (1-methoxycarbonylmethyl) -2-azetidinone (15 mg) was dissolved in dry hexamethylphosphoric triamide-tetrahydrofuran (1: 100) mixed solvent (0.2 ml), and sodium hydride and dimethylsulfoxide were used. Prepared 2.6
M sodium methylsulfinylmethide / dimethylsulfoxide solution (0.05 ml) was added dropwise at -20 ° C to -25 ° C. After stirring for 5 minutes, the mixture was heated to 0 to 5 ° C. and reacted for 30 minutes and at room temperature for 20 minutes. The mixture was cooled again to 0 to 5 ° C., and a pH 6.86 phosphate buffer was added to the reaction solution, followed by dilution with diethyl ether. After liquid separation, the aqueous layer was extracted once more with diethyl ether, combined with the above organic layer, washed three times with water and then with brine, and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (4S, 5R, 6).
S, 8R) -4-Methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.
0] Hept-3,7-dione-2-carboxylic acid methyl ester was obtained. The IR and NMR of the compound obtained here were the same as those of the compound obtained in Reference Example 22-1- (1).

Reference Example 22-1- (3)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethyloxyethyl] -4-[(1S) -1
-Phenylthiocarbonylethyl] -1-methoxycarbonylmethyl-2-azetidinone (15 mg) was dissolved in dry hexamethylphosphoric triamide-tetrahydrofuran (1: 100) mixed solvent (0.2 ml), and potassium t-butoxide (15 mg) was added at 0 to 5 ° C. The mixture was heated to room temperature and stirred for 30 minutes. Re-cool the reaction to 0-5 ° C.
After adding a pH 6.86 phosphate buffer, the mixture was diluted with diethyl ether. After liquid separation, the aqueous layer was extracted once more with diethyl ether, combined with the above organic layer, washed twice with water and then with brine, and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (4S, 5R,
6S, 8R) -4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-3,7-dione-2-carboxylic acid methyl ester was obtained. IR and NM of the compound obtained here
R was the same as the compound obtained in Reference Example 22-1- (1).

Reference Example 22-2

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Using the starting compounds shown in the following table, (4S, 5R, 6) was prepared in the same manner as in Reference Example 22-1- (1).
S, 8R) -4-Methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.
0] Hept-3,7-dione-2-carboxylic acid p-nitrobenzyl ester and t-butyl ester were obtained.

[0132]

[Table 3]

(4S, 5R, 6S, 8R) -4-methyl-6- (1-t-butyldimethylsilyloxyethyl)
-1-Azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic acid p-nitrobenzyl ester IR ^CHCl 3 (cm ⁻¹ ): 1780, 1760, 1720, 1520, 1345, 124
5,1178,835; NMR δ (CDCl ₃ ): 0.08 (3H, s), 0.10 (3H, s), 0.88 (9H,
s), 1.26 (3H, d, J = 6.8 Hz), 1.30 (3H, d, J = 6.2 Hz), 2.28 (1
H, m), 3.17 (1H, dd, J = 2.0 and 7.0Hz), 3.67 (1H, dd, J = 2.0 and
8.0Hz), 4.30 (1H, m), 4.80 (1H, s), 5.29 (2H, s), 7.53 (2
H, d, J = 9.0Hz), 8.24 (2H, d, J = 9.0Hz).

(4S, 5R, 6S, 8R) -4-methyl-6- (1-t-butyldimethylsilyloxyethyl)
-1-azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic acid t-butyl ester IR ^CHCl 3 (cm ⁻¹ ): 1760, 1730, 1360, 1142, 825; NMR δ (CDCl ₃ ): 0.10 (6H, s), 0.90 (9H, s), 1.27 (3H,
d, J = 6.9Hz), 1.30 (3H, d, J = 5.9Hz), 1.46 (9H, d), 2.24 (1
H, m), 3.12 (1H, dd, J = 2.0 and 6.3Hz), 3.66 (1H, dd, J = 1.9 and
8.1Hz), 4.29 (1H, m), 4.57 (1H, s).

Reference Example 22-3

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Using the starting compounds shown in the table below, (4S, 5R, 6S, 8R)-
4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-
3,7-dione-2-carboxylic acid t-butyl ester was obtained.

[0137]

[Table 4]

The IR and NMR of the compound obtained here were the same as those of the compound obtained in Reference Example 22-2.

Reference Example 1-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 30
1 mg, N, N'-carbonyldiimidazole 194 m
g of 8.6 ml of dry acetonitrile was stirred at room temperature for 1 hour. This was followed by a solution of 132 mg of thiophenol in 2.3 ml of dry acetonitrile, followed by triethylamine 121
mg of dry acetonitrile in 2 ml was added at room temperature.
Stirred for minutes. The reaction was diluted with ethyl acetate and washed with brine. The aqueous layer was further extracted twice with ethyl acetate, the organic layers were combined, washed with brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, and (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1
-Phenylthiocarbonylethyl] -2-azetidinone.

IR ^neat (cm ^-1 ): 3200 (br), 1760, 1700,
1370, 1250, 1140, 955, 830, 773, 740, 680.

Reference Example 1-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 40
0 mg, N, N'-carbonyldiimidazole 259 m
g of dry acetonitrile in 11 ml was stirred at room temperature for 1 hour. To this were added a solution of 281 mg of p-chlorothiophenol in 3.2 ml of dry acetonitrile and then a solution of 162 mg of triethylamine in 2.3 ml of dry acetonitrile, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether and brine, and separated. The aqueous layer was further extracted twice with diethyl ether. The organic layers were combined, washed with diluted hydrochloric acid and brine (3 times), and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography to give (3S, 4S) -3-[(1R) -1-t-
Butyldimethylsilyloxyethyl] -4-[(1R)
-1-p-chlorophenylthiocarbonylethyl] -2
-Azetidinone was obtained.

IR ^neat (cm ^-1 ): 3250 (br), 1770, 1750,
1700, 1478, 1247, 1140, 1090, 820, 770; NMR δ (CDCl ₃ ): 0.07 (6H, s), 0.88 (9H, s), 1.18 (3H,
d, J = 6.3Hz), 1.33 (3H, d, J = 6.9Hz), 2.97 (1H, m), 3.02 (1
H, m), 3.93 (1H, dd, J = 2.0 and 5.3Hz), 4.22 (1H, m), 5.86 (1
H, br.s), 7.36 (4H, m).

Reference Example 1-3

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone 1.00
g, 369 mg of triethylamine and 779 mg of p-methoxybenzyl chloride in 1 ml of dry N, N-dimethylformamide were stirred at 70 ° C. for 2 hours and 40 minutes. The reaction mixture was poured into iced water, adjusted to pH 2-3 with dilute hydrochloric acid, and extracted three times with diethyl ether. Combine the organic layers and cool 1
After washing with N-NaOH (3 times), water (3 times) and brine (3 times), the solution was dried over sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel chromatography (3S, 4S)-
3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-methoxybenzyloxycarbonylethyl] -2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 3225 (br), 1760, 1740,
1605, 1505, 1458, 1240, 1160, 1030, 950, 825, 76
7; NMRδ (CDCl ₃ ): 0.05 (6H, s), 0.86 (9H, s), 1.13 (3H,
d, J = 6.0Hz), 1.21 (3H, d, J = 7.0Hz), 2.70 (1H, m), 2.95 (1
H, dd, J = 2.0 and 4.0Hz), 3.81 (3H, s), 3.89 (1H, dd, J = 2.0
And 5.0Hz), 4.16 (1H, m), 5.05 (2H, s), 5.96 (1H, br.s),
6.87 (2H, d, J = 9.0Hz), 7.27 (2H, d, J = 9.0Hz).

Reference Example 2-1

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34 g of 4-carboxy-3- (1-hydroxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was dissolved in 310 ml of methanol, and 2.9 g of concentrated sulfuric acid was added. After stirring for 40 hours,
The mixture was cooled to neutralize with 15 ml of an 8% aqueous sodium hydroxide solution. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 1,2-dichloroethane (105 ml), washed with water, and the aqueous layer was again dissolved in 1,2-dichloroethane.
The mixture was extracted with 105 ml of 2-dichloroethane, and the organic layers were combined and washed with water. After drying the sodium sulfate, the solvent was distilled off and 4-methoxycarbonyl-3- (1-hydroxyethyl) -1-di- (p
-Anisyl) methyl-2-azetidinone was obtained.

Reference Example 2-2

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4-methoxycarbonyl-3- (1-hydroxyethyl) -1-di- (p-anisyl) methyl-2
32.5 g of azetidinone in dry tetrahydrofuran 310
The mixture was dissolved in ml and cooled on ice. Under a nitrogen stream, 370 g of a 1M-methylmagnesium bromide-tetrahydrofuran solution was added dropwise at 5 ° C. or lower, and the mixture was stirred for 1 hour, and then stirred at 350% for 20% hydrochloric acid.
ml was added dropwise at 20 to 25 ° C, and the mixture was stirred as it was for 1 hour. Next, 110 ml of ethyl acetate was added for extraction. The aqueous layer was re-extracted with 110 ml of ethyl acetate, and the organic layers were combined.
The extract was washed with saturated saline, saturated aqueous sodium hydrogen carbonate and water in that order, and dried over sodium sulfate. The solvent was distilled off and 4- (1-hydroxy-1-methylethyl) -3- (1-hydroxyethyl) -1-di-
(P-Anisyl) methyl-2-azetidinone was obtained. Melting point: 154-156 [deg.] C.

Reference Example 2-3

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4- (1-hydroxy-1-methylethyl) -3- (1-hydroxyethyl) -1-di- (p-
Anisyl) methyl-2-azetidinone (26 g) was dissolved in dry methylene chloride (200 ml), then N-dimethylaminopyridine (16 g) was added, and the mixture was cooled with ice. Under a nitrogen stream, 20 g of benzyl chloroformate was added dropwise over 1 hour, and the mixture was stirred for 2 hours, then at room temperature for 10 hours, ice-cooled, 100 ml of 5% hydrochloric acid was added, and the mixture was stirred for 30 minutes and separated. did. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline in that order, dried over sodium sulfate and evaporated to remove the solvent.
1-methylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 3450, 1750, 1615, 151
5,1250,1180,1030; NMRδ (CDCl ₃ ): 1.13 (6H, s), 1.38 (3H, d, J = 6.0Hz),
3.70 (3H, s), 3.75 (3H, s), 5.10 (2H, s), 5.55 (1H, br.
s), 7.29 (5H, s).

Reference Example 2-4

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30 g of 4- (1-hydroxy-1-methylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was dissolved in 350 ml of toluene, and pyridine was added. 1
0 ml, and then add 9.0 g of thionyl chloride at 20-30 ° C.
Then, the mixture was stirred as it was for 5 hours. 100 ml of water was added and the mixture was separated. The organic layer was washed with water, dried over sodium sulfate and evaporated, and the residue was crystallized from cyclohexane-ethyl acetate to give 4-
(1-Methylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was obtained. Melting point: 117-118 [deg.] C.

Reference Example 2-5

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4- (1-methylethenyl) -3- (1-
Benzyloxycarbonyloxyethyl) -1-di-
(P-anisyl) methyl-2-azetidinone (200
g, 0.388M) was dissolved in 3 liters of ethyl acetate, and a chlorine-carbon tetrachloride solution (3.85%, 870 g) was added dropwise at room temperature for 15 minutes, followed by stirring for 1 hour. Then 1 liter of water,
After adding and stirring 50 ml of 10% aqueous sodium thiosulfate solution, the organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent to give 4- (1-chloromethylethenyl)-. 3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-
Azetidinone was obtained. Melting point: 84-85 [deg.] C.

Reference Example 2-6

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4- (1-chloromethylethenyl) -3-
(1-benzyloxycarbonyloxyethyl) -1-
Di- (p-anisyl) methyl-2-azetidinone 20 g
Was dissolved in 160 ml of dimethyl sulfoxide, 40 ml of water was added with stirring, and then 6.76 g of cuprous oxide and p-
Add 7.6 g of toluenesulfonic acid monohydrate, and add 50 to 55 ° C.
For 2 hours. After cooling to room temperature, 90 ml of a 1% aqueous phosphoric acid solution was added, the mixture was diluted with 200 ml of ethyl acetate, and insolubles were removed by filtration on celite. Insoluble matter is ethyl acetate 20m
After washing three times with 1 l, the filtrate was separated. The aqueous layer was extracted with 200 ml of ethyl acetate, the organic layers were combined, washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and 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. Melting point: 118-120C.

Reference Example 2-7

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4- (1-hydroxymethylethenyl)-
3- (1-benzyloxycarbonyloxyethyl)-
1-di- (p-anisyl) methyl-2-azetidinone 2
0 g was dissolved in 45 ml of N, N-dimethylformamide, 5.6 g of imidazole and 6.77 g of t-butyldimethylchlorosilane were added at room temperature, and the mixture was stirred as it was for 2 hours. 200 ml of cold water and then 150 ml of ethyl acetate were added to carry out liquid separation. The aqueous layer was extracted with 150 ml of ethyl acetate, combined with the previous organic layer, twice with 80 ml of 5% aqueous hydrochloric acid, and then extracted with 5 ml of 5% hydrochloric acid.
Each was washed three times with 80 ml of a sodium chloride solution, and then dried over sodium sulfate. 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. Melting point: 90-92C.

Reference Example 2-8

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20 g of 4- (1-t-butyldimethylsilyloxymethylethenyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone was added to 200 ml of acetonitrile.
, And 4.0 g of a 5% platinum carbon catalyst and 4 ml of water were added thereto under a nitrogen stream. After hydrogen replacement at room temperature, hydrogenation was performed at 10 ° C. After filtering off the catalyst and washing the filtrate with ethyl acetate,
The filtrate was concentrated to give 4- (1-t-butyldimethylsilyloxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl) methyl-2-azetidinone. Obtained. This product was analyzed by liquid chromatography [Lichrosorb (registered trademark) RP-18, acetonitrile-water (85:15), flow rate 1 ml / min] and NMR measurement to find that 4- (1- (R) -t-butyldimethylsilyloxy (Methylethyl) form and the corresponding (S) form mixture, and the ratio was R / S = 7.7. About this mixture, ethyl acetate-n-hexane (1:10)
From a mixed solvent of 4- (1- (R) -tert-butyldimethylsilyloxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p
Only-(anisyl) methyl-2-azetidinone can be obtained.

Melting point: 78-81 ° C .; NMR δ (CDCl ₃ ): 0.01 (6H, s), 0.87 (9H, s), 1.40 (3H,
d, J = 6.0Hz), 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 (2
H, s), 7.38 (5H, s).

Reference Example 2-9

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4- (1- (R) -tert-butyldimethylsilyloxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -1-di- (p-anisyl)
20 g of methyl-2-azetidinone was dissolved in 200 ml of methylene chloride.
and 7.8 g of 1,3-dimethoxybenzene, and then 23 g of boron trifluoride etherate was added dropwise at 10 to 20 ° C., followed by stirring at room temperature for 3 hours, heating to 45 ° C., and refluxing for 3 to 5 hours. . After cooling to 10-15 ° C, 5
Wash twice with 200 ml of 2.5% sodium chloride solution, and then add 2.5%
The residue was purified by silica gel chromatography, and the residue was purified by silica gel chromatography to give 4- (1- (R) -hydroxymethylethyl) -3- (1-benzyl). Oxycarbonyloxyethyl) -2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 3350, 1750, 1740, 145
5,1382,1260,1030; NMRδ (CDCl ₃ ): 0.95 (3H, d, J = 7.0Hz), 1.48 (3H, d, J =
6.5Hz), 3.14 (1H, dd, J = 2.0 and 9.0Hz), 3.55 (1H, d, J = 2.0H
z), 5.15 (2H, s), 6.05 (1H, br.s), 7.37 (5H, s).

Reference Example 2-10

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A Jones reagent prepared from 2.78 g of chromium trioxide, 4.4 g of 98% sulfuric acid and 8.1 ml of water was treated with 4- (1
-(R) -Hydroxymethylethyl) -3- (1-benzyloxycarbonyloxyethyl) -2-azetidinone was added dropwise to a solution of 6.1 g of acetone (60 ml) at 10 to 20 ° C, and the mixture was stirred for 1 hour. Next, 0.5 ml of isopropyl alcohol was added, and the mixture was stirred for 15 minutes.
l, 122 ml of ethyl acetate was added thereto, and the mixture was separated. The aqueous layer was re-extracted with 61 ml of ethyl acetate.
Washed twice with 0 ml. Next, 61 ml of a 5% aqueous sodium bicarbonate solution was added thereto to carry out liquid separation, and the oil layer was extracted again with a 5% aqueous sodium bicarbonate solution. The aqueous layer was washed with 60 ml of methylene chloride, acidified by adding 20 ml of 10% aqueous hydrochloric acid under ice-cooling, and washed with 60 ml of methylene chloride.
It was extracted once, washed with 10% saline, and then dried over sodium sulfate. The solvent was distilled off and 4- (1- (R) -carboxyethyl) -3-
(1-benzyloxycarbonyloxyethyl) -2-
Azetidinone was obtained.

IR ^neat (cm ^-1 ): 3270, 1740, 1460, 138
5, 1270, 750; NMR δ (CDCl ₃ ): 1.19 (3H, d, J = 7.0 Hz), 1.40 (3H, d, J =
6.2Hz), 2.67 (1H, m), 3.22 (1H, br.d, J = 7.5Hz), 3.84 (1H
H, br.d, J = 5.5Hz), 5.14 (2H, s), 6.57 (1H, br.s), 7.35 (5
H, s), 7.63 (1H, br.s).

Reference Example 2-11

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4- (1- (R) -carboxyethyl)-
3- (1-benzyloxycarbonyloxyethyl)-
2-Azetidinone (51.69 g) was dissolved in 510 ml of acetone, anhydrous potassium carbonate (89 g), benzyl bromide 3
0.3 g was added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, insoluble materials were filtered off, and the filtrate and the washing solution were combined.
The solvent was distilled off, and the oily residue was subjected to silica gel chromatography to give (3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1R)
-1-benzyloxycarbonylethyl] -2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760 (sh), 1735, 1450,
1380, 1260, 1155; NMR δ (CDCl ₃ ): 1.22 (3H, d, J = 6.9 Hz), 1.39 (3H, d, J =
6.3Hz), 2.71 (1H, quintet, J = 6.9Hz), 3.19 (1H, dd, J = 2.0
7.9Hz), 3.83 (1H, dd, J = 2.0 and 6.3Hz), 5.92 (1H, s).

Reference Example 3-1

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(4R, 5R, 6S, 8R) -4-methyl-6- (1-tert-butyldimethylsilyloxyethyl)
Approximately 0.22 mmole of a crude product (including thiophenol) of -1-azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic acid phenylthioester was dissolved in 0.8 ml of dry acetonitrile, and the solution was cooled in a stream of nitrogen and iced. Under cooling, a solution of 59 mg of diisopropylethylamine in 0.5 ml of dry acetonitrile, and then a solution of 124 mg of diphenylchlorophosphate in 0.5 ml of dry acetonitrile were added.
The mixture was stirred at the same temperature for 1 hour. After diluting the reaction solution with diethyl ether, a pH 6.86 phosphate buffer solution was added to separate the solution. The aqueous layer was further extracted twice with diethyl ether, and the organic layers were combined.
1M potassium dihydrogen phosphate aqueous solution (3 times), water (2
Times) and saline. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (4R, 5R, 6S, 8R) -3- (diphenylphosphoryloxy) -4-methyl-6- [1. -T
-Butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
Carboxylic acid phenylthioester and (4R, 5S, 6
(S, 8R) -3-phenylthio-4-methyl-6- (1
-T-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-
2-Carboxylic acid phenylthioester was obtained.

(4R, 5R, 6S, 8R) -3- (Diphenylphosphoryloxy) -4-methyl-6- (1-t
-Butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
Carboxylic acid phenylthioester IR ^neat (cm ^-1 ): 1778,1673,1607,1582,1487,119
8, 1182, 1002, 962, 935, 767, 740, 680; NMR δ (CDCl ₃ ): 0.09 (3H, s), 0.11 (3H, s), 0.91 (9H,
s), 1.21 (3H, d, J = 7.3 Hz), 1.22 (3H, d, J = 6.0 Hz), 3.29 (1
H, dd, J = 3.0 and 5.0Hz), 3.52 (1H, m), 4.28 (2H, m).

(4R, 5S, 6S, 8R) -3-Phenylthio-4-methyl-6- [1-t-butyldimethylsilyloxyethyl] -1-azabicyclo [3,2,0]
-Hept-2-en-7-one-2-carboxylic acid phenylthioester IR ^CHCl 3 (cm ^-1 ): 1780, 1660 (sh), 1647, 1520, 147
8, 1285, 1260, 1115, 1018, 945, 837; NMR δ (CDCl ₃ ): 0.09 (3H, s), 0.13 (3H, s), 0.92 (9H,
s), 0.95 (3H, d, J = 7.6 Hz), 1.17 (3H, d, J = 6.3 Hz), 3.07 (1
H, m), 3.20 (1H, dd, J = 2.6 and 4.3Hz), 4.31 (1H, dd, J = 2.8 and
9.8Hz).

Reference Example 3-2- (1)

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(4R, 5R, 6S, 8R) -3- (Diphenylphosphoryloxy) -4-methyl-6- (1-t
-Butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
Dissolve 10 mg of carboxylic acid phenylthioester in 0.1 ml of dry acetonitrile, and in a stream of nitrogen, at -30 ° C, a solution of 5.2 mg of diisopropylethylamine in 0.2 ml of dry acetonitrile, and then 4.8 ml of N-acetylcysteamine.
g of a dry acetonitrile solution (0.2 ml) was added and the temperature was raised to -20 ° C. After confirming the disappearance of the raw materials, the reaction solution was diluted with diethyl ether, and then a pH 6.86 phosphate buffer was added to separate the solution. The aqueous layer was further extracted twice with diethyl ether, and the organic layers were combined and washed with a pH 6.86 phosphate buffer, a 0.1 M aqueous solution of potassium dihydrogen phosphate, and brine in this order. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (4R, 5S, 6S, 8R) -3-.
(2-acetaminoethylthio) -4-methyl-6-
(1-t-butyldimethylsilyloxyethyl) -1-
Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid phenylthioester was obtained.

IR ^CHCl 3 (cm ^-1 ): 3460, 1765, 1665, 125
0, 1102, 830; NMR δ (CDCl ₃ ): 0.11 (3H, s), 0.14 (3H, s), 0.94 (9H,
s), 1.25 (3H, d, J = 7.3 Hz), 1.25 (3H, d, J = 6.3 Hz), 1.97 (3
H, s), 5.90 (1H, br.s), 7.3 to 7.6 (5H, m).

Reference Example 3-2- (2)

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(4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2 Reference Example Using 6 mg of -en-7-one-2-carboxylic acid phenylthioester, 1.4 mg of diisopropylethylamine, and 4 mg of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine 3
-2- (1) (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-t-butyl Dimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid phenylthioester was obtained.

IR ^CHCl 3 (cm ^-1 ): 1767, 1700, 1650, 151
8, 1340, 1100.

Reference Example 3-2- (3)

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(4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2 Using 20 mg of -en-7-one-2-carboxylic acid phenylthioester, 5.2 mg of diisopropylethylamine, and 5 mg of benzylmercaptan, exactly as in Reference Example 3-2- (1), (4R, 5
S, 6S, 8R) -3-Benzylthio-4-methyl-6
-(1-t-butyldimethylsilyloxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylic acid phenylthioester was obtained.

IR ^CHCl 3 (cm ⁻¹ ): 1770, 1660 (sh), 164
0, 1298, 1266, 1250, 1142, 1102, 835; NMR δ (CDCl ₃ ): 0.10 (3H, s), 0.13 (3H, s), 0.92 (9H,
s), 3.24 (1H, dd, J = 2.6 and 5.3Hz), 3.37 (1H, m), 4.09 (2H,
m), 4.2 to 4.4 (2H, m), 7.30 (5H, s), 7.3 to 7.6 (5H, m).

Reference Example 4

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(4R, 5S, 6S, 8R, 2'S, 4 '
S) -3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl)
Thio] -4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylic acid p-nitrobenzyl ester (1 g, 1.3 mM) was added to tetrahydrofuran 1
0 ml, added with a phosphate buffer (8 ml) of pH 3 and stirred vigorously at room temperature for 2.5 hours.
, Washed with saline and dried over magnesium sulfate.
The solvent was distilled off and (4R, 5S, 6S, 8R, 2'S,
4'S) -3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-hydroxydiethyl) -1-azabicyclo [3 .2.0] hept-2-en-7-one-2-carboxylic acid p-nitrobenzyl ester was obtained.

IR ^neat (cm ^-1 ): 1760, 1705, 1645, 152
0, 1402, 1342, 1135, 1110; NMR δ (CDCl ₃ ): 1.30 (3H, d, J = 7.0 Hz), 1.35 (3H, d, J =
6.5Hz), 2.99 (3H, s), 3.02 (3H, d, J = 15.0Hz), 5.21 (2H,
s), 5.20 and 5.43 (2H, ABq, J = 14Hz), 7.51 (2H, d, J = 8.5H
z), 7.64 (2H, d, J = 8.5Hz), 8.20 (4H, d, J = 8.5Hz).

Reference Example 5-1

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(4R, 5S, 6S, 8R) -3-Phenylthio-4-methyl-6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] hept Dissolve 17 mg of -2-ene-7-one-2-carboxylic acid phenylthioester and 24 mg of p-nitrobenzyl alcohol in 0.6 mg of dry methylene chloride, and in a nitrogen stream, 7 mg of silver trifluoroacetate under light shielding.
Was added. Then, 1,8-diazabicyclo [5.4.
0] -7-undecene 5mg dry methylene chloride 0.3m
g solution was added at room temperature and stirred for 4.3 hours. The reaction solution was added with 3 ml of 0.1 M phosphate buffer at pH 7, and then diluted with methylene chloride. After filtering off the insoluble matter and washing with methylene chloride and water, the filtrate and washing solution are combined, and the mixture is washed with methylene chloride.
Extracted times. The organic layer was washed with a 2.5% aqueous solution of sodium dihydrogen phosphate and brine in that order, and dried using sodium sulfate and magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (4R, 5S, 6).
(S, 8R) -3-phenylthio-4-methyl-6- (1
-T-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-
2-carboxylic acid p-nitrobenzyl ester was obtained. The IR and NMR of the compound obtained here were the same as the compound obtained in Example 3.

Reference Example 5-2- (1)

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(4R, 5S, 6S, 8R) -3-phenylthio-4-methyl-6-[(1R) -1-tert-butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] hept 20 mg of -2-en-7-one-2-carboxylic acid phenylthioester was dissolved in 0.3 ml of dry tetrahydrofuran, and 0.14 ml of a 0.27 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran was added dropwise under cooling with ice in a nitrogen stream. Stirred for hours. pH 7,
After dilution with 0.1 M phosphate buffer, extraction was performed three times using methylene chloride. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (4R, 5S, 6S, 8R) -3-phenylthio-
4-methyl-6-[(1R) -1-hydroxyethyl]
-1-azabicyclo [3.2.0] hept-2-ene-
7-one-2-carboxylic acid phenylthioester was obtained.

IR ^CHCl 3 (cm ⁻¹ ): 3600 (br), 1775, 1660
(sh), 1645, 1300, 1273; NMR δ (CDCl ₃ ): 0.98 (3H, d, J = 7.3 Hz), 1.35 (3H, d, J =
6.3Hz), 3.11 (1H, m), 3.23 (1H, dd, J = 2.3 and 6.9Hz), 4.27
(1H, dd, J = 2.6 and 9.2Hz), 4.27 to 4.3 (1H, m), 7.3 to 7.6 (1
0H, m).

Reference Example 5-2- (2)

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(4R, 5S, 6S, 8R) -3-phenylthio-4-methyl-6-[(1R) -1-hydroxyethyl] -1-azabicyclo [3.2.0] hept-2
3 mg of -en-7-one-2-carboxylic acid phenylthioester and 14 mg of trimethylsilanol were dissolved in 0.1 ml of dry toluene, and 1.6 mg of silver trifluoroacetate was added in a nitrogen stream under light shielding. Next, a solution of 1.1 mg of 1,8-diazabicyclo [5.4.0] -7-undecene in 0.1 ml of dry toluene was added at room temperature, and the mixture was further heated and stirred at 80 ° C. for 15 minutes. The reaction was cooled to room temperature, pH 7, 0.
One ml of 1M phosphate buffer was added and then diluted with methylene chloride. After filtering off insolubles and washing with methylene chloride and water, the filtrate and washings were combined and extracted twice with methylene chloride. The aqueous layer was stirred at room temperature under reduced pressure to remove the organic solvent. High performance liquid chromatography (Lichrosorb (registered trademark) RP-18; methanol-pH 7.0 to 7.2, 0.005M)
Phosphate buffer (3: 7); 0.8 ml / min) and thin-layer chromatography (silica gel; chloroform-methanol-acetic acid (200: 50: 1)), which are consistent with the standard obtained in Reference Example 6-2. (4R, 5S, 6)
S, 8R) -3-Phenylthio-4-methyl-6
It was confirmed that [(1R) -1-hydroxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid was obtained.

Reference Example 6-1

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(4R, 5R, 6S, 8R) -4-methyl-6 [(1R) -1-hydroxyethyl] -1-azabicyclo [3.2.0] hept-3,7-dione-2-carboxylic 100 mg of acid p-nitrobenzyl ester was dissolved in 1 ml of dry acetonitrile, a solution of 67 mg of diphenylchlorophosphate in 0.5 ml of dry acetonitrile was added under ice-cooling in a nitrogen stream, and then a solution of 32 mg of diisopropylethylamine in 0.5 ml of dry acetonitrile was added. Stir at temperature for 30 minutes. The reaction solution was cooled to -30 ° C, and 37 mg of thiophenol in dry acetonitrile was added.
2 ml solution, then diisopropylethylamine 44 mg
0.2 ml of dry acetonitrile solution of
The mixture was stirred for 5 minutes and further under ice-cooling for 15 minutes. The reaction solution was diluted with ethyl acetate, washed with brine, washed with an aqueous solution of potassium phosphate, washed with brine, dried over magnesium sulfate-potassium carbonate, evaporated, and the residue was purified by silica gel chromatography (4R , 5S, 6S, 8R) -3-Phenylthio-4-methyl-6-[(1R) -1-hydroxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2 -Carboxylic acid p-nitrobenzyl ester was obtained.

IR ^neat (cm ^-1 ): 3480 (br), 1764, 1707,
1520, 1342, 1215, 1140; NMR δ (CDCl ₃ ): 0.97 (3H, d, J = 7.3 Hz), 1.31 (3H, d, J =
6.3Hz), 3.10 (1H, m), 3.21 (1H, dd, J = 2.8 and 6.8Hz), 4.18
(1H, dd, J = 2.8 and 9.4Hz), 4.23 (1H, m), 5.42 (2H, m), 7.3
~ 7.6 (5H, m), 7.69 (2H, d, J = 8.9Hz), 8.24 (2H, d, J = 8.9H
z).

Reference Example 6-2

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(4R, 5S, 6S, 8R) -3-phenylthio-4-methyl-6-[(1R) -1-hydroxyethyl] -1-azabicyclo [3.2.0] hept-2
37 mg of -en-7-one-2-carboxylic acid p-nitrobenzyl ester was dissolved in 2 ml of tetrahydrofuran, and 2 ml of buffer solution of pH 7.0 morpholinopropanesulfonic acid was added.
1 and 56 mg of 10% palladium-carbon,
Under normal hydrogen pressure, hydrogenation was performed at room temperature for 4.5 hours. After the catalyst was filtered off, tetrahydrofuran was distilled off under reduced pressure, the residue was washed with methylene chloride, the organic layer was again distilled off under reduced pressure from the organic solvent, and the residue was subjected to polymer chromatography (CHP-2).
0P), the part eluted with 2% and 5% aqueous tetrahydrofuran gives (4R, 5S, 6S, 8R)-
3-phenylthio-4-methyl-6-[(1R) -1-
Hydroxyethyl] -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylic acid was obtained.

UV ^H 2 ^O (nm): 306; IR ^KBr (cm ⁻¹ ): 3425 (br), 1745, 1595, 1400; NMR δ (D ₂ O): 0.90 (3H, d, J = 7.3 Hz) , 1.18 (3H, d, J = 6.3
Hz), 3.00 (1H, m), 3.32 (1H, dd, J = 2.6 and 5.9 Hz), 4.09 (1
H, dd, J = 2.6 and 9.2Hz), 4.16 (1H, m), 7.3-7.6 (5H, m).

Reference Example 7-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -2-azetidinone (755 mg) was dissolved in methylene chloride (10 ml), and α-bromoacetate t-butyl (1.88 g), a 50% aqueous sodium hydroxide solution (620 mg), and triethylbenzylammonium chloride (221 mg) were sequentially added. For 2 hours. Water and diethyl ether were added and the mixture was separated. The aqueous layer was further extracted twice with diethyl ether, combined with the above organic layer, washed twice with water and then three times with brine, and then dried over sodium sulfate. The solvent was distilled off, the residue was purified by silica gel chromatography, and (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-benzyloxycarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1755, 1730, 1450, 140
0, 1380, 1360, 1242, 1220, 1150, 830, 765, 740, 68
5; NMR δ (CDCl ₃ ): 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H,
s), 1.23 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 6.9 Hz), 1.44 (9
H, s), 2.90 (1H, qd, J = 3.6 and 6.9Hz), 2.99 (1H, dd, J = 2.0 and
6.6Hz), 3.83 (2H, m), 5.10 (2H, s), 7.35 (5H, s).

Reference Example 7-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone 0.45 g
Was dissolved in 6 ml of 99.5% ethanol, 90 mg of 10% palladium-carbon was added, and hydrogenation was performed at normal temperature and normal pressure.
After the catalyst was removed by filtration, the filtrate and the washing solution were combined, and the solvent was distilled off. (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1740, 1730, 145
5, 1360, 1245, 1224, 1150, 830, 770, 745; NMR δ (CDCl ₃ ): 0.06 (3H, s), 0.08 (3H, s), 0.87 (9H,
s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.3 Hz), 1.48 (9
H, s), 2.94 (1H, qd, J = 7.0 and 3.0Hz), 3.04 (1H, dd, J = 2.8 and
5.5Hz), 3.98 (2H, m), 4.00 (1H, m), 4.21 (1H, m).

Reference Example 7-3- (1)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 1.29 g of N, N′-carbonyldiimidazole 604 mg in 25 ml of dry acetonitrile was stirred at room temperature for 1 hour. To this, a solution of 410 mg of thiophenol in 6 ml of dry acetonitrile,
Next, a solution of 377 mg of triethylamine in 6 ml of dry acetonitrile was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and washed with dilute hydrochloric acid. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (3.
S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone Obtained. IR ^neat (cm ^-1 ): 1760, 1740, 1705, 1367, 1250, 122
7,835,770,740.

Reference Example 7-3- (2)

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According to the same method as in Reference Example 7-3- (1), thiophenol was changed to p-chlorothiophenol, and
(3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -1-tert-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1740, 1705, 148
0, 1365, 1260, 1230, 1155, 1095, 838, 775; NMR δ (CDCl ₃ ): 0.10 (6H, s), 0.89 (9H, s), 1.26 (3H,
d, J = 6.3Hz), 1.31 (3H, d, J = 6.9Hz), 1.43 (9H, s), 3.02 (1
H, dd, J = 2.3 and 6.9Hz), 3.14 (1H, qd, J = 3.3 and 6.9Hz), 3.92
(2H, m), 7.34 (4H, m).

Reference Example 7-3- (3)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 100 mg and 2,4,
33 mg of 5-trichlorophenol was dissolved in 4 ml of dry tetrahydrofuran and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride 96m
g was added and stirred overnight. The reaction solution was diluted with diethyl ether and water and extracted. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give (3S, 4S) -3-[(1R) -1.
-T-butyldimethylsilyloxyethyl] -4-
[(1R) -1- (2,4,5-trichlorophenyloxy) carbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained. IR ^neat (cm ^-1 ): 1760, 1740 (sh), 1455, 1362, 1250,
1225.

Reference Example 7-3- (4)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone (98 mg) was dissolved in dry methylene chloride (1 ml), and a solution of thionyl chloride (34 mg) in dry methylene chloride (0.5 ml) was added at room temperature. The mixture was further stirred for 3 hours while heating under reflux. After evaporating the solvent, the residue was redissolved in dry toluene, evaporated under reduced pressure, and dried under vacuum to give (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[( 1R) -1
-Chlorocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1800 (sh), 1740, 1450,
1360, 1244, 1220, 930, 825, 770.

Reference Example 7-3- (5)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 104 mg, 1-oxybenzotriazole 53 mg, 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride 93
mg (3S, 3S) in the same manner as in Reference Example 7-3- (3).
4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (1-benzotriazolyloxy) carbonylethyl] -1-t-butoxycarbonylmethyl -2-Azetidinone was obtained.

IR ^neat (cm ^-1 ): 1740 (sh), 1730, 1450,
1360, 1240, 1220, 822.

Reference Example 7-3- (6)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 100 mg, 2-mercaptopyridine 35 mg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 100 mg
(3S, 4) in the same manner as in Reference Example 7-3- (3).
S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (2-pyridylthio) carbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone I got

IR ^neat (cm ^-1 ): 1755, 1690, 1360, 124
7, 1220, 1142, 830, 770.

Reference Example 7-4

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Dry N, N- of 31 mg of sodium hydride
To a suspension of 4.3 ml of dimethylformamide was added 835 mg of t-butyl α-bromoacetate, and then (3S, 4S) -3-.
0.4 (g) of [(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -2-azetidinone was added, and the mixture was stirred at room temperature in a nitrogen stream for 1 hour. Next, diethyl ether and a pH 6.86 phosphate buffer solution were added under ice cooling to perform extraction. After the aqueous layer was further extracted twice with diethyl ether, the organic layers were combined, washed with brine three times, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (3)
S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone Obtained. The IR spectrum of the compound obtained here was the same as that obtained in Reference Example 7-3- (1).

Reference Example 7-5

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
-2-Azetidinone was prepared in the same manner as in Reference Example 7-1, using (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -1-tert-butoxycarbonylmethyl-2-azetidinone was obtained. The IR and NMR of the compound obtained here are shown in Reference Example 7-3-.
It was identical to that obtained in (2).

Reference Example 8-1

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(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1
R) -1-Benzyloxycarbonylethyl] -2-azetidinone (71.94 g) was dissolved in 700 ml of dry N, N-dimethylformamide, bromoacetic acid t-butyl ester (68.25 g) was added under ice cooling, and sodium hydride was further added. (50% oily) (9.24 g) was added and stirred for 1 hour. 500 ml of 10% aqueous ammonium chloride solution
After stirring for 30 minutes, the mixture was extracted with toluene (2 liters). The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give an oily residue. This was subjected to silica gel chromatography to give (3S, 4S) -3-[(1R) -1
-Benzyloxycarbonyloxyethyl] -4-
[(1R) -1-benzyloxycarbonylethyl]-
1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1765 (sh), 1740, 1455,
1370, 1268, 1160; NMR δ (CDCl ₃ ): 1.18 (3H, d, J = 6.9 Hz), 1.45 (3H, d, J =
6.3Hz), 1.45 (9H, s), 2.86 (1H, m), 3.26 (1H, dd, J = 2.0
9.0Hz), 3.55 (1H, d, J = 18.0Hz), 4.04 (1H, dd, J = 2.0 and 4.6
Hz), 4.10 (1H, d, J = 18.0Hz).

Reference Example 8-2

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(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1
R) -1-benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone (81.5
0g) was dissolved in 800 ml of ethanol, 10% palladium-carbon (8.15 g) was added, and hydrogenation was performed at normal temperature and normal pressure. After the catalyst was separated by filtration, the filtrate and the washings were combined, and the solvent was distilled off. (3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-carboxyethyl]
-1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^Nujol (cm ^-1 ): 1740, 1720, 1440, 136
0; NMR δ (CDCl ₃ ): 1.28 (3H, d, J = 6.9 Hz), 1.33 (3H, d, J =
6.6Hz), 2.84 (1H, m), 3.09 (1H, dd, J = 2.0 and 6.6Hz), 3.76
(1H, d, J = 18.0Hz), 4.03 (1H, dd, J = 2.0 and 5.3Hz).

Reference Example 8-3

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Using (3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-carboxyethyl] -1-tert-butoxycarbonylmethyl-2-azetidinone, The same treatment as in Reference Example 7-3- (1) was performed to obtain (3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl]. -1-t-butoxycarbonylmethyl-
2-azetidinone was obtained.

IR ^Nujol (cm ^-1 ): 1745, 1725, 1290, 123
0, 1140, 950, 750.

Reference Example 9-1

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(A) 4-[(1R) -1-hydroxymethylethyl] -3-[(1R) -1-benzyloxycarbonyloxyethyl] -2-azetidinone 30.7 g, potassium carbonate 27.6 g, bromoacetic acid t 300 ml of acetone was added to 33.0 g of -butyl, and the mixture was stirred under reflux with heating for 17 hours. The reaction solution was returned to room temperature, and insolubles were removed by filtration.

(B) After adding 15 ml of water to the filtrate, the mixture was ice-cooled and separately 49.2 g of water, 16.92 g of chromium trioxide, 26.52 of concentrated sulfuric acid.
g, and the Jones reagent adjusted using was dropped over 15 minutes. After stirring under ice-cooling for 60 minutes, ethyl acetate 1
One liter and 300 ml of water were added to carry out liquid separation. The ethyl acetate layer was washed four times with 300 ml of a saline solution, dried by adding 50 g of magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to give (3S, 4S)-
3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1R) -1-carboxyethyl]-
1-t-butoxycarbonylmethyl-2-azetidinone
23.73 g (54.5% yield) was obtained.

IR ^neat (cm ^-1 ): 1735, 1450, 1365, 125
0, 1150, 1040; NMR δ (CDCl ₃ ): 1.19 (3H, d, J = 6.9 Hz), 1.46 (9H, s),
3.26 (1H, dd, J = 2.3 and 8.6Hz), 4.06 (1H, dd, J = 2.3 and 4.0H
z), 7.36 (5H, s).

(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1
R) -1-Hydroxymethylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone IR ^neat (cm ^-1 ): 1735, 1360, 1250, 1150, 1030, 95
Five.

Reference Example 9-2

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(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone (23.75 g) was dissolved in acetonitrile (237 ml), and N, N′-carbonyldiimidazole (10.55 g) was added under ice-cooling. After stirring for 30 minutes under ice cooling, 7.21 g of thiophenol was added, and 6.62 g of triethylamine was further added. After stirring for 2.5 hours under ice-cooling, 500 ml of ethyl acetate and 200 ml of 1N hydrochloric acid were added to carry out liquid separation.
The aqueous layer was separated twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined and separated three times with 300 ml of brine. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography,
(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 19.46 g (Yield 67.64%)
I got

IR ^neat (cm ^-1 ): 1760, 1735, 1700, 144
0, 1365, 1255, 1150, 1045, 950, 740; NMR δ (CDCl ₃ ): 1.25 (3H, d, J = 6.9 Hz), 1.44 (9H, s),
1.47 (3H, d, J = 6.2Hz), 4.12 (1H, m), 4.13 (1H, dd, J = 2.6
4.5Hz), 7.36 (10H, m).

Reference Example 10-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -2-azetidinone (3.50 g) and a solution of t-butyl α-bromoacetate (8.73 g) in methylene chloride (45 ml), 50% aqueous sodium hydroxide solution (2.86 g) and triethylbenzylammonium chloride (1.02 g).
g in the same manner as in Reference Example 14-1 except that g was added.
S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-benzyloxycarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone Obtained. IR ^neat (cm ^-1 ): 1760 (sh), 1735, 1455, 1362, 1245,
1222, 835, 773.

Reference Example 10-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -1-t
-Butoxycarbonylmethyl-2-azetidinone 2.9 g
Was hydrogenated exactly as in Reference Example 7-2 (3S, 4
S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^Nujol (cm ^-1 ): 3300 (br), 1760 (sh), 1
742, 1690, 990, 940, 825, 767.

Reference Example 10-3- (1)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone and Reference Example 7-3
-By the same method as (1), (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-phenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1740 (sh), 1700,
1365, 1250, 1225, 950, 830, 773, 740, 680.

Reference Example 10-3- (2)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone in 100 mg of dry methylene chloride and 2 ml at room temperature with 37 mg of oxalyl chloride in the presence of a catalytic amount of N, N-dimethylformamide.
After stirring for an hour, the corresponding acid chloride was obtained. This is 4,6
-Dimethyl-2-mercaptopyrimidine 50 mg and 4-
44 mg of dimethylaminopyridine was added and stirred. The reaction solution was diluted with methylene chloride, washed with dilute sulfuric acid, water, an aqueous solution of sodium hydrogen carbonate and brine in that order, and dried over sodium sulfate.
After evaporating the solvent, the residue was purified by silica gel chromatography to give (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1
-(4,6-dimethylpyrimidin-2-ylthiocarbonyl) ethyl] -1-t-butoxycarbonylmethyl-
2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1740 (sh), 1580,
1362, 1247, 830, 770.

Reference Example 10-3- (3)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-t-butoxycarbonylmethyl-2-azetidinone 100 mg and N-hydroxysuccinimide 33 mg in dry N, N-dimethylformamide 0.3 ml solution dry N, N'-dicyclohexylcarbodiimide 74 mg Was added and the mixture was reacted at 0 to 5 ° C. overnight. After diluting the reaction solution with ethyl acetate, dilute sulfuric acid was added to separate the solution. The aqueous layer was further extracted twice with ethyl acetate, and the organic layers were combined, washed with water (4 times) and brine. The organic layer was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography to give (3S, 4S) -3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -4-
[(1S) -1-Imidoxycarbonylethyl succinate] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1805, 1760 (sh), 1740,
1455, 1360, 1200, 1145, 1055, 830, 762, 745.

Reference Example 10-3- (4)

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-tert-butoxycarbonylmethyl-2-azetidinone 42 mg and N, N'-
After stirring a solution of 19 mg of carbonyldiimidazole in 0.9 ml of dry acetonitrile at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give (3S, 4R) -3-[(1R) -1-t. -Butyldimethylsilyloxyethyl] -4-[(1S) -1- (1
-Imidazolyl) carbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone.

IR ^neat (cm ^-1 ): 1760 (sh), 1735, 1382,
1360, 1225, 1145, 935, 827, 745.

Reference Example 11-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-benzyloxycarbonylethyl] -2-azetidinone 1.56 g was dissolved in methylene chloride 20 ml.
916 mg of methyl-bromoacetate, 1.28 g of a 50% aqueous sodium hydroxide solution and 455 mg of triethylbenzylammonium chloride were sequentially added, and the mixture was stirred at room temperature for 2 hours. Water and diethyl ether were added to the reaction solution, and the mixture was separated. The aqueous layer was further extracted twice with diethyl ether. The organic layers were combined, washed twice with water and then three times with brine, and then dried over sodium sulfate. The solvent was distilled off, the residue was purified by silica gel chromatography, and a part of the raw material was recovered and (3S, 4S)-
3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-benzyloxycarbonylethyl] -1-methoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1740, 1460, 140
7, 1360, 1250, 1215, 1180, 1140, 835, 770, 745; NMR δ (CDCl ₃ ): 0.07 (3H, s), 0.08 (3H, s), 0.87 (9H,
s), 1.24 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.2 Hz), 2.77 (1
H, m), 3.63 (3H, s), 3.93 (2H, s), 3.96 (1H, dd, J = 2.0 and 9.
6Hz), 4.19 (1H, m), 5.09 (2H, s), 7.36 (5H, s).

Reference Example 11-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Benzyloxycarbonylethyl] -1-methoxycarbonylmethyl-2-azetidinone 400 mg
Was dissolved in 6 ml of 99.5% ethanol and 10% palladium-
80 mg of carbon was added and hydrogenated at normal temperature and normal pressure. The catalyst was filtered off, the back solution and the washing solution were combined, and the solvent was distilled off (3.
(S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-carboxyethyl] -1-methoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1740, 1705, 1435, 124
0, 1215, 1135, 830, 770.

Reference Example 11-3

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Carboxyethyl] -1-methoxycarbonylmethyl-2-azetidinone using Reference Example 7-3-
By the same method as (1), (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
4-[(1S) -1-phenylthiocarbonylethyl]
-1-Methoxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1750, 1695, 1437, 140
5, 1247, 1202, 950, 830, 770, 740; NMR δ (CDCl ₃ ): 0.07 (3H, s), 0.09 (3H, s), 0.87 (9H,
s), 2.88 (1H, dd, J = 2.3 and 6.6 Hz), 3.03 (1H, m), 3.70 (3H,
s), 4.02 (1H, dd, J = 2.0 and 9.2 Hz), 4.19 (1H, m), 7.41 (5H,
m).

Reference Example 12-1

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(A) (3S, 4S) -3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -4-
[(1R) -1-phenylthiocarbonylethyl] -1
-T-butoxycarbonylmethyl-2-azetidinone 1
1.5 ml of 6N hydrochloric acid was added to a solution of 90 mg of methanol in 4.5 ml, and the mixture was stirred at room temperature for 15 minutes. After confirming the disappearance of the raw materials, chloroform and brine were added to the reaction solution for extraction. After the aqueous layer was further extracted twice with chloroform, the organic layers were combined and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, a mixed solution of trifluoroacetic acid (1 ml) and anisole (0.1 ml) was added to the residue, and the mixture was added at room temperature for 25 minutes.
Stirred for minutes. After the trifluoroacetic acid was distilled off under reduced pressure, the residue was azeotroped twice with dry toluene to give (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
[Phenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone was obtained as a crude product.

(B) The crude product obtained in (a), 246 mg of t-butyldimethylsilyl chloride, imidazole 151
A solution of 2 mg of dry N, N-dimethylformamide was reacted overnight. The reaction solution was poured into water and extracted three times with ethyl acetate. Combine the organic layers and dilute sulfuric acid, water (5
Wash) and brine (twice) in that order, and dried over sodium sulfate.
The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, and (3S, 4S) -3-[(1R) -1-
t-butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone.

IR ^neat (cm ^-1 ): 3350 (br), 1760 (sh), 17
37, 1700, 1245, 1140, 830, 767, 742.

Reference Example 12-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone 154 mg, N, N '
A solution of 66 mg of carbonyldiimidazole in 2.9 ml of dry acetonitrile was stirred at room temperature for 1 hour. A solution of 56 mg of thiophenol in 1 ml of dry acetonitrile and then a solution of 52 mg of triethylamine in 0.5 ml of dry acetonitrile were added to the reaction solution, and the mixture was stirred for 30 minutes. The reaction was diluted with ethyl acetate and poured into cold dilute sulfuric acid. After extracting three times with ethyl acetate, the organic layers were combined and washed with diluted sulfuric acid and brine (twice). The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R ) -1-Phenylthiocarbonylethyl] -1-phenylthiocarbonylmethyl-2-azetidinone.

IR ^neat (cm ^-1 ): 1760, 1700, 1478, 144
0, 1250, 1140, 835, 773, 740, 682; NMR δ (CDCl ₃ ): 0.08 (3H, s), 0.10 (3H, s), 0.89 (9H,
s), 1.27 (3H, d, J = 6.3 Hz), 1.32 (3H, d, J = 7.3 Hz), 3.11 (1
H, dd, J = 2.0 and 6.9Hz), 3.20 (1H, m), 4.24 (1H, m), 4.30 (2
H, m), 7.41 (10H, s).

Reference Example 13-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Phenylthiocarbonylethyl] -1-t-
Butoxycarbonylmethyl-2-azetidinone 243m
g was purified after the reaction in exactly the same manner as in Reference Example 12-1.
(3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-phenylthiocarbonylethyl] -1-carboxymethyl-
2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 3350 (br), 1760 (sh), 17
40, 1250, 950, 825, 770, 740, 680.

Reference Example 13-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
S) -1-Phenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone 87 mg, N, N'-
Carbonyldiimidazole 37mg, thiophenol 2
Except that 5 mg and 23 mg of triethylamine were used, the procedure was the same as in Reference Example 12-2 (3S, 4S) -3-.
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-phenylthiocarbonylethyl] -1-phenylthiocarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1705, 1480, 144
2,1250,955,835,742,682.

Reference Example 14-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-methoxybenzyloxycarbonylethyl] -2-azetidinone (1.12 g) in methylene chloride (14 ml)
Was dissolved in 1.09 g of p-nitrobenzyl α-bromoacetate,
0.85 g of a 50% aqueous sodium hydroxide solution and 303 mg of triethylbenzylammonium chloride were added sequentially, and the mixture was added at room temperature.
Stirred for 0 minutes. Water and diethyl ether-methylene chloride (3: 1) were added to carry out liquid separation.
It was further extracted twice with methylene chloride (3: 1), combined with the previous organic layer, washed twice with water and then three times with brine, and then dried over sodium sulfate. The solvent is distilled off, the residue is purified by silica gel chromatography, and together with the raw material recovery (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-methoxybenzyloxycarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone I got

IR ^neat (cm ^-1 ): 1760, 1742, 1607, 151
5,1458, 1342, 1241, 1170, 830, 747; NMR δ (CDCl ₃ ): 0.01 (3H, s), 0.05 (3H, s), 0.83 (9H,
s), 2.86 (1H, qd, J = 7.2 and 3.0 Hz), 3.00 (1H, dd, J = 2.3 and 6.
6Hz), 3.80 (3H, s), 5.01 (2H, m), 5.20 (2H, s), 6.88 (2H,
d, J = 8.6Hz), 7.49 (2H, d, J = 8.9Hz), 8.22 (2H, d, J = 8.6H)
z).

Reference Example 14-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-methoxybenzyloxycarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone 142 mg of dry methylene chloride 1.4
163 mg of boron trifluoride diethyl ether complex was added to the ml solution under ice cooling, and the temperature was raised to room temperature. After the disappearance of the raw materials, the reaction solution was poured into a cold aqueous solution of sodium hydrogen carbonate. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate, combined with the above organic layer, washed with diluted hydrochloric acid and brine in that order, and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography.
S) -3-[(1R) -1-tert-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxyethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone and (3S , 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
Carboxyethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone was obtained.

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-carboxyethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone IR ^neat (cm ^-1 ): 3100 (br), 1760, 1730, 1520, 1342,
1245, 1180, 830, 770; NMR δ (CDCl ₃ ): 0.03 (3H, s), 0.07 (3H, s), 0.85 (9H,
s), 1.25 (2H, d, J = 6.3 Hz), 1.26 (2H, d, J = 7.3 Hz), 2.91 (1
H, qd, J = 7.3 and 3.0Hz), 3.05 (1H, dd, J = 2.3 and 5.9Hz), 4.13
(2H, m), 5.26 (2H, s), 7.52 (2H, d, J = 8.9Hz), 8.23 (2H, d,
J = 8.9Hz).

(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-carboxyethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone IR ^neat (cm ^-1 ): 3430 (br), 1760, 1735, 1705, 1520,
1345, 1180, 745.

Reference Example 15-1

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
200 mg of -1-t-butoxycarbonylmethyl-2-azetidinone was dissolved in 1.5 ml of dry methylene chloride, 263 mg of a boron trifluoride diethyl ether complex was added, and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was treated with methanol 0.
The mixture was redissolved in 5 ml, 1 ml of 1N hydrochloric acid was added, and after the disappearance of the raw materials, ethyl acetate and brine were added to the reaction mixture, and the mixture was separated.
The aqueous layer was further extracted twice with ethyl acetate, combined with the organic layer, washed with brine, and dried over sodium sulfate. Evaporate the solvent,
(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone was obtained. This was dissolved in 2.5 ml of dry N, N-dimethylformamide, 246 mg of t-butyldimethylsilyl chloride and 151 mg of imidazole were added, and reacted at room temperature overnight. The reaction solution was poured into cold saline and neutralized with a 1M aqueous solution of potassium hydrogen sulfate. Diethyl ether was added, and the aqueous layer was further adjusted to pH 2 with a 1M aqueous solution of potassium hydrogen sulfate.
It was extracted after adjusting to. The aqueous layer was further extracted twice with diethyl ether, combined with the previous organic layer, washed twice with brine, and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography to give (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 3300 (br), 1760, 1740,
1700, 1480, 1382, 1250, 1140, 1087, 830, 775.

Reference Example 15-2

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(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-chlorophenylthiocarbonylethyl]
-1-carboxymethyl-2-azetidinone 70 mg,
To a solution of 24 mg of p-nitrobenzyl alcohol in 0.3 ml of dry ethyl acetate was added a solution of 30 mg of N, N'-dicyclohexylcarbodiimide in 0.2 ml of dry ethyl acetate under ice-cooling, followed by reaction at 5 to 10 ° C overnight. The precipitated N, N'-dicyclohexylurea was separated by filtration and washed, and then the filtrate and the washing solution were combined and washed with water. The organic layer was further washed with brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography to give (3S, 4S) -3-[(1R)
-1-tert-butyldimethylsilyloxyethyl] -4-
[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1760, 1750, 1700, 160
2,1520,1478,1343,1250,1180,1090,835,775,7
42; NMR δ (CDCl ₃ ): 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H,
s), 1.27 (3H, d, J = 6.3 Hz), 1.31 (3H, d, J = 7.3 Hz), 3.01 (1
H, dd, J = 2.6 and 7.1Hz), 3.14 (1H, qd, J = 2.6 and 7.3Hz), 4.12
(2H, m), 4.17 (2H, m), 5.20 (2H, m), 7.34 (4H, m), 7.44 (2
H, d, J = 8.6Hz), 8.17 (2H, d, J = 8.9Hz).

Reference Example 16-1

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(A) (3S, 4S) -3-[(1R)-
To 1-hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone (72.0 g) was added 500 g of trichloroacetic acid, and the mixture was stirred under ice-cooling for 2 hours. . Reaction solution 5
The solution was concentrated under reduced pressure at 0 ° C. or less, and the oily residue was dissolved in
And the solvent was again distilled off.

(B) The obtained residue (72.1 g) was dissolved in dry acetonitrile (720 ml), and triethylamine (43.2) was dissolved.
5 g was added, and then 92.33 g of p-nitrobenzyl bromide was added, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with 1.5 l of ethyl acetate, washed several times with 20% saline, dried over sodium sulfate, and the solvent was distilled off. The oily residue was subjected to silica gel chromatography to give (3S, 4S) -3-[(1R)-
1-Hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone was obtained.

IR ^CHCl 3 (cm ^-1 ): 1740, 1680, 1600, 151
5, 1360, 1205, 1180, 950, 740.

Reference Example 16-2

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(3S, 4S) -3-[(1R) -1-benzyloxycarbonyloxyethyl] -4-[(1
R) -1-Phenylthiocarbonylethyl] -1-t-
8.5 g of butoxycarbonylmethyl-2-azetidinone was dissolved in 185 ml of ethylene dichloride and cooled to -10 ° C. While stirring, a solution of 26.4 g of boron tribromide in 100 ml of ethylene dichloride was added dropwise over 20 minutes. The reaction solution was stirred for 1 hour while keeping it at -10 ° C.
A solution of 40 g of sodium hydrogen carbonate and 600 g of ice water was added to the reaction solution, and the mixture was washed with 200 ml of ethyl acetate. 2N for water layer
After adding 200 ml of hydrochloric acid, 300 ml of ethyl acetate was added for extraction. After the aqueous layer was further extracted with 300 ml of ethyl acetate, the ethyl acetate layers were combined and extracted with 200 ml of brine.
Washed twice. After drying the organic layer with magnesium sulfate, the solvent was separately distilled off under reduced pressure to give (3S, 4S) -3-[(1
R) -1-Hydroxyethyl] -4-[(1R) -1-
[Phenylthiocarbonylethyl] -1-carboxymethyl-2-azetidinone (10.4 g, yield 87.9%) was obtained.

IR ^Nujol (cm ^-1 ): 1740, 1710, 1690, 121
0, 1130, 1070, 940, 740.

Reference Example 16-3

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(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone (52.36 g) was dissolved in 262 ml of dry N, N-dimethylformamide, and imidazole (16.6 g) and t-butyldimethylsilyl chloride (23.28 g) were added, followed by stirring at room temperature for 5 hours. The reaction solution was diluted with 1 liter of ethyl acetate and washed with 20% saline,
The aqueous layer was extracted with 500 ml of ethyl acetate, and the organic layers were combined and washed twice with 20% saline. After drying the sodium sulfate, the solvent was distilled off and the oily residue was subjected to silica gel chromatography to give (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
Phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone was obtained.

IR ^neat (cm ^-1 ): 1755, 1690, 1600, 151
5,1340, 1250, 1180, 835; NMR δ (CDCl ₃ ): 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H,
s), 1.28 (3H, d, J = 6.0 Hz), 1.32 (3H, d, J = 7.3 Hz), 3.01 (1
H, dd, J = 2.3 and 7.3Hz), 3.16 (1H, dd, J = 2.3 and 7.3Hz), 3.96
(1H, d, J = 17.8Hz), 4.17 (2H, m), 4.31 (1H, d, J = 17.8Hz),
5.20 (2H, ABq, J = 13.5Hz), 7.25 ~ 7.45 (5H), 8.12 (2H, d, J
= 8.9Hz).

Reference Example 16-4

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(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone Further, the same treatment as in Reference Example 16-3 was carried out except that t-butyldimethylsilyl chloride was replaced with trimethylsilyl chloride to obtain (3
(S, 4S) -3-[(1R) -1-trimethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -1-p-nitrobenzyloxycarbonylmethyl-2-azetidinone was obtained. .

IR ^neat (cm ^-1 ): 1760, 1695, 1600, 152
0, 1440, 1340, 1250, 1180, 950, 840, 740; NMR δ (CDCl ₃ ): 0.13 (9H, s), 3.04 (1H, dd, J = 2.3 and 7.6
Hz), 3.15 (1H, qd, J = 2.3 and 7.0Hz), 3.92 (1H, d, J = 18.0H
z), 4.38 (1H, d, J = 18.0Hz), 5.21 (2H, ABq, J = 13.5Hz), 8.
12 (2H, d, J = 8.9Hz).

Claims (6)

(57) [Claims] 1. A compound of the general formula (I-8 ⁰ ) [Wherein, R ₁ and R ₂ may be the same or different and each represent a hydrogen atom or a lower alkyl group;
R ⁰ ₃ is a hydrogen atom or a lower alkyl group, R _"4 represents a protecting group of a carboxyl group or a thiol carboxyl group, X 'represents a hydrogen atom or a protected hydroxy group, Y is an oxygen atom or a sulfur atom COZ ′ is an active ester of a carboxyl group or an active acid anhydride,
A thiolcarboxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group protected by a thiolcarboxyl group-protecting group. The compound represented by] treated with a base, the general formula Z in the reaction solution ^'- (wherein, Z' is as defined above.) Is residues or protected active esters or active acid anhydride represented by After capturing the thiol residue of the thiol carboxyl group with an alkylating agent or an acylating agent, and subsequently treating the thiol residue with a hydroxyl group active esterifying agent in the same reaction vessel, the compound represented by the general formula (IX): _{Wherein, R 1, R 2, R} 0 3, R "4, X ' and Y are as defined above, L is a substituted or unsubstituted arylsulfonyloxy group, a lower alkanesulfonyloxy group, a halogeno-lower Which represents an alkanesulfonyloxy group or a diarylphosphoryloxy group], and further, in the presence of a base, a compound represented by the general formula (X) R ₀ -SH (X) wherein R ₀ represents an organic group. Or a salt of the above-mentioned mercaptan compound (X) with a base is reacted with a mercaptan compound represented by the general formula (VII): _{Wherein, R 1, R 2, R} 0 3, R "4, R 0, X ' and Y have. As defined above] The method for producing a carbapenem compound represented by. 2. The reaction of the compound represented by the general formula (IX) with the mercaptan compound (X) or a salt thereof is continued without isolating the compound represented by the general formula (IX). 2. The method according to claim 1, wherein the method is carried out in a furnace. Wherein R ⁰ ₃ manufacturing method according to paragraph 1 claims a lower alkyl group. 4. The method according to claim 1, wherein Y is an oxygen atom.
The production method according to the paragraph. Wherein R ⁰ ₃ manufacturing method according to item 4 claims a methyl group. 6. The process according to the range wherein the fourth R ⁰ ₃ is a β- methyl claims.