JP2510860B2 - Process for producing new β-lactam derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) [In the formula, R ₁ represents a hydroxyl-protecting group, R ₆ represents a carboxyl-protecting group, R ₈ represents a hydrogen atom, a lower alkyl group,
Which represents a lower alkenyl group or a substituted or unsubstituted benzyl group].

A compound in which the methylene group at the 1-position of the carbapenem skeleton is substituted with an alkyl group, particularly a 1-methylcarbapenem compound, is superior in stability in vivo to conventional 1-position unsubstituted carbapenem compounds and is extremely useful as an antibacterial agent. (DH Shih et al., Heteyo
cycles., 21 , 29 (1984)).

The present inventors have found a production method for stereoselectively obtaining a β-lactam compound represented by the general formula (I), which is an intermediate useful in the production of 1-methylcarbapenem, and completed the present invention.

As the hydroxyl-protecting group represented by R ₁ in the general formula (I), a protecting group generally used for protecting the hydroxyl group can be applied, and examples thereof include trimethylsilyl, triethylsilyl, t- Trialkylsilyl groups such as butyldimethylsilyl, t-butyldiphenylsilyl, eg methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-
Alkoxy- or aralkoxy-substituted methyl groups such as methoxyethoxymethyl, eg tetrahydropyranyl groups, eg benzyl, p-methoxybenzyl, 2,4
-Substituted or unsubstituted monoarylmethyl group such as dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, etc., for example, triphenylmethyl, p-methoxyphenyldiphenylmethyl, bis (p-methoxyphenyl)
Substituted or unsubstituted triarylmethyl group such as phenylmethyl, acyl group such as acetyl, benzoyl, etc., alkoxycarbonyl group such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc. Can be mentioned.

The protecting group for the carboxyl group represented by R ₆ may be a commonly used one, but is preferably a straight chain having 1 to 5 carbon atoms such as methyl, ethyl, isopropyl and tert-butyl. Or branched lower alkyl groups, for example, halogeno lower alkyl groups having 1 to 5 carbon atoms such as 2-ethyl iodide and 2,2,2-trichloroethyl,
For example, a lower alkoxymethyl group having 1 to 5 carbon atoms such as methoxymethyl, ethoxymethyl and isobutoxymethyl, for example, lower aliphatic such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl. Acyloxymethyl group, eg 1
-C1-C5 1-lower alkoxycarbonyloxyethyl groups such as methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl, for example, allyl,
A substituted or unsubstituted lower alkenyl group having 3 to 7 carbon atoms such as 2-methylallyl, 3-methylallyl, and 3-phenylallyl, for example, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl,
Substituted or unsubstituted monoarylalkyl group such as p-nitrobenzyl, p-chlorobenzyl, for example, substituted or unsubstituted diarylalkyl group such as diphenylmethyl, di-p-anisylmethyl, for example, phenyl, p-chlorophenyl A substituted or unsubstituted aryl group such as, 2,4,5-trichlorophenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 Examples thereof include a heteroaryl group such as -pyrimidyl and 2- (4,6-dimethyl) pyrimidyl, and a phthalidyl group.

Examples of the lower alkyl group for R ₈ include C _{1 to} C ₅ alkyl groups such as methyl, ethyl, n-propyl and t-butyl. Examples of the lower alkenyl group include C ₃ -C ₇ lower alkenyl groups such as allyl, 2-butenyl, 3-methyl-2-butenyl and the like. Examples of the substituted or unsubstituted benzyl group include a benzyl group,
C ₁ such as p-nitrobenzyl group and p-methoxybenzyl group
-C ₄ lower alkyl groups, lower alkoxy groups C ₁ -C _4, and a nitro group, a benzyl group which may be substituted with a halogen atom or the like.

 The details of the method of the present invention are described below.

(1) General formula (II) [Wherein R ₁ has the same meaning as described above and L represents a leaving group] and a β-lactam derivative represented by the general formula (III) in the presence of zinc dust in an inert solvent. [In the formula, X represents a halogen atom, R ₂ , R ₃ , R ₄ and R ₅ may be the same or different and represent a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group, or R ₂ And R ₃ together represent a C ₂ -C ₆ alkylene chain, and simultaneously or separately R ₄ and R ₅ together represent a C ₂ -C ₆ alkylene chain. Alternatively, R ₂ , R ₃ , R ₄ and R ₅ are joined together o-
Represents a phenylene group, Y represents an oxygen atom or a nitrogen atom substituted with an alkyl group or an aryl group], and is reacted with a compound represented by the general formula (IV) [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y have the same meanings as described above] can be obtained.

L in the general formula (II) represents a leaving group, and particularly represents a leaving group which can be easily substituted by a nucleophile, such as an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, an alkylsulfonyl group. , An arylsulfonyl group, an arylthio group, or a halogen atom, and examples of the acyloxy group include acetoxy,
A substituted or unsubstituted C ₁ -C ₅ lower alkylcarbonyloxy group such as monochloroacetoxy, trichloroacetoxy, trifluoroacetoxy, propionyloxy, butyryloxy, such as benzoyloxy, p-chlorobenzoyl, p-nitrobenzoyloxy. And a substituted or unsubstituted arylcarbonyloxy group. Examples of the alkylsulfonyloxy group include a substituted or unsubstituted C _{1 to} C ₅ lower alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, and the arylsulfonyloxy group. , And substituted or unsubstituted arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy.

Examples of the alkylsulfonyl group include C _{1 to} C ₅ lower alkylsulfonyl groups such as methanesulfonyl and ethanesulfonyl, and examples of the arylsulfonyl group include benzenesulfonyl, p-chlorobenzenesulfonyl and toluenesulfonyl. A substituted or unsubstituted arylsulfonyl group is mentioned. Examples of the arylthio group include a phenylthio group.

Examples of the halogen atom include halogen atoms such as chlorine, bromine and iodine.

Y is an oxygen atom or a nitrogen atom substituted with an alkyl group or an aryl group, wherein the alkyl group is
For example, a C _{1 to} C ₅ lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and a pentyl group is represented, and an aryl group is, for example, a phenyl group,
It represents a substituted or unsubstituted phenyl group such as a p-chlorophenyl group and a p-methoxyphenyl group.

Examples of the β-lactam derivative represented by the general formula (II) obtained by a known method and used in this step include Etc. can be mentioned.

Examples of the halogen atom represented by X in the general formula (III) include chlorine, bromine, iodine and the like.

R ₂ , R ₃ , R ₄ and R ₅ may be the same or different and each represent a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group, or R ₂ and R ₃ together form C. ₂ represents an alkylene chain of -C _6, simultaneously or separately, R ₄ and R ₅ together such connexion, or an alkylene chain of C ₂ -C _6, or,
R ₂ , R ₃ , R ₄ and R ₅ are taken together to represent o-phenylene.
Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
It can be mentioned C ₁ -C ₅ alkyl group such as isobutyl. Examples of the aralkyl group include a benzyl group and p-
Methoxybenzyl group, 2,4-dimethoxybenzyl group, p
Examples thereof include a substituted or unsubstituted monoaryl lower alkyl group such as a chlorobenzyl group and a diphenylmethyl group, or a diaryl lower alkyl group.

R ₂ and R ₃ together represent a C ₂ -C ₆ alkylene chain,
Simultaneously or separately, when R ₄ and R ₅ are taken together to represent a C _{2 to} C ₆ alkylene chain, the alkylene chain is bonded to a carbon atom of the oxazolidin-2-one skeleton, and, for example, Cyclopropane, cyclobutane, cyclopentane,
Examples thereof include those that form a 3- to 7-membered ring such as cyclohexane and cycloheptane.

It is preferable that R ₂ , R ₃ , R ₄ and R ₅ may be the same or different and represent a hydrogen atom, a lower alkyl group or an aralkyl group, or R ₂ and R ₃ or R ₄ and R Mention may be made of those in which ₅ together represents an alkylene chain.

Particularly preferably, R ₂ and R _{3, which} may be the same or different, are a lower alkyl group or an aralkyl group, or R ₂ and R ₃ together represent an alkylene chain, and R ₄
And R ₅ may be the same or different and each is a hydrogen atom or a lower alkyl group, or R ₄ and R ₅ together represent an alkylene chain, and Y is a nitrogen atom substituted with an oxygen atom or an alkyl group. Mention may be made of those that represent an atom.

R ₂ , R ₃ , R ₄ , and R ₅ together to represent o-phenylene means that the following benzooxazolidin-2-one skeleton is represented.

[In the formula, X represents the same meaning as described above.] The reaction is carried out in an inert solvent.
Diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, benzene, toluene, hexane, hydrocarbon solvents such as cyclohexane, N, N-dimethylformamide, N, N-dimethylacetamide, A polar aprotic solvent such as hexamethylphosphoric triamide can be mentioned, and preferably tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane and N, N-dimethylformamide can be mentioned.

The zinc powder and the compound of the present invention represented by the general formula (III) are required in amounts sufficient for the reaction to proceed sufficiently with respect to the β-lactam derivative represented by the general formula (II), and are used in a large excess amount. However, zinc powder is usually represented by the general formula (I
The compound of the general formula (III) can be prepared by using 2 to 5 equivalents relative to the β-lactam derivative of the general formula (I).
It can be carried out usually in an amount of 1 to 3 equivalents relative to the β-lactam derivative of I).

The reaction can be suppressed or promoted by cooling or heating and can be carried out at a temperature in the range of -50 ° C to 150 ° C, but a preferable reaction temperature is 0 ° C to 10 ° C.
It is in the range of 0 ° C.

In this step, by preferentially selecting a substituent of R ₂ , R ₃ , R ₄ , and R ₅ and reaction conditions, it is possible to preferentially obtain a 1 ″ R compound that is advantageous for the production of β-lactam derivatives. You can

The 1 ″ R and 1 ″ S compounds can be separated by a conventional separation operation such as recrystallization or column chromatography, but they can be used as they are in the next reaction step.

(2) General formula (IV) [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y have the same meanings as described above] and a compound of the general formula (V) M-CH ₂ —COOR ₆ (V) [ In the formula, M represents an active ester of a hydroxyl group or a halogen atom, and R ₆ has the same meaning as described above], and is reacted with an acetic acid derivative represented by the general formula ( VI) [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y have the same meanings as described above].

In the general formula (V), preferable examples of M, which is an active ester of a hydroxyl group, include sulfonyl esters such as mesylate and tosylate.
Examples of the halogen atom include chlorine atom, bromine atom, iodine atom and the like.

As the inert solvent used in the present N-alkylation reaction, benzene, toluene, tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, hexamethylphosphoric triamide (HM
Preferable examples include single or mixed solvents such as PT), dimethyl sulfoxide, methylene chloride, dichloroethane, t-butanol, and water. Examples of suitable bases include organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide,
Examples thereof include metal salts of amines such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and various bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

The amount of the base is preferably such that the reaction proceeds sufficiently, and the reaction can be suppressed or promoted by appropriately cooling or heating.

The compound represented by the general formula (VI) is a novel compound which has not been described in the literature, and is a very useful compound for producing a carbapenem derivative in which the methylene group at the 1-position is substituted with a lower alkyl group as described below.

(3) General formula (VI) [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and Y have the same meanings as described above], a compound represented by the general formula M′-O—R ₇ [wherein M'represents a metal cation, R ₇ represents a lower alkyl group, a lower alkenyl group or a substituted or unsubstituted benzyl group] in an inert solvent to give a compound of the general formula [Wherein R ₁ , R ₆ and R ₈ have the same meanings as described above].

Examples of the lower alkyl group for R ₇ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and n.
Examples of the lower alkenyl group include a C _{1 to} C ₅ lower alkyl group such as a butyl group.
2-butenyl group, C ₃ ~, such as 3-methyl-2-butenyl group
A C ₇ lower alkenyl group may be mentioned.

As the substituent of the substituted benzyl alcohol, for example,
Lower alkoxy groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, methyl, ethyl, n-
C ₁ -C ₄ lower alkyl groups such as propyl and isopropyl,
A nitro group and a halogen atom can be mentioned.

Examples of M ′ include an alkali metal such as lithium, sodium and potassium, a cation, and an alkaline earth metal cation such as magnesium.

The inert solvent used in the reaction, diethyl ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, benzene, toluene, hexane, hydrocarbon solvents such as cyclohexane,
Solvents such as aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide can be mentioned, and mixed solvents thereof can also be used. Reaction is from -20 ℃ to 50
It is carried out at a temperature between ° C.

A notable feature of this reaction is that the reaction rate with the reaction reagent differs between the diastereomers at the 1 ″ position (corresponding to the 1 position of the carbapenem skeleton) of the compound represented by general formula (VI). That is, when a mixture of 1 ″ R isomer and 1 ″ S isomer is used as a raw material, the production ratio of 1 ″ R isomer / 1 ″ S isomer of the product is increased as compared with the raw material. By selecting appropriately, it is possible to obtain a highly pure 1 ″ R form (VII).

(4) General formula (VII) [Wherein R ₁ , R ₆ or R ₈ has the same meaning as described above], by selectively deprotecting R ₈ of the compound represented by the general formula [Wherein, R ₁ and R ₆ have the same meanings as described above] can be obtained.

The method for removing the protecting group R ₈ differs depending on the kind of the protecting group, but it should be carried out by a general method known per se, for example, hydrolysis, catalytic reduction method, treatment with acid or base or a reducing method. You can In order to selectively remove R ₈ only, a combination of R ₆ and R ₈ may be selected in advance so that such a selective reaction is possible.

For example, here, as an example, in the compound of the formula (VII), when R ₈ is a benzyl group and R ₆ is a protecting group that does not cleave under hydrogenation conditions, R ₈ by hydrogenation reaction that can be performed under mild reaction conditions The deprotection reaction of is described in detail. As the catalyst, palladium, platinum, rhodium or the like supported on carbon is used. As the hydrogenolysis solvent, acetic acid esters such as methyl acetate, ethyl acetate and amyl acetate, diethyl ether, tetrahydrofuran, dioxane, 1,
An ether solvent such as 2-dimethoxyethane or a hydrocarbon solvent such as benzene, toluene, hexane or cyclohexane is used. The reaction is under normal pressure hydrogen flow at -20 ℃
It progresses smoothly between 100 ℃ and 100 ℃.

The compound (VIII) obtained as described above is useful as an intermediate for producing a 1-methylcarbapenem compound as described later.

For example, the compound (VIII) obtained as described above has the general formula (IX) [In the formula, R ₁ and R ₆ have the same meanings as described above, COZ is an active ester of a carboxyl group or an active acid anhydride,
A thiol carboxyl group protected by a thiol carboxyl group protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group] can be easily derived to the β-lactam compound.

In the compound represented by the general formula (IX), COZ is an active ester of a carboxyl group, an active acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protecting group of a thiol carboxyl group, a substituted aryloxycarbonyl group or a heteroaryloxy group. A carbonyl group is shown, and when COZ is an active ester of a carboxyl group or an active acid anhydride, examples of the Z group include chlorine,
Halogen atoms such as bromine and iodine, for example, lower alkyloxycarbonyloxy groups such as ethoxycarbonyloxy, isopropyloxycarbonyloxy, sec-butyloxycarbonyloxy, for example lower alkanesulfonyloxy groups such as methanesulfonyloxy, for example , An arylsulfonyloxy group such as p-toluenesulfonyloxy, for example, a di (lower alkyl) phosphoryloxy group such as dimethylphosphoryloxy, diethylphosphoryloxy, and a diarylphosphoryloxy group such as di (phenyl) phosphoryloxy group. , For example, cyclic imidooxy groups such as N-succinimidooxy and N-phthalimidooxy, heteroaryl groups such as imidazole and triazole, for example,
Heterocycloalkyl groups such as 3- (2-thioxo) -thiazolidinyl can be mentioned. Further, as the protecting group for the thiol carboxyl group in which COZ is protected with the protecting group for the thiol carboxyl group, for example, a methyl group,
C ₁ -C _5, such as an ethyl group, an isopropyl group, sec- butyl group
A lower alkyl group, a phenyl group, a p-nitrophenyl group, a p-chlorophenyl group, a substituted or unsubstituted phenyl group such as p-methylphenyl group, a substituted or unsubstituted aryl group such as a naphthyl group, for example, dimethylphosphoryl, Examples thereof include di (lower alkyl) phosphoryl groups such as diethylphosphoryl, for example, diarylphosphoryl groups such as di (phenyl) phosphoryl, and cyclic imide groups such as N-succinimidooxy and N-phthalimidooxy. .

When COZ is a substituted aryloxycarbonyl group, examples of the substituted aryl group include p-nitrophenyl group,
p-chlorophenyl group, p-methoxyphenyl group, 0-
Examples thereof include nitrophenyl, 2,4,5-trichlorophenyl group, 1-naphthyl group, 2-naphthyl group and the like.

Examples of the heteroaryl group of the heteroaryloxycarbonyl group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2- (4,6-dimethyl) pyrimidyl group and the like.

The compound represented by the general formula (IX) can be produced by the general formula (VI
It can be carried out, for example, as follows using the compound represented by II).

(A) For example, 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 1,1′-carbonyldiimidazole.

(D) Thiazolidine-2-thione can be reacted in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) to produce an acylthiazolidine-2-thione derivative.

(E) Substituted or unsubstituted thiophene, 4,6-dimethyl-2-mercaptopyrimidine, 2-mercaptopyridine, etc. are condensed with a dehydrating agent such as DCC, or the aforementioned acid halide, mixed acid anhydride or The thiol ester can be produced by subjecting it to an ordinary acylation reaction of mercaptan such as reaction with an active ester such as an acylimidazole derivative.

(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.

The compound represented by the above general formula (IX) is EP-018881.
6 (Japanese Patent Application No. 60-290480) (see scheme below), various acylating agents can be obtained by treating with a base in an inert solvent to give compound (X) and then without isolation. Alternatively, it is treated with a halogenating agent or the like to give compound (XI),
It can lead to a carbapenem compound (XII) having antibacterial activity.

[Wherein R ₁ , R ₆ and Z have the same meanings as described above,
M ″ represents a base or metal cation, L ′ represents a reactive ester group of a hydroxyl group or a halogen atom, and R ₀ represents an organic group. Here, the reactive ester of a hydroxyl group represented by L ′ is
For example, a substituted or unsubstituted aryl sulfonic acid ester, a lower alkane sulfonic acid ester, a halogeno lower alkane sulfonic acid ester or a diaryl phosphoric acid ester is shown. Further, as the substituted or unsubstituted aryl sulfonic acid ester, for example, benzene sulfonic acid ester, p-toluene sulfonic acid ester, p-nitrobenzene sulfonic acid ester, p-bromobenzene sulfonic acid ester, and the like can be used as the lower alkane sulfonic acid ester. For example, methanesulfonic acid ester, ethanesulfonic acid ester, etc., halogeno lower alkanesulfonic acid ester, for example, trifluoromethanesulfonic acid ester, etc., diarylphosphoric acid ester, for example, diphenylphosphoric acid ester, etc. Examples include citrate esters. Preferable examples of the reactive ester of alcohol include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. Examples of the halogen atom include chlorine, bromine, and iodide.

Examples of M ″ include alkali metal cations such as lithium, sodium and potassium, and alkaline earth metal cations such as magnesium.

As described above, the compound of formula (VIII), which is an extremely useful intermediate as a key intermediate for producing a carbapenem derivative in which a lower alkyl group is substituted at the 1-position by the method of the present invention, is a very useful compound. The compounds represented can be prepared.

The 3-position, 4-position of the compound of the present invention represented by the general formula (I)
The carbon atom at the 4-position, the carbon atom bonded to the β-lactam ring in the substituent at the 4-position, or the carbon atom bonded to the β-lactam ring in the substituent at the 3-position are all asymmetric carbons. Therefore, the compound represented by the general formula (I) has optical isomers and stereoisomers based on an asymmetric carbon, and these isomers are all represented by a single formula. The scope of the description of the present invention is not limited. However, preferably, the compound (XIII) having the following arrangement can be mentioned.

[Wherein R ₁ , R ₆ and R ₈ have the same meanings as described above] The compound (XIII) can be used to induce a compound (IX) as described above while retaining the above-mentioned steric structure. You can
Similarly, the compound (X), (XI),
And (XII).

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

 The abbreviations have the following meanings.

Me; methyl group TBDMS; t-butyldimethylsilyl group Ac; acetyl group THF; tetrahydrofuran DME; 1,2-dimethoxyethane Et; ethyl group DMF; dimethylformamide Pr; propyl group Ph; phenyl group Bu; butyl group Bn; benzyl Group Reference Example 1 A solution of zinc powder (2.04 g, 31.21 mM) and THF (10.7 g) was heated under reflux to give 3- (2'-bromopropionyl) -4,4-dimethyloxazolidin-2-one. (5.74
g, 22.95 mM) and (1'R, 3R, 4R) -3- [1 '-(t-
Butyldimethylsilyloxy) ethyl] -4-acetoxyazetidin-2-one (3 g, 10.44 mM) in THF (16.0
g) The solution was added dropwise and refluxed for 30 minutes. THF was concentrated by 18.7 g, cooled, acetic acid (0.63 g) was added, and the mixture was stirred for 30 minutes. Dichloromethane was added to remove the insoluble matter, and the dichloromethane extract was washed successively with diluted hydrochloric acid, water, 5% sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated in a solvent. N-Heptane was added to the residue and the mixture was crystallized and filtered (1'R,
1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R) -3- [1 '
-(T-Butyldimethylsilyloxy) ethyl] -4-
[1 ″-(4-4-dimethyloxazolidine-2
-One-3-carbonyl) ethyl] -azetidine-2
A mixture of -ones (3.95 g, 95% yield) was obtained as a colorless solid. The production ratio of the .1 "R isomer and the 1" S isomer determined from the NMR spectrum was 81:19.

IR (KBr): 2950, 1762, 1713, 1460, 1380, 1310, 122
7, 1184, 1096, 1051, 840, 780 cm ^-1 ; H-NMR (CDCl ₃ ) δ = 0.06 (6H, s), 0.86 (9H, s), 2.
79 (0.19H ^{* 1} , dd, J = 5.3,1.1Hz), 3.00 (0.81H ^{* 2} ,
m), 4.00 (2H, s), 5.90 (1H, bs).

* 1 Signal of 1 "S body * 2 Signal of 1" R body Reference example 2 In the same manner as in Reference Example 1, a mixture of β-lactam derivatives (1′R, 1 ″ R, 3S, 4R) body and (1′R, 1 ″ S, 3S, 4R) body were obtained. The results are shown in the table below.

Further, the reaction was carried out in the same manner as in Reference Example 1, and the same results as above were obtained. The results are shown in the table below.

Reference Example 3 60% oily sodium hydride (0.33g, 8.25mM), THF
Add (4g) to the liquid at 25-30 ℃ (1'R, 1 "R, 3S,
4R) and (1'R, 1 "S, 3S, 4R) -3- [1 '-(t-
Butyldimethylsilyloxy) ethyl] -4- [1 ″-
(4,4-dimethyloxazolidin-2-one-3
-Carbonyl) ethyl] -azetidin-2-one mixture (3.0 g, 7.53 mM) and t-butyl bromoacetate (1.62 g, 8.31 mM) in THF (20 g) was added dropwise and the mixture was stirred for 1 hour ( 1'R, 1 "R, 3S, 4R) and (1'R,
1 "S, 3S, 4R) -1-t-Butyloxycarbonylmethyl-3- [1 '-(t-butyldimethylsilyloxy) ethyl] -4- [1"-(4,4-dimethyloxazolidine-2 A mixture of -one-3-carbonyl) ethyl] -azetidin-2-one was obtained.

 The physical property data after preparative collection are as follows.

IR (neat): 1770, 1750, 1695, 1460, 1365, 1302, 122
5, 1090, 833, 775, 765 cm ⁻¹ ; H-NMR (CDCl ₃ ): δ = 0.05 (3H, s), 0.08 (3H, s),
0.86 (9H, s), 1.21 (3H, d, J = 6.97Hz), 1.27 (3H, d, J
= 6.27Hz), 1.46 (9H, s), 1.55 (6H, s), 3.07 (1H, d)
d, J = 2.31Hz, J = 6.60Hz), 3.81 (1H, d, J = 17.82Hz),
4.02 (2H, s), 4.08 (1H, d, J = 17.82Hz), 4.10 to 4.25
(3H, m).

Reference example 4 (1'R, 1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R) -1-t-butyloxycarbonylmethyl-3- [1'- obtained in Example 1 50% of (t-butyldimethylsilyloxy) ethyl] -4- [1 ″-(benzyloxycarbonyl) ethyl] -azetidin-2-one in THF.
% Water containing 10% Pd-C (0.13 g) was added and hydrogenated.
After about 2 hours, when the absorption of hydrogen gas stopped, the catalyst was removed and the liquid was concentrated. To the residue were added n-heptane and a 2.5% sodium carbonate aqueous solution, and the layers were separated. The aqueous layer was adjusted to pH ~ 3 with hydrochloric acid, extracted with dichloromethane, washed with water and dried over magnesium sulfate, and then the solvent was distilled off (1'R, 1 "R, 3S, 4R) and (1'R, 1"). S, 3S, 4R) -1-t-Butyloxycarbonylmethyl-3- [1 ′-(t-butyldimethylsilyloxy) ethyl] -4- [1 ″ -carboxyethyl)
A mixture of -azetidin-2-one (2.63 g, 84% yield) was obtained as a colorless solid. The production ratio of the (1′R, 1 ″ R, 3S, 4R) body and the (1′R, 1 ″ S, 3S, 4R) body was 93: 7.

IR (neat): 1760, 1740, 1730, 1455, 1360, 1245, 122
4, 1150, 830, 770, 745 cm ⁻¹ ; H-NMR (CDCl ₃ ): δ = 0.06 (3H, s), 0.08 (3H, s),
0.87 (9H, s), 1.24 (3H, d, J = 6.3Hz), 1.25 (3H, d, J
= 7.3Hz), 1.48 (9H, s), 2.94 (1H, 8d, J = 7.1Hz, 3H
z), 3.04 (1H, dd, J = 2.3Hz, 5.5Hz), 3.98 (2H, m),
4.00 (1H, m), 4.21 (1H, m).

Example 1 Obtained by the method shown in Reference Example 3 (1′R, 1 ″ R, 3
S, 4R) and (1'R, 1 "S, 3S, 4R) -1-t-butyloxycarbonylmethyl-3- [1 '-(t-butyldimethylsilyloxy) ethyl] -4- [1" -(4,4
A solution of a mixture of -dimethyloxazolidin-2-one-3-carbonyl) ethyl] -azetidin-2-one was cooled to -10 to -5 ° C and a solution of lithium benzyl alkoxide in 0.5 M THF (15.1 ml, 7.55 mM) was added. The mixture was added dropwise and stirred at the same temperature for 1 hour. Acetic acid was added to the reaction solution to remove insoluble matter, and (1'R, 1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R)
-1-t-butyloxycarbonylmethyl-3- [1 '
-(T-Butyldimethylsilyloxy) ethyl] -4-
A mixture of [1 ″-(benzyloxycarbonyl) ethyl] -azetidin-2-one was obtained as a THF solution.

 The physical property values after fractionation are as follows.

IR (neat): 1755,1730,1450,1400,1380,1360,1242,122
0,1150,830,765,740,685 cm ⁻¹ ; H-NMR (CDCl ₃ ): δ = 0.04 (3H, s), 0.07 (3H, s),
0.85 (9H, s), 1.23 (3H, d, J = 6.3Hz), 1.24 (3H, d, J
= 6.9Hz), 1.44 (9H, s), 2.90 (1H, qd, J = 6.9Hz, 3.6H
z), 2.99 (1H, dd, J = 2.0Hz, 6.6Hz), 3.83 (2H, m),
5.10 (2H, s), 7.35 (5H, s).

Example 2 (1'R, 1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R) -3- [1 '-(t-butyldimethylsilyloxy) ethyl in the same manner as in Example 1. ] -4- [1 ″-(4,4
-Dimethyloxazolidin-2-one-3-carbonyl) ethyl] -azetidin-2-one mixture (1'R, 1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R) -1
-T-butyloxycarbonylmethyl-3- [1'-
(T-Butyldimethylsilyloxy) ethyl] -4-
[1 ″-(4,4-dimethyloxazolidine-2-
On-3-carbonyl) ethyl] -azetidine-2-
Via a mixture of ones, (1'R, 1 "R, 3S, 4R) and (1'R, 1" S, 3S, 4R) -1-t-butyloxycarbonylmethyl-3- [1 ' A mixture of-(t-butyldimethylsilyloxy) ethyl] -4- [1 "-(benzyloxycarbonyl) ethyl] -azetidin-2-one was obtained. The reaction conditions and results are shown in the table below.

Example 3 A 4- [1 ″-(benzyloxycarbonyl) ethyl] compound was obtained in the same manner as in Example 1. The results are shown in the table below.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoshio Ito 4-4-1 Nishionuma, Sagamihara-shi

Claims (1)

(57) [Claims] 1. A general formula [In the formula, R ₁ represents a hydroxyl-protecting group, R ₂ , R ₃ , R ₄ , and R ₅ may be the same or different, and are a hydrogen atom, a C _{1 to} C ₅ lower alkyl group, and an aralkyl group. Or an aryl group, or R ₂ and R ₃ together represent a C _{2 to} C ₆ alkylene chain, and R ₄ and R ₅ together or separately represent a C _{2 to} C ₆ alkylene chain Or R ₂ ,
R ₃ , R ₄ and R ₅ are taken together to represent an o-phenylene group, R ₆ is a carboxyl group-protecting group, and Y is a nitrogen atom substituted with an oxygen atom or an alkyl or aryl group. And a compound of the general formula M′-O—R ₇ ′ [wherein M ′ represents a metal cation, R ₇ ′ is a C _{1 to} C ₅ lower alkyl group, C _{3 to} C ₇ lower alkenyl. A group or a substituted or unsubstituted benzyl group], and a partial deprotection is carried out if necessary. [In the formula, R ₁ has the same meaning as described above, and R ₈ represents a hydrogen atom C ₁ to
A lower alkyl group of C _5, a lower alkenyl group of C _{3 to} C ₇ , or a substituted or unsubstituted benzyl group].