JPH0635432B2 - Novel β-lactam compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) [Wherein, R ₁ is a substituted or unsubstituted vinyl group at the 2-position, a hydroxymethyl group whose hydroxyl group is protected or unprotected, a protected or unprotected formyl group, or a compound represented by the formula: (In the formula, X represents an oxygen atom.), R ₂ represents a hydrogen atom or a protecting group of a carboxyl group, and R ₃ represents a hydrogen atom or a protecting group of a hydrogen group. ]
And a novel β-lactam compound represented by

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

The present inventors also conducted various studies to develop an advantageous method for producing a carbapenem derivative having a 1-hydroxyethyl group at the 6-position, and as a result, the compound of the present invention became an important intermediate in the production of the carbapenem derivative. The inventors have found out and completed the present invention.

The substituent R ₁ , the protecting group R _{2 for} the carboxyl group and the protecting group R ₃ for the hydroxyl group in the compound of the present invention will be described in detail below.

R ₁ is a substituted or unsubstituted vinyl group at the 2-position, a protected or unprotected hydroxymethyl group at the hydroxyl group, a protected or unprotected formyl group, or a formula (In the formula, X has the same meaning as described above.).

The substituted vinyl group has, for example, one or two substituents at the 2-position, and these substituents are the same or different. Examples of the substituent include a methyl group, an ethyl group, n
-C1-5 linear or branched lower alkyl group such as propyl group, n-butyl group, isopropyl group, 2-methylpropyl group, 2-methylbutyl group, and n-pentyl group, aryl group , An alkoxy group, an araalkoxy group, a C ₁ -C ₅ substituted lower alkyl group substituted with a halogen atom, an alkenyl group having a double bond and having 2 or more carbon atoms, such as a vinyl group, an allyl group, and a 2-methylallyl group. Examples thereof include an alkenyl group such as a 3-methylallyl group, a phenyl group, or a phenyl group substituted with a nitro group, an amino group, an alkoxy group, a halogen atom or the like.

Examples of the protected formyl group include a di (C ₁ -C ₄ ) lower alkoxymethyl group such as a dimethoxymethyl group, a diethoxymethyl group, and a di-n-propyloxymethyl group,
For example, a di (halogeno-substituted lower alkoxy) methyl group such as di (trichloroethoxy) methyl group, a di (aryloxy) methyl group such as dibenzyloxymethyl group, a formula [In the formula, Y represents an oxygen atom or a sulfur atom, and n represents 2 or 3. ] The cyclic group etc. which are represented by these can be mentioned.

Examples of the aryl group include a phenyl group such as a nitro group, an amino group, an alkoxy group, and a phenyl group substituted with a halogen atom. Examples of the alkoxy group as a substituent include a lower alkoxy group such as methoxy group, ethoxy group, and n-propyloxy group, and examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like.

The hydroxyl-protecting group and the hydroxyl-protecting group R _{3 in} R ₁ are not particularly limited as long as they are commonly used protecting groups, for example, a lower alkoxycarbonyl group such as t-butyloxycarbonyl group; Halogenated alkyloxycarbonyl groups such as ethyloxycarbonyl iodide, 2,2,2-trichloroethyloxycarbonyl group; for example, benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, Aralkyloxycarbonyl groups such as P-methoxybenzyloxycarbonyl group; trialkylsilyl groups such as trimethylsilyl group, t-butyldimethylsilyl group; eg methoxymethyl group,
Suitable examples include a substituted methyl group such as a 2-methoxyethoxymethyl group and a methylthiomethyl group; and a tetrahydropyranyl group.

The carboxyl group-protecting group R ₂ is not particularly limited as long as it is a group which functions as a carboxyl group-protecting group, and examples thereof include an alkyl group, an alkenyl group, a substituted lower alkyl group and an aryl group. .

Examples of the alkyl group include a methyl group, an ethyl group, n
-Propyl group, n-butyl group, 2-methylpropyl group,
n-pentyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 2-ethylbutyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, cyclopropylmethyl group, cyclohexylmethyl Group, an alkyl group having a linear, branched or cyclic alkane structure such as a cyclopentylmethyl group, wherein α
There may be mentioned a lower to middle alkyl group having 1 to 7 carbon atoms in which the carbon at the position is primary. Further, as the alkyl group, an α-position carbon secondary alkyl group, for example, isopropyl group, 1-methylethyl group, 1-methylpropyl group, 1-methylbutyl group, 1-methylpentyl group, 1-
Examples thereof include lower to intermediate alkyl groups such as ethylpropyl group, 1-ethylbutyl group, 1-cyclopentylethyl group and 1-cyclohexylmethylethyl group. Such an alkyl group having a secondary carbon atom at the α-position can be represented, for example, by the general formula [In the formula, R ₄ and R ₅ represent a lower alkyl group, a cyclic lower alkyl group or a cyclic lower alkyl-lower alkyl group. ] It can be represented by. Here, as the lower alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms, as the cyclic lower alkyl group, a cyclic alkyl group having 3 to 6 carbon atoms, cyclic lower alkyl-lower Examples of the alkyl group include an alkyl group having 1 to 5 carbon atoms which is substituted with a cyclic alkyl group having 3 to 6 carbon atoms.

Furthermore, as an alkyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo [2.2.
1] heptyl group, bicyclo [3.1.1] heptyl group,
Bicyclo [3.1.0] hexyl group, bicyclo [2.
2.2] A cyclic alkyl group such as an octyl group and a polycyclic condensed alkyl group or a cyclic alkyl group obtained by substituting a lower alkyl group for these cyclic alkyl groups, and a carbon atom at the α-position such as a t-butyl group having three carbon atoms. Examples thereof include primary alkyl groups.

The alkenyl group has a structure corresponding to the above alkyl group, has a double bond, has 3 or more carbon atoms, and has ordinary physicochemical stability, and is not particularly limited. Specific examples thereof include various alkenyl groups such as allyl group, 2-methylallyl group and 3-methylallyl group.

In the above alkyl group or alkenyl group, the alcohol represented by R ₂ OH is menthol, borneol, isoborneol, picocampheol, cholesterol,
It contains an alkyl group or an alkenyl group which is an alcohol having a terpene such as testosterone or a steroid skeleton. Also, these alkyl groups,
As the alkenyl group, an alkyl or alkenyl group having 8 to 30 carbon atoms can be used if necessary.

The substituent in the substituted lower alkyl group is not particularly limited, but preferred examples of the substituted lower alkyl group include a mono- or diarylalkyl group, a halogen-substituted alkyl group,
Examples thereof include alkoxy or alkalkoxy-substituted alkyl groups.

The mono- or diarylalkyl group has the general formula [In the formula, R ₆ represents an aryl group, and R ₇ represents a hydrogen atom, a lower alkyl group or an aryl group. ] The group represented by these can be mentioned. Here, examples of the aryl group include a phenyl group and a naphthyl group, and a phenyl group substituted with a lower alkyl group or a lower alkoxyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom or the like. Can be mentioned. Examples of the lower alkyl group for R ₇ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group. More specifically, examples of the monoarylalkyl group include benzyl group, p-methylbenzyl group, o-methylbenzyl group, 2,4-dimethylbenzyl group, p-methoxybenzyl group, o-methoxybenzyl group, 2 , 4-dimethoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, p-chlorobenzyl group, o-chlorobenzyl group, 2,4-dichlorobenzyl group, p-cyanobenzyl group, o-cyanobenzyl group Two
-Naphthylmethyl group, 1-naphthylmethyl group, 1-phenylethyl group, 1- (o-methylphenyl) ethyl group,
1- (p-methylphenyl) ethyl group, 1- (2,4-
Dimethylphenyl) ethyl group, 1- (o-methoxyphenyl) ethyl group, 1- (p-methoxyphenyl) ethyl group, 1- (p-nitrophenyl) ethyl group, 1- (o-
Nitrophenyl) ethyl group, 1- (o-chlorophenyl) ethyl group, 1- (2,4-dichlorophenyl) ethyl group, 1- (p-cyanophenyl) ethyl group, 1- (2
There may be mentioned a series of substituents such as -naphthyl) ethyl group, 1- (1-naphthyl) ethyl group, and 1-phenylpropyl group in which carbon number is further increased. Examples of the diarylalkyl group may include a diphenylmethyl group, a diphenylmethyl group, a di-p-anisylmethyl group, or the like, which is unsubstituted or substituted. Further, as examples of the arylalkyl group, 2-phenylethyl group, 3-phenylpropyl group, or phenyl group substituted with the above-mentioned various substituents 2
It is also possible to use -phenylethyl, 3-phenylpropyl groups and the like.

Next, regarding a halogen-substituted alkyl group, an alkoxy or alkalkoxy group alkyl group, for example, 2,2,2-trichloroethyl group, 2-iodoethyl group, etc. Examples thereof include a lower alkyl group, a benzyloxy group such as a benzyloxymethyl group and a methoxymethyl group, or a lower alkyl group having 1 to 3 carbon atoms substituted with a lower alkoxyl group having 1 to 3 carbon atoms.

As the aryl group as a protective group for the carboxyl group,
For example, there may be mentioned an unsubstituted or substituted phenyl group such as a phenyl group, a p-nitrophenyl group and a p-methoxyphenyl group.

The method for producing the compound of the present invention will be described in detail below for each step.

General formula (II) [In the formula, R ₁ and R ₂ have the same meanings as described above. ] The Schiff base represented by and diketene are reacted in the presence of an imidazole in an inert solvent to give a compound represented by the general formula (III) [In the formula, R ₁ and R ₂ have the same meanings as described above. ] 3-acetyl-2-azetidinone-4-carboxylic acid ester derivative represented by [In the formula, R ₁ and R ₂ have the same meanings as described above. ] By the 3- (1-hydroxyethyl) -2-azetidinone-4-carboxylic acid derivative represented by the formula (1), and by further subjecting it to a reaction for removing the protective group R _{2 for} the carboxyl group or a protective reaction for the hydroxyl group, if necessary. The compound of the present invention represented by the general formula (I) can be produced.

Examples of the imidazole used in the reaction include imidazole, various imidazole derivatives such as 4-methylimidazole, 2,4-dimethylimidazole, 2-methylimidazole, etc. 2- or 4-position lower alkyl-substituted imidazoles. Although it can be mentioned, imidazole or 4-methylimidazole is preferable.

The imidazoles can be used in a catalytic amount to a large excess amount, but it is preferable to use a 0.1-fold to 1.5-fold molar amount with respect to the Schiff base.

As the inert solvent, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane or mixtures thereof are preferred. Ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, nitriles such as acetonitrile, aliphatic hydrocarbons such as hexane, heptane, cyclohexane, pentane, dimethylformamide, dimethyl sulfoxide or methyl acetate, acetic acid such as ethyl acetate Various solvents such as esters can also be used.

The reaction can be suppressed or accelerated by cooling or heating, but the reaction temperature is from -20 ° C to 120 ° C.
It is carried out in the range of ℃, from the viewpoint of operability, etc.
It is preferably carried out in the range of 0 ° C.

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

In the reaction of, various methods generally carried out when reducing a carbonyl group to a hydroxyl group can be carried out. For example, sodium borohydride, lithium borohydride, potassium borohydride, zinc borohydride, diborane, borane This can be achieved by using a borohydride compound, such as a complex of benzene with various amines (for example, diisopropylamine-borane complex), as a reducing agent and performing reduction in an inert solvent. Further, a metal salt such as magnesium acetic acid, magnesium trifluoroacetic acid or zinc chloride may be added as a reaction aid to the reaction system to carry out the reduction reaction. The reducing agent is required in an amount sufficient for the reaction to proceed sufficiently, and the reaction can be suppressed or promoted by cooling or heating, but the reaction temperature is -7.
It can be said to be 8 ° C to 40 ° C.

As the solvent used in this reduction reaction, diethyl ether,
Tetrahydrofuran, dioxane, ether solvents such as ethylene glycol dimethyl ether, alcohol solvents such as methanol, ethanol and isopropyl alcohol, water and mixed solvents thereof can be mentioned.
It is also possible to use aromatic hydrocarbon solvents such as benzene and toluene, hydrocarbon solvents such as cyclohexane and n-hexane, and the like.

The target 1-hydroxyethyl derivative can also be derived by a catalytic reduction method using a platinum-based catalyst, a palladium-based catalyst or the like as a reduction method.

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

In the reaction for removing the protecting group R _{2 for} the carboxyl group, various methods generally used for converting an ester group into a carboxylic acid can be used. For example, in the presence of water, tetrahydrofuran, dioxane, methanol, ethanol or In an inert solvent such as a mixed solvent thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
This can be achieved by using a so-called alkaline hydrolysis method of reacting with a base such as sodium hydrogen carbonate. The reaction can be suppressed or promoted by cooling or heating, but the reaction temperature is -15 ° C to 50 ° C.
It can be said to be ° C. The base can be used in a catalytic amount to an excessive amount, but it is preferable to use 0.9 to 1.5 times the molar amount of the ester derivative.

In this step, a method using an acid such as trifluoroacetic acid, formic acid, or boron trifluoride etherate in the presence or absence of anisole, resorcinol dimethyl ether, or thioanisole, or a platinum-based catalyst, a palladium-based catalyst, or the like is used. The catalytic reduction method or the like used can also be used as necessary.

After completion of the reaction, the target compound can be taken out by a usual organic chemical means.

Next, the three-dimensional structure of the compounds represented by the general formulas (III) and (Ia) will be described.

In the compound represented by the general formula (III), stereoisomers exist because there are two steric relationships, cis and trans, between the 3-acetyl group and the ester group at the 4-position. Since it is an asymmetric carbon, optical isomers exist. All of those isomers are shown in a single formula for convenience, but this does not limit the scope of the present invention.

However, from the above-mentioned production method using the compound (II), it is possible to obtain very high selectivity for the 3-position acetyl group of the β-lactam ring and the 4-position.
It is possible to obtain a compound in which the steric relationship of the position ester group is trans.

Next, the optical isomers will be described. When the Schiff base represented by the general formula (II) does not have an asymmetric carbon in the R ₂ group, it is reacted with diketene to give a racemic 3-isomer.
An acetyl-2-azetidinone derivative (III) is produced.
On the other hand, regarding the case where the R ₂ group has an asymmetric carbon, first, the case where R ₂ has an asymmetric carbon and is a racemate will be described.

General formula When the relationship between the 3 and 4 positions in is a trans relationship and is explained only for the 4 position, the asymmetric carbon at the 4 position has an S configuration and an R configuration. On the other hand, when R ₂ has only one asymmetric carbon, it has two coordinations, S coordination and R coordination. Therefore, when expressed as (coordination of lactam ring 4-position, coordination of R ₂ ) in this case, (S, S), (S, R), (R, S), (R,
Four isomers of R) will be produced, and (S, S)
The body and the (R, R) body, and the (S, R) body and the (R, S) body each have a mirror image relationship, for example, the (S, S) body and the (S, R) body.
The body, the (R, S) body and the (R, R) body have a diastereomeric relationship. Therefore, diastereomers can be generally distinguished and identified by nuclear magnetic resonance spectrum, high performance liquid chromatography (HPLC), silica gel thin layer chromatography, etc. In this case, for example, separation by HPLC is possible. In this case, a mixture of (S, S) body- (R—R) body and (S, R) body
Each mixture of body- (R, S) body appears as one peak, and as a result, a chart showing two peaks is obtained.
The ratio of these two peaks differs depending on the R ₂ group used, but the production ratio of the (S, S) form to the (R, R) form and (S, S)
The production ratio of the (R) -form to the (R, S) -form is usually 1: 1.

From the above, R ₂ is an optically active substance, for example, S coordinated R _2.
In the case of two groups, two isomers, ie, (S, S) and (R, S) diastereomers, are obtained, and as described above, (S, S) and (R, S) isomers are obtained. Since the production ratio differs depending on the type of R ₂ group, it indicates that one diastereomer can be produced in a larger amount.

Next, the case where R ₂ group has an asymmetric carbon atom and is optically active R ₂ will be described. As already mentioned, the products in this case are represented by the general formulas (IIIa), (IIIb) [In the formula, R ₂ ^* represents an optically active substituent having an asymmetric carbon atom in the above R ₂ , and R ₁ has the same meaning as described above. ] Two isomers represented by the following formula are given, and (IIIa) and (IIIb) are in a diastereomeric relationship with each other and can be separated by a usual organic chemical means. Further, the production ratio of (IIIa) and (IIIb) varies depending on the type of R ₂ ^* used or its configuration, and the mixture can be obtained as a mixture of one of these ratios. Further, as described above, these mixtures are subjected to ordinary organic chemical means such as silica gel, alumina, etc., thin layer chromatography or column chromatography, high performance liquid chromatography (H
It can be separated by chromatography such as PLC) or by a crystallization method. In addition, the general formula (Ib) obtained by reducing these diastereomers and protecting the hydroxyl group as the case requires [In the formula, R ₂ ^* , R ₂ and R ₃ have the same meanings as described above. ] It is also possible to separate after induction into a derivative or the like.

The β-lactam compound of the present invention represented by the general formula (I) is useful as an intermediate for the production of various carbapenem derivatives having antibacterial activity, examples of which are shown below.

For example, the compound (D) known in the literature as an important intermediate for the production of carbapenem compounds can be obtained by the following method.

[Wherein R ₁ , R ₂ and R ₃ have the same meanings as described above, R ′ ₂ and R ″ ₂ each represent a different protecting group for a carboxyl group, Z is an active ester of a carboxylic acid or an active acid anhydride. Or a residue of a thioester.] Step 1 Compound (A) is obtained by, for example, reacting Compound I with an Arndt-Einstert reaction or a journal
Of American Chemical Society (J.Am.Chem.S
oc.) 102, pages 6161 to 6163 (1980), and the like, and can be obtained by subjecting to a carbon-increasing reaction.

Step 2 Compound (B) is a known oxidation reaction such as ozone oxidation or chromic acid oxidation of compound (A), a method using an acid such as mineral acid or Lewis acid, or a commonly used hydroxyl group such as catalytic reduction,
It can be obtained by combining it with a deprotection reaction of a protecting group of a formyl group to give a carboxylic acid, and then subjecting it to an esterification reaction which is generally used.

Step 3 Compound (B) the protecting group R _'2 carboxyl groups selectively removed, and then oxalyl chloride, with a halogenating agent such as thionyl chloride, an acid halide derivative is treated directly or the presence of a base Acyl imidazole by derivatization, derivatization to a mixed acid anhydride derivative using a chloroformate ester such as ethyl chloroformate, or treatment with 1,1′-carbonyldiimidazole, thiazolidine-2-thione, etc. It can be carried out by leading to a derivative or an active ester such as an acylthiazolidine-2-thione derivative or an active salt anhydride.
The after removing the protecting group R _'2 of compound (B), thiophenol, 4,6-dimethyl-2-mercapto pyrimidine, 2
-Conversion to a thiol ester by subjecting a mercapto derivative such as mercaptopyridine or the like to an acylation reaction of a thiol which is usually used, for example, a reaction with a dehydrating agent or a reaction of converting the active ester or the active acid anhydride to the above-mentioned treatment. be able to.

Step 4 Compound (D) was prepared by converting Compound (C) into tetrahedron letters (Tetrahedron Letters) Vol. 22, pp. 3883 to 3886 (1981).
Year), Tetrahedron 38, 2659-2
By the method known in the literature described on page 665 (1982),
That is, it can be obtained by subjecting to a Dieckmann type condensation reaction in the presence of a base such as sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide in an inert solvent such as tetrahydrofuran.

Regarding carbapenem compounds, recently, compounds in which the methylene group at the 1-position of the carbapenem skeleton has been substituted with an alkyl group have been synthesized, and especially 1-methylcarbapenem compounds have been transformed into conventional 1-position unsubstituted carbapenem compounds in terms of in vivo stability and the like. It has been reported that it is excellent as an antibacterial agent and is extremely useful as an antibacterial agent.

The compound (I) of the present invention is also useful as an intermediate for the production of the above-mentioned 1-methylcarbapenem compound, examples of which are shown below.

For example, as an important intermediate in the production of 1-methylcarbapenem compounds, Heterocycles Vol. 21, 29
The known compound (O) described on page (1984) and the like can be obtained by the following method.

[In the formula, R ₁ , R ₂ , R ₃ , R ″ ₂ and Z have the same meanings as described above, and R ′ ₃ represents a hydroxyl-protecting group different from R _3. ] Step 5 Compound (E) It can be obtained by reacting compound (I) with an organometallic compound such as methylmagnesium halide or methyllithium in an inert solvent.

Step 2 ′ Compound (F) can be obtained by subjecting compound (E) to the same reaction as in Step 2 described above.

Step 6 Compound (G) can be obtained by subjecting compound (F) to a dehydration reaction carried out with a dehydrating agent such as thionyl chloride or tosyl chloride in the presence or absence of a base.

Step 7 Compound (H) is obtained by reacting compound (G) with various chlorinating agents used for chlorinating an allylmethyl group in an inert solvent such as molecular chlorine and N-chlorosuccinimide. be able to.

Step 8 Compound (J) can be obtained by hydrolyzing Compound (H) in the presence of a low valent ionic salt of a heavy metal such as copper or silver.

Step 9 Compound (K) can be obtained by subjecting compound (J) to a general hydroxyl group protection reaction.

The compound (L) in step 10 can be obtained by subjecting the compound (K) to a general hydrogenation reaction for a double bond such as catalytic reduction using a heterogeneous transition metal catalyst.

Step 11 The compound (M) is obtained by subjecting the compound (L) to a deprotection reaction of a general protective group for a hydroxyl group, followed by various oxidation reactions such as chromic acid oxidation for converting a primary alcohol into a carboxylic acid. You can In this case, the deprotection reaction is selected under such a condition that the hydroxyl protecting group R ₃ is not affected.

Step 12 The compound (N) can be obtained by the same method as the method for producing the active ester, active acid anhydride or thiol ester described in the step 3 for the compound (M).

Step 4 ′ Compound (O) can be obtained by subjecting compound (N) to the same reaction as in Step 4 described above.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. The abbreviations used in the following examples and reference examples have the following meanings.

Men: 1-menthyl group TBMS: t-butyldimethylsilyl group Z: benzyloxycarbonyl group Ph: phenyl group Me: methyl group DAM: di (p-anisyl) methyl group Example 1-1 2.19 g (38.5 mM) of allylamine and 8.05 g (35 mM) of glyoxylic acid-1-menthyl monohydrate to 35 m of dry benzene
2.38 g (35 mM) imidazole in Schiff base prepared in
Was added, while keeping the temperature at 50 ° C, 3.53 g (42 mM) diketene.
A dry benzene (35 m) solution of was added dropwise over 1 hour, and the mixture was further stirred as it was at 50 ° C. for 15 minutes. After cooling to room temperature, it was diluted with 200 m of ethyl acetate and washed with diluted hydrochloric acid.
The aqueous layer was re-extracted with 100 m of ethyl acetate, the organic layers were combined, washed successively with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and evaporated to remove the solvent. The resulting oily residue was purified by silica gel chromatography. There was obtained 7.39 g (63%) of 1-allyl-3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone. This product was obtained from NMR 4
The production ratio of the (S) form and the 4 (R) form was 5: 3.

▲ IR ^neat _max ▼ (cm ^-1 ): 1775,1723,1358,1265,1220,118
5,1038,987 NMR δ (C ₆ D ₆ ): 1.88 (3H, s, 4 (S) form), 1.90 (3H, s, 4 (R))
Body), 4.01 (1H, d, J = 2.6Hz, 4 (S) body), 4.11 (1H, d, J = 2.
4Hz, 4 (R) body), 4.71 (1H, d, J = 2.4Hz) Example 1-2 (1) 473 mg of sodium borohydride was added to 27 m of dry tetrahydrofuran, cooled to 0 to 10 ° C., 2.67 g of boron trifluoride etherate was added dropwise, and the mixture was stirred for 1 hour.
Then, 2.66 g of benzylethanolamine was added, and the mixture was stirred as it was for 4 hours to prepare a benzylethanolamine borane-tetrahydrofuran solution.

(2) A solution of 3.35 g of 4-l-menthyloxycarbonyl-3-acetyl-1-allyl-2-azetidinone and 2.09 g of boron trifluoride etherate in toluene (19 m) was added to -1.
The mixture was cooled to 0 to -5 ° C, stirred for 1 hour, and then added dropwise to the benzylethanolamine borane solution (1) above cooled to the same temperature over 30 minutes. After stirring for 1.5 hours, 1.7N-hydrochloric acid 4 at -10 to 0 ° C
The reaction was stopped by adding m. The mixture was stirred at the same temperature for 1 hour.
Ice water (20 m) and ethyl acetate (100 m) were added to the reaction solution for extraction. The aqueous layer was extracted twice with 50 m of ethyl acetate, the organic layers were combined, washed with 100 m of brine, dried over sodium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography to give 4-l-methyloxycarbonyl-3- (1-hydroxyethyl) -1-allyl-2-azetidinone.

(3) The β-lactam derivative obtained in (2) above is a mixture of four isomers according to NMR, and the production ratio is 4S isomer / 4R isomer = 1.
3, threo body / erythro body = 1.4. This mixture 2.
51 g was subjected to silica gel column chromatography (silica gel 25 g) and eluted with benzene-ethyl acetate to separate a threo body and an erythro body. The obtained threo body is n
-By performing fractional crystallization using hexane (3
S, 4S) -4-l-Mentyloxycarbonyl-3-
(1- (R) -hydroxyethyl) -1-allyl-2-azetidinone was obtained. mp98-101 ℃ Threo body is (3R, 4R, 6S) body and (3S, 4
S, 6R) mixture, and erythro body is (3R,
It is a mixture of (4R, 6R) -form and (3S, 4S, 6S) -form.

Example 1-3 To a solution of 4-l-menthyloxycarbonyl-3- (1-hydroxyethyl) -1-allyl-2-azetidinone (337 mg) in acetone (5 m) -methanol (1.2 m) was added 8.0% aqueous sodium hydroxide solution (1 m), and the mixture was kept at 30 ° C for 3 hours. It was stirred. After confirming the disappearance of the raw materials, the reaction solution was transferred to a separating funnel and washed twice with 0.2 m of water and 10 m of diethyl ether.
Was extracted with. The organic layer was washed twice with 1 m of water,
The aqueous layers were combined. The aqueous layer was washed again with diethyl ether (10 m) and acidified with 6N-hydrochloric acid (1 m). After extraction with 5 m of methyl isobutyl ketone (5 times), the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 4-
Carboxy-3- (1-hydroxyethyl) -1-allyl-2-azetidinone was obtained.

Example 1-4 (3S, 4S) -3- (1- (R) -t-butyldimethylsilyloxyethyl) -4-methoxycarbonyl-2-
Dissolve 2.7 g of azetidinone in 30 m of methylene chloride,
Allyl bromide 2.3g, 50% sodium hydroxide aqueous solution 3
g, and then 1.1 g of benzyltriethylammonium chloride were sequentially added, and the mixture was vigorously stirred for 1 hour. Reaction solution is ethyl acetate
After diluting with 250 m, washing with water, drying with sodium sulfate, the solvent was distilled off, and the resulting oily residue was purified by silica gel column chromatography to obtain (3S, 4S) -1-allyl-3- (1-
(R) -t-butyldimethylsilyloxyethyl) -4-
Methoxycarbonyl-2-azetidinone was obtained.

Example 1-5 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -benzyloxycarbonyloxyethyl) -2-
31 mg of azetidinone and 48 mg of allyl bromide in dry N, N-
To a 0.46m solution of dimethylformamide, 6mg of 60% sodium hydride was added at 20-30 ° C. After stirring for 3 hours, the reaction solution was diluted with 5 m of a saturated aqueous solution of ammonium chloride and 5 m of brine and extracted with 20 m of ethyl acetate. The aqueous layer was further extracted with 8 m of ethyl acetate, the organic layers were combined, and washed with brine (5 times). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain (3S, 4S) -4-methoxycarbonyl-3- (1- (R) -benzyloxycarbonyloxyethyl) -1-allyl-2-azetidinone.

Reference example 1-1 (3S, 4S) -1-allyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -4-methoxycarbonyl-2-azetidinone (750 mg) was dissolved in dry tetrahydrofuran (6 m) and cooled with ice. 1M-methylmagnesium chloride-tetrahydrofuran solution 6 under nitrogen stream
m was added dropwise, the mixture was stirred for 1 hour, 1N-hydrochloric acid 6m was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Then, 15 m of ethyl acetate was added for extraction. Water layer 10m ethyl acetate
The extract was re-extracted with, and the organic layers were combined, washed successively with saturated saline, 10% aqueous sodium hydrogen carbonate and water, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 2: 1) and (3S, 4S) -1-allyl-3-
(1- (R) -t-butyldimethylsilyloxyethyl)
-4- (1-Hydroxy-1-methylethyl) -2-azetidinone was obtained.

Reference example 1-2 45 mg of (3S, 4S) -1-allyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -4- (1-hydroxy-1-methylethyl) -2-azetidinone was added to methylene chloride-methanol. It was dissolved in (1: 1) mixed liquid 2 m, cooled to −78 ° C., and then oxygen gas containing ozone was blown thereinto. After disappearance of the raw materials, the temperature was raised to room temperature while blowing nitrogen gas. After adding 40 mg of triphenylphosphine and stirring for 15 minutes, the solvent was evaporated and the residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 1: 1) to give (6S, 7S) -3-hydroxy-4-. Oxa
5,5-Dimethyl-7- (1- (R) -t-butyldimethylsilyloxyethyl) -8-oxo-1-azabicyclo [4.2.0] octane (Compound A) and (3S, 4
S) -1-formylmethyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -4- (1-hydroxy-1-methylethyl) -2-azetidinone (Compound B) was obtained as a mixture. It was

Compound A Compound B Reference example 1-3 (1) (6S, 7S) -3-Hydroxy-4-oxa-
5,5-Dimethyl-7- (1- (R) -t-butyldimethylsilyloxyethyl) -8-oxo-1-azabicyclo [4.2.0] octane and (3S, 4S) -1-formylmethyl A mixture of 3- (1- (R) -t-butyldimethylsilyloxyethyl) -4- (1-hydroxy-1-methylethyl) -2-azetidinone (65 mg) was dissolved in acetone (2 m) and ice-cooled (Jones). ) The reagent was added little by little until the orange yellow color did not disappear, and after stirring for 10 minutes, 2 drops of isopropyl alcohol were added to decompose excess Jones reagent. Ethyl acetate 15m, ice water 15 in the reaction solution
m was added for liquid separation, the aqueous layer was re-extracted with 10 m of ethyl acetate, and the organic layer was washed with water until neutral. Glauber's salt dried and the solvent was distilled off to obtain oily (3S, 4S) -1-carboxymethyl-3-
(1- (R) -t-butyldimethylsilyloxyethyl)
-4- (1-Hydroxy-1-methylethyl) -2-azetidinone was obtained.

NMR δ (CDCl ₃ ): 0.04 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 5.3
(1H, bs) (2) The carboxylic acid obtained in (1) above was treated with ethyl ether (3 m),
Dissolve in 0.5 m of methanol and diazomethane under ice cooling.
The ether solution was added dropwise until the pale yellow color disappeared. After stirring for 10 minutes as it was, 1 drop of 10% acetic acid-ether solution was added. The solvent was evaporated under reduced pressure, and the obtained oily residue was subjected to thin-layer silica gel chromatography (silica gel; benzene-ethyl acetate 1: 1) to give (3S, 4S) -1-
Methoxycarbonylmethyl-3- (1- (R) -t-butyldimethylsilyloxy) -4- (1-hydroxy-1)
-Methylethyl) -2-azetidinone was obtained.

Reference example 1-4 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -t-butyldimethylsilyloxyethyl)
70 mg of -4- (1-hydroxy-1-methylethyl) -2-azetidinone was dissolved in 0.35 m of dry pyridine, 30 mg of thionyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with 5 m of ethyl acetate, washed with cold 1N-hydrochloric acid, and then washed with water repeatedly, dried with sodium sulfate, and the solvent was distilled off. The resulting oily residue was subjected to thin layer chromatography (silica gel; benzene-ethyl acetate 9 : 1) and purified (3S,
4S) -1-methoxycarbonylmethyl-3- (1-
(R) -t-butyldimethylsilyloxyethyl) -4-
(1-Methylethenyl) -2-azetidinone was obtained.

Reference Example 1-5 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -t-butyldimethylsilyloxyethyl)
-4- (1-Methylethenyl) -2-azetidinone 150m
g was dissolved in 1.5 m of methanol, and 6N-hydrochloric acid 0.15 was added under ice cooling.
m was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with 30 m of ethyl acetate, washed with 5% aqueous sodium hydrogencarbonate and water in that order, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to thin layer chromatography (silica gel; benzene-ethyl acetate 1:
(3S, 4S) -1-methoxycarbonylmethyl-3- (1- (R) -hydroxyethyl) -4-
(1-Methylethenyl) -2-azetidinone was obtained.

Reference Example 1-6 (3S, 4S) -1-Methoxycarbonylmethyl-3-
52 mg of (1- (R) -hydroxyethyl) -4- (1-methylethenyl) -2-azetidinone was dissolved in 2 m of dry methylene chloride, 30 mg of N-dimethylaminopyridine was added, and the mixture was ice-cooled. 40 mg of benzyl chloroformate was added dropwise under a nitrogen stream, and the mixture was stirred as it was for 2 hours. Then, the mixture was left standing overnight at room temperature, diluted with 15 m of ethyl acetate, washed successively with 5% hydrochloric acid and then with water, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to thin-layer silica gel chromatography (silica gel; benzene-ethyl acetate). 2: 1), (3S, 4
S) -1-methoxycarbonylmethyl-3- (1- (R)
-Benzyloxycarbonyloxyethyl) -4- (1
-Methylethenyl) -2-azetidinone was obtained.

Reference Example 1-7 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
-4- (1-methylethenyl) -2-azetidinone 180m
g was dissolved in 4 m of ethyl acetate, 1.5 g of a 3% chlorine-carbon tetrachloride solution was added under ice cooling, and the mixture was stirred for 1 hour.
To the reaction solution was added saturated sodium bicarbonate water 3m and ethyl acetate 7m,
The layers were separated, the organic layer was washed with a 10% aqueous sodium thiosulfate solution, further washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain an oily residue. This was subjected to thin layer chromatography (silica gel; benzene-ethyl acetate 4: 1),
(3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
-4- (1-Chloromethylethenyl) -2-azetidinone was obtained.

Reference Example 1-8 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
-4- (1-Chloromethylethenyl) -2-azetidinone (1.55 g) was dissolved in dimethyl sulfoxide (17 m), water (4 m) was added, and then cuprous oxide (0.733 g) and P-toluenesulfonic acid monohydrate (0.848 g) were added. In addition, it stirred at 50-55 degreeC for 2 hours. Methylene chloride (10 m) and Celite (2 g) were added to the reaction solution, and the mixture was stirred for 30 minutes, then filtered. The excess residue was washed twice with methylene chloride (3 m), combined with the solution, and 20% saline solution (15 m) and 5% hydrochloric acid (1.5 m) were added. The layers were separated, the aqueous layer was re-extracted with 10 m of methylene chloride, the organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The obtained oily residue was subjected to silica gel column chromatography to obtain (3S, 4S) -1-
1.11 g of methoxycarbonylmethyl-3- (1- (R) -benzyloxycarbonyloxyethyl) -4- (1-hydroxymethylethenyl) -2-azetidinone was obtained.
(75%) Reference Example 1-9 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
1.0 g of -4- (1-hydroxymethylethenyl) -2-azetidinone and 0.4 g of imidazole were dissolved in 3.5 m of dimethylformamide, and 0.45 g of t-butyldimethylchlorosilane was added at room temperature, and after stirring for 3 hours, ice water of 14 m was added. Was added, and then 10 m of benzene was added for liquid separation, the aqueous layer was re-extracted with 10 m of benzene, and the organic layer was washed with brine (10%) repeatedly, dried over magnesium sulfate, and the solvent was distilled off.
The obtained oily residue was subjected to silica gel column chromatography, and (3S, 4S) -1-methoxycarbonylmethyl-3- (1- (R) -benzyloxycarbonyloxyethyl) -4- (1-t- 1.12 g of butyldimethylsilyloxymethylethenyl) -2-azetidinone was obtained.

Reference Example 1-10 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
360 mg of -4- (1-t-butyldimethylsilyloxymethylethenyl) -2-azetidinone was added to acetonitrile 6
m, and 5% platinum-activated carbon (50%
% Water-containing product) (180 mg), and hydrogen substitution was carried out at room temperature, followed by hydrogenation at atmospheric pressure. The catalyst was removed and the liquid was concentrated, and the resulting oily residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 4: 1) to give (3S, 4S).
-1-Methoxycarbonylmethyl-3- (1- (R) -benzyloxycarbonyloxyethyl) -4- (1-methyl-2-t-butyldimethylsilyloxyethyl)-
2-azetidinone was obtained.

According to NMR, the production ratio of stereoisomers of the methyl group on the 4-position side chain, 5R and 5S, was 3: 2.

5R body and 5S body 5R NMR δ (CDCl ₃ ): 0.02 (3H, s), 0.03 (3H, s), 0.87 (9H, s), 0.9
1 (3H, d, J = 6.9Hz), 3.21 (1H, dd, J = 2.3Hz and 8.6Hz), 3.92
(3H, s), 5.14 (2H, s), 7.35 (5H, s) 5S NMR δ (CDCl ₃ ): 0.89 (3H, d, J = 3.6Hz), 3.10 (1H, dd, J = 2.
3Hz and 8.6Hz) Reference example 1-11 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
-4- (1-Methyl-2-t-butyldimethylsilyloxyethyl) -2-azetidinone 160 mg in methanol 2
The mixture was dissolved in m.m., 6N-hydrochloric acid (0.16 m) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture under ice cooling, 13m of 0.1N sodium bicarbonate water
Was added, and then 30 m of ethyl acetate was added to separate the layers,
The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to thin layer chromatography (silica gel; benzene-ethyl acetate 1: 1) to give (3S, 4S) -1-methoxycarbonylmethyl-3. 120 mg of-(1- (R) -benzyloxycarbonyloxyethyl) -4- (1-methyl-2-hydroxyethyl) -2-azetidinone was obtained.

NMR δ (CDCl ₃ ): 5R form 0.96 (3H, d, J = 6.9Hz), 1.48 (3H, d,
J = 6.3Hz), 3.20 (1H, dd, J = 2.7Hz and 9.5Hz), 3.74 (3H, s),
5.16 (2H, s), 7.37 (5H, s) 5S body 0.89 (3H, d, J = 7.2Hz), 1.49 (3H, d, J = 6.3Hz), 3.12
(1H, dd, J = 2.6Hz and 8.9Hz) Reference example 1-12 (3S, 4S) -1-Methoxycarbonylmethyl-3-
(1- (R) -benzyloxycarbonyloxyethyl)
120 mg of -4- (1-methyl-2-hydroxyethyl) -2-azetidinone was subjected to Jones oxidation according to the method of Reference example 1-3 (1) to give (3S, 4S) -1-methoxycarbonylmethyl. -3- (1- (R) -benzyloxycarbonyloxyethyl) -4- (1-carboxyethyl)
2-Azetidinone was obtained.

5R NMR δ (CDCl ₃ ): 1.13 (3H, d, J = 2.1Hz), 1.39 (3H, d, J = 6.3)
Hz), 3.21 (1H, dd, J = 2.3Hz and 8.2Hz), 3.67 (3H, s), 5.09 (2
H, s), 7.29 (5H, s) 5S NMR δ (CDCl ₃ ): 1.40 (3H, d, J = 6.3Hz), 3.00 (1H, dd, J = 2.
3Hz and 8.5Hz) Reference example 1-13 (1) (3S, 4S) -1-methoxycarbonylmethyl-
3- (1- (R) -benzyloxycarbonyloxyethyl) -4- (1-carboxyethyl) -2-azetidinone (110 mg) was dissolved in ethanol (2.2 m), and 10% palladium-activated carbon (22 mg) was added under nitrogen atmosphere. After replacing with hydrogen at room temperature, hydrogenation was carried out under normal pressure. The catalyst was removed, the liquid was concentrated, and crude (3S, 4S) -1-methoxycarbonylmethyl-3- (1- (R) -hydroxyethyl) -4- (1
-Carboxyethyl) -2-azetidinone was obtained.

(2) 70 mg of the carboxylic acid obtained in (1) above and 110 m of imidazole
g was dissolved in 2 m of dimethylformamide, 180 mg of t-butyldimethylchlorosilane was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with 10 m of ethyl acetate, washed with water repeatedly, dried over magnesium sulfate, and the solvent was distilled off to obtain an oily residue. The residue was dissolved in 1.2 m of a mixed solution of methanol-tetrahydrofuran (3: 1), 1.2 m of a 10% potassium carbonate aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. Water 10m was added to the reaction solution, and then ethyl ether 10m
Was added to separate the layers, and the aqueous layer was acidified with 1N hydrochloric acid under ice cooling,
It was extracted twice with 10 m of ethyl acetate, dried over magnesium sulfate and the solvent was distilled off to give (3S, 4S) -1-methoxycarbonylmethyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -4. -(1-carboxyethyl)-
2-azetidinone was obtained.

5R NMR δ (CDCl ₃ ): 0.82 (9H, s), 3.69 (3H, s) 5S NMR δ (CDCl ₃ ): 0.83 (9H, s), 3.66 (3H, s) Reference Example 1-14 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-carboxyethyl] -1- (1-methoxycarbonylmethyl) -2-azetidinone A solution of 321 mg and 167 mg of N, N'-carbonyldiimidazole in 8 m of dry acetonitrile was stirred at room temperature for 1 hour. Thiophenol 113mg
Solution of dry acetonitrile in 2.3 m, followed by addition of 104 mg of triethylamine in 1.7 m of dry acetonitrile,
Stir for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate and brine and separated. The aqueous layer was extracted twice more with ethyl acetate, combined with the previous organic layer, washed with diluted hydrochloric acid, brine, saturated aqueous solution of sodium hydrogencarbonate, and brine (3 times), dried over sodium sulfate, and evaporated to remove the residue. Is purified by silica gel chromatography to give (3S, 4S) -3-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
4-[(1S) -1-phenylthiocarbonylethyl]
-1- (1-Methoxycarbonylmethyl) -2-azetidinone was obtained.

Reference Example 1-15 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1S) -1-phenylthiocarbonylethyl] -1- (1-methoxycarbonylmethyl) -2 -Azetidinone (50 mg) was dissolved in a dry hexamethylphosphoric triamide-tetrahydrofuran (1: 100) mixed solvent (0.6 m), and 0.44 m of a 1M tetrahydrofuran solution of lithium bis (trimethylsilyl) amide was added dropwise at -30 ° C. The reaction solution was heated to room temperature, and after disappearance of the raw materials, the reaction solution was cooled with ice. A neutral (pH6.86) phosphate buffer was added to the reaction mixture, which was then diluted with diethyl ether. After separation, the aqueous layer is further diluted with diethyl ether to 2
The extract was extracted twice, combined with the above organic layer, washed 5 times with brine, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (4S, 5R, 6S, 8R)-
Methyl-4-methyl-6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-azabicyclo [3.2.0] -hept-3,7-dione-2-carboxylate was obtained. .

Example 1-6 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -benzyloxycarbonyloxyethyl) -1-
Allyl-2-azetidinone (1.1 g) was dissolved in dry 1,2-dichloroethane (60 m) and ice-cooled. Under nitrogen stream 1.5
7 m of M boron tribromide-1,2-dichloroethane solution was added dropwise and stirred for 1 hour. Add 20m saturated sodium bicarbonate water,
Next, washing with water was repeated to dry magnesium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (3S, 4S) -4-methoxycarbonyl-3.
-(1- (R) -Hydroxyethyl) -1-allyl-2-
I got azetidinone.

Example 1-7 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -Hydroxyethyl) -1-allyl-2-azetidinone (100 mg), imidazole (70 mg) and t-butyldimethylchlorosilane (100 mg) were used and the reaction and post-treatment were carried out according to the method of Reference Example 5-2 (3S, 4S ) -4-Methoxycarbonyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -1-allyl-2-azetidinone was obtained. This product was in agreement with those obtained by the method of Example 1-4 in IR and NMR.

Example 2-1 1.33 g (8.8 mM) of 2-benzyloxyethylamine and 1.83 g (8.0 mM) of glyoxylic acid-l-menthyl monohydrate were azeotropically dehydrated in 50 m of toluene to form a Schiff base, which was the same amount as the distilled amount. Toluene was added, 0.55 g (8.0 mM) of imidazole was added at room temperature, and the mixture was dissolved and ice-cooled. Diketene 0.8
A solution of g (9.6 mM) in dry toluene (8 m) was added dropwise over 30 minutes and then stirred at room temperature for 2 hours. The reaction solution was diluted with 60 m of ethyl acetate, washed successively with cold dilute hydrochloric acid and water, dried over magnesium sulfate, and the solvent was distilled off. The resulting oily residue was produced by silica gel chromatography, 1- (2-
Benzyloxyethyl) -3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone 2.94 g (87.5
%).

Example 2-2 (1) Sodium borohydride (0.19 g, 5 mM) was added to dry tetrahydrofuran (11 m), cooled to 0 to 10 ° C, boron trifluoride etherate (1.07 g, 7.52 mM) was added at the same temperature, and the mixture was stirred for 1 hour. Then benzyl ethanolamine 1.
06 g (7.02 mM) was added and the mixture was stirred for 10 hours as it was to prepare benzylethanolamine borane. Separately, 1.67 g (4 mM) of 1- (2-benzyloxyethyl) -3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone was dissolved in 7.6 m of dry toluene, and the mixture was cooled to -10 to -5 ° C. 0.84 g (5.88 mM) of boron fluoride etherate was added dropwise, and the mixture was stirred at the same temperature for 1 hour and then added dropwise to the above benzylethanolamine borane solution in 30 minutes, and further stirred for 1.5 hours.
Next, after adding 2.0% of 5% hydrochloric acid, the temperature was raised to 40 ° C,
Further 6.5% hydrochloric acid (6.5 m) was added and the mixture was stirred for 1 hour. Ethyl acetate (30 m) and ice water (10 m) were added for liquid separation, the aqueous layer was re-extracted with ethyl acetate (15 m), the organic layers were combined and washed with water, dried with sodium sulfate, and the solvent was distilled off. 1- (2-benzyloxyethyl)
-3- (1-Hydroxyethyl) -4-l-menthyloxycarbonyl-2-azetidinone was obtained.

(2) The β-lactam derivative obtained in (1) above is a mixture of four isomers according to NMR, and the production ratio is 4S isomer / 4R isomer = 1.15,
The threo / erythro body was 2.2. This mixture was subjected to silica gel column chromatography, and benzene-
Elution with ethyl acetate separated the threo body and the erythro body. The obtained threo compound was fractionally crystallized from n-hexane to give (3S, 4S) -4-l-menthyloxycarbonyl-3- (1- (R) -hydroxyethyl) -1- (2-benzyloxyethyl). 2-Azetidinone was obtained.

mp 67-68 ° C Example 2-3 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -t-butyldimethylsilyloxyethyl) -2-
280 mg of azetidinone and 12 m of dry dimethylformamide
, 2-benzyloxyethyl bromide (700 mg) was added, and the mixture was ice-cooled. 50% sodium hydride 50 under nitrogen stream
After adding mg and stirring for 1 hour, 50 m of ethyl acetate, 3 cold water
0 m was added and the layers were separated.

The aqueous layer was re-extracted with 30 m of ethyl acetate, the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 9: 1) (3S, 4S) -4.
-Methoxycarbonyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-benzyloxyethyl) -2-azetidinone was obtained.

Reference example 2-1 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -t-butyldimethylsilyloxyethyl) -1-
(2-benzyloxyethyl) -2-azetidinone 56
mg was dissolved in 1 m of dry tetrahydrofuran, and a 1M-methylmagnesium chloride-tetrahydrofuran solution was added.
Using 27 m, the reaction and post-treatment were carried out according to the method of Reference Example 1-1, (3S, 4S) -4- (1-hydroxy-1).
-Methylethyl) -3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-benzyloxyethyl) -2-azetidinone was obtained.

Reference example 2-2 (3S, 4S) -4- (1-Hydroxy-1-methylethyl) -3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-benzyloxyethyl) -2
-Azetidinone (30 mg) was dissolved in ethanol (1 m), and 10% palladium-activated carbon (30 mg) was added under a nitrogen atmosphere. After hydrogen substitution, hydrogenation was carried out at room temperature for 8 hours under normal pressure. The catalyst was removed, the liquid was concentrated, and the residue was subjected to thin layer chromatography (silica gel; chloroform-methanol 9: 1).
Purified by (3S, 4S) -4- (1-hydroxy-1-)
Methylethyl) -3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-hydroxyethyl)
2-Azetidinone was obtained.

Reference example 2-3 24 mg of (3S, 4S) -4- (1-hydroxy-1-methylethyl) -3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-hydroxyethyl) -2-azetidinone Was subjected to a reaction and post-treatment according to the methods of (1) and (2) of Reference Example 1-3, (3S, 4S) -4-
(1-Hydroxy-1-methylethyl) -3- (1-
(R) -t-butyldimethyloxyethyl) -1-methoxycarbonylmethyl-2-azetidinone was obtained. This product was in agreement with those obtained in Reference Example 1-3 by IR and NMR.

Example 2-4 (3S, 4S) -4-l-menthyloxycarbonyl-
According to the method of Example 2-3, 340 mg of 3- (1- (R) -t-butyldimethylsilyloxyethyl) -2-azetidinone, 850 mg of 2-benzyloxyethyl iodide and 43 mg of 50% sodium hydride were used. Reaction and post-treatment are carried out to give (3S, 4S) -4-l-menthyloxycarbonyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-benzyloxyethyl)- 2-azetidinone was obtained.

Example 2-5 (3S, 4S) -4-l-menthyloxycarbonyl-
Using 3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-benzyloxyethyl) -2-azetidinone 300 mg, 5% palladium-activated carbon 30 mg,
The reaction and post-treatment are performed according to the method of Reference Example 2-2,
(3S, 4S) -4-l-menthyloxycarbonyl-
3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-hydroxyethyl) -2-azetidinone was obtained.

Reference example 2-4 (3S, 4S) -4-l-menthyloxycarbonyl-
Using 3- (1- (R) -t-butyldimethylsilyloxyethyl) -1- (2-hydroxyethyl) -2-azetidinone (130 mg) and 1M-methylmagnesium chloride-tetrahydrofuran solution (1 m) in Reference Example 1-1. Reaction and post-treatment are performed according to the method, and (3S, 4S) -4-
(1-Hydroxy-1-methylethyl) -3- (1-
(R) -t-butyldimethylsilyloxyethyl) -1-
(2-Hydroxyethyl) -2-azetidinone was obtained.
This product was in agreement with those obtained in Reference Example 2-2 by IR and NMR.

Example 3-1 Furfurylamine 1.87 g (19.25 mM), glyoxylic acid-
l-menthyl monohydrate 4,025 g (17.5 mM), diketene 1.77
g (21 mM) and imidazole 1.2 g (17.5 mM) were used to carry out the reaction and post-treatment according to the method of Example 2-1.
-Furylmethyl) -3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone was obtained.

Example 3-2 (1) 0.38 g of sodium borohydride, 2.14 g of boron trifluoride etherate, 2.12 g of benzylethanolamine and 22 m of dry tetrahydrofuran were used to prepare a benzylethanolamine borane solution according to the method of Example 2-2. A solution of 1- (2-furylmethyl) -3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone (3.03 g, 8 mM) and boron trifluoride etherate (1.68 g) in dry toluene (15.2 m) was treated with 1- ( 2.59 g of 2-furylmethyl) -3- (1-hydroxyethyl) -4-l-menthyloxycarbonyl-2-azetidinone was obtained. Yield 85% (2) The β-lactam derivative obtained in (1) above was a mixture of four isomers according to NMR, and the production ratios were 4S isomer / 4R = 1.2 and threo isomer / erythro isomer = 2.5. This mixture was subjected to silica gel column chromatography and eluted with benzene-ethyl acetate to separate a threo body and an erythro body.
The obtained threo body was fractionally crystallized from n-hexane, and the crystals were recrystallized from n-hexane-diethyl ether. (Crystal I) The recrystallized solution was concentrated, subjected to thin layer chromatography (silica gel) to scrape off the highly polar portion, and crystallized again with n-hexane. (Crystal II) Crystals I and II are Example 3-3 and Reference Example 3 described later.
4-l-menthyloxycarbonyl-
3- (1-t-butyldimethylsilyloxyethyl)-
The structure was confirmed by NMR after induction with 1-methoxycarbonylmethyl-2-azetidinone. As a result, the crystal I was (3R, 4R) -4-l-menthyloxycarbonyl-
3- (1- (S) -hydroxyethyl) -1- (2-furylmethyl) -2-azetidinone [mp117-119.5 ° C] and crystal II are (3S, 4S) -4-l-menthyloxycarbonyl-3. -(1- (R) -Hydroxyethyl) -1-
(2-furylmethyl) -2-azetidinone [mp88-9
0.5 ° C].

Example 3-3 4-l-menthyloxycarbonyl-3- (1-hydroxyethyl) -1- (2-furylmethyl) -2-azetidinone 110 mg, imidazole 45 mg, t-butyldimethylchlorosilane 61 mg were used, and Reference Example 5 described later Reaction and post-treatment were carried out in the same manner as in method 2 to obtain 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1- (2-furylmethyl) -2-azetidinone. .

Reference example 3-1 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1- (2-furylmethyl) -2-azetidinone 40 mg, 1M-methylmagnesium chloride-tetrahydrofuran solution 0.2 m Reference example Reaction and post-treatment were carried out in the same manner as in the method described in 1-1, 4- (1-hydroxy-1-methylethyl) -3
-(1-t-butyldimethylsilyloxyethyl) -1
-(2-Furylmethyl) -2-azetidinone was obtained.

Reference example 3-2 (1) 4- (1-hydroxy-1-methylethyl) -3-
(1-t-butyldimethylsilyloxyethyl) -1-
10 mg of (2-furylmethyl) -2-azetidinone was dissolved in 2 m of methylene chloride-methanol (1: 1) and ozonolysis reaction was carried out according to the method of Reference Example 1-2. 10 mg of triphenylphosphine was added to the post-treatment. Then 4- (1-
Hydroxy-1-methylethyl) -3- (1-t-butyldimethylsilyloxyethyl) -1-carboxymethyl-2-azetidinone was obtained. This product is from Reference Example 1-3
It was in agreement with that obtained in (1) on thin layer chromatography. (Silica gel; chloroform-methanol 4:
1) (2) The carboxylic acid obtained in (1) above is used in Reference Example 1-3 (2)
Was subjected to the same treatment as above to obtain 4- (1-hydroxy-1-methylethyl) -3- (1-t-butyldimethylsilyloxyethyl) -1-methoxycarbonylmethyl-2-azetidinone. This product was in agreement with that obtained in (2) of Reference Example 1-3 by thin layer chromatography and IR. N
It was a mixture of 4 isomers from MR.

Reference example 3-3 23 mg of 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1- (2-furylmethyl) -2-azetidinone was treated in the same manner as in the method of Reference Example 3-2. , 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1-methoxycarbonylmethyl-2-azetidinone was obtained.

This product had the same IR as that obtained in Reference Example 6-3 described below.

Example 4-1 Aminoacetaldehyde dimethyl acetal 1.16g (11m
M), glyoxylic acid-1-menthyl monohydrate 2.3 g (10 m
M), diketene 1.01 g (12 mM), imidazole 0.68 g (10 mM)
Was subjected to the reaction and post-treatment according to the method of Example 2-1, and 1- (2,2-dimethoxyethyl) -3-acetyl-4-l-menthyloxycarbonyl-2-azetidinone 3.0 g ( 80%).

Example 4-2 A benzylethanolamine borane solution obtained according to the method of Example 2-2 using 95 mg of sodium borohydride, 0.47 m of boron trifluoride etherate, 540 mg of benzylethanolamine and 5.5 m of dry tetrahydrofuran. (2,2-dimethoxyethyl) -3
-Acetyl-4-l-menthyloxycarbonyl-2-
Azetidinone 0.75 g and boron trifluoride etherate 0.
37 m of dry toluene (3.8 m) was treated in the same manner as in Example 2 to give 1- (2,2-dimethoxyethyl)-
3- (1-hydroxyethyl) -4-l-menthyloxycarbonyl-2-azetidinone was obtained.

This product is a mixture of four isomers according to NMR, and the production ratio thereof is 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1 according to Reference Example 4-5 described later. Determined by induction with -methoxycarbonylmethyl-2-azetidinone. As a result, 4S body / 4R
Body = 1.2 and threo / erythro body = 1.3.

Example 4-3 4-l-menthyloxycarbonyl-3- (1-hydroxyethyl) -1- (2,2-dimethoxyethyl) -2
-Using 186 mg of azetidinone, 75 mg of imidazole and 106 mg of t-butyldimethylchlorosilane, the reaction and post-treatment were carried out in the same manner as in the method described in Reference Example 5-2 to be described later.
-1-L-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1- (2,2-dimethoxyethyl) -2-azetidinone was obtained.

Example 4-4 Hexamethyldisilane 0.05m was added to iodine 60mg,
It stirred at 50-60 degreeC for 1 hour. To this was added 60 mg of 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1- (2,2-dimethoxyethyl) -2-azetidinone in dry methylene chloride (0.
5m) solution was added at room temperature and stirred as such for 1 hour.
The reaction solution was diluted with 5 m of ethyl acetate, 10% aqueous sodium hydrogen carbonate,
It was washed successively with water, 5% aqueous sodium thiosulfate solution and then with brine, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 5: 1) to give 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1-formylmethyl-. 2-azetidinone was obtained.

Example 4-5 15 mg of 4-l-menthyloxycarbonyl-3- (1-t-butyldimethylsilyloxyethyl) -1-formylmethyl-2-azetidinone was dissolved in 2 m of isopropyl alcohol, 0.5 m of water was added, and the mixture was ice-cooled. Sodium borohydride (3 mg) was added, the mixture was stirred for 20 minutes, ethyl acetate (15 m) was added, and then 1N-hydrochloric acid (5 m) was added to separate the layers. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by thin layer chromatography (silica gel; benzene-ethyl acetate 4: 1) to give 4-l-menthyloxycarbonyl-3-. (1-t-
Butyldimethylsilyloxyethyl) -1- (2-hydroxyethyl) -2-azetidinone was obtained. This product was in agreement with that obtained in Example 2-5 by thin layer chromatography and IR. NMR revealed a mixture of 4 isomers.

Reference example 5-1 (3S, 4S) -4-Carboxy-3- (1- (R) -hydroxyethyl) -1-di (P-anisyl) methyl-2
-Dissolving 34 g of azetidinone in 310 m of methanol,
Next, add 2.9 g of concentrated sulfuric acid and stir at 65 ° C. for 3 hours.
Cool to 40 ° C and 8m of 8% aqueous sodium hydroxide solution
Neutralized with. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 105 m of 1,2-dichloroethane and washed with water. Water layer 1,
It was extracted with 2-dichloroethane (105 m), the organic layers were combined, washed with water, dried over sodium sulfate, and the solvent was distilled off to obtain (3S, 4S) -4-methoxycarbonyl-3- (1- (R) -hydroxyethyl) -1-di ( p-anisyl) methyl-2-azetidinone was obtained.

mp 102-104 ℃ Reference example 5-2 (3S, 4S) -1-di (p-anisyl) methyl-3-
1.8 g of (1- (R) -hydroxyethyl) -4-methoxycarbonyl-2-azetidinone was dissolved in 18 m of dry dimethylformamide, 0.67 g of imidazole and then t-
Add butyldimethylchlorosilane (0.93g) at room temperature for 21
Stir for hours. Cold water 100m, ethyl acetate 100m in the reaction solution
Was added to separate the layers, and the aqueous layer was reextracted with 100 m of ethyl acetate. The organic layer was washed repeatedly with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained oily residue was subjected to silica gel column chromatography to obtain (3S, 4S) -1-
Di (p-anisyl) methyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -4-methoxycarbonyl-2-azetidinone was obtained.

Reference example 5-3 (3S, 4S) -1-di (p-anisyl) methyl-3-
(1- (R) -t-butyldimethylsilyloxyethyl)
8.23 g of -4-methoxycarbonyl-2-azetidinone was dissolved in 200 m of acetonitrile-water (9: 1), 19 g of cerium ammonium nitrate was added in 3 portions under ice cooling, and the mixture was stirred at 5 ° C or lower for 1 hour. 500m ethyl acetate,
Water (500 m) was added for liquid separation. The water layer is 250m ethyl acetate
The extract was re-extracted with, and the organic layers were combined, washed successively with water, 10% aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was dissolved in 30 m of methanol and stirred under ice cooling. The generated crystals were separated, the liquid was concentrated under reduced pressure, and purified by silica gel column chromatography, (3S, 4S) -3-
(1- (R) -t-butyldimethylsilyloxyethyl)
-4-Methoxycarbonyl-2-azetidinone was obtained.

Reference example 6-1 (3S, 4S) -1-di (p-anisyl) methyl-3-
(1- (R) -hydroxyethyl) -4-l-menthyloxycarbonyl-2-azetidinone (JP-A-60-3276)
No. 5) 11.8 g, imidazole 3.35 g and t
-Butyldimethylchlorosilane 4.65 g was used and Reference Example 5 was used.
-(3S, 4S) by the same processing as the method described in -2.
-1-di (p-anisyl) methyl-3- (1- (R) -t
-Butyldimethylsilyloxyethyl) -4-l-menthyloxycarbonyl-2-azetidinone was obtained.

Reference example 6-2 (3S, 4S) -4-l-menthyloxycarbonyl-
Dissolve 6.7 g of 3- (1- (R) -t-butyldimethylsilyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone in 240 m of acetonitrile-water (9: 1), and cool with ice. Add 17.26 g of cerium ammonium nitrate,
Stir for 30 minutes. Ethyl acetate (500 m) and water (500 m) were added for liquid separation, the aqueous layer was re-extracted with ethyl acetate (250 m), the organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent is methanol 30
m, and cooled with water with stirring. The generated crystals were separated, the liquid was concentrated and subjected to silica gel column chromatography to obtain (3S, 4S) -4-l-menthyloxycarbonyl-3- (1- (R) -t-butyldimethylsilyloxy. Ethyl) -2-azetidinone was obtained.

NMR δ (CDCl ₃ ): 0.77 (3H, d, J = 6.9Hz), 1.24 (3H, d, J = 6.3)
Hz), 3.21 (1H, dd, J = 1.7 and 2.6Hz), 4.26 (1H, d, J = 2.6Hz),
4.77 (1H, dt, J = 4.6 and 11Hz), 5.95 (1H, broads) Reference example 6-3 (3S, 4S) -4-l-menthyloxycarbonyl-
210 mg of 3- (1- (R) -t-butyldimethylsilyloxyethyl) -2-azetidinone was dissolved in 5 m of methylene oxide, 160 mg of methyl bromoacetate and 80 mg of 50% sodium hydroxide aqueous solution were added, and finally benzintriethylammonium chloride. After adding 60 mg and stirring at room temperature for 30 minutes, the reaction solution was diluted with ethyl acetate, washed with diluted hydrochloric acid and water, dried over magnesium sulfate, and the residue was purified by thin-layer silica gel chromatography, (3S, 4S) -4. -1-L-menthyloxycarbonyl-3- (1- (R) -t-butyldimethylsilyloxyethyl) -1-methoxycarbonylmethyl-2-azetidinone was obtained.

Reference Example 7-1 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -Hydroxyethyl) -1-di (p-anisyl) methyl-2-azetidinone 20.7 g and 4-dimethylaminopyridine 12.66 g were made into a dry methylene chloride 519 m solution, and benzyloxycarbonyl chloride 15.92 g was added under ice cooling. Dropped. After standing at 20 to 30 ° C. overnight, the reaction solution was diluted with chloroform and water. After separating the layers, the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with water (twice) and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (3
S, 4S) -4-Methoxycarbonyl-3- (1- (R)
-Benzyloxycarbonyloxyethyl) -1-di (p-anisyl) methyl-2-azetidinone was obtained.

Reference Example 7-2 (3S, 4S) -4-Methoxycarbonyl-3- (1-
(R) -benzyloxycarbonyloxyethyl) -1-
Di (p-anisyl) methyl-2-azetidinone 24.43g
And 62.84 g of cerium ammonium nitrate and Reference Example 5
Reaction and post-treatment are performed in the same manner as in the method described in (3) (3
S, 4S) -4-Methoxycarbonyl-3- (1- (R)
-Benzyloxycarbonyloxyethyl) -2-azetidinone was obtained.

 ─────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-58-96060 (JP, A) JP-A-58-99463 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula, R ₁ is a substituted or unsubstituted vinyl group at the 2-position, a hydroxymethyl group whose hydroxyl group is protected or unprotected, a protected or unprotected formyl group, or a formula (In the formula, X represents an oxygen atom.), R ₂ represents a hydrogen atom or a carboxyl-protecting group, and R ₃ represents a hydrogen atom or a hydroxyl-protecting group. ] The beta-lactam compound represented by these.