JPH09157262A - Azetidinone derivative and production of its synthetic intermediate - Google Patents

Abstract

(57) Abstract: The present invention is useful as a starting material for a carbapenem antibacterial agent having improved operability as compared with conventional methods (3R,
The present invention provides a method for synthesizing a 4R) -4-acetoxy-2-azetidinone derivative. The present invention is characterized by using an enzyme capable of asymmetric esterification and is represented by the general formula [XI] (In the formula, R ² represents a hydroxyl-protecting group, R ³ represents a lower alkyl group which may be substituted with an aryl group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, and R ⁶ represents a hydrogen atom. Or represents an aralkyl group,
Alternatively, R ⁵ and R ⁶ are terminally joined to each other to form a phthalimido group with the adjacent nitrogen atom. ) Is a method for producing the compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an azetidinone derivative useful as a raw material for medicines and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art General formula [I]

[0003]

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(In the formula, R ² represents a hydroxyl-protecting group.)
The (3R, 4R) -4-acetoxy-2-azetidinone derivative represented by is a compound useful as a starting material for a carbapenem antibacterial drug, and is, for example, 2- (pyrrolidine-2).
It is used as a raw material for 4-on-4-ylthio) -6- (1-hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylic acid (JP-A-2-49783).
issue).

A conventionally known method for producing a (3R, 4R) -4-acetoxy-2-azetidinone derivative [I] is, for example, methyl 2- (N-benzoylaminomethyl) -3-oxobutanoate and ruthenium-optically active phosphine. Asymmetric hydrogenation was carried out in the presence of a complex to obtain (2S, 3R) -2.
Hydrolysis of methyl-(N-benzoylaminomethyl) -3-hydroxybutanoate followed by neutralization and further lactamization yielded (1'R, 3S) -3-hydroxyethylazetidin-2-one, then General formula [II] obtained by protecting a hydroxyl group

[0006]

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A method is known in which a compound represented by the formula (wherein R ² has the same meaning as described above) is reacted with acetic acid and an oxidizing agent using a ruthenium compound as a catalyst (JP-A-2-231471). .

Further, 2- (phthalimidomethyl) acetoacetic acid benzyl ester was obtained by asymmetric hydrogenation in the presence of a ruthenium-optically active phosphine complex (2S, 3R).
It is obtained by reacting benzyl 3-hydroxy-2- (phthalimidomethyl) butyric acid with t-butyldimethylchlorosilane, and further reacting with hydrazine (2
S, 3R) -2-Aminomethyl-3- (t-butyldimethylsilyloxy) butyric acid benzyl ester was catalytically reduced using a palladium catalyst to give (2S, 3R) -2-aminomethyl-3- (t-butyl). Dimethylsilyloxy) butyric acid is prepared, and then the compound is lactamized to give compound [I
I] is also known (JP-A-5-23901).
No. 9).

However, since all of these methods require asymmetric hydrogenation using an expensive ruthenium-optically active phosphine complex as a catalyst, they are satisfactory in terms of cost and operability as industrial methods. It wasn't something.

[0010]

DISCLOSURE OF THE INVENTION The present invention significantly reduces the manufacturing cost as compared with the conventional method and improves the operability of the (3R, 4R) -4-acetoxy-2-azetidinone derivative [I] and The present invention provides a method for synthesizing the synthetic intermediate.

[0011]

The inventors of the present invention have (3R,
As a result of various studies on the production method of the 4R) -4-acetoxy-2-azetidinone derivative [I], the compound represented by the general formula [II]
I-a]

[0012]

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(In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , and R ⁴ represents a hydrogen atom or a substituent. Z is a substituted or unsubstituted methylene group, R ⁵ is an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ is a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are the same as each other. A phthalimide group is formed together with the adjacent nitrogen atom by binding at the terminal.), And a (3R, 4R) -4-acetoxy-2-azetidinone derivative [I] is obtained from the compound. The present invention has been completed successfully.

That is, according to the present invention, the compound [III-
a] is represented by the general formula [IV]

[0015]

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A compound represented by the formula (wherein rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above) is reacted with acetaldehyde or a reactive derivative thereof to obtain a general formula [III]

[0017]

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It can be produced by optical resolution of a compound represented by the formula (rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above).

Z may be a substituted methylene group having at least one asymmetric center or a substituted or unsubstituted methylene group having no asymmetric center.

When Ring B has a substituent, any substituent can be used as long as it does not participate in the reaction. Preferable examples of the substituent in ring B include a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, a nitro group, a lower alkylthio group and a di-lower alkylamino, and these substituents are the same or different and ~
It may be substituted on four benzene rings.

Examples of the substituent R ⁴ on the nitrogen atom in Y include a lower alkyl group, an acyl group and an aralkyloxycarbonyl group. As the substituent on the methylene group in Z, the number of carbon atoms which may have a substituent is 3 to
1 to 7 selected from an alkylene group of 7, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group, an aralkyl group and a heterocyclic group.
There are two groups.

Of the groups shown above, the alkyl group has 1 to 20 carbon atoms, and particularly 1 to 1 carbon atoms.
5 is preferable, and a cycloalkyl group having 4 to 7 carbon atoms is preferable. Examples of the acyl group include a lower alkanoyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted phenylcarbonyl group or a substituted or unsubstituted phenyl lower alkoxycarbonyl group, and an aryl group includes a substituted or unsubstituted phenyl group or a substituted or non-substituted group. Examples thereof include a substituted naphthyl group, and examples of the aralkyl group include a lower alkyl group substituted with a substituted or unsubstituted phenyl group and a lower alkyl group substituted with a substituted or unsubstituted naphthyl group, and a heterocyclic group. Is a 4- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a substituted or unsubstituted hetero atom (for example, a furyl group, a pyrrolyl group, a thienyl group, etc.). Examples of the substituent on the alkylene group, the alkyl group and the cycloalkyl group, the aryl group, the substituent on the phenyl group and the naphthyl group in the aralkyl group, and the substituent on the heterocyclic group include, for example, a lower alkyl group and a lower alkoxy group. Preferred examples thereof include halogen atom and optionally protected amino group. As the amino-protecting group, any of those commonly used as an amino-protecting group in peptide chemistry and the like can be used.

The reaction of compound [IV] with acetaldehyde or its reactive derivative is preferably carried out in the presence of a metal catalyst in a suitable solvent, particularly preferably in the presence of a metal catalyst and a base. . An acetal is mentioned as an example of a reactive derivative of acetaldehyde.

The metal catalyst is represented by the general formula [V]

[0025]

LJnQm [V] (In the formula, L represents a metal atom, J represents a halogen atom, Q represents a lower alkyl group, a lower alkoxy group, a phenoxy group, a substituted phenoxy group, or a cyclopentadienyl group. In the case of two or more, they may be different and n
And m are 0, 1, 2, 3, 4 or 5 respectively and n +
m represents the valence of L. )). As the metal atom, titanium (Ti), zinc (Zn),
Tin (Sn), boron (B), zirconium (Zr),
Aluminum (Al), magnesium (Mg), etc. can be used conveniently. Specific examples of the metal catalyst include titanium tetrachloride [TiCl ₄ ], titanium trichloride monomethoxide [TiCl ₃ (OCH ₃ )], titanium trichloride monoethoxide [TiCl ₃ (OC ₂ H ₅ )], and titanium trichloride. Mono (n-propoxide) [TiCl ₃ (OC ₃ H ₇ ⁿ )], titanium trichloride mono (i-propoxide) [TiCl ₃ (O
C ₃ H ₇ ⁱ )], titanium trichloride mono (n-butoxide)
[TiCl ₃ (OC ₄ H ₉ ⁿ )], titanium trichloride mono (i-
Butoxide) [TiCl ₃ (OC ₄ H ₉ ⁱ )], titanium trichloride mono (s-butoxide) [TiCl ₃ (OC
₄ H ₉ ^s )], titanium trichloride mono (t-butoxide) [T
iCl ₃ (OC ₄ H ₉ ^t )], titanium dichloride dimethoxide [TiCl ₂ (OCH ₃ ) ₂ ], titanium dichloride dietoxide [TiCl ₂ (OC ₂ H ₅ ) ₂ ], titanium dichloride di (n
-Propoxide) [TiCl ₂ (OC ₃ H ₇ ⁿ ) ₂ ], titanium dichloride di (i-propoxide) [TiCl ₂ (OC ₃ H
₇ ⁱ ) ₂ ], titanium dichloride di (n-butoxide) [TiC
l ₂ (OC ₄ H ₉ ⁿ ) ₂ ], a titanium catalyst such as zinc chloride (Z
nCl ₂ ), zinc iodide (ZnI ₂ ), tin (IV) chloride
(SnCl ₄ ), tin bis (trifluoromethanesulfonate) [Sn (OTf) ₂ ], di (n-butyl) boron (trifluoromethanesulfonate) [BOTf (C
₄ H ₉ ⁿ ) ₂ ], zirconium (IV) chloride [ZrC
l ₄ ], zirconium trichloride monomethoxide [ZrC
l ₃ (OCH ₃ )] _, zirconium trichloride monoethoxide [ZrCl ₃ (OC ₂ H ₅ )], zirconium trichloride mono (n-propoxide) [ZrCl ₃ (OC ₃ H ₇ ⁿ )],
Zirconium trichloride mono (i-propoxide) [TiC
l ₃ (OC ₃ H ₇ ⁱ )], zirconium trichloride mono (i-butoxide) [ZrCl ₃ (OC ₄ H ₉ ⁱ )], zirconium trichloride mono (t-butoxide) [ZrCl ₃ (OC
₄ H ₉ ^t )], aluminum trichloride (AlCl ₃ ), aluminum trimethoxide [Al (OCH ₃ ) ₃ ] _, aluminum triethoxide [Al (OC ₂ H ₅ ) ₃ ], aluminum tri (i-propoxide). ) [Al (OC
₃ H ₇ ⁱ ) ₃ ], ethyl aluminum dichloride (AlCl
₂ C ₂ H ₅ ), diethyl aluminum chloride [AlCl
(C ₂ H ₅ ) ₂ ], triethylaluminum [Al (C ₂ H 5
₅ ) ₃ ], methylaluminum dichloride (AlCl ₂ C
H ₃ ), dimethyl aluminum chloride [AlCl (C
H _{3) 2],} trimethyl aluminum [Al (C
H _{3) 3],} magnesium diethoxide [Mg (OC
₂ H _{5) 2],} magnesium iodide (MgI _2), magnesium perchlorate [Mg (ClO _{4) 2]} and the like can be exemplified. Of these, a titanium catalyst is particularly preferable.

Examples of the base include secondary and tertiary amines and pyridines. For example, alkylamines such as dimethylamine, diethylamine, diisopropylamine and dicyclohexylamine, alkylanilines such as N-methylaniline, piperidine, pyrrolidine, and 2 , 2, 6, 6-
Secondary amines such as heterocyclic amines such as tetramethylpiperidine, morpholine and piperazine, alkylamines such as diisopropylethylamine, diisopropylmethylamine and triethylamine, dialkylanilines such as N, N-dimethylaniline, 1-ethylpiperidine, 1- Heterocyclic amines such as methylmorpholine, 1-ethylpyrrolidine, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] undes-7-ene or N, N, Tertiary amines such as diamines such as N ′, N′-tetramethylethylenediamine, α,
β or γ-pyricon, 2,3-, 2,4-, 2,5
-, 2,6-, 3,4- or 3,5-lutidine, 2,
Examples thereof include alkylpyridines such as 4,6-collidine, dialkylaminopyridines such as dimethylaminopyridine, and pyridines such as condensed heterocyclic pyridines such as quinoline, and sodium hexamethyldisilazane and lithium hexamethyl. Alkali metal hexa-lower alkyldisilazanes such as disilazane can also be used. Of these, triethylamine and sodium hexamethyldisilazane are particularly preferable.

As the solvent, tetrahydrofuran, dichloromethane, dichloroethane, dimethoxyethane, toluene, dimethylformamide, dimethylsulfoxide,
Preference is given to using hexamethylphosphoric triamide. Of these, tetrahydrofuran and dichloromethane are particularly preferable.

This reaction suitably proceeds at -78 ° C to 10 ° C.

By this reaction, the compound [III] is mainly represented by the general formula [III-b] which is an enantiomer of the compound [III-a] and the compound [III-a].

[0030]

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(In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above), which is obtained as a mixture of the compounds, but other stereoisomerism may be obtained. The body may be included as a byproduct.

Optical resolution of the compound [III] can be carried out by chromatographic separation and / or asymmetric esterification reaction and the like.

For example, the compound [III], that is, a mixture of the compound [III-a] and the compound [III-b] is added to the compound of the general formula [VI].

[0034]

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(In the formula, R ¹ represents an organic group and R represents an ester residue.) In the presence of an ester compound, an enzyme having the ability to asymmetrically esterify is reacted with the compound [I
II-a] was esterified to produce a general formula [VII]

[0036]

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This is carried out by separating the compound represented by the formula (wherein rings B, W, Y, Z, R ¹ , R ⁵ and R ⁶ have the same meanings as described above) and hydrolyzing them. be able to.

Compound [III-a] and compound [III-
The esterification reaction of the mixture of b] can be carried out by contacting it with an enzyme capable of asymmetric esterification in the presence of compound [VI] in a suitable solvent. Compound [II
The molar ratio of Ia] to the compound [III-b] may or may not be equimolar and can be used for the asymmetric esterification reaction.

As the organic group R ¹ , any organic group suitable for asymmetric esterification can be used.
Bulky organic groups are preferred. As such an organic group, an organic group having 5 or more carbon atoms can be mentioned, and preferably an alkyl group having 5 to 20 carbon atoms, particularly an undecyl group can be used.

As the ester residue R, any conventional ester residue can be used, but an ester residue that suppresses the reverse reaction of esterification (hydrolysis or transesterification) is preferable. Such ester residues include 2,
Corresponding alcohols such as 2,2-trifluoroethyl group and 2,2,2-trichloroethyl group are ester residues having relatively strong acidity, and ester residues such as vinyl groups in which the corresponding alcohol is isomerized to aldehyde. Group, an ester residue such as an isopropenyl group in which the corresponding alcohol isomerizes to a ketone can be mentioned, but a vinyl group is particularly preferable.

Examples of enzymes include a group of enzymes called lipase, esterase or protease. Such an enzyme may be derived from a microorganism or may be extracted from an animal cell or a plant cell by a known method, but a microorganism-derived enzyme is particularly preferable.

When the enzymes used in the present invention are derived from microorganisms, examples of microorganisms producing these enzymes include fungi, bacteria, actinomycetes, and the like. For example, the fungi include Aspergillus spp., Bear uberia spp., Geotricum spp. Genus, Penicillium genus, Candida genus, Rhizopus genus, Mucor genus, Humicola genus, there are microorganisms belonging to the genus Humicola, bacteria include, Acetobacter, Bacillus, Brevibacterium, Corynebacterium, Pseudomonas,
The microorganisms belonging to the genus Rhodococcus, the genus Serratia and the genus Chromobacterium are mentioned, and the actinomycetes include the microorganisms belonging to the genus Nocardia and the genus Streptomyces.

Specific examples of such microorganisms include, for example,
Aspergillus
flavus) IFO 5839, Aspergillus usamii IF
O 4388, Beauvelia Bassiana
ria bassiana) ATCC 7159, Geotrichum candi dam (Geotrichum ca)
ndidum) IFO 4598, Penicillium oxalicum (Penicillium oxalicu)
m) IFO 5748, Acetobacter pasteurian
us) IFO 3223, Bacillus licheniformis A
TCC 14580, Bacillus pumilus
lus pumilus) IFO12086, the same IF
O 12087, IFO 12089, Bacillus
Subtilis (Bacillus subtilis)
ATCC 6633, Brevibacterium flavum AT
CC 14067, Corynebacterium glutamicum
um) ATCC 13761, Pseudomonas aeruginos
a) ATCC 10145, ATCC 7700, Pseudomonas pu
tida) ATCC 12633, ATCC 17
426, IFO 12996, Rhodococcus sp. ATCC
15592, Rhodococcus rhodochrous (Rhod
ococcus rhodochrous) ATCC
29670, Serratia Marcescens
a marcescens) ATCC 21074, FERM BP-487, Nocardia asteroides IF
O 3424, Streptomyces scavies (St
reptomyces scavies) IFO 31
11 etc.

These microorganisms may be wild strains or mutant strains. Furthermore, gene recombination from these microorganisms,
It may be derived by a bioengineering technique such as cell fusion.

The enzyme that can be used in the present invention may be a commercially available enzyme, and examples of such commercially available enzyme include lipase QL (derived from Alcaligenes sp., Manufactured by Meito Sangyo Co., Ltd.), lipase OF (derived from Candida cylindracea, Sugar Industry), Lipase MY (from Candida cylindracea,
Meito Sangyo Co., Ltd., Lipase AY (from Candida cylindracea, manufactured by Amano Pharmaceuticals), Lipase A (Aspergillus)
Derived from Niger, manufactured by Amano Pharmaceuticals, Denapsin 10P (derived from Aspergillus niger, manufactured by Nagase Seikagaku), Protease M (derived from Aspergillus oryzae, manufactured by Amano Pharmaceuticals), Alcalase 2.5L (derived from Bacillus licheniformis, Denmark, Novo Nordisk) ), Esperase 8.0L (from Bacillus species, manufactured by Novo Nordisk, Denmark), XP-415 (derived from Rhizopus derema, manufactured by Nagase Seikagaku), Lipase Saiken 100 (derived from Rhizopus japonicas, manufactured by Nagase Biochemical) , Neurase (from Rhizopus niveus, manufactured by Amano Pharmaceuticals), Lipase P (Pseudomonas)
Species origin, Amano Pharmaceuticals, Lipase P (Pseudomonas species origin, Nagase Seikagaku),
Lipase CES (from Pseudomonas species,
Amano Pharmaceuticals), Lipase YS (Pseudomonas species origin, Amano Pharmaceuticals), Lipase G (Penicillium)
Derived from cyclopium, manufactured by Amano Pharmaceuticals, lipase R (derived from Penicillium roqueforti, manufactured by Amano Pharmaceuticals), lipase CE (derived from Humicola Langinosa, manufactured by Amano Pharmaceuticals), paratase M (derived from Mucor Mihei, Denmark, Novo Nordisk), Lipase GC (from Geotricum Candidum, manufactured by Amano Pharmaceuticals), Lipase L
Examples include P (derived from Chromobacterium viscosum, manufactured by Asahi Kasei), SP398 (manufactured by Novo Nordisk, Denmark).

The asymmetric esterification ability of the enzyme that can be used in the present invention varies depending on the type of substrate and reaction conditions (type of solvent, etc.).
Candida cylindracea, Pseudomonas species, Aspergillus niger, Aspergillus oryzae, Serratia marcescens, Corynebacterium glutamicum, Geotrichum candidam, Bacillus subtilis, Rhodococcus rhodochrous, Mucor mihei, Humicola langinosa, and other enzymes derived from microorganisms.

When the enzyme used in the present invention is obtained by culturing a microorganism, the method for culturing the microorganism is according to a conventional method, and the microorganism is usually used in this field, for example, in a medium containing a conventional carbon source, nitrogen source and inorganic salts. At room temperature or under heating (preferably about 20 to 40 ° C.) and under aerobic conditions, p
It may be cultured in H2-8. Further, as an example of a method of culturing a microorganism and separating / collecting or purifying an enzyme, the description in JP-A-4-228070 can be followed.

In the method of the present invention, the enzyme may be used in the form of the enzyme itself, a culture solution of a microorganism having the ability to produce the enzyme (a solid medium may be used), a treated product of the culture solution, or the culture solution. The cells can be used in any form, such as the cells isolated by the conventional method from E. coli or a treated product of the cells.

Examples of the treated microbial cells include freeze-dried microbial cells, acetone-dried microbial cells, autolyzed microbial cells,
Examples include bacterial cell extracts, bacterial cell grinds, and ultrasonicated products of bacterial cells.

Further, the enzyme, microbial cell, and cell-treated product used in the present invention include, for example, polyacrylamide method, sulfur-containing polysaccharide gel method (carrageenan gel method, etc.), alginic acid gel method,
It can be used after being immobilized by a known method such as an agar gel method, a photocrosslinkable resin, polyethylene glycol or the like.

In the enzymatic reaction of the present invention, the concentration of the mixture of the compound [III-a] and the compound [III-b], which is the substrate, is about 0.01 to 20%, particularly 0.05 to 10%.
%, The reaction is at room temperature or under heating, preferably 1
It suitably proceeds at 0 to 50 ° C, especially 25 to 40 ° C.
In the reaction, the pH of the reaction solution is 7 or less, especially p
It is preferable to adjust to H5.0 to 6.0.
As the solvent used for the enzymatic reaction, water or alkanol (eg, methanol, ethanol, n-propanol, n-butanol, n-octanol, etc.) can be used, and the compound [III-a] and the compound [III] are used.
Depending on the solubility and stability of the mixture of -b], not only water or alkanol can be used, but also water or alkanol to which an organic solvent other than alkanol is added can be used. Examples of the organic solvent include benzene, n-hexane, isooctane, diethyl ether, diisopropyl ether, toluene, cyclohexane, carbon tetrachloride, methylene chloride, ethyl acetate, methyl acetate, acetone, dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, Examples include pyridine and the like. In the enzymatic reaction, the mixture of the compound [III-a] and the compound [III-b] may be added all at once at the beginning, or may be added several times during the reaction.

After the enzymatic reaction, the ester compound [V
[II] can be separated by a conventional method, for example, silica gel chromatography.

Hydrolysis of compound [VII] can be carried out by a conventional method. For example, it can be carried out in the presence of an enzyme capable of hydrolyzing in a suitable solvent. As the enzyme, lipase QL, lipase AL, lipase PL, lipase OF, etc. can be used, and as the solvent, water or a mixture of water and a lower alkanol can be used. This reaction is preferably carried out in the presence of a phosphate buffer, and it suitably proceeds at 0 ° C to 70 ° C, and optimally proceeds at 20 ° C to 40 ° C.

The compound [III-a] thus obtained is the (3R) -2-azetidinone derivative [II] or (3
R, 4R) -4-acetoxyazetidinone derivative [I]
It can lead to a known compound that becomes a precursor of.

For example, compound [III-a] and general formula [VIII]

[0056]

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(Wherein, X represents a reactive residue and R ² has the same meaning as described above), and the compound represented by the general formula [IX] is obtained.

[0058]

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(Wherein the rings B, W, Y, Z, R ² , R ⁵ and R ⁶ have the same meanings as described above), the compound represented by the general formula [X]

[0060]

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(Wherein M represents an alkali metal and R ³ has the same meaning as described above), and the compound represented by the general formula [XI] is reacted.

[0062]

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The compound represented by the formula (wherein R ² , R ³ , R ⁵ and R ⁶ have the same meanings as described above) can be prepared.

Compound [III-a] and compound [VII
The reaction with I] can be carried out by a conventional method. Examples of the reactive residue X include a halogen atom and a trifluoromethanesulfonyloxy group. As the protective group R ² for the hydroxyl group, any conventional protective group can be used, but a silyl group substituted with three substituents selected from a linear or branched lower alkyl group and a phenyl group can be used. preferable. Examples of such a tri-substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a methyldiisopropylsilyl group, a t-butyldiphenylsilyl group and a triphenylsilyl group. This reaction can be carried out, for example, in a solvent such as dichloromethane in the presence of a base such as 2,6-lutidine under cooling to room temperature.

The reaction between the compound [IX] and the compound [X] can be carried out by a conventional method. As the alkali metal of the compound [X], sodium, lithium or the like can be preferably used. This reaction can be carried out, for example, in a solvent such as tetrahydrofuran under cooling to room temperature.

The compound [IV] is a novel compound, for example, the compound of the general formula [XII]

[0067]

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(Wherein rings B, W, Y and Z have the same meanings as described above) and 3-phthalimidopropionic acid chloride are combined with a base (eg diisopropylethylamine) and a catalyst (eg copper chloride ( It can be produced by reacting under heat in the presence of I)).

The compound [XI] obtained by the above method is a known method (for example, JP-A-2-231471 and JP-A-4-3).
21665 and the method described in JP-A No. 5-239019)
, Which is useful as a raw material for antibacterial drugs according to
It can be led to a 4-acetoxy-2-azetidinone derivative [I]. For example, a compound of general formula [XIII] obtained by reacting compound [XI] with hydrazine

[0070]

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(In the formula, R ² and R ³ have the same meanings as described above.) The compound represented by the general formula [XI] is catalytically reduced using a palladium catalyst (for example, palladium-carbon).
V]

[0072]

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(Wherein R ² has the same meaning as described above), and then the compound [XI
V] can be dehydrated and lactamed to obtain compound [II], and an acetoxy group can be introduced to prepare (3R, 4R) -4-acetoxy-2-azetidinone derivative [I].

In the present invention, examples of the lower alkyl group and the lower alkoxy group include those having 1 to 6 carbon atoms, those having 1 to 4 carbon atoms are particularly preferable, and the lower alkanoyl group has 2 to 2 carbon atoms. Although those having 6 carbon atoms are listed, those having 1 to 4 carbon atoms are particularly preferable.

[0075]

【Example】

Example 1 (1) A mixture of 89 g of β-alanine and 148 g of phthalic anhydride is heated at 180 to 190 ° C. for 30 minutes. The mixture is cooled to 60 ° C., 500 ml of ethyl acetate are added, and the mixture is further stirred at 0 ° C. for 1 hour. N-Hexane is added to the reaction solution, and the precipitated crystals are collected by filtration to obtain 219.5 g of 3-phthalimidopropionic acid as colorless crystals.

M. p. 149-151 ° C.

(2) A mixture of 3.29 g of this product and 45 ml of thionyl chloride was refluxed for 15 minutes and then concentrated to obtain 3.6 g of 2,3-phthalimidopropionic acid chloride.
A mixture of 2.05 g of 3-dihydro-2,2-diethyl-4H-1,3-benzoxazin-4-one, 2.91 g of diisopropylethylamine and 19 mg of copper (I) chloride is stirred at 80 to 90 ° C. for 3 hours. . After the reaction, the mixture was washed and dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =).
7: 1) purified to give 2,3-dihydro-2,2-diethyl-3- (3-phthalimidopropionyl) -4H-
2.92 g of 1,3-benzoxazin-4-one are obtained as colorless crystals.

M. p. 141-144 ° C.

(3) To a solution of 0.813 g of this product in 8 ml of tetrahydrofuran was added dropwise 2 ml of sodium hexamethyldisilazane (1M tetrahydrofuran solution) at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. Furthermore -78 ° C
Then, 2 ml of triisopropyl chloride titanate (1M hexane solution) is added dropwise, and the mixture is stirred at -78 ° C for 100 minutes. Acetaldehyde 0.34 was added to the mixture at -78 ° C.
ml is added and the temperature is gradually raised to 5 ° C. in 2 hours. The mixture was mixed with 10 ml of pH 7 phosphate buffer and 10 m of ethyl acetate.
Dilute with l. The deposited white precipitate is filtered through Celite, the organic layer of the filtrate is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 3: 1) to give 2,3-dihydro-2,2.
-Diethyl-3-[(2S) -3-phthalimido-2-
((1R) -1-hydroxyethyl) propionyl]-
4H-1,3-benzoxazin-4-one and 2,3
-Dihydro-2,2-diethyl-3-[(2R) -3-
0.405 g of a mixture of phthalimido-2-((1S) -1-hydroxyethyl) propionyl] -4H-1,3-benzoxazin-4-one is obtained as colorless crystals.

M. p. 135-136 ° C.

(4) 2 g of this product, 2 m of vinyl laurate
A mixture of 1, 400 mg of lipase QL and 40 ml of diisopropyl ether is stirred at 30 ° C. for 72 hours. After the reaction, the mixture is filtered and concentrated. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =
4: 1 and 2: 1) purified to give 2,3-dihydro-
2,2-diethyl-3-[(2S) -3-phthalimido-2-((1R) -1-lauryloxyethyl) propionyl] -4H-1,3-benzoxazin-4-one 1.41 g colorless syrup As an oil.

IR (KBr) νmax: 1721,16
11,1467cm ^-1 [α] _D ²⁵ + 3.57 ° (c = 1.23, methanol).

(5) 800 mg of this product, lipase QL8
00 mg, phosphate buffer 20 ml (0.1 M, pH 7)
And a mixture of 1 ml of ethanol are stirred at 40 ° C. for 20 hours. After the reaction, the mixture is filtered and the filtrate is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1 to 2: 1) to give 2,3-
Dihydro-2,2-diethyl-3-[(2S) -3-phthalimido-2-((1R) -1-hydroxyethyl)
Propionyl] -4H-1,3-benzoxazine-4
399 mg of -one are obtained as colorless crystals.

M. p. 115-117 ° C.

[Α] _D ²⁵ -7.22 ° (c = 1.1
1, methanol).

(6) To 0.5 ml of this product in 5 ml of dichloromethane, 0.4 g of t-butyldimethylsilyl triflate and 0.37 g of 2,6-lutidine are added at 5 ° C., and the mixture is stirred at the same temperature for 10 minutes. The reaction mixture is poured into water, washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 12: 1) to give 2,3-dihydro-.
2,2-Diethyl-3-[(2S) -3-phthalimido-2-((1R) -1-t-butyldimethylsilyloxyethyl) propionyl] -4H-1,3-benzoxazin-4-one 0 0.65 g are obtained as colorless crystals.

IR (KBr) νmax: 1774,17
19,1611,1468cm ^-1 [α] _D ²⁵ -28.4 ° (c = 0.98, methanol).

(7) Benzyl alcohol 0.055 m
0.29 ml of n-butyllithium (1.6M hexane solution) is added to a solution of 1 in 2 ml of tetrahydrofuran at -60 ° C, and the temperature is raised to 25 ° C. 2,3-dihydro-2,2-diethyl- was added to the obtained benzyloxylithium solution.
3-[(2S) -3-phthalimido-2-((1R)-
After adding 0.2 g of 1-t-butyldimethylsilyloxyethyl) propionyl] -4H-1,3-benzoxazin-4-one at -78 ° C, the mixture is stirred at 3 ° C for 17 hours. Water and ethyl acetate are added to the mixture, the organic layer is washed and dried, and then the solvent is distilled off. The residue is subjected to silica gel column chromatography (solvent; chloroform: hexane:
Ethyl acetate = 10: 1: 0.5) and purified (2S)-
Benzyl 3-phthalimido-2-[(1R) -1-t-butyldimethylsilyloxyethyl] propionate
103 g are obtained as a colorless oil.

IR (KBr) νmax: 1770, 17
18 cm ^-1 MS m / z: 468 (M ⁺ +1) [α] _D ²⁵ + 15.2 ° (c = 0.99, methanol).

Production Example 1 (1) (2S) -3-phthalimido-2-[(1R)
-1-t-Butyldimethylsilyloxyethyl] benzyl benzyl propionate 1.12 g, hydrazine monohydrate 61
A mixture of 2 mg and 20 ml ethanol was added at 25 ° C to 17
Stir for hours. The precipitated crystals are filtered off and the filtrate is concentrated. The residue is suspended in hexane and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 40: 1) to give (2S) -3.
-Amino-2-[(1R) -1-t-butyldimethylsilyloxyethyl] benzyl benzyl propionate 642.2m
g as a colorless oil.

IR (KBr) νmax: 1732 cm ^-1 MS m / z: 338 (M ⁺ +1) [α] _D ²⁵ -24.2 ° (c = 1.2, methanol).

(2) A mixture of 390 mg of this product, 770 mg (50%) of 10% palladium carbon and 30 ml of methanol was pressurized with hydrogen (3.5 atm) using a pressure device.
Hydrogenate at 25 ° C. for 1 hour. The mixture is heated to 50 ° C. and filtered. The solvent of the filtrate was distilled off, and the precipitated crystals were collected while adding acetone and ether, and 200 mg of (2S) -3-amino-2-[(1R) -1-t-butyldimethylsilyloxyethyl] propionic acid was colorless. Obtained as crystals.

M. p. 192-194 ° C (3) To a solution of 70 mg of this product in 57 ml of acetonitrile, 75 mg of triphenylphosphine and 75 mg of 2,2'-dipyridyl disulfide are added at 25 ° C. The mixture is stirred at 60 ° C. for 5 hours and at 40 ° C. for 8 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give (1′R, 3S) -3- (1′-t-butyldimethylsilyloxyethyl). 49 mg of azetidin-2-one are obtained as colorless crystals.

M. p. 66-67 ° C [α] _D ²⁵ -68.7 ° (c = 0.6, methanol).

(4) 100 mg of this product, 29 mg of sodium acetate, ruthenium (III) chloride hydrate 18.3
14 ml of ethyl acetate and 0.7 ml of acetic acid in a mixture of mg
And stirred for 30 minutes at 40 ° C. in an oxygen atmosphere. Next, 0.15 ml of acetaldehyde is added, and the mixture is stirred at 40 ° C. for 3 hours. The mixture is poured into 60 ml of 10% aqueous sodium sulfite solution and extracted twice with ethyl acetate. The combined extracts are collected, washed, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 3: 1) to give (1′R, 3
R, 4R) -4-acetoxy-3- (1′-t-butyldimethylsilyloxyethyl) -2-azetidinone 1
55 mg are obtained as colorless crystals.

M. p. 104-107 ° C [α] _D ²⁵ + 29.3 ° (c = 0.9, methanol).

Production Example 2 (2S) -3-Amino-2-[(1R) -1-t-butyldimethylsilyloxyethyl] benzyl propionate (100 mg) was dissolved in tetrahydrofuran (2 ml) solution with ethylmagnesium bromide (1M tetrahydrofuran solution).
1.38 ml is added dropwise at -15 ° C over 1 hour. The reaction solution is stirred at −10 ° C. for 2 hours and heated to 25 ° C. in 30 minutes. Then, the mixture is poured into water, extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 4: 1) to give (1′R, 3S).
31 mg of -3- (1'-t-butyldimethylsilyloxyethyl) azetidin-2-one is obtained as colorless crystals.

M. p. 66-67 ° C. [α] ^{_{D 25 -68.7 ° (c = 0.6}} , methanol).

[0099]

INDUSTRIAL APPLICABILITY According to the present invention, compound [III-a] can be produced from compound [IV] in a higher yield and a higher stereoselectivity, so that an expensive ruthenium-optically active phosphine complex can be obtained. Useful as a starting material for carbapenem antibacterial agents without asymmetric hydrogenation as a catalyst (3
The compound [XI], which is a precursor of the R, 4R) -4-acetoxy-2-azetidinone derivative [I], can be stereoselectively produced.

Therefore, the present invention is advantageous as an industrial manufacturing method having improved operability as compared with the conventional method.

[0101]

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07D 265/20 C07D 265/22 265/22 279/08 279/08 9159-4C C07D 205/08 F // C07M 7:00 9159-4CP

Claims (8)

[Claims] 1. A compound represented by the general formula [III]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. And form a phthalimido group together with the adjacent nitrogen atom.) By optically resolving the compound represented by the general formula [III-
a] (In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) 2. A compound represented by the general formula [IV]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. To form a phthalimido group together with the adjacent nitrogen atom) and an acetaldehyde or a reactive derivative thereof are reacted to give a compound of the general formula [III] (In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) A compound represented by the general formula [III-a] ] (In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) 3. A compound represented by the general formula [III-a]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. To form a phthalimido group with the adjacent nitrogen atom) and a compound represented by the general formula [III-b]: (Wherein rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above), and a mixture of compounds represented by the general formula [V
I] (In the formula, R ¹ represents an organic group and R represents an ester residue.) In the presence of an ester compound, an enzyme having the ability to asymmetrically esterify is reacted to esterify the compound [III-a]. Of the general formula [VII] (Wherein rings B, W, Y, Z, R ¹ , R ⁵ and R ⁶ have the same meanings as described above). 4. A compound represented by the general formula [IV]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. To form a phthalimido group with the adjacent nitrogen atom) and acetaldehyde or a reactive derivative thereof are reacted to give a compound of the general formula [III] (In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) And a compound represented by the general formula [III-
b] (Wherein rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above), and a mixture of compounds represented by the general formula [V
I] (In the formula, R ¹ represents an organic group and R represents an ester residue.) In the presence of an ester compound, an enzyme having the ability to asymmetrically esterify is reacted to esterify the compound [III-a]. Of the general formula [VII], characterized in that the formed ester is separated. (Wherein rings B, W, Y, Z, R ¹ , R ⁵ and R ⁶ have the same meanings as described above). 5. A compound represented by the general formula [III-a]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. To form a phthalimido group with the adjacent nitrogen atom) and a compound represented by the general formula [III-b]: (Wherein rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above), and a mixture of compounds represented by the general formula [V
I] (In the formula, R ¹ represents an organic group and R represents an ester residue.) In the presence of an ester compound, an enzyme having the ability to asymmetrically esterify is reacted to esterify the compound [III-a]. , The generated general formula [VII] (In the formula, rings B, W, Y, Z, R ¹ , R ⁵ and R ⁶ have the same meanings as described above.) A compound characterized by separating and hydrolyzing the compound [ III-a]
Recipe. 6. A compound represented by the general formula [III]: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z represents a substituted or unsubstituted methylene group, R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminals. And form a phthalimido group with the adjacent nitrogen atom.) Is optically resolved to obtain the compound of the general formula [III-a] embedded image (In the formula, rings B, W, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) The compound represented by the general formula [VII
I] (Wherein R ² is a hydroxyl-protecting group and X represents a reactive residue), and the compound of the general formula [IX] (Wherein rings B, W, Y, Z, R ² , R ⁵ and R ⁶ have the same meanings as described above), and a compound represented by the general formula [X] (Wherein R ³ is a lower alkyl group which may be substituted with an aryl group, M is an alkali metal), and the compound is reacted with a compound of the general formula [XI] (In the formula, R ² , R ³ , R ⁵ and R ⁶ have the same meanings as described above.) 7. A compound [X obtained by the method of claim 6]
I] is represented by the general formula [II] (Wherein R ² represents a hydroxyl-protecting group) or a (3R) -2-azetidinone derivative represented by the general formula [I] (In the formula, R ² has the same meaning as described above.) A method for producing an azetidinone derivative, which comprises converting to a (3R, 4R) -4-acetoxy-2-azetidinone derivative or a salt thereof. 8. A general formula: (In the formula, ring B represents an optionally substituted benzene ring, W represents an oxygen atom or a sulfur atom, Y represents O, S or NR ⁴ , R ⁴ represents a hydrogen atom or a substituent, Z ¹ represents a substituted or unsubstituted methylene group having no asymmetric center,
R ⁵ represents an aralkyloxycarbonyl group or an alkyloxycarbonyl group, R ⁶ represents a hydrogen atom or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other at the terminal to form a phthalimide group together with an adjacent nitrogen atom. Form. ).