JPH0250107B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ¹ represents a carboxyl protecting group, and R ² represents a hydrogen atom or an amino protecting group. ] This invention relates to a novel method for producing (4R)-4-(3-substituted carboxy-2-oxo-propyl)-2-azetidinone. In recent years, with the discovery of thienamycin (US Pat. No. 3,950,357), which has useful biological activity, research has been actively conducted to obtain various carbapenems purely synthetically. As is clear from the structural formula of carbapenems, various isomers exist, but useful compounds are optically active forms with a specific three-dimensional structure. Therefore, the present inventors focused on the fact that if optically active intermediates could be obtained, they could be advantageously derived into various optically active carbapenems, and developed a novel method for producing optically active compounds of general formula (). As a result of extensive research, a method for chemically deriving this from L-aspartic acid was discovered, and the present invention was completed. According to the present invention, a novel method for producing an optically active compound represented by the general formula () which is extremely useful as an intermediate for various useful carbapenems is provided. The present invention will be explained in detail below. In the general formula (), the carboxyl group-protecting group for R ¹ includes all groups commonly known as carboxyl group-protecting groups of β-lactam compounds, such as pharmaceutically usable protecting groups or intermediates. Protecting groups that can be used as Specifically, the following can be mentioned. (a) Alkyl groups; especially straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and pentyl; (b) Substituted alkyl groups; in particular substituted alkyl groups such as trichloromethyl, tribromomethyl, 2,2,2-trichloroethyl, trifluoroethyl, 2-bromopropyl, iodomethyl, diiodomethyl, 2-chloroethyl, 2-bromoethyl and the following substituents: Alkyl group substituted with one or more selected substituents Acyl group such as acetyl, propionyl, pivaloyl, benzoyl, p-bromobenzoyl, p-tert.-butylbenzoyl, acetoxyacetyl, pivaloyloxyacetyl, etc. ,4-
Cycloalkadienylmethyl groups such as hexadien-1-yl-methyl, alkoxy groups such as methoxy, ethoxy, isopropoxy, decyloxy, cycloalkyloxy groups such as cyclohexyloxy, acetoxy, dimethylaminoacetoxy, propionyloxy, pivaloyloxy, etc. Acyloxy groups, mono- and di-alkylamino groups such as methylamino, dimethylamino, diethylamino, acylamino and imino groups such as acetamide, phthalimide, succinimide, 2-thienyl, 2-
Heterocyclic groups such as furyl, 3-tert.-butyl-5-isothiazolyl, 6-pivaloyloxy-3-pyridazinyl, 5-phenylthio-1-tetrazolyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 4-nitrophenoxy, 4-benzyloxyphenoxy, 4
-Aryloxy groups such as methylphenoxy, 4-benzyloxyphenoxy, 2-methylphenoxy, 2-methoxyphenoxy, and 4-aminophenoxy; arylthio groups such as phenylthio, 4-methoxyphenylthio, and 4-chlorophenylthio; Aralkoxy groups such as benzyloxy, 4-nitrobenzyloxy, and 4-chlorobenzyloxy, alkylthio groups such as methylthio, ethylthio, isopropylthio, and decylthio, cycloalkylthio groups such as cyclohexylthio, tetrahydrofuran-2-yl, and tetrahydropyran- 2-yl, furan-
Heterocyclic groups such as 2-yl, 4-pyridyl, methoxycarbonyl, ethoxycarbonyl, tert.
alkoxycarbonyl groups such as -butyloxycarbonyl, tert.-acyloxycarbonyl,
Aralkyloxycarbonyl groups such as benzyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, p
-Aryl groups such as methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl,
Acylthio groups such as acetylthio and pivaloylthio, cyano groups, arylsulfonylmethyl groups, 2-dimethylsulfoniummethyl groups, phthalidyl groups, carboxyl groups, etc. (c) Alkenyl groups; allyl, 2-propenyl, 2
-Methyl-2-propenyl, 3-phenyl-2
-propenyl, 2-butenyl, 3-butenyl,
4-butenyl, 3-methyl-3-butenyl, 3
-Alkenyl group (di)alkynyl group such as pentenyl, 4-pentenyl, methallyl; ethynyl, propargyl, 3
-Alkynyl group (ho)aralkyl group such as butyn-1-yl; benzyl, benzhydryl, p-chlorobenzyl, p-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl, m-benzoylbenzyl, p- tert.
-butylbenzyl, m-phenoxybenzyl,
p-acetoxybenzyl, p-pivaloylbenzyl, p-benzoylbenzyl, 3,5-dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl, p-carboxybenzyl (which is the free acid, ester or sodium salt) ), 2,4,6-trimethylbenzyl,
p-pivaloyloxybenzyl, p-tert.-butoxycarbonylbenzyl, p-methoxybenzhydryl, 2,2-dimethyl-5-coumaranmethyl, 5-indanylmethyl, p-trimethylsilylbenzyl, isopropoxybenzyl,
Alkyl groups (he)aryl groups such as 3,5-bis-tert.-butoxy-4-hydroxybenzyl, phenylethyl, 2-(p-methylphenyl)ethyl, trityl; phenyl, 4-methylphenyl, 4-hydroxyphenyl, Aryl groups such as 4-tert.-butylphenyl, 4-nitrophenyl, 3,5-dinitrophenyl, carboxyphenyl (which is in the free acid or sodium salt form), etc.; phthalidyl group, indanyl group, chronolactone- 3-yl group, furyl group, quinolyl group, N-(methylpyridyl) group, trimethylsilyl group In addition, as the amino-protecting group for ^R2 , all commonly known protecting groups for the amino group of β-lactam compounds can be used. Contains groups of Specifically, the following can be mentioned. (a) Aralkyl group; benzyl, benzhydryl, p-chlorobenzyl, p-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl, m-benzoylbenzyl, p-tert.
-butylbenzyl, m-phenoxybenzyl,
p-acetoxybenzyl, p-pivaloylbenzyl, p-benzoylbenzyl, 3,5-dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl, p-carboxybenzyl (which is the free acid, ester or sodium salt) ), 2,4,6-trimethylbenzyl,
p-pivaloyloxybenzyl, p-tert.-butoxycarbonylbenzyl, p-methoxybenzhydryl, 2,2-dimethyl-5-coumaranmethyl, 5-indanylmethyl, p-trimethylsilylbenzyl, isopropoxybenzyl,
Aralkyl groups such as 3,5-bis-tert.-butoxy-4-hydroxybenzyl, phenylethyl, 2-(p-methylphenyl)ethyl, trityl, etc. (b) Others; 2-nitrophenylthio group, 2,4
-dinitrophenylthio group, tetrahydrofuryl group, tetrahydropyranyl group Next, a method for producing the optically active compound of the general formula () will be explained. The optically active compound of general formula () can be produced according to the reaction shown below. [In the formula, R ¹ and R ² have the above-mentioned meanings. ^R3 ,
R ⁴ and R ⁵ represent a protecting group commonly known as a protecting group for a carboxyl group or an amino group. ] That is, (1) The compound represented by the general formula (
601 (1961).
The carboxyl protecting group for R ³ is an easily removable group, such as an alkyl group such as methyl or ethyl, or benzyl, diphenylmethyl,
Aralkyl groups such as trityl can be suitably used. (2) The compound represented by the general formula () or () is L-aspartic acid or the compound represented by the general formula ()
A compound represented by can be obtained by subjecting it to a conventional reaction for protecting an amino group. As the amino protecting group for R ⁴ , easily removable groups such as alkoxycarbonyl or aralkoxycarbonyl groups such as tert.-butoxycarbonyl and benzyloxycarbonyl can be suitably used. (3) The compound represented by the general formula () can be easily obtained by, for example, subjecting the compound represented by the general formula () to a conventional esterification reaction. (4) The compound represented by the general formula () can be easily obtained from the compound represented by the general formula () by subjecting it to a conventional hydrolysis reaction, for example. (5) The compound represented by the general formula () is obtained by adding the compound represented by the general formula () to the compound represented by the general formula () in the presence of a base.
For example, after reacting a halocarbonic ester such as isobutyl chloroformate to produce a mixed acid anhydride, reacting it with diazomethane or converting the compound represented by the general formula () into an acid halide derivative by a conventional method. It can be obtained by reacting diazomethane. This reaction is first carried out in a solvent such as benzene, diethyl ether, diisopylpur ether, or tetrahydrofuran at cooling or room temperature for several tens of minutes to several hours to produce a mixed acid anhydride, which is then mixed with diazomethane. It is carried out by reacting under cooling. (6) The compound represented by the general formula () is prepared by reacting a catalyst such as silver acetate or silver benzoate on the compound represented by the general formula () in the presence or absence of a base such as triethylamine or pyridine. obtained by This reaction is usually carried out in the presence of an alcohol, optionally in a solvent that does not participate in the reaction, such as dioxane, at room temperature or under solvent reflux for several tens of minutes to several hours.
The carboxyl group-protecting group for R ⁵ is a group that is eliminated by a normal hydrolysis reaction, such as methyl,
Alkyl groups such as ethyl or groups that are eliminated by ordinary reduction reactions, such as aralkyl groups such as benzyl, diphenylmethyl, and trityl, are preferably used. (7) The compound represented by the general formula () can be prepared by subjecting the compound represented by the general formula () to a reaction that removes the usual carboxyl-protecting group and amino-protecting group, for example, at room temperature in the presence of a catalyst such as palladium-carbon. It can be obtained by subjecting it to catalytic reduction with hydrogen or hydrolysis at normal pressure. (8) The compound represented by the general formula () has the amino protecting group of the compound represented by the general formula ()
It can be obtained by elimination using a conventional method. This reaction typically involves ethyl acetate, water,
The reaction may be carried out using hydrogen halide or the like in a solvent such as tetrahydrofuran at cooling or room temperature for several hours. (9) The compound represented by the general formula () is a compound represented by the general formula (), an aldehyde,
For example, it can be obtained by reacting benzaldehyde or the like and then subjecting the resulting compound to reduction treatment. In this reaction, as a reduction treatment, for example, catalytic reduction with hydrogen in the presence of a catalyst such as palladium-carbon at room temperature and normal pressure results in the reaction of the compound represented by the general formula () with aldehydes. The base is reduced and
The protecting group on R ³ is removed. Alternatively, the compound of general formula () can be obtained in the same way by reducing Schizuff's base with sodium borohydride as a reduction treatment and then performing catalytic reduction with hydrogen at room temperature and pressure in the presence of a catalyst such as palladium on carbon. Can be done. Alternatively, after protecting the amino group of the compound represented by the general formula () with a group represented by R ² by a conventional method, the carboxyl protecting group can be removed by a conventional method such as hydrolysis, reduction, or treatment under mild conditions. It can also be obtained by selective elimination. (10) To obtain a compound represented by general formula (XI) or () from a compound represented by general formula () or (), respectively, the compound represented by general formula () or () is subjected to a ring-closing reaction. It can be obtained by The ring closure reaction is
After reacting with an active halogen compound such as thionyl chloride, phosphorus trichloride, or phosphorus pentachloride in the presence or absence of a solvent, triethylamine,
This is carried out by the action of a base such as pyridine or N,N-dimethylaniline. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include diethyl ether, tetrahydrofuran, dioxane, chloroform, benzene, toluene, and the like. The reaction takes place between 1 and 10 under cooling or heating.
All you have to do is take your time. (11) The compound represented by the general formula (XII) can be obtained by subjecting the compound represented by the general formula (XI) to, for example, a conventional hydrolysis reaction. (12) The compound represented by the general formula () can be obtained by removing the amino protecting group of the compound represented by the general formula (XII) and then subjecting it to a reaction that protects the carboxyl group.
Conditions are appropriately selected so that the amino-protecting group elimination reaction can be carried out without cleaving the azetidinone ring. Specifically, this can be easily carried out by applying metallic sodium or the like in liquid ammonia. Next, the reaction for protecting the carboxyl group is carried out by cooling or heating the obtained product,
For example, it can be obtained by subjecting it to a normal esterification reaction. (13) To obtain the compound represented by formula () from the obtained compound represented by general formula (), the compound represented by general formula It is carried out by subjecting it to a decomposition reaction, such as alkaline hydrolysis, a reduction reaction, or an elimination reaction under mild conditions. This reduction reaction or elimination reaction under mild conditions can be carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane, anisole, ethyl acetate, or trifluoroacetic acid at normal temperature and pressure in the presence of a catalyst such as palladium on carbon. This is carried out by exposing the reaction mixture to hydrogen for several hours or by treating it with trifluoroacetic acid, etc. After the reaction, it can be isolated and purified by vacuum concentration, solvent treatment, crystallization, recrystallization, chromatography, etc. In addition, the compound represented by formula () can be replaced by the compound represented by general formula (XII) as described in (12) instead of (12) and (13) above.
By performing only the elimination reaction of the amino protecting group of ^R2 ,
You can also get it directly. In (1) to (13) above, when L-aspartic acid is used as the first starting material, the corresponding optically active general formulas () to ()
and a compound of formula () are obtained, but using an optically inactive compound as a starting material, the optically inactive compound of formula () obtained is optically resolved via the corresponding optically inactive compound. An optically active compound of formula () can also be obtained by (14) The optically active compound represented by the general formula () is prepared by adding a compound represented by the general formula (XII) or (4S)-4-carboxymethyl-2-azetidinone represented by the formula () to a carboxyl group by a conventional method. It can be obtained by reacting a reactive derivative of the formula (2) with an alkali metal enolate of an acetic acid derivative represented by the general formula (2). Examples of the compound represented by the general formula (XII) or the reactive derivative of (4S)-4-carboxymethyl-2-azetidinone represented by the formula () include mixed acid anhydrides; If a compound represented by the formula () is reacted with, for example, a halocarbonate in the presence of a base in a solvent unrelated to the reaction such as tetrahydrofuran, dioxane, toluene, diethyl ether, etc. for several hours at -30°C to room temperature, A mixed acid anhydride is obtained. Examples of the halocarbonate ester include ethyl chloroformate and isobutyl chloroformate. Furthermore, examples of acetic acid derivatives include those having the carboxyl protecting group for R ¹ described above. The condensation reaction of a reactive derivative of the compound represented by general formula (XII) or formula () with an alkali metal enolate of an acetic acid derivative represented by general formula () is preferably carried out using, for example, diisopropylamine, 2,2,6,6 - In the presence of a base such as a secondary amine such as tetramethylpiperidine or cyclohexylisopropylamine, one or two solvents unrelated to the reaction, such as tetrahydrofuran, dioxane, toluene, diethyl ether, etc.
The reaction may be carried out in a mixed solvent of more than one species, preferably in an inert gas atmosphere such as argon, at -80°C to -30°C for several tens of minutes to several hours. Further, the optically active compound represented by the general formula () can be converted into a compound having a free carboxyl group by performing an elimination reaction of the carboxyl group protecting group at a low temperature. Furthermore, the free compound is converted into a normal salt by a normal method, or
Alternatively, an optically active compound represented by the general formula () can be obtained by subjecting it to a conventional carboxyl group-protecting reaction. The intermediates obtained by the above method, the optically active compounds of general formulas (XI) to () and formula (), are new compounds, and like the optically active compounds of general formula (), carbapenems and azetidinones It has utility as an intermediate in the synthesis of derivatives. And, the optically active compound of general formula () is
Tetrahedron Letters
Letters) Vol. 21, pp 31-34 (1980) to produce a 1-azabicyclo[3.2.0]heptane-2-carboxylic acid derivative, and then by introducing various substituents, It can be similarly derived into various thienamycin type compounds by forming it into various thienamycin type compounds, or by introducing various substituents into the 3-position and then subjecting it to a cyclization reaction. Therefore, the optically active compound of the general formula () can be used as a known or new important intermediate that is a variety of useful optically active compounds. Next, the present invention will be explained using examples. Example 1 (1) 80% sulfuric acid and 250 g of benzyl alcohol are sequentially added to 100 g of L-aspartic acid, and the mixture is stirred on a water bath at 70°C. After stirring at the same temperature for 2 hours and 30 minutes, the mixture was concentrated under reduced pressure. The residue is poured into 500 ml of cold water containing 140 g of sodium bicarbonate. Add 300 ml of diethyl ether, stir well, and filter the precipitated crystals. Place the obtained crystals in cold water at 150 mL.
If washed with ml and recrystallized from water, the melting point is 222℃.
86 g (yield: 52%) of L-aspartic acid-β-benzyl ester shown below was obtained. (2) L-aspartic acid-β-benzyl ester
Add 106 g to a mixed solution of 300 ml of acetone and 300 ml of water, and then add 99 ml of triethylamine to dissolve. 117 g of 2-tert.-butoxycarbonyloxyimino-2-phenylacetonitrile is added to the obtained solution, and the mixture is stirred at room temperature for 2 hours. Add water to the solution in which acetone has been distilled off under reduced pressure.
Add 200 ml and wash three times with 150 ml each of ethyl acetate. After washing, acidify with citric acid, add 500 ml of ethyl acetate for extraction, and separate the organic layer. The separated organic layer is washed with 100 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Add 400 ml of ethyl acetate-petroleum ether (1:5) to the resulting residue and collect the crystals by filtration.
-tert.-butoxycarbonyl-L-aspartic acid-β-benzyl ester 122g (yield 80%)
get. (3) Add 10.3 g of N-tert.-butoxycarbonyl-L-aspartic acid-β-benzyl ester to 120 ml of anhydrous benzene, and then add 2.4 ml of tetramethylethylenediamine to dissolve.
4.6 ml of isobutyl chloroformate was added dropwise to the resulting solution at 5 to 7°C over a period of 5 minutes. After stirring at the same temperature for 40 minutes, a diethyl ether solution of diazomethane (prepared using 22 g of nitrosomethylurea) was prepared separately.
Add to the inside at -10℃. The mixture is heated at 0 to 5° C. for 1 hour, and then gradually heated to room temperature over an additional 30 minutes while stirring. Thereafter, excess diazomethane is distilled off under reduced pressure, and insoluble matter is filtered off. The solvent of the filtrate was distilled off under reduced pressure to obtain 11.9 g of benzyl (3S)-5-diazo-3-(tert.-butoxycarbonyl)amino-4-oxopentanoate. Dissolve this in 45 ml of anhydrous methanol and add a triethylamine solution of silver benzoate (silver benzoate
Add 0.45 ml (prepared by dissolving 0.5 g in 4.5 ml of triethylamine) and stir. After further stirring for 1 hour, 0.5 g of activated carbon was added and the mixture was refluxed for 10 minutes, and then insoluble matter was filtered off. The solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was diluted with diethyl ether.
Dissolve in 120ml. Add diethyl ether solution to 20 ml of water, 20 ml of saturated sodium hydrogen carbonate aqueous solution,
After successively washing with 20 ml of saturated brine, drying over anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure. The resulting residue was purified by column chromatography (silica gel C-200; eluent; benzine:ethyl acetate = 35:1) to obtain oily benzyl (3R)-3-(tert.-butoxycarbonyl). )
Amino-4-methoxycarbonylbutanoate
Obtain 7.8 g (yield 69%). IR (neat) cm ^-1 ; νNH3360, νC=0 1670
~1740 NMR ( _CDCl3 ) δ; 1.43 (s, 9H, CH3 _x 3) 2.55 ~ 2.85 (m, 4H, CH2 _x 2) 3.65 (s, 3H, _OCH3 ) 4.33 (m, 1H, CH) 5.13(s, 2H,

[Formula]) 5.35 (d, 1H, NH) 7.35 (s, 5H, C ₆ H ₅ ) Elemental analysis value (C ₁₈ H ₂₅ NO ₆ ) C H N Calculated value (%) 61.52 7.17 3.99 Actual value (%) 61.22 7.18 3.82 [α] ²⁰ _D = +3.4° (C = 4.05, benzene) (4) Add ice to 35 g of benzyl = (3R)-3-(tert.-butoxycarbonyl)amino-4-methoxycarbonylbutanoate While cooling, add 115 ml of 2.6N hydrogen chloride-ethyl acetate solution. Then stir at room temperature for 1.5 hours. Add 100 ml of water to the obtained solution and separate the aqueous layer. The separated aqueous layer is washed with ethyl acetate. Add 100 ml of ethyl acetate to the resulting aqueous layer, and make it alkaline by adding sodium hydrogen carbonate. The ethyl acetate layer was separated, washed with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain oily benzyl (3R)-3-amino-4-methoxycarbonylbutano. 22.5 g (90% yield) of ate are obtained. IR (neat) cm ^-1 ; νNH 3300-3400 νC=O 1720 NMR (CDCl ₃ ) δ; 1.85 (bs, 2H,
NH ₂ ) 2.30-2.65 (m, 4H, CH ₂ ×2) 3.65 (m, 1H, CH) 3.67 (s, 3H, OCH ₃ ) 5.15 (s, 2H,

[Formula]) 7.36 (s, 5H, C ₆ H ₅ ) [α] ²⁰ _D = −2.6° (c = 2.22, benzene) (5) (a) Benzyl = (3R)-3-amino-4-methoxy Add 22.5 g of carbonyl butanoate and 10 g of benzaldehyde to 200 ml of benzene,
Add molecular sieves 4A22 to the resulting solution.
g and stirred at room temperature for 2 hours. The molecular sieves are filtered off, and the solvent of the filtrate is distilled off under reduced pressure. The resulting residue was dissolved in methanol.
Dissolve in 20 ml, add 7 g of 5% palladium on carbon, and perform catalytic reduction at room temperature in the presence of hydrogen. After filtering off insoluble matter, the solvent is distilled off under reduced pressure. Treatment of the resulting residue with ethyl acetate yields 17.8 g of (3S)-3-benzylamino-4-methoxycarbonylbutanoic acid as an amorphous solid.
(yield 79%). If this is recrystallized from methanol diethyl ether, the melting point is 114° ~
A prismatic crystal exhibiting a temperature of 115.5°C is obtained. IR (KBr) cm ^-1 ; 1740, 1580 NMR (CDCl ₃ ) δ; 2.35-3.05 (M, 4H, CH ₂
×2) 3.40~3.95 (m, 1H, CH) 3.72 (s, 3H, OCH ₃ ) 4.11 (bs, 2H,

[Formula]) 7.45 (s, 5H, C ₆ H ₅ ) Elemental analysis value (C ₁₃ H ₁₇ N ₁ O ₄ ) C H N Calculated value (%) 62.14 6.82 5.57 Actual value (%) 61.85 6.85 5.62 [α] ²⁰ _D = -16.1゜ (c = 0.982, methanol) (b) Dissolve 1.7 g of benzyl (3R)-3-amino-4-methoxycarbonylbutanoate and 0.72 g of benzaldehyde in 17 ml of benzene and prepare 3 g of molecular sieves 4A. was added and stirred at room temperature for 4 hours, then heated to around 40℃.
After filtering off the molecular sieves and distilling off the solvent under reduced pressure, a yellow oily benzyl
(3R)-3-Benzylideneamino-4-methoxycarbonylbutanoate is obtained. IR (neat) cm ^-1 , νC=O 1725 νC=N 1640 Next, this was dissolved in 20 ml of ethanol, 0.75 g of sodium borohydride was added under ice cooling, and after stirring for 2 hours, it was dissolved in an ice bath. The solvent is removed under reduced pressure. Add 30 ml of diethyl ether and 10 ml of saturated saline to the resulting residue, shake thoroughly, and then separate the organic layer. After drying the separated organic layer over anhydrous magnesium sulfate, the solvent is distilled off. The residue was subjected to column chromatography (silica gel C-200;
If purified with eluent (benzene), benzyl =
0.93 g (yield 40%) of (3R)-3-benzylamino-4-methoxycarbonylbutanoate is obtained. IR (neat) cm ^-1 : νC=O 1720 NMR (CDCl ₃ ) δ; 2.47 to 2.77 (m, 4H, CH ₂ ×2) 3.25 to 3.72 (m, 1H, CH) 3.64 (s, 3H, OCH ₃ ) 3.77 (bs, 2H,

[Formula]) 5.15 (s, 2H,

[Formula]) 7.36 (s, 10H, C ₆ H ₅ ×2) Furthermore, dissolve this in 50 ml of anhydrous methanol,
After adding 0.19 g of 5% palladium on carbon, the mixture was allowed to absorb hydrogen for 30 minutes at room temperature while stirring, and the palladium on carbon was filtered off. Wash this with 25 ml of methanol. Combine the filtrate and washing solution,
The solvent was distilled off under reduced pressure to obtain 0.64 g of an oil. If this is treated with ethyl acetate, (3S)-3
0.4 g (yield 58%) of -benzylamino-4-methoxycarbonylbutanoic acid is obtained. (6) Add 3.2 g of (3S)-3-benzylamino-4-methoxycarbonylbutanoic acid to 15 ml of thionyl chloride under ice cooling. After stirring at room temperature for 1.5 hours, excess thionyl chloride was distilled off under reduced pressure. Adding anhydrous benzene to the obtained residue and distilling it off under reduced pressure is repeated three times. The resulting residue was dissolved in 200 ml of anhydrous benzene, and this was added dropwise over 5 hours into 750 ml of anhydrous benzene containing 3.6 ml of triethylamine. After stirring for another 3 hours,
Wash twice with 100 ml of 0.5N hydrochloric acid, 100 ml of water, 80 ml of saturated aqueous sodium bicarbonate solution, and 80 ml of saturated saline solution, dry over anhydrous magnesium sulfate, and then evaporate the solvent under reduced pressure. The obtained residue was subjected to column chromatography (silica gel C-200;
Eluent; benzene:ethyl acetate = 5:1) to obtain crystalline (4S)-1-benzyl-4
-Methoxycarbonylmethyl-2-azetidinone 1.96 g (yield 66%) is obtained. If this is recrystallized from diethyl ether-2-hexane,
Colorless prismatic crystals with a melting point of 43.5° to 44.5°C are obtained. IR (CHCl ₃ ) cm ^-1 ; νC=O 1730-1755 NMR (CDCl ₃ ) δ; 2.45-2.87 (m, 3H, C ₃
−Hβ, CH ₂ COOCH ₃ ) 3.16 (dd, 1H, J=5, 15, C ₃ −Hα) 3.59 (s, 3H, OCH ₃ ) 3.98 (m, 1H, C ₄ −H) 4.35 (ABq, 2H ,

[Formula]) 7.25 (s, 5H, C ₆ H ₅ ) Elemental analysis value (C ₁₃ H ₁₅ N ₁ O ₃ ) C H N Calculated value (%) 66.94 6.48 6.00 Actual value (%) 66.74 6.51 5.99 [α] ²⁰ _D = +23.8° (c = 1.01, benzene) (7) Dissolve 1.6 g of (4S)-1-benzyl-4-methoxycarbonylmethyl-2-azetidinone in 16 ml of methanol, and add 1N sodium hydroxide under ice cooling. After adding 7.3 ml of aqueous solution and reacting for 1 hour,
Methanol is distilled off under reduced pressure. The resulting aqueous solution was washed with a small amount of ethyl acetate, and 7.6 ml of 1N hydrochloric acid was added.
Add to make acidic, extract with 20ml of ethyl acetate,
Separate the ethyl acetate layer. The separated ethyl acetate layer was washed with 5 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Add diethyl ether to the residue and filter it.
1.3 g of pale yellow (4S)-1-benzyl-4-carboxymethyl-2-azetidinone (86% yield)
get. If this is recrystallized from benzene, colorless prism crystals with a melting point of 109-11°C are obtained. IR (KBr) cm ^-1 ; νC=O 1730, 1690 νC=O 1745, 1720 (shoulder) NMR (CDCl ₃ ) δ; 2.50 to 2.75 (m, 2H, - CH ₂ CO ₂ H) 2.80 to 3.45 (m , 2H, C-3-Hα, Hβ) 3.97 (m, 1H, C ₄ -H) 4.47 (ABq, 2H,

[Formula]) 7.39 (s, 5H, C ₆ H ₅ ) Elemental analysis value (C ₁₂ H ₁₃ N ₁ O ₃ ) C H N Calculated value (%) 65.74 5.98 6.38 Actual value (%) 65.74 6.02 6.24 [α] ²⁰ _D = +12.2° (c = 0.866, ethanol) (8) Metallic sodium in 150ml of liquid ammonia
Add 0.15g in small pieces in portions and stir for 20 minutes. At liquid ammonia reflux temperature, (4S)-1-
0.31 g of benzyl-4-carboxymethyl-2-azetidinone was added in portions over 5 minutes, and
After reacting for 5 minutes, ammonia is distilled off under reduced pressure. 30 ml of ethanol containing 7.8 ml of 1N hydrochloric acid cooled to -20°C is added to the obtained off-white solid, and the solid is dissolved while gradually increasing the temperature. Add 3g of diphenyldiazomethane to this and let it cool to room temperature.
Incubate for 60 minutes. After the reaction is complete, ethanol is distilled off under reduced pressure, and 30 ml of ethyl acetate is added to the residue.
Add and separate the organic layer. The separated organic layer is washed with water.
After sequentially washing with 10 ml and 5 ml of saturated saline, drying over anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure. The resulting residue was purified by column chromatography (silica gel C-200; eluent; benzene:ethyl acetate = 10:1) to obtain pale yellow crystals of (4S)-4-diphenylmethoxycarbonylmethyl-2. - Obtain 0.35 g of azetidinone (85% yield). If this is recrystallized from diethyl ether, colorless needle crystals with a melting point of 65.5-66.5°C are obtained. IR (CHCl ₃ ) cm ^-1 ; νC=O 1760, 1735) shoulder) νNH 3310 NMR (CDCl ₃ ) δ; 2.41-3.37 (m, 4H, CH ₂ ×2) 3.89 (m, 1H, CH) 6.40 ( m, 1H, NH) 6.96 (s, 1H,

[Formula]) 7.40 (s, 10H, C ₆ H ₅ ×2) Elemental analysis value (C ₁₈ H ₁₇ N ₁ O ₃ ) C H N Calculated value (%) 73.20 5.80 4.74 Actual value (%) 73.04 5.81 4.87 [ α〕 ²⁰ _D = +46.6゜ (c = 0.956, benzene) (9) (a) Dissolve 0.3 g of (4S)-4-diphenylmethoxycarbonylmethyl-2-azetidinone in 10 ml of ethanol, and add 5% palladium on carbon.
Add 0.09g and shake in a hydrogen stream for 1.5 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure.
When the obtained residue is treated with diethyl ether, 0.115 g of (4S)-4-carboxymethyl-2-azetidinone (yield 88%) is obtained as a white powder.
get. If this is recrystallized from tetrahydrofuran, colorless prismatic crystals having a melting point of 169-171°C (decomposition) are obtained. IR (KBr) cm ^-1 ; νNH 3250 νC=O 1690-1740 NMR (D ₂ O) δ; 2.52-2・92 (m, 3H, CH ₂
×1, C ₃ −Hβ) 3.16 (dd, 1H, C ₃ Hα) 3.95 (m, 1H, C ₄ −CH) Elemental analysis value (C ₅ H ₇ N ₁ O ₃ ) C H N Calculated value (%) 46.51 5.46 10.85 Actual value (%) 46.77 5.49 10.86 [α] ²⁰ _D = +12.3° (c = 0.504, ethanol) In addition, tetrahydrofuran was used instead of ethanol, and the above was carried out at 50 to 90°C for 3 hours. After hydrogenation and treatment, (4S)-4-carboxymethyl-2-azetidinone is obtained. (b) 0.5 ml of anisole and 0.5 ml of trifluoroacetic acid were added to 0.052 g of (4S)-4-diphenylmethoxycarbonylmethyl-2-azetidinone under ice cooling, and after stirring for 20 minutes, the solvent was distilled off under reduced pressure. do. Next, 5 ml of toluene was added and this was distilled off under reduced pressure twice to obtain diethyl ether-ethyl acetate (2:1) 3
ml, stir, and filter to obtain (4S)-4
-carboxymethyl-2-azetidinone
Obtain 0.014 g (60% yield). (10) Dissolve 0.065 g of (4S)-4-carboxymethyl-2-azetidinone in 5 ml of anhydrous tetrahydrofuran under an argon atmosphere, add 1 ml of an anhydrous tetrahydrofuran solution of triethylamine (containing 0.375 ml of triethylamine in 5 ml), and -20
1 ml of an anhydrous tetrahydrofuran solution of isobutyl chloroformate (5 ml contains 0.375 ml of isobutyl chloroformate) is added at °C, and the mixture is stirred at the same temperature for 1 hour. On the other hand, under an argon atmosphere, 0.25 ml of 2,2,6,6-tetramethylpiperidine was dissolved in 2 ml of anhydrous tetrahydrofuran, and a solution of n-butyllithium in n-hexane (n-butyllithium) was added to the solution under ice cooling.
After stirring at the same temperature for 30 minutes, cool to -78°C, add 0.21 ml of benzyl acetate, and stir for 15 minutes. The previously prepared solution is introduced into the solution thus prepared at -78°C under an argon atmosphere.
After stirring for an additional 20 minutes, 4 ml of saturated ammonium chloride aqueous solution was added, and then 20 ml of ethyl acetate was added.
After adding ml, separate the organic layer. The separated organic layer was washed with 5 ml of diluted hydrochloric acid, 3 ml of water, 3 ml of saturated aqueous sodium bicarbonate solution, and 3 ml of saturated saline solution,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.24 g of an oil. If this oil is purified by preparative thin layer chromatography (developing solution: chloroform:acetone = 3:1), a colorless oil (4R)-4-(3-benzyloxycarbonyl-2-oxopropyl) is produced. -2-azetidinone
Obtain 0.023 g (18% yield). IR (neat) cm ^-1 ; νNH 3250-3360 νC=O 1700-1770 NMR ( _CDCl3 ) δ: 2.32-3.34 (m, 4H, _C3-
Hα, Hβ, − CH ₂ COCH ₂ −) 3.48 (s, 2H,

[Formula]) 3.91 (m, 1H, C ₄ −H) 5.15 (s, 2H,

[Formula] 6.30 (m, 1H, NH) 7.33 (s, 5H, C ₆ H ₅ ) [α] ²⁰ _D = +43.2° (c = 0.370, benzene) Example 2 (1) L-aspartic acid 26.6 g in 200 ml of water, and while maintaining the temperature at 10 to 15°C, a 4N aqueous sodium hydroxide solution was added dropwise over 30 minutes to dissolve L-aspartic acid. Next, 34.3 ml of benzyloxycarbonyl chloride and 50 ml of 4N aqueous sodium hydroxide solution were simultaneously added dropwise over 80 minutes while maintaining the temperature at 5 to 7°C. After the dropwise addition is completed, the mixture is allowed to react while stirring for 1.5 hours while gradually raising the temperature to room temperature. After the reaction is complete, unreacted benzyloxycarbonyl chloride is removed by extraction with 100 ml of diethyl ether, and 33 ml of concentrated hydrochloric acid is added dropwise to the resulting aqueous solution under ice cooling. The oily substance that precipitates at this time is extracted with ethyl acetate.
Extract with 150ml and separate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was crystallized with diethyl ether petroleum ether (1:2) and filtered. If taken, the melting point is 109.5
~111°C N-benzyloxycarbonyl-L
- 34.4 g (yield 64.4%) of aspartic acid are obtained. (2) 26.7 g of N-benzyloxycarbonyl-L-aspartic acid, 120 ml of benzyl alcohol, and 1.5 g of p-toluenesulfonic acid monohydrate were dissolved in 150 ml of toluene and azeotropically dehydrated for 1 hour.
Then, toluene is removed by distillation under reduced pressure, and excess benzyl alcohol is distilled off at 87-89°C/6 mmHg. The resulting residue is washed with petroleum ether and decanted. The oil layer is dissolved in 200 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. Then, by crystallizing with petroleum ether and filtering the crystals, N-benzyloxycarbonyl-L
38.1 g of -aspartic acid-α,β-di-benzyl ester are obtained. Melting point 65-65.5°C (recrystallized from diethyl ether-petroleum ether) [α] ²⁵ _D = -1.84° (c = 10.24, acetic acid) (3) N-benzyloxycarbonyl-L-aspartic acid-α,β-di −Benzyl ester 22.4
A solution of 2.4 g of lithium hydroxide monohydrate dissolved in 50 ml of water was added dropwise at room temperature over a period of 3 hours. After the addition is complete, the acetone is distilled off, washed with diethyl ether, and 4.5 ml of concentrated hydrochloric acid is added to the aqueous layer under ice cooling, followed by stirring to precipitate crystals. The precipitated crystals were collected by filtration and washed with water and petroleum ether.
Benzyloxycarbonyl-L-aspartic acid-β-benzyl ester 12.3g (yield 69%)
get. Melting point 108-109°C (recrystallized from benzene) [α] ²⁶ _D = +11.9° (c = 1.49, acetic acid) (4) N-benzyloxycarbonyl-L-aspartic acid-β-benzyl ester under nitrogen atmosphere
Add 1.43 g to 15 ml of benzene, then add 0.30 ml of tetramethylethylenediamine and dissolve. To this, 0.58 ml of isobutyl chloroformate diluted with 2 ml of benzene was added dropwise over 2 minutes at an internal temperature of 5 to 7°C. After stirring for 20 minutes at 5-7°C, the precipitated hydrochloride of tetramethylethylenediamine is filtered under an argon atmosphere. The filtrate is added dropwise to 30 ml of a solution of diazomethane in diethyl ether (prepared in advance using 2.7 g of nitrosomethylurea) at below 5°C. then
After stirring for 1.5 hours, the temperature was gradually raised to room temperature.
After removing excess diazomethane, the solvent is distilled off under reduced pressure to obtain crude benzyl as a pale yellow oil.
(3S)-5-diazo-3-benzyloxycarbonylamino-4-oxopentanoate 1.76
get g. IR (neat) cm ^-1 ; νN ₂ 2120 νC=O 1690-1740 (5) Under nitrogen atmosphere, crude benzyl = (3S)-5-diazo-3-benzyloxycarbonylamino-
1.76 g of 4-oxopentanoate is dissolved in 6 ml of methanol. This solution was then added with a triethylamine solution containing 0.5 g of silver benzoate at room temperature.
Add 0.15ml [At this time, foaming and heat generation (rise to 40℃) occur, and the precipitated silver becomes dark brown. ]
After the reaction is completed, 0.2 g of carbon is added and the mixture is refluxed for 10 minutes to decolorize and deactivate excess silver benzoate. The mixture was filtered through Celite, and the solvent of the obtained filtrate was distilled off under reduced pressure. Dissolve the residue in 15 ml of ethyl acetate, add 5 ml of saturated aqueous sodium bicarbonate solution,
After washing with 3 ml of saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel C-
200; Eluent; Benzene: Ethyl acetate = 30:1)
When purified, 0.905 g (yield 58.7%) of benzyl (3S)-3-benzyloxycarbonylamino-4-methoxycarbonylbutanoate is obtained. Melting point: 48-49°C (recrystallized from diethyl ether-n-hexane) Elemental analysis value (C ₂₁ H ₂₃ N ₁ O ₆ ) C H N Calculated value (%) 65.44 6.02 3.63 Actual value (%) 65.25 5.98 3.75 [α ] ²⁰ _D = +0.52° (c = 3.16, benzene) (6) Dissolve 1.33 g of benzyl (3S)-3-benzyloxycarbonylamino-4-methoxycarbonylbutanoate in 67 ml of methanol,
After adding 0.4 g of % palladium on carbon, hydrogen was absorbed for 1.5 hours at room temperature with stirring, and palladium on carbon was filtered off. Wash this with 10 ml of methanol. The filtrate and washing solution are combined, the solvent is distilled off under reduced pressure, the resulting residue is the chloroform washing solution, and the crystals are collected by filtration to obtain 0.467 g of (3S)-3-amino-4-methoxycarbonylbutanoic acid.
(yield 84.1%). Melting point 186-187℃ (decomposition) (recrystallized from methanol) Elemental analysis value (C ₆ H ₁₁ N ₁ O ₄ ) C H N Calculated value (%) 44.72 6.88 8.69 Actual value (%) 44.74 6.89 8.42 [α] ²⁰ _D = -13.3° (c = 1.77, methanol: water = 2:1) (7) Add 0.320 g of benzyl (3S)-3-amino-4-methoxycarbonylbutanoic acid to 3.2 ml of thionyl chloride under ice cooling. After stirring for 1.5 hours at room temperature, thionyl chloride is distilled off under reduced pressure. The operation of adding 5 ml of anhydrous benzene to the residue and distilling it off under reduced pressure was repeated twice. The resulting residue was dissolved in 50 ml of dioxane and added dropwise over 4 hours into 50 ml of a separately prepared dioxane solution containing 0.55 ml of triethylamine. After leaving this reaction solution overnight,
Insoluble matters are removed by filtration, and the solvent of the filtrate is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel C=200; eluent; chloroform:
After removing the origin portion with acetone = 5:1), preparative thin layer chromatography (developing solution; benzene: ethyl acetate = 1:3) was used to develop the sample three times.
Scrape off the desired spot and add 30% ethyl acetate.
ml, the solvent was distilled off from the eluate under reduced pressure) to obtain 0.010 g of (4S)-4-methoxycarbonylmethyl-2-azetidinone.
get. IR (CHCl ₃ ) cm ^-1 ; νNH 3420 νC=O 1760, 1735 NMR (CDCl ₃ ) δ; 2.31 to 2.90 (m, 3H, C ₃ −Hβ, −CH ₂
CO ₂ CH ₃ ) 3.21 (ddd, 1H, C ₃ −Hα) 3.76 (s, 3H, OCH ₃ ) 4.03 (m, 1H, C ₄ −H) 6.63 (m, 1H, NH) [α] ²⁰ _D = +63° (C=0.23, benzene) If the thus obtained (4S)-4-methoxycarbonylmethyl-2-azetidinone is hydrolyzed by a conventional method, (4S)-4-carboxymethyl-2-azetidinone is obtained. get. This was reacted in the same manner as in Example 1 (10), and (4R)-4-
(3-benzyloxycarbonyl-2-oxo-propyl)-2-azetidinone is obtained. Example 3 0.11 g of (4S)-1-benzyl-4-carboxymethyl-2-azetidinone was added under an argon atmosphere.
Dissolve in 5 ml of anhydrous tetrahydrofuran, and add 0.5 ml of anhydrous tetrahydrofuran solution of triethylamine (0.7 ml of triethylamine in 5.0 ml).
Add. Add 5.0 ml of anhydrous tetrahydrofuran solution of isobutyl chloroformate (0.7 ml of isobutyl chloroformate to the resulting solution at -20 to -15°C).
Add 0.5 ml of the liquid contained in the mixture and stir at the same temperature for 1 hour. On the other hand, diisopropylamine under argon atmosphere
Dissolve 0.21 ml in 2 ml of anhydrous tetrahydrofuran, and add n-hexane solution of n-butyllithium (n-butyllithium) at -78 to -70°C.
After adding 0.83 ml (containing 1.50 mmol) and stirring at the same temperature for 1 hour, 0.15 ml of ethyl acetate was added at -78°C and stirred for 30 minutes. The previously prepared solution is introduced into the solution thus prepared at -78°C under an argon atmosphere.
After stirring for an additional 45 minutes, 1.5 ml of a saturated aqueous ammonium chloride solution is added, followed by 20 ml of ethyl acetate, the mixture is heated to room temperature, and the organic layer is separated. The separated organic layer was mixed with 5 ml of 0.5N hydrochloric acid, 3 ml of water, 5 ml of saturated aqueous sodium bicarbonate solution, and 3 ml of saturated aqueous sodium chloride solution.
After successively washing with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. 0.14 g of the obtained oil was subjected to preparative thin layer chromatography (developing solution; benzene:
Purification with ethyl acetate = 2:1) yields (4R)-4-(3-ethoxycarbonyl-2) as a pale yellow oil.
0.047 g (yield 32%) of -1-benzyl-2-azetidinone (1-oxo-propyl) is obtained. IR (CHCl ₃ ) cm ^-1 ; νC=O 1743 1720 (shoulder) NMR (CDCl ₃ ) δ; 1.24 (t, 3H, -CH ₂ CH ₃ ) 2.35-3.40 (m, 4H, C ₃ -Hα, Hβ , _−CH2
COCH ₂ −) 3.20 (s, 2H, −COCH ₂ CO−) 3.95 (m, 1H, C ₄ −H) 4.14 (q, 2H, − CH ₂ CH ₃ ) 4.3 (bs, 2H,

[Formula]) 7.27 (s, 5H, C ₆ H ₅ ) Reference example 1 (1) (4R)-4-(3-benzyloxycarbonyl-2-oxopropyl)-2-azetidinone
Add 0.83 g and 0.076 g of p-carboxybenzenesulfonyl azide to 1.5 ml of acetonitrile, and then add and dissolve 0.13 ml of triethylamine under ice cooling. Then, the temperature was raised to room temperature, and after stirring at the same temperature for 1 hour, insoluble matter was removed by filtration, the filtrate was diluted with 10 ml of diethyl ether, and then washed successively with 2 ml of water, 2 ml of saturated aqueous sodium bicarbonate solution, and 2 ml of saturated brine. After drying with anhydrous magnesium sulfate,
The solvent is removed under reduced pressure. The obtained residue is n
-0.079 g of amorphous solid when treated with hexane
(yield 87%). When this is recrystallized from diethyl ether, it shows a melting point of 99-102°C (4R)-4-[3-benzyloxycarbonyl]
-3-diazo-2-oxopropyl]-2-azetidinone is obtained. IR (CH ₂ Cl ₂ ) cm ⁻¹ ; 3405, 2140, 1765, 1715, 1647 NMR (CDCl ₃ ) δ; 2.50 to 3.36 (m, 3H, C ₃ −Hα, Hβ,

【formula】) 3.38 (dd, 1H,

[Formula]) 3.99 (m, 1H, C ₄ −H) 5.26 (s, 2H,

[Formula]) 6.06 (m, 1H, NH) 7.37 (s, 5H, C ₆ H ₅ ) [α] ²⁰ _D = +68.8° (c = 0.276, benzene) (2) (4R) −4− [ 3-(benzyloxycarbonyl)-3-diazo-2-oxopropyl]-2-
Dissolve 0.059 g of azetidinone in 20 ml of anhydrous benzene, add 0.3 mg of rhodium acetate, and
Stir for 45 minutes at 85°C. Next, the volume of this solution was concentrated to half under reduced pressure, and 15 ml of diethyl ether was added.
was added, insoluble matter was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel; C-200, eluent;
If purified with benzene:ethyl acetate=10:1), pale yellow crystalline benzyl=(2R,5R)-
3,7-dioxo-1-azabicyclo[3,
2,0]heptane-2-carboxylate
Obtain 0.044 g (83% yield). If this is recrystallized from diethyl ether, colorless needle crystals having a melting point of 68-69°C are obtained. IR (CH ₂ Cl ₂ ) cm ^-1 ; νC=O 1772, 1745 (CCl ₄ ) cm ^-1 ; νC=O 1785, 1775, 1745 NMR (CDCl ₃ ) δ; 2.36 (dd, 1H, J=8.0Hz , 19.1Hz,
C ₄ −Ha) 2.74-3.05 (m, 2H, C ₄ −Hb, C ₆ −Hβ) 3.63 (dd, 1H, J=5.0Hz, 16.0Hz,
C ₆ −Hα) 4.14 (m, 1H, C ₅ −H) 4.73 (s, 1H, C ₂ −H) 5.21 (s, 2H,

[Formula]) 7.36 (s, 5H, C ₆ H ₅ ) Elemental analysis value (C ₁₄ H ₁₃ N ₁ O ₄ ) C H N Calculated value (%) 64.86 5.05 5.40 Actual value (%) 64.91 5.10 5.41 [α] ²⁰ _D = +323° (c = 0.67, benzene)

Claims (1)

[Claims] 1. General formula (4S)-4-carboxymethyl ^-2 represented by "In the formula, R2 represents a hydrogen atom or an amino protecting group."
- a reactive derivative at the carboxyl group of the azetidinone is reacted with an alkali metal enolate of an acetic acid derivative represented by the general formula CH ₃ COOR ¹ (wherein R ¹ represents a carboxyl protecting group); general formula A method for producing (4R)-4-(3-substituted carboxy-2-oxo-propyl)-2-azetidinones represented by the following formula: "In the formula, ^R1 and ^R2 have the above-mentioned meanings." ( ^4R )-4-(3-substituted carboxy-
Method for producing 2-oxo-propyl)-2-azetidinones. 3. Claim 1, characterized in that the reaction between a reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinone and an alkali metal enolate of an acetic acid derivative is carried out in the presence of a base, or (4R)-4-(3 described in paragraph 2)
-substituted carboxy-2-oxo-propyl)-2
- A method for producing azetidinones. 4 Reactive derivatives at the carboxyl group of (4S)-carboxymethyl-2-azetidinones are
(4R) according to any one of claims 1 to 3, which is a mixed acid anhydride obtained by reacting (4S)-4-carboxymethyl-2-azetidinone with a halocarbonate in the presence of a base. - A method for producing 4-(3-substituted carboxy-2-oxo-propyl)-2-azetidinones.