JPS6254310B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (1) [In the formula, R represents a hydrogen atom, a protecting group for a carboxyl group, or a salt-forming cation. ] (2R,5R)-3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2
- Concerning carboxylic acids and their production methods. In recent years, with the discovery of thienamycin (USP 3950357) having useful biological activity, active research has been conducted to obtain various carbapenems by pure synthesis. As is clear from their structural formulas, carbapenems exist in various isomers, but useful compounds are optically active compounds with a specific three-dimensional structure. Generally, optically active substances can be synthesized using optical resolution methods, asymmetric synthesis methods, or derivation methods from optically active compounds. However, there has been no example of synthesizing a biologically active carbapenem as an optically active substance, and there is also the drawback that at least half of the final target substance cannot be utilized if it is optically resolved. Therefore, the present inventors focused on the fact that if a novel optically active intermediate could be obtained, various optically active carbapenems could be advantageously derived,
As a result of various studies on the novel optically active compound of formula (1) and its production method, the present invention was completed by discovering a method of chemically deriving it from L-aspartic acid. According to the present invention, optically active compounds of formula (1) and novel optically active compounds of formula (1) are expected to be useful as β-lactamase inhibitors or as intermediates for various useful carbapenems or themselves as β-lactamase inhibitors. It is possible to provide a novel method for producing a compound of the formula ) from an optically active raw material or intermediate. The present invention will be explained in detail below. In the general formula (), the protecting group for the carboxyl group of R includes all groups commonly known as protecting groups for the carboxyl group of β-lactam compounds, such as pharmaceutically usable protecting groups or intermediate Protective groups that can be used as protection groups include: Specifically, the following can be mentioned, for example. (i) 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; especially substituted alkyl groups such as trichloromethyl, tribromomethyl, 2,2,2-trichloroethyl, trifluoroethyl, 2-bromopropyl, iodomethyl, diiodomethyl, 2-chloroethyl, 2-bromoethyl; and Alkyl group substituted with one or more substituents selected from the following substituents: acetyl, propionyl, piparoyl, benzoyl, p-bromobenzoyl, p-tert.-
Acyl groups such as butylbenzoyl, acetoxyacetyl, piparoyloxyacetyl, 1,4-
Cycloalkadienylmethyl groups such as hexadien-1-yl-methyl, methoxy, ethoxy,
Alkoxy groups such as isopropoxy and decyloxy, cycloalkyloxy groups such as cyclohexyloxy, acyloxy groups such as acetoxy, dimethylaminoacetoxy, propionyloxy, piperoyloxy, mono- and di- such as methylamino, dimethylamino, diethylamino, etc.
Alkylamino groups, acylamino and imino groups such as acetamide, phthalimide, succinimide, 2-thienyl, 2-furyl, 3-
Heterocyclic groups such as tert.-butyl-5-isothiazolyl, 6-piparoyloxy-3-pyridazinyl, 5-phenylthio-1-tetrazolyl,
Phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 4-nitrophenoxy, 4-
Benzyloxyphenoxy, 4-methylphenoxy, 4-benzyloxyphenoxy, 2-methylphenoxy, 2-methoxyphenoxy, 4
-Aryloxy group such as aminophenoxy, phenylthio, 4-methoxyphenylthio, 4-
Arylthio groups such as chlorophenylthio, benzyloxy, 4-nitrobenzyloxy, 4-
Aralkoxy groups such as clobenzyloxy, alkylthio groups such as methylthio, ethylthio, isopropylthio, and decylthio, cycloalkylthio groups such as cyclohexylthio, tetrahydrofuran-2-yl, tetrahydrofuran-2-
Heterocyclic groups such as yl, tetrahydropyran-2-yl, furan-2-yl, 4-pyridyl, methoxycarbonyl, ethoxycarbonyl,
Alkoxycarbonyl groups such as tert.-butyloxycarbonyl and tert.-acyloxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, diphenylmethoxycarbonyl, and triphenylmethoxycarbonyl;
Aryl groups such as p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl,
Acylthio groups such as acetylthio and piparoylthio, cyano groups, arylsulfonylmethyl groups,
2-dimethylsulfonium methyl group, phthalidyl group, carboxyl group, etc. (c) Alkenyl group; allyl, 2-propenyl, 2
-Methyl-2-propenyl, 3-phenyl-2
-propenyl, 2-butenyl, 3-butenyl,
4-butenyl, 3-methyl-3-butenyl, 3
-Alkenyl groups such as pentenyl, 4-pentenyl, methallyl, etc. (d) Alkynyl group; ethynyl, propargyl, 3
-Alkynyl group such as butyn-1-yl. (e) Aralkyl group; benzyl, benzhydryl, p-chlorobenzyl, p-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl, m-benzoylbenzyl, p-
tert.-butylbenzyl, m-phenoxybenzyl, p-acetoxybenzyl, p-piparoylbenzyl, p-benzoylbenzyl, 3,5
-dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl, p-carboxylbenzyl (which is the free acid, ester or sodium salt), 2,4,6-trimethylbenzyl, p-piparoyloxybenzyl, p-
tert.-butoxycarbonylbenzyl, p-methoxybenzhydryl, 2,2-dimethyl-5
-coumaranmethyl, 5-indanylmethyl, p
-trimethylsilylbenzyl, isopropoxybenzyl, 3,5-bis-tert.-butoxy-
4-hydroxybenzyl, phenylethyl, 2
-(p-methylphenyl)Aralkyl groups such as ethyl and trityl. (f) Aryl group; phenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-tert.-butylphenyl, 4-nitrophenyl, 3,5-
Aryl groups such as dinitrophenyl, carboxyphenyl (which is in the free acid or sodium salt form). (g) Others; phthalidyl group, indanyl group, chronolactone-3-yl group, furyl group, quinolyl group, N-(methylpyridyl) group. Next, a method for producing the optically active compound of general formula () of the present invention will be explained. The optically active compound of the general formula () of the present invention is
It can be obtained according to the reaction shown below.

【table】

【table】

[Table] [In the above formula, R represents the meaning described above. R ¹ represents a carboxyl group-protecting group, and R ² , R ³ , R ⁴ and R ₅ represent protective groups commonly known as carboxyl or amino group-protecting groups. ] That is, (1) The compound represented by the general formula () is derived from L-aspartic acid, for example, in Nippon Kagaku Zasshi 82 ,
601, (1961). The carboxyl protecting group for R ² 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) A compound represented by the general formula () or () can be obtained by a conventional reaction of protecting an amino group on L-aspartic acid or a compound represented by the general formula (). The protecting group for the amino group of R ³ is preferably a group that can be easily eliminated, such as an alkoxycarbonyl or aralkoxycarbonyl group such as tert.-butoxycarbonyl or benzyloxycarbonyl. (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 prepared by reacting the compound represented by the general formula () with a halocarbonic acid ester such as isobutyl chloroformate in the presence of a base to obtain a mixed acid anhydride. It can be obtained by producing a compound and then reacting it with diazomethane, or by converting the compound represented by the general formula () into an acid hydride derivative by a conventional method and then reacting it with diazomethane. This reaction is first carried out in a solvent such as benzene, diethyl ether, diisopropyl ether, or tetrahydrofuran by cooling or at room temperature for several tens of minutes to several hours to produce a mixed acid anhydride, which is then mixed with diazomethane under cooling. It is carried out by reacting with (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 may normally be 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 protecting group for the carboxyl group of ^R4 is a group that is eliminated by a normal hydrolysis reaction, such as an alkyl group such as methyl or ethyl, or a group that is eliminated by a normal reduction reaction, such as benzyl, diphenylmethyl, trityl, etc. An aralkyl group is preferred. (7) The compound represented by the general formula () can be prepared by a reaction in which the compound represented by the general formula () is removed from the usual carboxyl-protecting group and amino-protecting group.
For example, it can be obtained by subjecting it to catalytic reduction or hydrolysis with hydrogen at room temperature and pressure in the presence of a catalyst such as palladium on carbon. (8) The compound represented by the general formula () can be obtained by removing the protecting group of the amino group of the compound represented by the general formula () by a conventional method. This reaction is usually carried out using ethyl acetate,
The reaction may be carried out in a solvent such as water or tetrahydrofuran using hydrogen halide or the like under cooling or room temperature for several hours. (9) A 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,
If catalytic reduction with hydrogen is carried out at room temperature and pressure in the presence of a catalyst such as palladium on carbon, the compound represented by the general formula () and aldehydes will react and the resulting Schiff's base will be reduced.
The protecting group on R ² 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. As the protecting group for the amino group of R ⁵ , easily removable groups such as aralkyl groups such as benzyl, diphenylmethyl, and trityl can be suitably used. (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 For the ring-closing reaction, an active halogen compound such as thionyl chloride, phosphorus trichloride, or phosphorus pentachloride is reacted in the presence or absence of a solvent, followed by a base such as triethylamine, pyridine, N,N-dimethylaniline, etc. It is done by making it work. 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 may be carried out for 1 to 10 hours under cooling or heating. (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 protecting group from the compound represented by the general formula (XII) and then subjecting it to a reaction that protects the carboxyl group. The protective group elimination reaction is appropriately selected under conditions that allow it to be carried out without cleaving the azetidinone ring. Specifically, this can be easily carried out by using metallic sodium or the like in liquid ammonia. Next, the reaction to protect the carboxyl group is
It can be obtained by subjecting the obtained product to, for example, a conventional esterification reaction while cooling or heating. (13) In order to obtain the compound represented by the general formula () from the obtained compound represented by the general formula (), the compound represented by the general formula () is subjected to a conventional protective group elimination reaction, such as the usual It is carried out by subjecting it to a hydrolysis reaction, such as alkaline hydrolysis, a reduction reaction, or an elimination reaction under mild conditions. This reduction reaction or elimination reaction under mild conditions is carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane, anisole, ethyl acetate, trifluoroacetic acid, etc., at normal temperature and pressure, in the presence of a catalyst such as palladium on carbon. This is done by allowing hydrogen to act on the surface for several hours or by treating it with trifluoroacetic acid, etc.
After reaction, vacuum concentration, solvent treatment, crystallization, recrystallization,
It can be isolated and purified by chromatography or the like. In addition, the compound represented by the general formula () can be obtained from the compound represented by the general formula (XII) in place of the above-mentioned (12) and (13), with the amino protecting group of R ⁵ as described in (12). It can also be obtained directly by performing only an elimination reaction. In (1) to (13) above, when L-aspartic acid is used as the first starting material, the corresponding optically active compounds of general formulas () to () and () are obtained, but
Using an optically inactive compound as a starting material,
An optically active () compound can also be obtained by optically resolving the obtained optically inactive () compound via a corresponding optically inactive compound. (14) Next, the optically active compound represented by the general formula () is obtained by converting (4S)-4-carboxymethyl-2-azetidinone into a reactive derivative at the carboxyl group by a conventional method, and then forming the optically active compound represented by the general formula (). It can be obtained by reacting the acetic acid derivative shown with an alkali metal enolate. Examples of reactive derivatives of (4S)-4-carboxymethyl-2-azetidinone include mixed acid anhydrides. For example, a mixed acid anhydride can be obtained by reacting a halocarbonic acid ester in a solvent unrelated to the reaction, such as toluene or diethyl ether, for several hours at -30°C to room temperature. Examples of the halocarbonate ester include ethyl chloroformate and isobutyl chloroformate. Further, examples of acetic acid derivatives include those having the carboxyl protecting group of R described above. The condensation reaction of a reactive derivative of (4S)-4-carboxymethyl-2-azetidinone with an alkali metal enolate of an acetic acid derivative represented by the general formula () is preferably carried out using, for example, triethylamine, diisopropylamine, 2,2,
In the presence of a base such as 6,6-tetramethylpiperidine, in a solvent unrelated to the reaction, such as one or a mixed solvent of two or more of tetrahydrofuran, dioxane, toluene, diethyl ether, etc., preferably an inert gas such as argon. It may be carried out in an atmosphere at -80° to -30°C for several tens of minutes to several hours. (15) Furthermore, the optically active compound represented by the general formula () is described in Tetrahedron Letters Vol. 21, pp 31-34.
(1980), the general formula (
It can be obtained by reacting an optically active compound represented by ) with a diazotizing agent. Examples of the diazotizing agent include p-carboxybenzenesulfonyl azide, p-toluenesulfonyl azide, and benzenesulfonyl azide. This reaction is preferably carried out in the presence of a base such as triethylamine or pyridine.
Solvents irrelevant to the reaction, e.g. acetonitrile,
The reaction may be carried out in propionitrile at −10° C. or higher for several tens of minutes to several hours. (16) Furthermore, the optically active compound represented by the general formula () is described in Tetrahedron Letters Vol.21, p31-34.
(1980), the general formula (
) can be obtained by subjecting it to a ring-closing reaction, preferably in the presence of a metal salt catalyst. This reaction is usually carried out in a solvent unrelated to the reaction, such as benzene, toluene, dioxane, or tetrahydrofuran, preferably at 60 DEG to 90 DEG C. for several tens of minutes to several hours. In addition, as metal salt catalysts, rhodium acetate [Ph ₂ (OAc) ₄ ], RhCl _{3.3H 2} O, RhCl [P(Ph) ₃ ] ₃ , etc. are used, and the amount used is as follows: A ratio of 1/100 to 1/300 is sufficient for the optically active compound represented by the general formula (). In addition, after the reaction in each step of (14) to (16), the objective can be achieved by performing usual isolation and purification operations such as solvent distillation, vacuum concentration, solvent treatment, chromatography, crystallization, recrystallization, etc. isolate something In addition, when R of the optically active compound represented by the general formula () is a carboxyl protecting group, the optically active compound represented by the general formula () can be protected by a normal hydrolysis reaction, reduction reaction, treatment under mild conditions, etc. A compound in which the carboxyl group is in a free state can be used.
Furthermore, the free compound is converted into a normal salt by a normal method, or an optically active compound represented by the general formula () with a protected carboxyl group is obtained by subjecting the free compound to a normal carboxyl group-protecting reaction. You can also do that. The intermediate () obtained by the above method
Compounds of formula () and () and ()
The optically active compound of the formula (XI) is a new compound, and the optically active compound of formulas (XI) to () is similar to the optically active compound of the formula () of the present invention,
It has utility as a synthetic intermediate for carbapenem and azetidinone derivatives. The optically active compound of formula () of the present invention can be prepared by adding a thienamycin type substituent at the 6-position and an oxo group at the 2-position, for example, p-toluenesulfonyl. After becoming
By reacting with various thiol compounds or amino compounds, various thienamycin type substituents can be introduced, and therefore, the optically active compound of formula ( ) of the present invention can be used for various useful compounds. It can be used as an intermediate for known or new important optically active compounds. Next, the present invention will be explained with reference to Examples. Example 1 (1) 80% sulfuric acid and 250 g of pendyl 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 collect the precipitated crystals. Place the obtained crystals in cold water at 150 mL.
ml and recrystallized from water to obtain 86 g (yield 52%) of L-aspartic acid-β-benzyl ester having a melting point of 222°C. (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 resulting 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. If 400 ml of ethyl acetate-petroleum ether (1:5) is added to the resulting residue and crystals are collected, N-
tert.-butoxycarbonyl-L-aspartic acid-β-benzyl ester 122 g (yield 80
%). (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. To the resulting solution, 4.6 ml of isobutyl chloroformate was added dropwise over 5 minutes at 5° to 7°C. After stirring at the same temperature for 40 minutes, this was added to a separately prepared diethyl ether solution of diazomethane (prepared using 22 g of nitrosomethylurea) at -10°C. 1 at 0-5℃
The temperature was gradually raised to room temperature over an additional 30 minutes while stirring. Thereafter, excess diazomethane is distilled off under reduced pressure, and insoluble materials are separated. If the solvent of the liquid is distilled off under reduced pressure, benzyl = (3S)
-5-diazo-3-(tert.-butoxycarbonyl)amino-4-oxopentanoate 11.9
get g. This was dissolved in 45 ml of anhydrous methanol, and 0.45 ml of a solution of silver benzoate in triethylamine (prepared by dissolving 0.5 g of silver benzoate in 4.5 ml of triethylamine) was added and stirred. After stirring for an additional hour, add 0.5 g of activated carbon.
After refluxing for a minute, insoluble matter is separated. The solvent of the liquid was distilled off under reduced pressure, and the resulting residue was dissolved in 120 ml of diethyl ether. The diethyl ether solution is washed successively with 20 ml of water, 20 ml of saturated aqueous sodium bicarbonate solution, and 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If the obtained residue is purified by column chromatography (silica gel C-200; eluent; benzene:ethyl acetate = 35:1),
7.8 g (yield: 69%) of oily benzyl (3R)-3-(tert.-butoxycarbonyl)amino-4-methoxycarbonylbutanoate is obtained. IR (neat) cm ^-1 ; νNH3360, νC=O1670
~1740 NMR (CDCl ₃ ) δ value; 1.43 (s, 9H, CH ₃ × 3) 2.55 – 2.85 (m, 4H, CH ₂ × 2) 3.65 (s, 3H, OCH ₃ ) 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) 35 g of benzyl = (3R) -3-(tert.-butoxycarbonyl)amino-4-methoxycarbonylbutanoate and ice While cooling, add 115 ml of 2.6N hydrogen chloride-ethyl acetate solution. then at room temperature 1.5
Stir for an hour. 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% ethyl acetate to the resulting aqueous layer.
ml and add sodium bicarbonate to make it alkaline. Separate the ethyl acetate layer,
After washing this with 20 ml of saturated saline, drying over anhydrous magnesium sulfate and distilling off the solvent, 22.5 g of oily benzyl (3R)-3-amino-4-methoxycarbonylbutanoate (yield 90%) was obtained. ). IR (neat) cm ^-1 ; νNH3300~3400 νC=O1720 NMR ( _CDCl3 )δ; 1.85 (bs, 2H, _NH2 ) 2.30~2.65 (m, 4H, _CH2 × 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) Benzyl = (3R) -3-amino-4-methoxycarbonylbutanoate Add 22.5 g and 10 g of benzaldehyde to 200 ml of benzene, add 22 g of Molecular Sieves 4A to the resulting solution, and stir at room temperature for 2 hours. The molecular sieves are separated and the solvent of the liquid is distilled off under reduced pressure. The obtained residue is dissolved in 20 ml of methanol, 7 g of 5% palladium on carbon is added, and catalytic reduction is carried out at room temperature in the presence of hydrogen. After separating the insoluble matter, the solvent is distilled off under reduced pressure. The resulting residue is treated with ethyl acetate to obtain 17.8 g (79% yield) of (3S)-3-benzylamino-4-methoxycarbonylbutanoic acid as an amorphous solid.
If this is recrystallized from MeOH-Et ₂ O, the melting point will be
A prismatic crystal exhibiting a temperature of 114° to 115.5°C is obtained. IR (KBr) cm ^-1 ; 1740, 1580 NMR (CDCl ₃ ) δ; 2.35 to 3.05 (m, 4H, CH ₂ ×2) 3.400 to 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) Benzyl = (3R)-3-amino-4-methoxycarbonylbutanoate 1.7g and benzaldehyde 0.72g are dissolved in benzene 17ml and Molecular Sieves 4A 3g was added, stirred at room temperature for 4 hours, heated to around 40℃, separated from the molecular sieves, and distilled off the solvent under reduced pressure to obtain benzyl (3R)-3-benzylideneamino as a yellow oil. -4-methoxycarbonylbutanoate is obtained. IR (neat) cm ^-1 , νC=O 1725 νC=N 1640 Next, this was dissolved in 20 ml of ethanol,
Under ice cooling, 0.75 g of sodium borohydride was added, and after stirring for 2 hours, the solvent was distilled off under reduced pressure in an ice bath. Diethyl ether 30% to the resulting residue
ml and 10 ml of saturated saline, and after shaking thoroughly, separate the organic layer. After drying the separated organic layer over anhydrous magnesium sulfate, the solvent is distilled off.
Purification of the residue by column chromatography (silica gel C-200; eluent: benzene) yields benzyl = (3R)-3-benzylamino-4.
- Obtain 0.93 g (yield 40%) of methoxycarbonyl butanoate. IR (neat) cm ^-1 : νC=O1720 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-carbon to this, hydrogen was absorbed for 30 minutes at room temperature while stirring, and the palladium-carbon was separated. Wash this with 25 ml of methanol. If you combine the liquid and washing liquid and distill off the solvent under reduced pressure, an oily substance will be produced.
Obtain 0.64g. When this is treated with ethyl acetate, 0.4 g (yield 58%) of (3S)-3-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 for 1.5 hours at room temperature,
Excess thionyl chloride is 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 poured into 750 ml of anhydrous benzene containing 3.6 ml of triethylamine.
It takes time to drip. After stirring for another 3 hours,
0.5N - twice with 100ml of diluted hydrochloric acid, 100ml of water, 80ml of saturated aqueous sodium bicarbonate solution, 80ml of saturated saline
After washing with water and drying with anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel c-
200; Eluent; Benzene: Ethyl acetate = 5:
If purified by 1), crystalline (4S)-1-benzyl-4-methoxycarbonylmethyl-2-
1.96 g of azetidinone (66% yield) is obtained. If this is recrystallized from ether-n-hexane, colorless prism crystals having a melting point of 43.5° to 44.5°C are obtained. IR( _CHCl2 )cm ^-1 ; νC=O1730~1755 NMR( _CDCl3 )δ; 2.45~2.87(m, 3H, C3 _- H〓, _CH2 ,
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 caustic soda under ice cooling. After adding 7.3 ml of aqueous solution and reacting for 1 hour, methanol was distilled off under reduced pressure. The resulting aqueous solution is washed with a small amount of ethyl acetate, made acidic by adding 7.6 ml of 1N hydrochloric acid, extracted with 20 ml of ethyl acetate, and the ethyl acetate layer is separated. 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. Adding diethyl ether to the residue yields pale yellow (4S)-1-benzyl-4.
-Carboxymethyl-2-azetidinone 1.3g
(yield 86%). If this is recrystallized from benzene, colorless prism crystals with a melting point of 109-110°C are obtained. IR (KBr) cm ^-1 ; νC=O1730, 1690 νC=O1745, 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, Hδ) 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 = +122° (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 further,
After reacting for 5 minutes, ammonia is distilled off under reduced pressure. The resulting off-white solid was cooled to -20°C.
30 ethyl alcohol containing 7.8 ml of 1N hydrochloric acid
ml and dissolve while gradually raising the temperature.
Add 3 g of diphenyldiazomethane to this and allow to react at room temperature for 60 minutes. After the reaction is complete, ethyl alcohol is distilled off under reduced pressure, and 300 ml of ethyl acetate is added to the residue to separate the organic layer. The separated organic layer was washed successively with 10 ml of water and 5 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off 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-diphenylmethyloxycarbonylmethyl- 2-azetidinone 0.35g (yield 85
%). If this is recrystallized from diethyl ether, colorless needle crystals having a melting point of 65.5-66.5°C are obtained. IR (CHCl ₃ ) cm ^-1 ; νC=O1760, 1735 (shoulder) νNH3310 NMR (CDCl ₃ ) δ value; 2.41 to 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) (4S) -4-diphenylmethyloxycarbonylmethyl-2-azetidinone 0.3g
Dissolve in 10 ml of ethanol, add 0.09 g of 5% palladium on carbon, and shake in a hydrogen stream for 1.5 hours. After separating the catalyst, the solvent was distilled off under reduced pressure, and the resulting residue was treated with diethyl ether to obtain 0.115 g (yield: 88%) of (4S)-4-carboxymethyl-2-azetidinone as a white powder. obtain. If this is recrystallized from tetrahydrofuran, colorless prismatic crystals having a melting point of 169-171°C (decomposition) are obtained. IR (KBr) cm ^-1 ; νNH3250 νC=O1690~1740 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) Also, if you use tetrahydrofuran instead of ethyl alcohol and hydrogenate as described above at 50 to 90℃ for 3 hours, (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 distilled off under reduced pressure twice to obtain diethyl ether-ethyl acetate (2:1).
Add 3ml, stir, and remove (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 argo atmosphere, add 1 ml of an anhydrous tetrahydrofuran solution of triethylamine (containing 0.375 ml of triethylamine in 5 ml), and -
At 20°C, add 1 ml of an anhydrous tetrahydrofuran solution of isobutyl chloroformate (5 ml contains 0.375 ml of isobutyl chloroformate), and stir 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 to this was added an n-hexane solution of n-butyllithium (containing 1.5 mmol of n-butyllithium) under ice cooling. Add 1ml and keep at the same temperature.
After stirring for 30 minutes, cool to -78℃ and add benzyl acetate.
Add 0.21ml 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 a saturated aqueous ammonium chloride solution was added, followed by 20 ml of ethyl acetate, and the organic layer was separated.
The separated organic layer was mixed with 5 ml of dilute hydrochloric acid, 3 ml of water, 3 ml of saturated aqueous sodium bicarbonate solution, and 3 ml of saturated brine.
ml of water, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure to obtain 0.24 g of an oily substance.
get. This oil was subjected to preparative thin layer chromatography (developing solution: chloroform:acetone = 3:
If purified by 1), colorless oil (4R)-4-
(3-benzyloxycarbonyl-2-oxopropyl)-2-azetidinone 0.023g (yield
18%). IR (neat) cm ^-1 ; νNH3250~3360 νC=O1700~1770 NMR ( _CDCl3 )δ; 2.32~3.34 (m, 4}H, _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) (11) (4R) -4 - ( Add 0.83 g of 3-benzyloxycarbonyl-2-oxopropyl)-2-azetidinone and 0.076 g of p-carboxybenzenesulfonyl azide to 1.5 ml of acetonitrile, and then add 0.13 ml of triethylamine under ice cooling.
Add and dissolve. The temperature was then raised to room temperature, and after stirring at the same temperature for 1 hour, the insoluble matter was separated, the liquid was diluted with 10 ml of diethyl ether, and the mixture was 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
-0.079g of amorphous solid when treated with hexane
(yield 87%). If this is recrystallized from diethyl ether, it will show a melting point of 99-102℃ (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 value; 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) (12) (4R) -4 - [ 3-(benzyloxycarbonyl)-3-diazo-2-oxopropyl]
-2-Azetidinone 0.059g anhydrous penzene 20
ml, add 0.3 mg of rhodium acetate, and stir at 80-85°C for 45 minutes. Next, the volume of this solution is concentrated to half under reduced pressure, 15 ml of diethyl ether is added, insoluble matter is separated, and the solvent of the liquid is distilled off 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 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=O1772, 1745 (CCl ₄ ) cm ^-1 ; νC=O1785, 1775, 1745 NMR (CDCl ₃ ) δ value; 2.36 (dd, 1H, J=8.0Hz, 19.1Hz, _C4 ―
Ha) 2.74-3.05 (m, 2H, C ₄ -Hb, C ₆ -Hβ) 3.63 (dd, 1H, J = 5.0Hz, 16.0Hz, C ₆ -H
α) 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) Example 2 (1) 26.6 g of L-aspartic acid was suspended in 200 ml of water, and 4N-sodium hydroxide aqueous solution was added for 30 minutes while maintaining the temperature at 10 to 15°C. to dissolve L-aspartic acid. Next, 34.3 ml of benzyloxycarbonyl chloride and 50 ml of 4N-sodium hydroxide aqueous solution were mixed while maintaining the temperature at 5 to 7°C.
Drop simultaneously over 80 minutes. 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, unreacted benzyloxycarbonyl chloride was removed by extraction with 100 ml of diethyl ether, and the resulting aqueous solution was added with 33 mL of concentrated hydrochloric acid under ice cooling.
Drop ml. The oily substance precipitated at this time is extracted with 150 ml of ethyl acetate and fractionated. After washing the separated organic layer with saturated brine and drying 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 collected. Melting point: 109.5~
N-benzyloxycarbonyl-L- at 111℃
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 to 86°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. Next, crystallize with petroleum ether and remove the crystals to obtain N-benzyloxycarbonyl-L.
-38.1g of aspartic acid-α,β-di-benzyl ester is 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 prepared at room temperature for 3 hours. After the dropwise addition, the acetone was distilled off and diethyl ether was dissolved. Remove the neutral part, cool the aqueous layer with ice, add 4.5 ml of concentrated hydrochloric acid,
Crystals precipitate when stirred. The precipitated crystals were collected and washed with water and petroleum ether to obtain N-benzyloxycarbonyl-L-aspartic acid-β.
- Obtain 12.3 g (yield 69%) of benzyl ester. Melting point: 108-109°C (recrystallized from benzene) [α] ²⁰ _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 solution is added dropwise to 30 ml of diazomethane diethyl ether solution (prepared from 2.7 g of CH ₃ N(NO)CONH ₂ ) at below 5°C. After stirring for 1.5 hours, the temperature was gradually raised to room temperature, excess diazomethane was removed, and the solvent was distilled off under reduced pressure to obtain crude benzyl (3S) as a pale yellow oil.
1.76 g of -5-diazo-3-benzyloxycarbonylamino-4-oxopentanoate is obtained. IR (neat) cm ^-1 : νH22120 νC=O1690~1740 (5) Under nitrogen atmosphere, crude benzyl = (3S)-5-diazo-3-benzyloxycarbonylamino-
Dissolve 1.76 g of 4-oxopentanoate 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 (40℃)
), and the silver that precipitates becomes dark brown. ) After the reaction is complete, add 0.2 g of carbon and reflux for 10 minutes to decolorize and deactivate excess silver benzoate. The mixture was filtered through Celite, and the resulting liquid was distilled off under reduced pressure. The residue was dissolved in 15 ml of ethyl acetate, washed with 5 ml of saturated aqueous sodium bicarbonate solution and 3 ml of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel c=
200, benzene:ethyl acetate=30:1) to obtain 0.905 g (yield 58.7%) of benzyl (3S)-3-benzyloxycarbonylamino-4-methoxycarbonylbutanoate. Melting point 48-49℃ (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 the palladium on carbon was separated. Wash this with 10 ml of methanol. The solution and washing solution are combined, the solvent is distilled off under reduced pressure, the resulting residue is washed with chloroform, and the crystals are collected to obtain 0.467 g of (3S)-3-amino-4-methoxycarbonylbutanoic acid.
(yield 84.1%). Melting point 186-187℃ (decomposed) (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) 0.320 g of (3S)-3-amino-4-methoxycarbonylbutanoic acid was mixed with 3.2 g of thionyl chloride under ice cooling.
After stirring at room temperature for 1.5 hours, thionyl chloride was 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 this reaction solution was left to stand overnight, insoluble materials were separated and the solvent of the solution was 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, and the solvent is distilled off from the eluate under reduced pressure) to obtain 0.010 g of (4S)-4-methoxycarbonylmethyl-2-azetidinone. IR (CHCl ₃ ) cm ^-1 ; νNH3420 ν ₃₌₀ 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-carbosimethyl-2- Obtain azetidinone. Example 1
(10), (11) and then reacted in the same manner as (12) to obtain benzyl=(2R,5R)-3-oxo-7-oxo-1-azabicyclo[3,2,0]heptane-2-carboxy Get the latkes.

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom, a protecting group for a carboxyl group, or a salt-forming cation. ] (2R,5R)-3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2
-Carboxylic acids. 2 General formula [In the formula, R ¹ represents a carboxyl group protecting group. ] The (4R)-diazo-2-azetidinone derivative represented by is subjected to a ring-closing reaction, and if desired, the protecting group of the carboxyl group is removed, or after removal, salting or a protecting group is introduced. general formula to [In the formula, R represents a hydrogen atom, a protecting group for a carboxyl group, or a salt-forming cation. ] (2R,5R)-3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2
-Production method of carboxylic acids. 3. (2R, 5R) according to claim 2, characterized in that the ring-closing reaction is carried out in the presence of a catalyst.
-Production method of 3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acids. 4. (2R, 5R) according to claim 3, characterized in that the catalyst is rhodium acetate (2R, 5R).
A method for producing 3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acids. 5 formula (4S)-4-carboxymethyl-
The reactive derivative at the carboxyl group of 2-azetidinone has the general formula CH ₃ COOR ¹ [wherein R ¹ represents a protecting group for the carboxyl group. ] By reacting an alkali metal enolate of an acetic acid derivative represented by the general formula [In the formula, R ¹ represents the above meaning. ] A (4R)-2-azetidinone derivative represented by [In the formula, R ¹ represents the above meaning. ] Obtain a (4R)-diazo-2-azetidinone derivative represented by the formula, then perform a ring-closing reaction, and optionally remove the protecting group of the carboxyl group, or after removing it, salt it or introduce a protecting group. A general formula characterized by [In the formula, R represents a hydrogen atom, a protecting group for a carboxyl group, or a salt-forming cation. ] (2R,5R)-3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2
-Production method of carboxylic acids. 6. (2R, 5R) according to claim 5, characterized in that the ring-closing reaction is carried out in the presence of a catalyst.
-Production method of 3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acids. 7. (2R, 5R) according to claim 6, characterized in that the catalyst is rhodium acetate (2R, 5R)
A method for producing 3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acids. 8. Claims 5 to 7, characterized in that the reaction between the reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinone and the alkali metal enolate of the acetic acid derivative is carried out in the presence of a base. Either (2R, 5R) -
A method for producing 3-oxo-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acids. 9. A mixture in which a reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinone is obtained by reacting (4S)-4-carboxymethyl-2-azetidinone with a halocarbonate in the presence of a base. (2R,5R)-3-oxo-7-oxo-1-azabicyclo [3.2.0] according to any one of claims 5 to 8, which is an acid anhydride.
A method for producing heptane-2-carboxylic acids.