JPH0147466B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ₁ represents a hydrogen atom, a salt-forming cation, or a carboxyl group-protecting group, R ₂ represents a carboxyl group-protecting group, and R ₃ represents a hydrogen atom or an amino group-protecting group. ] The present invention relates to a (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative represented by and a method for producing the same. In recent years, with the discovery of thienamycin (USP 3950357), which has useful biological activities,
Research is being actively conducted to obtain various useful carbapenems through pure synthesis. As is clear from their structural formulas, carbapenems exist in various isomers, but useful compounds are known to be optically active compounds with a specific steric structure. Therefore, when conducting research on the synthesis of carbapenems, it is extremely important to take care to efficiently introduce a specific three-dimensional structure into the final target substance. From this point of view, the present inventors have conducted intensive research on pure synthesis methods for carbapenems, and have found that the novel optically active compound represented by the above-mentioned general formula () is extremely useful as a synthetic intermediate thereof. They discovered that this product can be easily obtained and completed the present invention. The present invention provides a method for producing a novel optically active compound represented by the general formula (), which is useful as an intermediate for various useful carbapenems. The present invention will be explained in detail below. In the general formula (), the carboxyl group-protecting groups for R ₁ and R ₂ include all groups commonly known as carboxyl group-protecting groups of β-lactam compounds, such as those that can be used pharmaceutically. Protecting groups that can be used as protecting groups or intermediates are mentioned. Specifically, the following can be mentioned, for example. (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; especially substituted alkyl groups such as trichloromethyl, tripromomethyl, 2,2,2-trichloroethyl, trifluoroethyl, 2-bromopropyl, iodomethyl, diiodomethyl, 2-chloroethyl, 2-bromoethyl; and An alkyl group substituted with one or more substituents selected from the following substituents: Acyl groups such as acetyl, propionyl, pivaloyl, benzoyl, p-promobenzoyl, p-tert.-butylbenzoyl, acetoxyacetyl, pivaloyloxyacetyl, cycloalkadine groups such as 1,4-hexadien-1-yl-methyl, etc. enylmethyl group, alkoxy groups such as methoxy, ethoxy, isopropoxy, decyloxy, cycloalkyloxy groups such as cyclohexyloxy, acyloxy groups such as acetoxy, dimethylaminoacetoxy, propionyloxy, pivaloyloxy, methylamino, dimethylamino, diethylamino, etc. Mono and Gee
Alkylamino groups, acylamino and imino groups such as acetamido, phthalimide, succinimide, 2-thienyl, 2-furyl, 3-tert.
-Heterocyclic groups such as butyl-5-isothiazolyl, 6-pivaloyloxy-3-pyridazinyl, 5-phenylthio-1-tetrazolyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 4-nitrophenoxy, 4- Benzyloxyphenoxy, 4-methylphenoxy,
Aryloxy groups such as 4-benzyloxyphenoxy, 2-methylphenoxy, 2-methoxyphenoxy, 4-aminophenoxy, arylthio groups such as phenylthio, 4-methoxyphenylthio, 4-chlorophenylthio, benzyloxy, Aralkoxy groups such as 4-nitrobenzyloxy and 4-chlorobenzyloxy, alkylthio groups such as methylthio, ethylthio, isopropylthio, and decylthio, cycloalkylthio groups such as cyclohexylthio, tetrahydroflu-2-yl, and tetrahydropyran-2-yl. ,
Heterocyclic groups such as flu-2-yl and 4-pyridyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert.-butyloxycarbonyl, tert.-acyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl, triphenyl Aralkyloxycarbonyl groups such as enylmethoxycarbonyl, aryl groups such as p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, acylthio groups such as acetylthio and pivaloylthio, 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, and methallyl. (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-pivaloylbenzyl, 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-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, and trityl. (f) Aryl group; phenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-tert.-butylphenyl, 4-nitrophenyl, 3,5-dinitrophenyl, carboxyphenyl (which is in the free acid or sodium salt form) Aryl groups such as. (g) Others; phthalidyl group, indanyl group, chronolactone-3-yl group, furyl group, quinolyl group, (N-(methylpyridyl) group, trimethylsilyl group. Also, as an amino protecting group for R ₃ , β- It includes all groups commonly known as protecting groups for the amino group of lactam compounds.Specifically, the following may 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-carboxylbenzyl (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-hydroxylbenzyl, phenylethyl, 2-(p-methylphenyl)ethyl, and trityl. (b) Others; 2-nitrophenylthio group, 2,4
-dinitrophenylthio group, tetrahydrofuryl group, tetrahydropyranyl group. In addition, in the general formula (), the salt-forming cation for R ₁ is, for example, lithium, sodium,
Examples include alkali metals such as potassium, and alkaline earth metals such as beryllium, calcium, and magnesium. Among the compounds of general formula (), particularly suitable intermediates include, for example, compounds in which R ₁ is H, or compounds in which R ₁ and R ₂ are the same or different and are aralkyl groups, or R ₁ and R ₂ Examples include compounds in which is a protecting group that can be easily removed by enzymes,
Also, R ₃ is an aralkyl group, especially the formula (In the formula, A, B, C and D are each a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a halogen atom, an acyloxy group, a nitro group,
Indicates an amino group or an acylamino group. ) is particularly preferred. Next, a method for producing the compound of general formula () of the present invention will be described below, for example, when L-aspartic acid is used as a starting material. [In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings,
R ₄ and R ₅ represent a carboxyl group-protecting group, and R ₆ represents an amino group-protecting group. ] That is, (1) The compound represented by the general formula (
(1961). The carboxyl protecting group for R ₅ 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 ()
It can be obtained by a conventional reaction in which an amino group is protected in a compound represented by As the protecting group for the amino group of R ₆ , an easily removable group,
For example, alkoxycarbonyl groups such as tert.-butoxycarbonyl and benzyloxycarbonyl can be suitably used. (3) The compound represented by the general formula () can be easily obtained by subjecting the compound represented by the general formula () to a normal esterification reaction. (4) By subjecting the compound represented by the general formula () to a normal hydrolysis reaction, the compound represented by the general formula ()
The compound represented by can be easily obtained. (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, a halocarbonic acid ester such as isobutyl chloroformate is reacted to produce a mixed acid anhydride, and then diazomethane is reacted, or a compound represented by the general formula () is converted into an acid halide derivative by a conventional method. It can then be obtained by reacting with diazomethane. This reaction is first carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, benzene, etc. under cooling or at room temperature for several tens of minutes to several hours to produce a mixed acid anhydride.
This is carried out by reacting this with diazomethane. (6) The compound represented by the general formula () is a compound represented by the general formula () with triethylamine,
It can be obtained by allowing a catalyst such as silver acetate or silver benzoate to act in the presence or absence of a base such as pyridine. This reaction may be carried out in the presence of water, optionally in a solvent that does not participate in the reaction, such as dioxane, at room temperature or under heating for several tens of minutes to several hours. (7) The compound represented by the general formula () can be obtained by subjecting the compound represented by the general formula () to a conventional esterification reaction. It can also be obtained by subjecting the compound of general formula () to the same reaction conditions as described in (6) in the presence of an alcohol. The carboxyl protecting group for R ₄ 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,
Aralkyl groups such as diphenylmethyl and trityl are preferably used. (8) 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, in the presence of a catalyst such as palladium on carbon.
It can be obtained by subjecting it to catalytic reduction with hydrogen or hydrolysis at room temperature and pressure. (9) 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 usually involves using ethyl acetate, dioxane,
The reaction may be carried out in a solvent such as diethyl ether using hydrogen halide or the like under cooling or room temperature for several hours. (10) The compound represented by the general formula (XI) is obtained by reacting the compound represented by the general formula () with an aldehyde such as benzaldehyde, 3,5-di-tert.-butyl-4-hydroxy-benzaldehyde, etc. It can be obtained by successively reducing the resulting compound. In this reaction, as a reduction treatment, for example,
If catalytic reduction with hydrogen is performed in the presence of a catalyst such as palladium on carbon at room temperature and pressure, the general formula () is obtained.
Schiff's base obtained by the reaction of the compound represented by the formula with aldehydes is reduced, and the protecting group of R ₅ is removed. Alternatively, the compound of general formula (XI) can be obtained in the same manner 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. be able to. Alternatively, after protecting the amino group of the compound represented by the general formula () with a group represented by R ₃ 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. (11) The compound represented by the general formula (XII) or (XI) can be obtained by subjecting the compound represented by the general formula (XI) or () to a ring-closing reaction. In the ring-closing reaction, a compound represented by the general formula () or (XI) is reacted with an active halogen compound such as thionyl chloride, phosphorus trichloride, or phosphorus pentachloride in the presence or absence of a solvent to form a compound represented by the general formula ( ) or (XI) is obtained, which is then treated with triethylamine, pyridine, N,N
- by treatment with a base such as dimethylaniline. The solvent used may be any solvent that does not participate in the reaction, and examples thereof include methylene chloride, diethyl ether, dioxane, and benzene. The reaction may be carried out for 1 to 10 hours under cooling or heating. The compound of general formula (XI) can also be obtained by removing the amino protecting group of the compound of general formula (XII). In the elimination reaction of the amino protecting group, a method and conditions are selected that are suitable for each amino protecting group and do not cause damage to the azetidinone ring. For example, when the amino protecting group is a benzyl group, a method of reacting with metallic sodium in liquid ammonia can also be used.
In the case of a butyl-4-hydroxybenzyl group, an oxidizing agent such as DDQ (dicyano-dichloro-p-benzoquinone) is applied in methanol,
A method of subsequent acid treatment is chosen. (12) The compound represented by the general formula () or () can be obtained by subjecting the compound represented by the general formula (XII) or (XI) to a conventional hydrolysis reaction. The compound of general formula () can also be obtained by removing the amino protecting group of the compound of general formula (). In the elimination reaction of the amino-protecting group, a method and conditions are selected that are suitable for each amino-protecting group and do not pose a risk of impairing azetidinone reduction. For example, when the amino protecting group is a benzyl group, the method of reacting with metallic sodium in liquid ammonia is used, and when the amino protecting group is a 3,5-di-tert.-butyl-4-hydroxybenzyl group, methanol is used. Among them, the method of applying an oxidizing agent such as DDQ (dicyano-dichloro-p-benzoquinone) and subsequent acid treatment is selected. (13) From the compound represented by the general formula () or () obtained in this way, the general formula ()
To obtain the compound represented by the general formula () or (), the compound represented by the general formula () or () is first converted into a reactive derivative at its carboxyl group, and then the alkali metal derivative of the malonic acid derivative represented by the general formula () is converted into a reactive derivative at the carboxyl group. It can be reacted with enolate. Examples of reactive derivatives at the carboxyl group of the compound represented by formula () or () include mixed acid anhydrides and acid halides. A compound represented by the general formula () or () in the presence of a base,
For example, in a solvent that does not participate in the reaction, such as methylene chloride, tetrahydrofuran, diethyl ether, toluene, etc., at -30°C to room temperature for several tens of minutes to several hours.
By reacting halocarbonate esters, mixed acid anhydrides can be obtained. Examples of the halocarbonate ester include ethyl chloroformate and isobutyl chloroformate. In addition, the compound represented by the general formula () or (),
In an inert solvent, in the presence or absence of N,N-dimethylformamide, N,N-dimethylacetamide, etc., at -30°C to room temperature, several tens of minutes to
After several hours of reaction with an active halogenating agent, the acid halide is obtained. Examples of the inert solvent include those mentioned above, and examples of the active halogenating agent include thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride. The thus obtained reactive derivative at the carboxyl group of the compound represented by the general formula () or () is mixed with one or more of an inert solvent such as methylene chloride, tetrahydrofuran, diethyl ether, toluene, dioxane, etc. In a solvent, preferably in an inert gas atmosphere such as argon, at -60 to 0°C for several tens of minutes to several hours, an alkali metal enolate of a malonic acid derivative represented by the general formula ()
By reacting with 3 times the equivalent, preferably 2 times the equivalent, a compound represented by the general formula () can be obtained. The target compound () of the present invention obtained by the above method is a new compound and can be used as a synthetic intermediate that can be advantageously derived into optically active carbapenems and azetidinones. An example of such usage is the method shown in the following formula. [In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings. ] Then, using a known reaction, the compound represented by the above general formula () has 1-
By p-toluenesulfonylating the hydroxy-ethyl group or the oxo group at the 3-position, for example, and then reacting it with various thiol compounds, various thienamycin-type substituents can be introduced. Therefore, the compound of the present invention is an extremely important compound as a synthetic intermediate for pharmaceuticals and the like. 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 70°C water bath. 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. Add 117 g of 2-tert.-butoxycarbonyloxyimino-2-phenylacetonitrile to the resulting solution, and stir 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 saturated brine, 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 crystals to obtain N-tert. with a melting point of 102-103°C.
-Budoxycarbonyl-L-aspartic acid-
122 g of β-benzyl ester (yield 80%) is obtained. (3) Add 10.3 g of N-tert.-butoxycarbonyl-L-aspartic acid-β-benzyl ester to 120 ml of anhydrous benzene, and further add 2.4 ml of tetramethylethylenediamine to dissolve.
4.6 ml of isobutyl chloroformate is added dropwise to the resulting solution at 5-7°C over a period of 5 minutes. After stirring at the same temperature for 40 minutes, add a separately prepared diethyl ether solution of diazomethane (prepared using 22 g of nitrosomethylurea).
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 30 minutes while stirring. Thereafter, excess diazomethane is distilled off under reduced pressure, and insoluble materials are separated. The solvent of the liquid 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 the insoluble materials were separated. The solvent of the liquid 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; benzene:ethyl acetate = 35:1) to obtain oily benzyl (3R)-3-(tert.-butoxycarbonyl). ) 7.8 g (yield 69%) of amino-4-methoxycarbonylbutanoate are obtained. IR (neat) cm ^-1 ; νNH3360, νC=O1670~
NMR (CDCl ₃ ) δ; 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,

[Formula]) 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 115 ml of a 2.6N hydrogen chloride-ethyl acetate solution to 35 g of benzyl (3R)-3-(tert.-butoxycarbonyl)amino-4-methoxycarbonyl butanoate under ice cooling. 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. Separate the ethyl acetate layer, wash it with 20 ml of saturated brine, dry over anhydrous magnesium sulfate, and distill off the solvent to obtain oily benzyl (3R)-3-amino-4-methoxycarbonylbutano. Eight
Obtain 22.5 g (90% yield). 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,

[Formula]) [α] ²⁰ _D = -2.6゜ (C = 2.22, benzene) (5) Benzyl = (3R) -3-amino-4-methoxycarbonylbutanoate 37.2g and 3,5-di-tert Add 38 g of .-butyl-4-hydroxybenzaldehyde to 300 ml of benzene and react for 2.5 hours while performing azeotropic dehydration. The reaction solution was distilled off under reduced pressure, 500 ml of methanol was added to the resulting residue, and insoluble materials were separated.
Add 15 g of 5% palladium on carbon to the solution and perform catalytic reduction in the presence of hydrogen at room temperature. After the reaction is completed, the palladium on carbon is separated and the solvent is distilled off under reduced pressure.
The resulting residue was dissolved in 300 ml of ethyl acetate,
This is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained residue is treated with 150 ml of acetone, it becomes (3S)-3-(3,
37.1 g of 5-di-tert.-butyl-4-hydroxybenzylamino)-4-methoxycarbonylbutanoic acid are obtained. (Yield 66.1%) IR (KBr) cm ^-1 ; νC=O 1718, νNH 3450,
νOH 3620 NMR (d ₆ -DMSO) δ; 1.45 (s, 18H, -C(CH ₃ ) ₃ ×2) 2.15-2.82 (m, 5H,

【formula】) 3.56 (m, 2H,

[Formula]) 3.63 (s, 3H, -OCH ₃ ) 3.78 (s, 1H, -OH) 6.95 (bs, 1H, -NH-) 7.09 (s, 2H,

[Formula]) [α] ²⁰ _D = -7.7゜ (C = 1, methanol) (6) (3S) -3-(3,5-di-tert.-butyl-4-hydroxybenzylamino) -4- After adding 6.0 g of methoxycarbonyl butanoic acid to 60 ml of methylene chloride, 3.45 g of thionyl chloride was added.
ml dropwise under ice cooling. After stirring for 3 hours at room temperature, the solvent is distilled off under reduced pressure. Adding anhydrous benzene to the obtained residue and distilling it off under reduced pressure is repeated twice. The resulting residue was dissolved in 160 ml of methylene chloride, and in this solution was added a methylene chloride solution containing 2.75 ml of triethylamine at 25°C.
Add 23ml dropwise over 1 hour. After dripping, further
After stirring for 30 minutes, the reaction solution is concentrated under reduced pressure. The resulting residue was dissolved in 90 ml of ethyl acetate and water.
After dissolving in 50 ml of mixed solvent, separate the organic layer. Add 30ml of water to the separated organic layer and stir
Add 2N hydrochloric acid dropwise to adjust the pH to 2. The organic layer is separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure and the resulting residue is treated with n-hexane, (4S)-1- exhibits a melting point of 75-77°C.
(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-methoxycarbonylmethyl-
5.2 g (yield 91.0%) of 2-azetidinone is obtained. IR (KBr) cm ^-1 ; νC=O 1720, 1740
νOH3550 NMR (CDCl ₃ ) δ; 1.40 (s, 18H, —C(CH ₃ ) ₃ ×2) 2.30–4.00 (m, 5H, C ₃ —Hα, Hβ, C ₄ —
Hα, -C H ₂ CO ₂ CH ₃ ) 3.55 (s, 3H, -OCH ₃ ) 4.21 (q, 2H,

【formula】) 5.14 (s, 1H, -OH) 6.96(s, 2H,

[Formula]) [α] ²⁰ _D = +28.0゜ (C = 1, benzene) (7) (4S) -1- (3,5-di-tert.-butyl-4-hydroxybenzyl) -4- Dissolve 7.40 g of methoxycarbonylmethyl-2-azetidinone in 22 ml of tetrahydrofuran, and cool with ice under N-
After adding 40.95 ml of an aqueous sodium hydroxide solution and 7.4 ml of methanol, the mixture is allowed to react at room temperature for 20 minutes with stirring. Add 2N hydrochloric acid to the reaction solution to adjust the pH to 6.5, and then concentrate under reduced pressure until the liquid volume becomes about 1/2.
Add 20 ml of ethyl acetate to the resulting residual liquid, adjust the pH to 8.0 with potassium carbonate, separate the aqueous layer, and wash the separated aqueous layer with 20 ml of ethyl acetate. Add 30 ml of ethyl acetate to this aqueous layer, then add 2N hydrochloric acid dropwise to adjust the pH to 2.0. Separate the organic layer,
After washing with saturated saline, decolorizing with carbon and drying with anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure to crystallize, and this is treated with diethyl ether, (4S)-1- exhibits a melting point of 158°C.
5.9 g (yield: 84.1%) of (3,5-di-tert.-butyl-4-hydroxybenzyl)-4-carboxymethyl-2-azetidinone is obtained. IR (KBr) cm ^-1 ; νC=O 1680, 1725
νOH3620 NMR (CDCl ₃ ) δ; 1.44 (s, 18H, ―C(CH ₃ ) ₃ × 2) 2.15 to 4.05 (m, 5H, C ₃ ―H〓, H〓, C ₄ ―H〓,
-C H ₂ CO ₂ H) 4.25 (q, 2H,

【formula】) 5.23 (bs, 1H, -OH) 6.99(s, 2H,

[Formula]) 10.50 (bs, 1H, -CO ₂ H) [α] ²⁰ _D = +17.9° (C = 1, ethanol) (8) (4S) -1 - (3,5-G-tert. Dissolve 1 g of (butyl-4-hydroxybenzyl)-4-carboxymethyl-2-azetidinone in 5 ml of anhydrous methylene chloride, and add 0.42 g of thionyl chloride under ice cooling.
ml and react at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure, anhydrous benzene is added to the obtained residue, and the solvent is distilled off under reduced pressure.
Repeatedly, the oily acid chloride [IR (CH ₂ Cl ₂ )
cm ⁻¹ ; νC=O 1780, 1750]. Dissolve this in 10 ml of methylene chloride. Meanwhile, 2.5 g of diphenylmethyl-4-nitrobenzyl-malonate was dissolved in 20 ml of anhydrous tetrahydrofuran, and 0.300 g of sodium hydride (purity 50%) was added at -20°C.
Raise the temperature to 0℃ while generating cc. This is cooled to -30°C, and the previously prepared solution of acid chloride in methylene chloride (10 ml) is added dropwise over about 2 minutes. After further reacting at -20 to -10°C for 30 minutes, 0.165 ml of acetic acid was added, the temperature was raised, and the solvent was distilled off under reduced pressure. Add 30 ml of water and 30 ml of ethyl acetate to the obtained residue, and pH the mixture with sodium hydrogen carbonate.
Adjust to 7.5 and separate the organic layer. Furthermore, add 30ml of water to the separated organic layer, and add 2N-hydrochloric acid to pH2.0.
and separate the organic layer. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel C-200; eluent; benzene; benzene;
If purified with ethyl acetate = 10:1), oily (4R)-1-(3,5-di-tert.-butyl-4
-hydroxybenzyl)-4-[3-(diphenylmethyloxycarbonyl)-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone 1.46 g (yield
69.03%). IR (KBr) cm ^-1 ; νC=O 1740 NMR (CDCl ₃ ) δ; 1.4 (s, 18H, -C(CH ₃ ) ₃ ×2) 2.5-3.2 (m, 4H,

[Formula] C ₃ ―H〓, H〓) 3.6 to 4.7 (m, 4H, C ₄ ―H〓,

【formula】

[Formula]) 5.13 (s, 1H, -OH) 5.2 (s, 2H,

【formula】) 6.9(s, 3H,

【formula】

【formula】) 7.2(s, 10H,

[Formula]×2) 7.25(d, 2H,

【formula】) 7.9(d, 2H,

[Formula]) Example 2 (4S)-1-(3,5-di-tert.-butyl-
Dissolve 0.5 g of 4-hydroxybenzyl)-4-carboxymethyl-2-azetidinone in 5 ml of methylene chloride, add 0.16 ml of N-methylmorpholine,
Then, add 0.144 ml of ethyl chlorocarbonate at -20℃,
React at -10 to -20°C for 1 hour. On the other hand, an anhydrous tetrahydrofuran solution of sodium diphenyl-p-nitrobenzylmalonate prepared in the same manner as in Example 1-(8) was cooled to -30°C, and mixed with the previously prepared mixed acid. Anhydrous −30
After dropping into the solution cooled to ℃ for about 1 minute, if treated in the same manner as in Example 1-(8), (4R)-1
-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3-(diphenylmethyloxycarbonyl)-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]- 2-
0.74 g of azetidinone (yield 69.8%) is obtained. The following compound was obtained in the same manner. 〇 (4S)-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3,3-
Bis(diphenylmethyloxycarbonyl)-
2-Oxopropyl]-2-azetidinone Yield: 79.2% Melting point: 126-127°C IR (KBr) cm ^-1 ; νC=O 1740, 1715 NMR (CDCl ₃ ) δ; 1.38 (s, 18H, -C (CH ₃ ) ₃ × 2) 2.23 to 2.9 (m, 4H, C ₃ ―H〓, H〓,

[Formula]) 3.65~4.6 (m, 3H, C ₄ -H〓,

【formula】) 5.13 (s, 1H, -OH) 6.93(s, 2H,

[Formula]) 6.98(s, 2H,

【formula】) 7.2(s, 20H,

【formula】) 13.78(s, 1H,

[Formula]) [α] ²⁰ _D = +29.4゜ (C = 1.0, benzene) 〇 (4S)-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3 ,3-
Bis(4-nitrobenzyloxycarbonyl)
-2-oxysopropyl]-2-azetidinone yield; 67.1% IR (neat) cm ^-1 ; νC=O 1730 NMR (CDCl ₃ ) δ; 1.43 (s, 18H, -C(CH ₃ ) ₃ ×2 ) 2.35~3.3 (m, 4H, C ₃ ―H〓, H〓, ―C H ₂
COCH) 3.7~4.7 (m, 3H, C ₄ -H〓,

[Formula]) 5.15 to 5.35 (m, 5H, -OH,

【formula】) 6.98(s, 2H,

【formula】) 7.4(d, 4H,

【formula】) 8.18(d, 4H,

【formula】) 13.64(s, 1H,

[Formula]) 〇 (4R)-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3-(diphenylmethyloxycarbonyl)-3-(phthalidyloxycarbonyl) -2-oxopropyl]-2-azetidinone yield; 57.3% IR (neat) cm ^-1 ; νC=O 1785, 1740 NMR (CDCl ₃ ) δ; 1.40 (s, 18H, -C(CH ₃ ) ₃ × 2) 2.4 to 3.3 (m, 4H, C ₃ ―H〓, H〓, ―C H ₂ ―
CO―) 3.5~4.6 (m, 3H, C ₄ -H〓,

【formula】) 5.13 (s, 1H, -OH) 6.82(s, 1H,

【formula】) 6.94(s, 2H,

【formula】) 7.05(s, 10H,

【formula】) 7.1~8.0 (m, 5H,

【formula】) 13.7(s, 1H,

[Formula]) 〇 (4R)-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3-(diphenylmethyloxycarbonyl)-3-(pivaloyloxymethyl oxycarbonyl)-2
-Oxopropyl]-2-azetidinone yield; 30.0% IR (neat) cm ^-1 ; νC=O 1740 NMR (CDCl ₃ ) δ; 1.19 (s, 9H, -OCOC (CH ₃ ) ₃ ) 1.41 ( s, 18H,

[Formula]) 2.21~3.02 (m, 4H, C ₃ -H〓, H〓,

[Formula]) 3.60 to 4.60 (m, 3H, C ₄ -H,

[Formula]) 5.20 (s, 1H, -OH) 5.86 (s, 2H, -OC H ₂ OCOC (CH ₃ ) ₃ ) 7.00 (s, 3H,

【formula】

【formula】) 7.31(s, 10H,

【formula】) 13.70(s, 1H,

[Formula]) Example 3 (4S)-1-(3,5-di-tert.-butyl-
1.56 g of 4-hydroxybenzyl)-4-carboxymethyl-2-azetidinone and 15 ml of methylene chloride.
Add 0.66 ml of thionyl chloride and incubate at 25℃.
Incubate for 60 minutes. The reaction solution is concentrated under reduced pressure, anhydrous benzene is added to the resulting residue, and the process is repeated twice to evaporate under reduced pressure to obtain an oily acid chloride. Meanwhile, under a nitrogen atmosphere, 3.65 g of malonic acid monobenzhydryl ester was added to 146 g of anhydrous tetrahydrofuran.
ml and cooled to -50°C. Next, add 1.5M of n-butyllithium into this solution.
Add 18 ml of hexane solution dropwise over 20 minutes and raise the temperature to -10°C. After the addition was completed, the mixture was stirred at -10°C for 3 minutes, then cooled to -60°C, and the previously prepared solution of acid chloride dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise over 3 minutes. After dropping, react at -60℃ for 10 minutes (4R)
-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4-[3-carboxy-3-
After producing (diphenylmethyloxycarbonyl)-2-oxopropyl]-2-azetidinone, 1.54 ml of acetic acid is added. Next, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in diethyl ether.
After dissolving in a mixed solvent of 50 ml and 20 ml of water, the organic layer is separated. The separated organic layer is washed successively with a saturated aqueous sodium bicarbonate solution, water, dilute hydrochloric acid, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent 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 (4R)-1-(3,5-di-
tert.-butyl-4-hydroxybenzyl)-4-
(3-diphenylmethyloxycarbonyl-2-
Oxopropyl)-2-azetidinone 1.71g
(68.6%). IR (neat) cm ^-1 ; νOH 3600, νC=O 1735,
1720 NMR (CDCl ₃ ) δ; 1.40 (s, 18H, -C (CH ₃ ) ₃ × 2) 2.18 - 3.03 (m, 4H, C ₃ -H〓, H〓, -C H ₂
COCH ₂ −COO−) 3.23 (s, 2H, −COC H ₂ COO−) 3.85 (m, 1H, C ₄ −H〓) 4.12 (ABq, 2H,

【formula】) 5.18 (s, 1H, -OH) 6.90(s, 1H,

【formula】) 7.00(s, 2H,

【formula】) 7.28(s, 10H,

[Formula]) Similarly, using malonic acid mono-p-nitrobenzyl ester, (4R)-1-(3,5-di-tert.-butyl-4-hydroxybenzyl)-4
-[3-carboxy-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2
-(4R)-1-(3,
5-di-tert.-butyl-4-hydroxybenzyl)-4-[3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone is obtained. IR (neat) cm ^-1 ; νC=O 1740 NMR (CDCl ₃ ) δ; 1.4 (s, 18H, -C(CH ₃ ) ₃ × 2) 2.45-3.1 (m, 4H, -C H ₂ COCH ₂ COO --,
C ₃ ―H〓, H〓) 3.25 (s, 2H, ―COC H ₂ COO―) 3.6 to 4.45 (m, 3H, C ₄ ―H〓,

[Formula]) 5.2(s, 3H, -OH,

【formula】) 6.98(s, 2H,

【formula】) 7.43(d, 2H,

【formula】) 8.13(d, 2H,

【formula】)

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a hydrogen atom, a salt-forming cation, or a carboxyl group-protecting group, R ₂ represents a carboxyl group-protecting group, and R ₃ represents a hydrogen atom or an amino group-protecting group. ] (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. ( _4R )-4-[ _3,3
-Bis(carboxy)-2-oxo-propyl]
-2-Azetidinone derivative. ( _4R )-4-[3 _,
3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 4 (4R)-4-[3,3-bis(carboxy)-2 according to claim 1, wherein R ₁ or R ₂ is a protecting group that can be easily removed by an enzyme.
-oxo-propyl]-2-azetidinone derivative. ₅ (4R)-4-[ ₃ ,
3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. (4R)-4-[3,3-bis(carboxy)-2-oxo-] according to any one of claims 1 to 5, wherein 6 R ₃ is an aralkyl group substituted with at least a hydroxyl group Propyl]-2-azetidinone derivative. 7 R ₃ is the general formula [In the formula, A, B, C and D are each a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a halogen atom, an acyloxy group, a nitro group,
Indicates an amino group or an acylamino group. ] (4R)-4-[3,3-bis(carboxy) according to claim 6, which is a group represented by
-2-oxo-propyl]-2-azetidinone derivative. 8 (4R)-4-[3,3-bis(carboxy) according to claim 7, wherein R ₃ is a 3,5-di-tert.-butyl-4-hydroxybenzyl group
-2-oxo-propyl]-2-azetidinone derivative. 9 formula (4R) stated in claim 1 expressed as
-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 10 formula (4R) stated in claim 1 expressed as
-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 11 formula (4R) stated in claim 1 expressed as
-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 12 formula (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2 according to claim 1, which is a compound represented by and a salt thereof;
-Azetidinone derivative. 13 formula (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2 according to claim 1, which is a compound represented by and a salt thereof;
-Azetidinone derivative. 14 formula (4R) stated in claim 1 expressed as
-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 15 formula (4R) stated in claim 1 expressed as
-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 16 General formula [In the formula, R ₃ represents a hydrogen atom or a protecting group for an amino group. ] (4S)-4-carboxymethyl-
General formula for reactive derivatives at the carboxyl group of 2-azetidinones [In the formula, R ₁ represents a hydrogen atom, a salt-forming cation, or a carboxyl group-protecting group, and R ₂ represents a carboxyl group-protecting group. ] A general formula characterized by reacting an alkali metal enolate of a malonic acid derivative represented by [In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings. ] A method for producing a (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative represented by: 17 (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2 according to claim 16, wherein R ₃ is a protecting group for an amino group
-Production method of azetidinone derivatives. 18 A reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinones is obtained by reacting a halocarbonate with (4S)-4-carboxymethyl-2-azetidinones in the presence of a base. (4R) according to claim 16 or 17, which is the obtained mixed acid anhydride.
-4- [3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative manufacturing method. 19 The reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinones is an acid halogen obtained by reacting (4S)-4-carboxymethyl-2-azetidinones with an active halogenating agent. Claim 1 which is a compound
(4R)-4-[3,
A method for producing a 3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative. 20 (4R)-4 according to claim 19, wherein the active halogenating agent is thionyl chloride, oxalyl chloride, phosphorus pentachloride or phosphorus trichloride
-[3,3-bis(carboxy)-2-oxo-
A method for producing a propyl]-2-azetidinone derivative. 21 General formula [In the formula, R ₃ represents a hydrogen atom or an amino group-protecting group, and R ₄ represents a carboxyl group-protecting group. ] (3S)-3-(substituted)amino-4 represented by
-By ring-closing reaction of substituted carboxyl butanoic acid,
general formula [In the formula, R ₃ and R ₄ have the above-mentioned meanings. ] Obtain (4R)-2-azetidinones represented by
Then, the protective group of the carboxyl group is removed to form the general formula [In the formula, R ₃ has the above-mentioned meaning. ] (4S)-4-carboxymethyl-
2-Azetidinones are obtained, and then reacted with a carboxyl group activator to obtain a reactive derivative at the carboxyl group, which has the general formula [In the formula, R ₁ represents a hydrogen atom, a salt-forming cation, or a carboxyl group-protecting group, and R ₂ represents a carboxyl group-protecting group. ] A general formula characterized by reacting an alkali metal enolate of a malonic acid derivative represented by [In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings. ] A method for producing a (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative represented by: 22 Reactive derivatives at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinones were obtained by reacting (4S)-4-carboxymethyl-2-azetidinones with a halocarbonate in the presence of a base. (4R)-4-[3,3-
Bis(carboxy)-2-oxo-propyl]-
Method for producing a 2-azetidinone derivative. 23 A reactive derivative at the carboxyl group of (4S)-4-carboxymethyl-2-azetidinones is an acid obtained by reacting an active halogenating agent with (4S)-4-carboxymethyl-2-azetidinones. A method for producing the (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative according to claim 21, which is a halide. 24 (4R)-4 according to claim 23, wherein the active halogenating agent is thionyl chloride, oxalyl chloride, phosphorus pentachloride or phosphorus trichloride
-[3,3-bis(carboxy)-2-oxo-
A method for producing a propyl]-2-azetidinone derivative. 25 Hydrohalic acid of (3S)-3-(substituted)amino-4-substituted carboxylbutanoyl halide by reacting (3S)-3-(substituted)amino-4-substituted carboxylbutanoic acid with an active halogenating agent (4R)-4-[3,3-bis(carboxy)-2-] according to any one of claims 21 to 24, characterized in that the salt is obtained and ring-closed in the presence of a base. Oxo-propyl]-2-
A method for producing an azetidinone derivative. 26 Claim 2 in which the active halogenating agent is thionyl chloride, phosphorus pentachloride or phosphorus trichloride
A method for producing a (4R)-4-[3,3-bis(carboxy)-2-oxo-propyl]-2-azetidinone derivative according to Item 5.