HU197742B - Process for producing antibiotical derivatives of isoxazolidinyl-tetrahydrofurane carboxylic acid and pharmaceutical compositions containing them as active components - Google Patents

Abstract

The process according to the invention is general (I) Compounds of Formula I - Formula II R1 is an acyl-protected amino group. . powder R2 is an esterified or amidated carboxyl group; R3 is hydrogen, optionally substituted alkyl, phenyl, alkoxy carbonyl or carbamoyl, R5 is hydrogen, alkyl, phenylthio or optionally alkylcarbonylamino substituted alkylthio, R6 is hydrogen or alkyl; R7 is hydrogen, optionally phenyl or substituted with alkoxy alkyl, R8 is hydrogen, or R5 and R7 form a second carbon-carbon bond, or R5, R6, R7 and arc with furan ring 1.3- -dihydro-isobenzofuranyl - and the preparation of their salts with a base. The above compounds are novel and antibacterial by their action as an active ingredient in pharmaceuticals They can be used.

Description

FIELD OF THE INVENTION This invention relates to 2- [4- (substituted) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-betahydro-uranium carboxylic acid derivatives, and to pharmaceutical compositions containing the above antimicrobial compounds as active ingredients.

It is known that a novel antibiotic, TAN-588, obtained from cultures of soil-isolated microorganisms of the genus Empedobacter or Lysobacter, has activity against Gram-positive and Gram-negative bacteria.

The antibiotic TAN-588, briefly referred to herein as TAN-588, contains a completely new 3-oxo'-isoxazolidine backbone with a 5-oxo-2-tetrahydrofuran carboxylic acid attached to its nitrogen atom.

We have found that certain derivatives of TAN-588 have excellent antimicrobial activity and can be used as active ingredients in pharmaceutical formulations due to their effect.

Tsuji and Yamana (Heterocycles, 8, 153 (1977)) have known the synthesis of a 2-oxoisoxazolidine ring compound which has a 1-methylacetic acid substituent on its nitrogen atom. However, the antimicrobial activity of the above compound has not been reported.

It is an object of the present invention to provide novel 2- [4- (substituted) amino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylic acid derivatives having useful antimicrobial activity.

It has been found that 2- [4- (substituted) amino-3-oxo is optionally substituted at the 5-position of the 3-oxo-isoxazolidine ring or at the 3 or 4-position of the 5-oxo-tetrahydrofuran ring. -2-Isoxazolidinyl] -5-oxo-2-ethydro-uranium carboxylic acid derivatives can be prepared chemically.

More particularly, the process of the present invention is a process for the preparation of novel compounds of formula (I)

R 'is a group of formula (a) wherein

R ¹³ is C 1-4 alkyl substituted with phenyl or thienyl, or C 1-6 alkoxy optionally substituted with phenyl or nitrophenyl, in which R ²⁰ is amino or [halo]. thiazolyl substituted with (C 1-4) alkyl] carbonylamino;

R ² 'is C 1-4 alkyl;

R ² is a group of formula (p) wherein

R ⁴⁷ is C 1 -C 4 alkyl optionally substituted by a nitrophenyl group, a C 1-6 alkylcarbonyloxy group, or two phenyl groups, or a group of formula (q) wherein R ⁴⁸ is phenyl or C 1-5 alkyl, and R ⁴⁹ is hydrogen, or R ⁴⁸ and R ⁴⁹ together with the nitrogen to which they are attached form pyrrolidinyl; R ³ is hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyloxy (C 1-4) alkyl,

C 1-4 alkoxycarbonyl, phenyl or carbamoyl;

R ⁵ is hydrogen, C 1-4 alkyl, phenylthio, or C 1-4 alkylthio optionally substituted with (C 1-4) alkylcarbonylamino;

R ⁶ is hydrogen or C 1-4 alkyl;

R ⁷ is hydrogen, C 1-4 alkyl, phenyl, phenyl (C 1-4) alkyl, C 1-4 alkoxy (C 1-4) alkyl, C 1-4 alkoxy, or phenylthio -group;

R ⁸ is hydrogen, or

R ⁵ and R ^{7 form} a second carbon-carbon bond, or

R ⁵ , R ⁶ , R ⁷ and R ⁸ together with the furan ring form a 1,3-dihydro-isobenzofuranyl group and are intended for the preparation of their salts with a base.

According to the present invention, ^a ) a compound of the formula (III): wherein:

R ¹ and R ³ are as defined above for a compound of formula II

R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above - or a reactive derivative thereof, or

b) a compound of formula (III) with a compound of formula (IV): wherein:

Y is hydrogen or a leaving group, and

R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above and, if desired, (i) to prepare compounds of formula I wherein R ⁵ and R ⁷ are hydrogen, a compound of formula (I); ) of the general formula wherein

R ⁵ and R ⁷ together represent a second carbon-carbon bond is reduced, or (ii) an acylamino group transzamináljuk consisting of R ¹ is a compound of formula (I) obtained, _(and / or (iii) is obtained ( The ester of formula I is converted to a salt with a base.

The invention further relates to a process for the preparation of an antibiotic medicament containing the compound of the formula I according to the invention or a salt thereof as an active ingredient.

R ¹ can be a group of formula (a).

In the group (a) above, R ¹³ is an optionally substituted alkyl or alkoxy group; or (d) wherein

^R2 is thiazolyl optionally substituted with a substituent, and

R ²¹ is alkyl.

The group (d) for R ¹³ represents both the syn (d) and the anti-isomer (d ₂ ), or a mixture thereof.

The aforementioned formula (a) preferably has a weight of up to 500 moles.

In the above formulas, the group designated for R ² is a group of formula (p) -

R ⁴⁷ is an alkyl group optionally substituted with one or two substituents, or a group of formula (d) wherein

R ⁴⁸ is alkyl or phenyl,

R ⁴⁹ is hydrogen, or

R ⁴⁸ and R ⁴⁹ together with the nitrogen atom to which they are attached form a pyrrolidinyl group.

The above groups of formulas (p) and (q) preferably have a molecular weight of up to 500.

In the above formulas, the alkyl group preferably has from 1 to 6 carbon atoms, for example methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethyl-. propyl, n-pentyl, isopentyl, n-hexyl or isohexyl.

R ¹ is alkyl

It may have from 1 to 4 carbon atoms and is substituted by phenyl or thienyl.

R ²¹ is alkyl

It may have from 1 to 4 carbon atoms.

The radical R ² (p) in the alkyl group represented by R ⁴⁷ is C 1-4 and may be substituted by a nitrophenyl group, a C 1-6 alkylcarbonyloxy group, or two phenyl groups.

In the formula R ² (q), the alkyl group designated for R ^{48 may} have from 1 to 5 carbon atoms.

The alkoxy group represented by R ¹ contains from 1 to 4 carbon atoms, for example methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, tert-butoxy.

The above alkoxy group may be substituted by phenyl or nitrophenyl.

R ^f (d) is a thiazolyl group represented by R ²⁰ , optionally substituted with amino or [halo (C 1-4) alkylcarbonylamino].

As the acyl moiety of the acylamino group of formula (R) represented by R ¹ , the group of formula (s) in which

Q * is an amino group optionally protected by a [halo (C 1 -C 4) alkyl] carbonyl group, and

Q ² is C 1-4 alkyl. Further preferred acyl groups are thienylacetyl or phenylacetyl.

The acylamino group represented by the above formula (a) may be more particularly methoxycarbonylamino or benzyloxycarbonylamino.

The acylamino group represented by the above formula (a) is more particularly, for example

2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetylamino;

2- (2-amino-4-thiazolyl) -2-methoxyimino-acetylamino,

2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetylamino;

2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetylamino or

It may be 2- (2-amino-4-thiazolyl) -2-butoxyiminoacetylamino.

In particular, the above-mentioned group of formula (p) is methyl ester, ethyl ester, π-propyl ester, isopropyl ester, tert-butyl ester, 4-nitrobenzyl ester, 2-nitrobenzyl ester. , an acetoxymethyl ester or a pivaloyl aximethyl ester.

In particular, the above-defined group of formula (q) may be methylamido, ethylamido, propylamido, benzylamido or pyrrolidinamido.

In the above formulas, the group represented by R ³ is C 1-4 alkyl optionally substituted with (C 1-4) alkoxycarbonyl, or carboxyl, phenyl or carbcamoyl esterified with C 1-4 alkyl.

Preferably, the above group for R ³ is, for example, hydrogen, methyl, ethyl, isopropyl, phenyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methoxycarbonylmethyl.

As defined for R ^5, R ⁶ and R ⁷ particularly preferably to groups such as methyl, ethyl, phenyl, benzyl, methoxymethyl, 2-acetamido-ethylthio group, a phenylthio group.

In the case where R ⁵ , R ⁵ , R ⁷ and R ⁸ form a ring, the ring is formed by the 3 and 4 carbon atoms of the 5-oxo-tetrahydrofuran ring and 1,3-dihydroisobenzofuranyl represents a group.

In the above formulas, the group represented by the symbol Y may be hydrogen or a leaving group capable of replacing the 2-position hydrogen of the compound of formula III, for example a halogen atom such as bromine or chlorine; a sulforyloxy group such as p-toluenesulfonyloxy, p-nitrophenylsilyloxy, methanesulfonyloxy which may have a substituent such as an alkyl or aryl group;

-3197742, and substituted phosphoryloxy groups such as diphenylphosphoryloxy or diethylphosphoryloxy may be mentioned. The alkyl or aryl group mentioned as a substituent on the sulfonyloxy group may be the aforementioned group.

According to the process of the invention, a compound of formula (III) is reacted with a compound of formula (II) or a reactive derivative thereof to give a compound of formula (I)

R ¹ , R ² , R ³ , R ¹ , R ⁶ , R ⁷ and R ⁸ are as defined above, including when R ⁵ , R ⁶ , R ⁷ and R ^{8 are} simultaneously hydrogen, and the resulting ( I) optionally reacting the compound of formula is converted into another compound of formula as defined ^R1 are substituents (I) ^R1 is.

The compounds of formula (II) are reacted with the compounds of formula (III) in a solvent, in the presence of a condensing agent or a Lewis acid. The reactive derivative of the compound of formula II is reacted in a solvent with the compound of formula III.

More particularly, the condensing agent is Ν, Ν'-dicyclohexylcarbodiimide (DCC);

A mixture of DCC and N-hydroxysuccinimide or 1-hydroxybenzotriazole;

N-ethyl-N '- [3- (dimethylamino) propyl] carbodiimide;

carbonyldiimidazole;

N-ethyl-5-isoxazolium-3'-sulfonate;

2-ethyl-7-hydroxybenzisoxazolium trifluoro borate;

ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; A mixture of 2,2'-dipyridyl disulfide and triphenylphosphine;

a mixture of carbon tetrachloride and triphenylphosphine; A 2-halopyridinium salt such as 2-chloro-1-methylpyridinium iodide or 2-fluoro-1-methylpyridinium tosylate;

pyrimidinium salts such as 2-chloro-1-methylpyridinium fluorosulphate; and azalene-onium salts such as 2-chloro-3-ethylbenzoxazolium tetrafluoroborate or 2-fluoro-3-methylbenzthiazolium fluorosulphate (Angewandte Chemie, International Ed., 1979, 18, 707). ].

Examples of Lewis acids are boron trifluoride diethyl ether, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, boron trichloride, and the like. can be used.

As the reactive derivative of the compound of formula II, derivatives which are used in C-terminal activation of peptide synthesis may be used. The above reactive derivatives, prepared in a solvent, can be used directly in the condensation reaction without isolation. In particular, the reactive derivative of the carboxylic acids in the process of the invention is an acid halide, such as acid chloride or acid bromide; acid 4 azide; with carboxylic monoalkyl ester mixed anhydride - for example, an aliphatic carboxylic acid such as acetic acid, pivalic acid, v ⁱ leriánsavval, isovaleric acid, trichloroacetic acid, etc. mixed anhydride, an acid such as phosphoric acid such as diphenylphosphoric acid, diethylphosphoric acid, and the like. or a mixed anhydride with sulfuric acid or the like, an anhydride with an organic acid such as benzoic acid, or a symmetric acid anhydride; amido compounds in which the acyl group is attached to a nitrogen atom in the ring, such as the nitrogen of the pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, thiazolidine-2-thione ring; active esters such as 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, cyanomethyl, N-hydroxysuccinimido-, N-hydroxy phthalimido esters; or active thioesters, including esters with heterocyclic thiols, such as 2-pyridylthio, 2-benzothiazolylthioesters.

The reaction is carried out in a solvent by reacting a compound of formula (III) with an equimolar amount or a small excess of a compound of formula (II) in the presence of an equimolar amount or a small excess of a condensing agent or a catalytic amount of Lewis acid, or reacting the compound of formula (III) with an equimolar amount or a slight excess of the reactive derivative of the compound of formula (II). Suitable solvents include any of the reaction solvents, such as dichloromethane, chloroform, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, benzene, fillers, n-hexane, acetonitrile, or N, N-dimethylmercuryamide.

In some cases, the above reaction may also be carried out in the presence of a base, such as, for example, 2-chloro-1-methylpyridinium iodide, 2,2'-dipyridyldisulfide triphenylphosphite, carbon tetrachloride triphenylphosphine , etc. used as a condensing agent.

Suitable bases are, for example, trimethylamine, isopropylethylamine, N-methylmorpholine, and 3,4-dihydro-2H-pyrido [1,2-a] pyrimidin-2-one; 4-Dihydro-2H-pyrido [1,2-a] pyrimidin-2-one.

There are also cases where the above reaction is carried out in the presence of, for example, silver chloride, silver tetrafluoroborate or silver perchlorate, for example when 2,2'-dipyridyldisulfide triphenylphosphine is used as a condensing agent.

The reaction temperature is not critical, but the reaction is usually carried out at a temperature of about -50 ° C to 150 ° C, preferably at -10 ° C to 190 ° C. The reaction time varies depending on the starting materials, reactants and solvent used, generally about 5 minutes to about

The reaction is carried out over a period of -4197742 hours.

When the condensation is carried out in the presence of a Lewis acid, the reaction mixture may, in some cases, use a dehydrating agent such as a molecular sieve.

The compounds of formula (I) may also be prepared by reacting a compound of formula (III) with a compound of formula (IV) and, if desired, converting the R ¹ group of the resulting compound of formula I into another group designated for R ^1. .

The compounds of formula (III) are reacted with the compounds of formula (IV) in a solvent in the presence of a base. Examples of bases are organic amines such as triethylamine, tripropylamine, tri (n-butyl) amine, diisopropylethylamine, triethylene diamine (DABCO),

1,8-diazabicyclo [5.4.0] -7-undecene (DBU), N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, 3,4-dihydro-2H-pyrido [1, 2-a] pyrimidin-2-one, 4- (dimethylamino) pyridine, pyridine, lutidine, γ-collidine, etc .; alkali metals such as lithium, sodium, potassium, cesium, etc .; alkaline earth metals such as magnesium, calcium, etc .; or their hydrides, hydroxides, carbonates, or alcoholates.

Suitable solvents are, for example, conventional solvents such as dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylacetamide, dimethylformamide, and the like. can be used. Of the above bases, the liquid state can be used as a dual purpose solvent and base. In the above reaction, the compound of formula (IV) and the base are usually used in an amount of 1 mole per mole of the compound of formula (III), but may also be used in small excess, provided that the reaction is not inhibited. The reaction time may range from 5 minutes to 30 hours.

If desired, the R * group of the compound of formula (I) obtained above may be modified to produce other compounds of formula (I). By the above modification is meant transamination, i.e. the conversion of the protected amino group R ¹ into a free amino group, followed by the protection of the free amino group by another protecting group (acylation).

Deprotection is accomplished by a conventional method, such as treatment or reduction with an acid, base or hydrazine, depending on the particular protecting group. When deprotected with an acid, the acid is an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like. -; an organic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, and the like. -; or an acidic ion exchange resin, depending on the type of protecting group and other conditions. When the deprotection is carried out with a base, the base is, for example, inorganic bases such as the carbonates of alkali metals such as sodium or potassium or alkaline earth metals such as calcium or magnesium; organic bases such as metal alkoxides, organic amines or quaternary ammonium salts; and basic ion-exchange resins, depending on the type of protecting group and other conditions. In the above cases, when acids or bases are used and a solvent is required, the solvent may be a hydrophilic organic solvent, water or mixtures thereof.

In the case of deprotection, the reduction is carried out with a metal such as tin, zinc, or a metal compound such as chromium dichloride, chromium acetate, and the like. And an organic or inorganic acid such as acetic acid, propionic acid, hydrochloric acid, and the like. - or catalytic reduction in the presence of a metal catalyst. Examples of catalysts include platinum catalysts such as platinum wire, platinum sponge, platinum carbon black, platinum oxide or colloidal platinum; palladium catalysts such as palladium sponge, palladium carbon black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium on carbon, palladium on silica or colloidal palladium; reducing nickel, nickel oxide, Raney nickel or Ul ushibara nickel can be used.

In the case of reduction with metal and an acid, the metal used is iron or chromium and the acid used is an inorganic acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid or propionic acid. The above reduction procedures are usually carried out in a solvent. In the catalytic reduction process, the solvent used is, for example, methanol, ethanol, propanes or isopropanol, preferably ethyl acetate.

When the reduction is carried out using metal and acid, the solvent is usually water, acetone, and the like. but when the acid is in a liquid state, the acid itself can serve as a solvent.

In deprotection processes by acidic or alkaline treatment or reduction, the reaction temperature can be varied over a wide range, both under cooling and heating.

After carrying out the above deprotection reaction of a compound of formula (I), a compound of formula (I-3), i.e. a compound of formula (I) in which

R ¹ is amino, and

² is a carboxyl group derived from R - was obtained.

The resulting compound (1-3) is acylated to give the desired compound (I)

-5197742 nos by reacting with an acylating agent containing an acyl group in R ¹ . An acylating agent is, for example, a reactive derivative of a carboxylic acid in a solvent.

Suitable reactive derivatives of the carboxylic acid include, for example, acid halides, acid anhydrides, amides, active esters, or active thioesters, in particular the following reactive derivatives.

1) Acid halides

The acid halides used are, for example, acid chlorides or acid bromides.

2) Acid anhydrides

Acid anhydrides are, for example, mixed anhydrides with monoalkyl carboxylic acids, aliphatic carboxylic acids such as acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, and the like. Formed mixed anhydrides, mixed anhydrides with aromatic carboxylic acids such as benzoic acid or symmetric acid anhydrides.

3) Amide derivatives

Examples of the amide derivative are compounds containing an acyl group attached to a ring nitrogen atom, such as pyrazole, imidazole, 4-substituted-imidazole, dimethylpyrazole or benzotriazole.

4) Active esters

Examples of active esters are methyl esters, ethyl esters, methoxymethyl esters, propargyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, trichlorophenyl esters, pentachlorophenyl esters , and mesylphenyl esters, as well as 1-hydroxy-1, 2-pyrrolidone, N-hydroxysuccinimide or N-hydroxyphthalimide, and the like. skilled esters may be used.

5) Active thioesters

For example, thioesters with heterocyclic thiols such as 2-pyridylthiol or 2-benzothiazolylthiol may be used as active thioesters.

The above types of reactive derivatives are selected depending on the carboxylic acid.

In some cases, the above reaction is carried out in the presence of a base. Examples of the base include aliphatic tertiary amines such as trimethylamine, triethylamine, tripropylamine, tri (n-butyl) amine, and the like. -, tertiary amines such as N-methylpiperidine, N-methylpyrrolidine, cyclohexyldimethylamine, N-methylmorpholine, dialkylamines such as di (n-butyl) amine, diisobutylamine, or dicyclohexylamine; aromatic amines such as pyridine, lutidine or γ-collidine; hydroxides or carbonates of alkali metals such as lithium, sodium or potassium;

In the above reaction, the reactive derivative of the carboxylic acid is usually used in an amount of 1 mole per mole of the compound (I-3), but may also be used in small excess, provided the reaction is not disturbed. When the reaction is carried out in the presence of a base, the base is usually employed in an amount of 1 to 30 moles, preferably close to 1 to 10 moles, per mole of the compound of formula (1-3). and reactive carboxylic acid derivatives, and other reaction conditions.

The reaction is usually carried out in a solvent. The solvent may be any conventional solvent, either alone or in the form of a solvent mixture. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, propylene oxide or butylene oxide, esters such as ethyl acetate and ethyl formate, halogenated hydrocarbons such as chloroform, dichloromethane, Or 2-dichloroethane

1,1,1-trichloroethane, hydrocarbons such as benzene, toluene, n-hexane, amides such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide, or nitriles such as acetonitrile may be used. .

When the base is a liquid compound, the base may also serve as a solvent.

The reaction temperature is not critical, but is usually in the range of -50 ° C to 150 ° C, preferably in the range of -30 ° C to 80 ° C. The reaction usually takes a few tens of minutes to a few tens of hours, depending on the starting materials, the base, the reaction temperature and the solvent, but in some cases it may take several tens of days to complete the reaction.

In the case where a compound of formula (I) is prepared wherein

R ⁵ forms an additional chemical bond with R ⁷ (ie

5-oxo-2,5-dihydro-2-uranium carboxylic acid derivatives), the double bond of the above compound can be hydrogenated if desired. The hydrogenation may be carried out in a similar manner to the reduction procedures described above to remove the protecting group.

The compounds of formula (I) prepared according to the above methods may be isolated and purified by conventional means, for example by concentration, adjusting the pH; solvent extraction, lyophilization, crystallization, recrystallization, fractional distillation and chromatography.

-6197742

Due to the two asymmetric carbon atoms in the backbone of the compounds of formula I, the above compounds may exist in four stereoisomeric forms. Both the individual stereoisomers and mixtures thereof may be prepared by the process of the invention. Similarly, if the group ^R'-R8 ^ symbols groups candidate, or the ^{3-oxo-izoxazolfdin:} rings 5 position and / or further asymmetric 5-oxo-tetrahydrofuran ring 3 or 4 position carbon atoms are present, new stereoisomers may exist and their preparation and the preparation of isomer mixtures are also within the scope of the present invention.

In the case where a mixture of stereoisomers is obtained as a product of the process according to the invention, the individual stereoisomers can be prepared, if desired, by conventional methods, for example, various chromatographic methods and recrystallization.

In some cases, the compounds of formula I may form salts with bases. The base may be, for example, an inorganic base such as sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide or an organic base such as pyridine, collidine, triethylamine or triethanolamine.

In the case where the compound of formula (I) is prepared in free form, the resulting compound can be converted into a salt in a conventional manner or, if desired, a salt of compound (I) into a free-form compound of formula (I).

Stereoisomers of the compounds of formula I, or mixtures of isomers, may be used as active ingredients in pharmaceutical compositions.

The compounds of formula (IV) used as starting materials for the process of the invention may be prepared by the following procedures. In the formulas, R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ and Y are as defined above.

1) Preparation of a compound of formula IV from a compound of formula II

The compound of formula II can be converted into the compound of formula IV by reaction with an activating agent. Examples of activating agents include halogenating agents such as thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, chlorine, bromine or carbon tetrachloride and triphenylphosphine; sulfonylating agents such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-trisisopropylphenylsulfonic anhydride, methanesulfonic anhydride, p-toluenesulfonyl chloride, and p-toluenesulfonyl chloride; chlorobenzenesulfonyl chloride; and phosphorylating agents such as diphenylphosphoryl chloride, dimethylphosphoryl chloride and diethylphosphorylchloride can be used. The reaction is carried out by reacting a compound of formula II with an equimolar amount or a small excess of the above activator in a solvent or in the absence of a solvent.

The above reaction is carried out with a base such as triethylamine, diisopropylamine, pyridine, 4- (dimethylamino) pyridine, and the like. in the presence of the reaction, provided that the reaction is not hindered. Examples of the solvent include dichloromethane, chloroform, carbon tetrachloride,

1,2-dichloroethane, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, acetonitrile, tetrahydrofran, benzene, toluene, and the like. can be used. The reaction temperature is usually from about -20 ° C to about 100 ° C, and the reaction time is from about 30 minutes to about 50 hours.

2) Preparation of compounds of formula IV from compounds of formula VI

The preparation of compounds of formula (IV) by the above process are described in the case when R ⁵ and R ⁷ is a bond in general formula (IV) and Y is halogen.

The above compounds are prepared by reacting the starting material of formula VI with a halogenating agent.

Starting compounds of formula (VI) wherein R ² 'is methyl and R ⁶ and R ^{8 are} hydrogen are known in Japanese Patent Publication No. Sho35 (1960) -9031 while other compounds of formula VI are known. adjustable in a manner similar to the above known method.

The compound of formula (VI) is conjugated with an equimolar amount or a small excess of the halogenating agent in a solvent. Preferred halogenating agents are chlorine, bromine, and the like. used. Examples of the solvent include chloroform, carbon tetrachloride, dichloroethane, 1,2-dichloroethane, benzene, acetonitrile, and the like. can be used. The reaction temperature may range from about 0 ° C to about 80 ° C, and may be from about 10 minutes to about 10 hours.

Compounds of formula (IV) may also be prepared by esterifying or amidating a parent compound of formula (IV) wherein R ² is a carboxyl group under known conditions.

For example, the compounds of formula (II) used as starting materials for the process of the invention may be prepared according to the following procedures. In the formulas, R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above.

1) Preparation of a compound of formula II from a compound of formula V

According to the above procedure, a semi-ester derivative of compound (II) is prepared by selective esterification of the carboxyl group at the 1-position of the compound (V).

The above reaction is carried out by reacting the compound of formula (V) with an equivalent amount or a small excess of the esterifying agent in a solvent in the presence of an equivalent amount of a base.

-7197742

Suitable esterifying agents are, for example, halides such as methyl iodide, benzyl bromide, p-nitrobenzyl bromide, m-phenoxybenzyl bromide, p- (leebutyl) benzyl bromide, diphenylmethyl bromide, pivaloyloxy methyl chloride, etc. -; and dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and the like. - we can use. Examples of the base include organic amines such as diisopropylamine, dicyclohexylamine, cyclohexylisopropylamine, triethylamine, tripropylamine, tri (n-butyl) amine, diisopropylethylamine, DABCO, DBU, N-. methyl morpholine, N-methylpiperidine, N-methylpyrrolidine, 3,4-dihydro-2H-pyrid [1,2-a] pyrimidin-2-one, 4- (dimethylamino) pyridine, pyridine, lutidine, γ-collidine, etc. -; or an inorganic base such as alkali metals such as lithium, sodium, potassium, cesium, etc. hydrides, hydroxides or carbonates.

Suitable solvents are, for example, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, dichloromethane, acetonitrile or tetrahydrofuran. The reaction temperature is usually about -20 ° C to about 100 ° C, and the reaction time is about 5 minutes to 30 hours.

2) Preparation of compound (II) from compound (V) via intermediates (VII) and (VIP)

In the above procedure, the compound of formula (V) is reacted with benzyl carbamate, the resulting compound of formula (VII) is esterified and the ester derivative of formula (VII ') obtained is treated with an acid.

In the above reaction, the compound of formula (V) is condensed with about equivalent or a small excess of benzyl carbamate under water at reduced pressure (12.9 to 6450 Pa), usually by heating in the absence of solvent. The reaction temperature is usually about 50 ° C to about 120 ° C, and the reaction time is about 30 minutes to 20 hours. The resulting compound (VII) is then converted by esterification to the compound (VII '). The esterification is carried out under the conditions already described for the conversion of compounds of formula (V) to compounds of formula (II). The esterification may also be carried out using diazoalkanes such as diazomethane and, for example, methanol, ethanol or benzyl alcohol in the presence of a carbodiimide condensing agent such as DCC. While the esterification process is selected depending on the ester to be prepared, the ester is preferably an ester which is relatively stable to the acid given that the resulting compound of formula (VIP) is then subjected to acid treatment to produce the compound of formula II . As the acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, perchloric acid, periodic acid, formic acid, acetic acid, trifluoro

acetic acid or p-toluenesulfonic acid may be used, individually or in combination. Preferably, a mixture of hydrobromic acid and acetic acid is used. The reaction temperature may range from about 0 ° C to about 50 ° C, and may be from 15 minutes to 5 hours.

3 · Preparation of Compound (II) from Compound (V) via Intermediate (VIII) According to the above procedure, the compound (V) is reacted with a halocarboxylic acid ester to give the compound (VIII) decarboxylation affords the compound of formula (II).

It is known that 2-oxo-glutaric acid-ethyl-ester (i.e., a (II) compound of formula wherein R ^s, R ^6, R ^7, R ⁸ = H) is prepared by adding 2- oxoglutaric acid is reacted with ethyl chlorocarbonate and the resulting compound is decarboxylated (JMDomagala, Tetrahedron Letters, 21, 4997 (1980)). According to the process of the present invention, the compound of formula (V) is reacted with a halocarboxylic acid ester in a solvent in the presence of a base, and the resulting compound is converted to the compound of formula (II) by decarboxylation. As the halogen carboxylic acid ester, for example, methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate, 2,2,2-trichloroethyl chlorocarbonate, and the like. can be used. Suitable bases and solvents are, for example, the bases and solvents mentioned in connection with the conversion of compounds of formula (IV) to compounds of formula (1-2). In the above reaction, approximately equivalent amounts of base and halocarboxylic acid are used based on the compound of formula (V). The reaction temperature is usually about -30 ° C to about 60 ° C, and the reaction time is about 1 minute to 2 hours. It is not necessary to isolate the compounds of formula VIII, the decarboxylation under the above reaction conditions may be carried out immediately after the above reaction, in the same reaction mixture, to obtain the compounds of formula II.

4) Preparation of compound of formula II from compound of formula V via intermediate of formula IX

According to the above procedure, the compound of formula (V) is converted to the compound of formula (IX) by treatment with a hydrating agent, and the resulting acid anhydride of formula (IX) is reacted with an alcohol to give the compound of formula (II).

Examples of dehydrating agents include halides such as phosphorus oxychloride, thionyl chloride and chlorosulfonic acid, acid anhydrides of lower fatty acids such as acetic anhydride, trifluoroacetic anhydride, e.g. Β-carbonyldiimidazole, N-trifluoroacetylimidazole, and DCC can be used. When an acid halide is used as a dehydrating agent, an organic base such as pyridine or triethylamine is added to the reaction mixture. The reaction employs an equivalent amount of dehydrating agent, or a small excess, based on the compound of formula (V), and the reaction is carried out in a solvent. When the dehydrating agent is in liquid form, it may also serve as a solvent. Examples of the solvent include dichloromethane, benzene, toluene, acetonitrile, and the like. can be used. The reaction temperature may range from about 0 ° C to 100 ° C, and may be from about 15 minutes to about 30 hours.

The resulting compound of formula IX is then reacted with an almost equivalent amount or excess of alcohol to give compound II. As the alcohol, for example, methanol, ethanol, benzyl alcohol, p-nitrobenzyl alcohol, tert-butyl alcohol or trimethylsilyl ethanol can be used. In some cases, the catalysts used in the above reaction include sulfuric acid, p-toluenesulfonic acid, zinc chloride, sodium acetate, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine and calcium carbonate. The reaction temperature may range from about 0 ° C to about 100 ° C and may be from about 10 minutes to about 4 days.

5) Preparation of Compound (II) from Compound (V) via Intermediates (X), (xi) and (XII)

According to the above procedure, the compound of formula (V) is diesterated to give the compound of formula (X), which is selectively hydrolyzed at the 1-position of the ester group to give the compound of formula (XI). The carboxyl group at the 1-position of the resulting compound is esterified with a group other than the ester 5-group and then the 5-ester group of the resulting compound (XII) is selectively cleaved to the carboxyl group.

In the above formulas (X), (XI) and (XII), R ⁵⁰ is an alkyl group such as methyl, ethyl; or an aralkyl group such as benzyl, p-bromobenzyl or p-nitrobenzyl.

The amount of esterifying agent and base used is two or more times the molar amount of compound (V) to convert the compound (V) to the compound (X).

The compound of formula (X) is generally hydrolyzed in a solvent medium to give a compound of formula (XI), for example, a base such as an alkali metal such as lithium, sodium, potassium, cesium, etc. in the presence of hydroxides, carbonates, alcoholates. For example, water, methanol, ethanol, tetrahydrofuran or dimethylsulfoxide may be used alone or in combination with one another. Nearly one equivalent of base is used to carry out the hydrolysis with respect to the compound of formula (X). The reaction temperature may range from about 0 ° C to about 80 ° C and may be from about 10 minutes to about 20 hours.

The esterification of compound (XI) to compound (ΧΠ) may be carried out under conditions similar to those described above for the preparation of compound (II) from compound (V). In some cases, the compound of formula XI is reacted with isobutene in the presence of an acid catalyst.

In the case where the 1-ester group of the compound of formula XII is stable to the base but the 5-ester group is not, for example when R ² is tert-butoxycarbonyl and R ⁵⁰ is methyl, The compound of formula (XII) may be hydrolyzed under basic conditions to the compound of formula (II) as described above for the conversion of compound (X) into compound (XI). If the ester group at position 1 is stable under reducing conditions and the ester group at position 5 is not, for example, R ² is tert-butoxycarbonyl and R ⁵⁰ is benzyl, the semi-ester of formula II can be selectively produced by reduction. The reduction is carried out, inter alia, by catalytic hydrogenation, for example using palladium on carbon, palladium on carbon, palladium on barium carbonate, platinum oxide, platinum carbon or Raney nickel as the metal catalyst; or a metal such as zinc, iron or chromium, and an acid such as hydrochloric acid, formic acid or acetic acid. The reduction is usually carried out in a solvent such as water, methanol, ethanol, ethyl acetate, acetone, or an acid mentioned above. The reaction temperature may range from about 0 ° C to about 60 ° C, and may be from about 10 minutes to about 20 hours.

6) Preparation of Compounds of Formula II from Compounds of Formula XIII via Intermediates of Formulas XIV, XV, XVI, and XII

The compound of formula (II) is prepared according to the above procedure by esterifying a compound of formula (XIII), hydrolyzing the resulting compound of formula (XIV), and re-esterifying the resulting compound of formula (XV) into the compound of formula (XVI). The hydroxyl group of the compound of formula (II) is oxidized and the resultant compound of formula (XII) is converted to the compound of formula (II) as already mentioned in process (5).

-9197742

The starting compounds of formula (ΧΙΠ) in which R ⁵ , R ⁷ , R ⁷ and R ⁸ are identical hydrogen are known and can be easily prepared from glutamic acid [M. Taniguchi et al., Tetrahedron 30, 3547 (1974)]. Substituted derivatives of R ⁵ -R ⁸ other than hydrogen may be prepared by a procedure similar to that described above.

Conversion of compounds of formula (XIII) to compounds of formula (XIV) can be accomplished by a similar procedure to that described above for the preparation of compounds of formula (II) 'by esterification of compounds of formula (V). In some cases, the tertiary alkyl ester is prepared by addition of a compound of formula XIII with an alkene such as isobutene in the presence of a catalyst such as sulfuric acid or boron trifluoride. The reaction is usually carried out in a solvent such as dichloromethane, chloroform, dioxane, diethyl ether, tetrahydrofuran or benzene, and the reaction vessel is sealed after the addition of excess isobutene. The reaction temperature can range from about 0 ° C to about 50 ° C, with a reaction time of about 5 hours to a few days.

The alkaline hydrolysis of the compounds of formula (XIV) to the compounds of formula (XV) may be carried out under the conditions already mentioned in connection with the conversion of compounds of formula (X) to compounds of formula (XI). The above reaction requires the use of a compound of formula (XIV) which has a relatively stable ester group, for example, R ² is t-butoxycarbonyl-c.

Conversion of compounds of formula (XV) to compounds of formula (XVI) may be carried out by esterification in a similar manner to that described above for the conversion of compounds of formula (VII) to compounds of formula (VIP).

Compounds of formula (XVI) are oxidized to compounds of formula (XII) by treating compound (XVI) in a solvent with an oxidizing agent. Examples of oxidizing agents include potassium permanganate, manganese dioxide, dimethylsulfoxide (DMSO) -DCC, DMSO-oxalyl chloride, and DMSO-phosphorus pentachloride. Examples of the solvent used include dichloromethane, chloroform, acetonitrile, ethyl acetate, benzene, toluene, DMSO, Ν, Ν-dimethylformamide, acetone, diethyl ether, and the like. may. The oxidizing agent is usually used in an amount or excess of approximately equivalent to the compound of formula (XVI). The reaction temperature may range from about -80 ° C to about 60 ° C, and may be from about 10 minutes to about 30 hours.

Compounds of formula (II) wherein R ² represents a carboxyl group may be prepared by amidating the carboxyl group of compound (XI) by the aforementioned procedure, followed by the preparation of compound (II) (XII). ) from a compound of formula (I).

The compounds of formula (V) used as starting materials for the process of the invention may be prepared by a variety of known methods. Some of the compounds of formula (V) are known from the literature and others may be prepared by methods similar to those known in the art.

(1) Organic Synthesis, Volume 3, 510 (1955) (2) M.E.E. Blaise et al., Bulletin de la Societe Chimique de Franse 9, 458 (1911) (3) W.H. Perkin et al., Journal of the Chemical Society 79, 729 (1901) (4) J.C. Bardhi; Journal of the Chemical Society, 1928, 2591 (5) W.N. Haworth et al., Journal of the Chemical Society 105, 1342 (1914) (6) F.C. Hartman, Biochemistry 20, 894 (1981) (7). G. Hasse et al.

Compounds of formula (V) wherein R ⁵ is hydrogen may be prepared, for example, by the process outlined in Scheme 1. In the formulas, R ² ', R ⁷ , R ⁷ and R ⁸ are as defined above.

The compounds of formula (XVII) can be converted to the compounds of formula (XIX) by known Claisen condensation processes. Claisen condensation involves condensing a compound of formula XVII with a compound of formula XVIII in a solvent in the presence of a base. As the base, for example, alkali metals such as lithium, sodium, potassium; alkaline earth metals such as magnesium or calcium; and their hydrides, alcoholates, amides and alkyl metal compounds; and quaternary ammonium salts such as tetra- (n-butyl) ammonium hydroxide. Suitable solvents are, for example, alcohols such as methanol, ethanol, in the case of alcoholates the same alcohols as ester alkoxy groups, ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, dichloromethane, benzene, toluene, etc. can be used. The reaction temperature is usually from about 0 ° C to about 80 ° C, with a reaction time of about 10 minutes to 10 hours,

Compounds of formula (XIX) may be converted to compounds of formula (V) by treatment with acid, alkaline or reductive agents. The above conversion can be accomplished by converting compounds of formula (X) to compounds of formula (XI) or compounds of formula (XII) to compounds of formula (II) as described previously in the art.

-10197742

Compounds of formula (III), which are another starting material for the process of the invention, may be prepared by a variety of known methods. The compounds of formula (111) are either known, for example, from the following literature, or may be prepared by methods analogous thereto.

(1) Eg A. Plattner et al., Hevetica

Chimica Acta 40, 1531 (1957) (2) C.H. Stammer et al., Journal of the American Chemical Society 79, 3236 (1957) (3) C.H. Stammer et al., Journal of the Medical Chemistry 21, 709 (1978). The compounds of formula (III) may be prepared, for example, by the method outlined in Scheme 2. In the formulas of the reaction scheme, the symbols have the meaning given above.

The esterification of the compounds of formula (XX) to the compounds of formula (XXI) may be carried out by standard esterification procedures, for example one of the esterification processes mentioned above. The esterification is preferably carried out with thionyl chloride in alcohol. In this case, the amino group sometimes forms a salt, such as the hydrochloride salt, but this does not hinder the reaction.

In converting compounds of formula (XXI) to compounds of formula (XXII), the hydroxyl group is converted to the leaving group (Y). The above reaction may be carried out in a similar manner for the conversion of compounds of formula II to compounds of formula IV.

The compounds of formula (XXII) are then reacted with hydroxylamine in the presence of a base. The resulting compound (XXIII) is isolated or converted without isolation to the compound (XXIV) in the same reaction mixture. The above reaction is carried out as a solvent in water and the hydroxylamine is used in an equivalent amount or a small excess relative to the compound of formula (XXII) and is carried out in the presence of an equivalent amount or a small excess of the base. Suitable bases are, for example, hydroxides or carbonates of alkali metals such as lithium, sodium or potassium or alkaline earth metals such as magnesium or calcium. The reaction temperature may range from about -20 ° C to about 60 ° C, with reaction times ranging from 10 minutes to 10 hours.

The compound of formula XXIV can be used as starting material in the next step without isolation or purification. The conversion of the compound of formula (XXIV) to the compound of formula (III) is carried out by converting the amino group of the above compound to R ¹ . The above reaction may be carried out under the reaction conditions already described for the acylation of the compounds of formula (13).

The various intermediates obtained in the above processes can be isolated by conventional means such as concentration, pH adjustment, solvent extraction, lyophilization, crystallization, recrystallization, fractional distillation and chromatography. The compounds of formula (II), (III) and (IV) thus obtained can be used as starting materials in the process of the invention, for example, for the preparation of compounds of formula (I).

The compounds of formula (I) obtained by the process of the present invention have activity against various gram-positive and gram-negative bacteria.

The antibacterial spectrum of the compound of formula I prepared according to Example 25 is shown in Table 1.

Table 1: Antibacterial spectrum of compound (25)

Micro-organism Minimum inhibitory concentration * (με / ml) Staphylococcus aureus FDA 209P 6.25 Escherichia coli NIHJ JC-2 3.13 Klebsiella pneumoniae DT 3.13 Pseudomonas aeruginosa 1FO 3455 100

Trypticase S '

10 * CFU / ml

The toxicity of the compounds of formula I is low.

As mentioned above, the compounds of the formula I and their salts have an activity against certain Gram-positive and Gram-negative bacteria, because of their antibacterial activity, bacterial infections are active ingredients of the pharmaceutical preparations, such as' respiratory tract infections, urinary tract infections, infections, gynecological infections, surgical infections, etc. Can be used to treat infections caused by drug-sensitive bacteria in mammals such as mice, rats, dogs, pigs, cattle, and humans.

The daily dose of the compounds of formula (I) or their salts is about 2 to 100 mg / kg, preferably 5 to 50 mg / kg, more preferably 5 to 40 mg / kg of the compound of formula (I).

The compounds of formula (I) or salts thereof are formulated into pharmaceutical compositions by the customary pharmaceutical formulations using pharmaceutically acceptable carriers, diluents and other excipients. The pharmaceutical composition may be, for example, tablets, granules, capsules or pills for oral administration; for parenteral administration, they may be formulated for injection into a sterile vehicle in a conventional manner.

The oral pharmaceutical compositions - such as tablets - preferably the active ingredient is a binder such as ^{hydrochloride:} propyl cellulose, hydroxypropyl methyl cellulose, poppy-11197742 ROGOLO; a disintegrating agent; starch, carboxymethylcellulose calcium, etc .; excipients such as lactose, starch, etc .; lubricants such as magnesium stearate, talc, etc. And other similar substances.

Non-oral or parenteral formulations, such as injection solutions, are preferably isotonic agents such as glucose, D-sorbitol, D-mannitol, sodium chloride, etc .; cobalt preservatives such as benzyl alcohol, chlorobutanol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc .; buffering agents such as phosphate buffers, sodium acetate buffers, and the like. and the like may be prepared by conventional means.

The invention is further illustrated by the following non-limiting Examples and Examples.

Of the resins, only those with an abbreviation denote the following resins:

HP-20: Diainon HP-20 (manufactured by Mitsubishi

Chemical Industries, Ltd, Japan) XAD-2: Amberlite XAD-2 (manufactured by Rohm and

Haas Co., USA)

Abbreviations used in NMR data are as follows:

s: singlet; d: doublet; dd: doublet of doublets; t: triplet; q: quadruplet; m: multiplet; b: broad (has the same meaning in the IR spectrum).

Reference Example 1 Preparation of (4S, 5R) -4-Benzyloxycarbonylamino-5-methyl-3-isoxazolidinone

A solution of 1.88 g of sodium hydroxide in 4 ml of water was cooled in a brine bath and 1.88 g of methyl (2S, 3S) -2-amino-3-chlorobutyrate hydrochloride (Helvetica Chimica Acta) was added. 40, 1531 (1957)] and stirred for 30 minutes. After stirring for a further 30 minutes under ice-cooling, 10 ml of tetrahydrofuran, 5 ml of water and 2.14 ml of a solution of benzyloxycarbonyl chloride in 5 ml of tetrahydrofuran are added under ice-cooling, respectively. The mixture was stirred for 30 minutes while maintaining its pH at 7.0 by adding an aqueous solution of sodium bicarbonate. The reaction mixture was adjusted to pH 3.0 with 30 mL of ethyl acetate. The organic phase is separated and concentrated. The concentrate was dissolved in ethyl acetate and the solution was extracted twice with 1.6 g of sodium carbonate solution in 30 ml of water. The aqueous solution was adjusted to pH 2.5 with 5N hydrochloric acid and then extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Diethyl ether was added to the concentrate and the precipitated crystalline material was filtered off. 1.16 g of the title compound are obtained, m.p. 141-143 ° C.

IR (cm < -1 >): 3300, 1710, 1695, 1680, 1545, 1330, 1250

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -D ₆ -DMSO)?

1.19 (3H, d, J = 5Hz), 4.5-5.0 (2H, m),

5.11 (2H, s), 6.14 (1H, d, J = 7Hz), 7.34 (5H, s)

Elemental analysis results for C _{) 2} H ₁₄ N ₂ O ₄ :

Calculated: C, 57.79; H, 5.64; N, 11.19; Found: C, 57.67; H, 5.52; N, 104.94.

REFERENCE EXAMPLE 2 Preparation of N, N-benzyloxycarbonylamino-6-methyl-3-isoxazolidinone

5.09 g of L-allotreonine are suspended in 30 ml of dichloromethane. To the suspension was added 6.56 g of phosphorus pentachloride in small portions, with ice-cooling and stirring, and the reaction mixture was kept at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The precipitated crystalline material is filtered off and washed with ethyl acetate. 5.6 g of methyl (2S, 3R) -2-amino-3-chlorobutyrate hydrochloride are obtained.

The product was converted to the title compound as described in Reference Example 1. 1.86 g of the title compound are obtained in the form of a colorless crystalline solid, m.p. 127-128 ° C. IR spectra (cm- ¹ ): 1735, 1695, 1540, 196 ° C.

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.46 (3H, d, J = 5Hz), 4.0-4.6 (2H, m), 5.11 (2H, s), δ, 75 (1H, bs), 7.34 (5H, s), 8.8 (1H, bs)

EJemanual analysis based on the formula C _{) 2} H _{) 4} N ₂ O ₄ :

Calculated: C, 57.79; H, 5.64; N, 11.19; Found: C, 57.58; H, 5.55; N, 10.90.

REFERENCE EXAMPLE 3 Preparation of (4R) -4-Benzyloxycarbonylamino-3-isoxazolidinone

To a solution of (4R) -4-amino-3-isoxazolidinone (1.02 g) in tetrahydrofuran (15 mL) and water (15 mL) was added sodium bicarbonate (1.25 g) with stirring. After stirring for 1 hour, ethyl acetate was added and the aqueous phase was separated. The ethyl acetate layer was extracted with 5% aqueous sodium carbonate. The extract was combined with the aqueous phase and washed with ethyl acetate. The aqueous phase was adjusted to pH 3-4 with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound (1.80 g) as a colorless crystalline solid, m.p. 133-134 ° C.

IR spectra? * ¹ (cm ^-1 ): 3325, 1700, 1550,

1310, 1280

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 4.03 (1H, m), 4.67 (2H, m), 5.10 (2H, s), 6.0 (1H, b), 7.33 (5H, s).

-12197742

Reference Example 4 Preparation of (4S) -4-Benzyloxycarbonylamino-3-isoxazolldinone

In the same manner as in Reference Example 3, but using (4S) -4-amino-3-isoxazolidinone instead of (4R) -4-amino-3-isoxazolidinone: The title compound is obtained, m.p. 135-136 ° C. The IR and NMR spectra were identical to those of the product of Reference Example 3.

Reference Example 5 Preparation of (4S) -4- (4-nitrobenzyloxycarbonylamino) -3-isoxazolidinone

In the same manner as in Reference Example 3, but instead of (4R) -4-amino-3-isoxazolidinone, (4S) -4-amino-3-isoxazolidinone and 4-nitrobenzyloxy are substituted for benzyloxycarbonyl chloride. carbonyl chloride is used. The title compound is obtained as a colorless crystalline solid, m.p. 160-161 ° C IR (cm- ¹ ): 3280, 1705, 1550, 1520, 1350, 1275, 1100

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 4.07 (1H, dd, J = 11.15 Hz), 4.65 (2H, m),

5.21 (2H, s), 6.6 (1H, b), 7.53 (2H, d, J = 9Hz),

8.21 (2H, d, J = 9Hz)

Elemental analysis results for the Ό ,, Η ,, Ν ^ β aggregate formula:

H, 3.94; N, 14.94. Found: C, 47.20; H, 3.89; N, 14.93.

Reference Example 6 (4S *, 5R *) - 2, Benzyloxycarbonyl-4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone [(R-6-A)] and (4S, *, 5S *) - 2-Benzyloxycarbonyl-4-benzyloxycarbonylamino-5-methoxycarbonyl-4-isoxazolidinone ((R-6-B))

1.87 g of diethyl trans-aziridine-2,3-dicarboxylate are obtained from the Journal of Medicine! Chemistry 21, 709 (1978)], prepared as described in 4-amino-5-methoxycarbonyl-3-isoxazolidinone, is dissolved in 10 ml of water and 10 ml of tetrahydrofuran. To the solution was added 0.571 ml of benzyloxycarbonyl chloride with stirring and ice-cooling, and the mixture was stirred for 1 hour while maintaining the pH at 7.0 with aqueous sodium bicarbonate. The reaction mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 2). 0.36 g of the title compound (R-6-A) NMR (90 MHz, CDCl ₃ ) δ: 3.76 (3H, s), 4.6-5.1 (2H, m), δ 10 (2H, s), 5.30 (2H, s), 5.90 (1H, d, J = 7Hz), 7.35 (5H, s),

7.39 (5 H, s); and 0.76 g of the title compound (R-6-B) are obtained,

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.61 (3H, s), 5.0-5.3 (2H, m), 5.13 (2H, s),

5.34 (2H, s), 5.70 (Here, d, J = 5Hz), 7.2-

7.5 (10 H, m).

Reference Example 7 Preparation of (4S *, 5R *) - 4-Benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone

0.36 g of (4S *, 5R *) - 2-benzyloxycarbonyl-4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone is dissolved in 30 ml of ethyl acetate. To the solution was added 120 mg of 5% palladium on carbon. The mixture was stirred under ice-cooling under a stream of hydrogen for 20 minutes. The catalyst was filtered off and washed with ethyl acetate. The filtrate and the washings were combined and concentrated. The concentrate is chromatographed on silica gel, eluting with a 50:50: 1 by volume mixture of hexane, ethyl acetate and acetic acid. 150 mg of the title compound are obtained.

IR ^(cm-1): 3340, 1765, 1730, 1695, 1535, 1290, 1245, 1225 NMR (90MHz, CDCl ₃ - (CD _{3) 2} CO) 6: 3.74 (3H, s ), 4.6-5.0 (2H, m), 5.10 (2H, s), 7.00 (1H, broad s), 7.32 (5H, s).

Reference Example 8 Preparation of (4S *, 5R *) - 4-Benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone

In the same manner as in Reference Example 7, 176 mg of (4S *, 5S *) -2-benzyloxycarbonyl-4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone was used as starting material. . 54 mg of the title compound are obtained.

IR (λ max 5 cm -1): 3300, 1750, 1710 (shoulder), 1690, 1540, 1255, 1225 NMR (90 MHz, CDCl ₃ - (CD ₃ ) ₂ CO) δ: 3.65 (3H, s), 4.9-5.4 (2H, m), 5.12 (2H, s),

6.42 (1H, bs), 7.34 (5H, s).

Reference Example 9

Preparation of 5-Phenyl-4- (2-thienylacetamido) -3-isoxazolidinone

1.6 g of hydroxylamino-hydrochloride and

2.3 g of sodium hydroxide are dissolved in a mixture of 12 ml of water and 2 ml of methanol. Ethyl 2-amino-3-chlorophenylpropionate hydrochloride (3.0 g) was added in small portions under ice-cooling. The mixture was stirred for 2.5 hours. The reaction mixture was neutralized with concentrated hydrochloric acid and 15 ml of tetrahydrofuran were added. To the resulting solution was added dropwise a solution of 2.73 g of 2-thiopheneacetic acid chloride in 1 ml of tetrahydrofuran under ice-cooling while maintaining the pH at 7 by the addition of sodium bicarbonate and stirring under ice-cooling for 1 hour. Ethyl acetate (30 mL) was added to the reaction mixture. The aqueous phase is adjusted to acidic pH with hydrochloric acid and the organic phase is separated. The aqueous phase was extracted with ethyl acetate. The organic phases are combined and concentrated. The 13th

Concentrate -13197742 was dissolved in aqueous sodium carbonate solution and extracted with ethyl acetate. The aqueous layer was separated and acidified again with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, eluting with a 98: 2 mixture of chloroform and methanol. 613 mg of the title compound are obtained.

IR spectra (cm- ¹ ): 3300, 1705, 1660, 1510, 740, 690

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -D ₆ -DMSO) δ: 3.50 (2H, s), 5.05 (1H, t, J = 8Hz), 5.56 (1H, d), δ , 56-7.10 (3H, m), 7.21 (5H, s),

7.92 (1H, d, J = 8Hz).

Reference Example 10

Preparation of 5-phenyl-4- (2-phenylacetamido) -3-isoxazolidinone

In the same manner as in Reference Example 9, 4.7 g of ethyl 2-amino-3-chloro-3-phenylpropionate hydrochloride and 4.1 g of phenylacetic acid chloride were used as starting material. 617 mg of the title compound are obtained. IR spectrum (cm ^- '): 3300, 1690, 1640, 1495 1450 695

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 3.27 (2H, s), 5.00 (1H, t, J = 7Hz), 5.56 (1H, d, J = 7Hz), 6.79-7.03 (1H, m), 7.16-7.33 (1H, bs), 8.27 (1H, d, J = 7Hz).

Reference Example 11

Preparation of 4- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5-phenyl-3-isoxazolidinone

In the same manner as in Reference Example 9, starting from 2.67 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (methoxyimino) acetyl chloride-hydrochloride and Ethyl 2-amino-3-chloro-3-phenylpropionate hydrochloride (0 g) was used. 420 mg of the title compound are obtained.

IR spectrum? (Cm ^-1 ): 1680, 1540, 1450, 690

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 3.92 (3H, s), 4.29 (2H, bs), 5.19 (1H, t, J = 8Hz), δ , 68 (1H, d, J = 8Hz), 7.33 (5H, s), 7.69 (1H, s), 8.36 (1H, d, J = 8Hz).

Reference Example 12 Preparation of (4S) -4- (2-Thienylacetamido) -3-isoxazolidinone

Following the procedure of Reference Example 9, starting with methyl (2S) -2-amino-3-chloropropionate hydrochloride, the title compound is obtained.

IR (λ max ¹ cm ^-1 ): 3300, 1720, 1660, 1520, 1250, 1100

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -CD ₃ OD) δ: 3.72-4.13 (5H, m), 4.59-4.91 (2H, m), 6.90-7.29 ( 3H, m).

Example 1 Preparation of 1- (4-nitrobenzyl) -2-oxoglutarate (Compound 1) (a) A solution of 2.93 g of 2-oxoglutaric acid in 20 ml of N, N-dimethylformamide, 63 g of dicyclohexylamine are added. The mixture is heated to 50 ° C, 4.75 g of 4-nitrobenzyl bromide are added and the mixture is stirred at 70 ° C for 15 minutes. The reaction was cooled and 100 mL of ethyl acetate was added. The precipitated crystalline material is filtered off and washed with ethyl acetate. The filtrate and wash were combined, washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with 50:50: 1 hexane: ethyl acetate: acetic acid. 5.2 g of the title compound (1) are obtained in crystalline form, m.p. 100-102 ° C. IR spectra? 1 (cm ^-1 ): 1735, 1707, 1530, 1345, 1275, 1085

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 2.5-2.8 (2H, m), 2.9-3.3 (2H, m), 5.40 (2H, s) ), 7.62 (2H, d, J = 9Hz), 8.28 (2H, d, J = 9Hz)

E'emanagement results based on the formula C, ₂ H ,, NO ₇ :

Calculated: C, 51.25; H, 3.94; N, 4.98; Found: C, 51.17; H, 3.29; N, 4.96.

(b) To a solution of 2.93 g of 2-oxoglutaric acid in 20 ml of N, N-dimethylformamide was added 2.79 ml of triethylamine followed by 4.53 g of 4-nitrobenzyl bromide. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, extracted twice with ethyl acetate, and the procedure of Example 1 (a) was repeated. 3.6 g of the title compound (1) are obtained.

(c) To a solution of 3.36 g of monosodium 2-oxoglutarate in 30 ml of Ν, Ν-dimethylformamide

4.53 g of 4-nitrobenzyl bromide are added. After stirring at 50-60 ° C for 2 hours, the mixture was poured into ice water, extracted twice with ethyl acetate and finally the procedure of Example 1 (a) was repeated. 3.92 g of the title compound (1) are obtained in crystalline form.

Example 2 (4-Nitrobenzyl) -2 - [(4S, 5R) -4-benzyloxycarbonylamino-5-methyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran Preparation of Carboxylate (Compound 2) In dichloromethane (ml), 125 mg of (4S, 5R) -benzyloxycarbonylamino-5-methyl-3 isoxazolidinone and 155 mg of the compound of Example 1 (1) are dissolved. To the solution was added 114 mg of N, N'-dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred at room temperature for 30 minutes. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with hexane and

-14197742 with a 1: 1 by volume mixture of ethyl acetate. 185 mg of the title compound (2) are obtained in the form of a colorless foam. IR (cm ^-1 ): 3325, 1805, 1770 (shoulder), 1730, 1530, 1350, 1050

Nuclear Magnetic Resonance Spectrum (90 MHz, · CDCl ₃ ) δ: 1.17, 1.23 (both 1.5 H, d, J = 6 Hz), 2.3-3.3 (4H, m), 4 6-5.1 (2H, s); 5.37 (2H, s); 5.48 (1H, d, J = 5Hz), 7.33 (5H, s), 7.51, 8.10 (both 2H, d, J = 9Hz).

Example 3

Preparation of Sodium 2 - [(4S, 5R) -4- (2-Tlenylacetamido) -5-methyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate (Compound 3) of ethyl acetate (5 ml) and water (5 ml) were dissolved in compound (2). To the solution was added 200 mg of 5% palladium on carbon. The mixture was stirred at room temperature under a stream of hydrogen for 50 minutes. The catalyst is filtered off and washed with water. The filtrate and the washings are combined. To the aqueous phase was added tetrahydrofuran (5 mL), followed by ice-cooling and stirring, followed by addition of 67 μΙ of 2-thienylacetyl chloride and aqueous sodium bicarbonate solution. The reaction mixture was maintained at pH 7 for 30 minutes and then the tetrahydrofuran was evaporated under reduced pressure. The resulting aqueous solution was washed with ethyl acetate and the aqueous phase was purified on a column packed with XAD-2. The eluted fractions were lyophilized to give 87 g of the title compound (3) as a pale yellow powder. IR (cm ^-1 ): 1775, 1720, 1655, 1380, 1195

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ 1.08 (3H, d, J = 6Hz), 2.2-3.3 (4H, m), 3.76 (2H, s), 4.4-5.0 (2H, m), 6.8-7.4 (3H, m), 8.81, 8.85 (both 0, 5H, d, J = 8Hz). results for C, _s H ₁₅ N ₂ NaO ₇ S:

Calculated: C, 44.12; H, 4.20; N, 6.86. Found: C, 44.35; H, 4.23; N, 6.82.

Example 4

Sodium] (4S, 5R) -4- [2- (2-amino-4-thiazoloyl) - (Z) -2- (methoxyimino) acetamido] -5-methyl-3-oxo-2-isoxazolidinyl Preparation of} -5-oxo-2-tetrahydrofuran carboxylate (Compound 4) In a mixture of ethyl acetate (5 ml) and water (5 ml) was dissolved 257 mg of the compound of Example 2 (250 mg of 5% palladium-on-carbon). and the mixture was stirred at room temperature under a stream of hydrogen for 45 minutes. The catalyst was filtered off and washed with water. -acetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride and aqueous sodium bicarbonate solution were added and the reaction was continued at pH 28.0 and sodium N-methyldithiocarbamate (165 mg) was added to the reaction mixture at room temperature for 45 minutes. The concentrate was washed with ethyl acetate and chromatographed on a column packed with XAD-2. Elution is carried out with water. The fractions containing the desired product were lyophilized to give 149 mg of the title compound (4) as a yellow powder. IR spectra (cm ^-1 ): 1775, 1720, 1660, 1535, 1380, 1040

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 1.21 (3H-, d, J = 6Hz), 2.2-3.3 (4H, m), 3.86 (3H) , s), 4.5-5.1 (2H, m), 6.72 (1H, s), 7.07 (2H, s), 9.02, 9.19 (both 0.5d, J = ~ 8 Hz)

Found: C, 37.82; H, 4.02; N, 14.70 Found: C, ₅ H, ₆ N ₅ NaO ₈ SX X1.5H ₂ O. Found: C, 38.01; H, 4.07; N, 14.76.

Example 5

4-Nitrobenzyl 2 - [(4S, 5S) -4-benzyloxycarbonylamino-5-methyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran-carboxylate [(5 )

In the same manner as in Example 2, starting material (4S, 5S) -4-benzyloxycarbonylamino-5-methyl-3-isoxazolidinone (376 mg) prepared in Reference Example 2 and 464 mg (Example 1) were prepared. Compound 1) was used. 593 mg of the title compound (5) are obtained in the form of a colorless foam. IR spectrum or? (cm ^-1): 3350, 1805, 1760 (shoulder), 1730, 1530, 1350, 1185 1055 NMR (90MHz, CDC1 ₃₎ δ: 1.38,

1.42 (both 5H, d, J = 5Hz), 2.2-3.3 (4H, m), 4.0-4.7 (2H, m), 5.07 (2H, s),

5.32 (2H, s), 5.57 (1H, d, J = 7Hz), 7.31 (5H, s), 7.47, 7.50 (both 1H, d, J = 11Hz) ), 8.16 (2H, d, J = 11Hz).

Example 6

Preparation of Sodium 2 - [(4S, 5S) -4- (2-thienylacetamido) -5-methyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate (Compound 6)

Starting from 265 mg of Example 5, Example 5 gave 162 mg of the title compound 6 as a colorless powder.

IR (cm ^-1 ): 1780, 1730, 1655, 1380, 1200

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -d ₆ -DMSO) δ: 1.28 (3H, d, J = 6Hz), 2.2-3.3 (4H, m), 3.73, 3, 75 (both 1H, s), 4.0-4.8 (2H, m), 6.8-7.3 (3H, m), 8.77 (1H, d, J = 8Hz).

Example 7

Sodium 2 -] (4S, 5S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5-methyl-3-oxo-2 -thiazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate] (Compound 7)

-15197742

From 257 mg of Example 5, Example 5, 149 mg of the title compound 7 was obtained in the form of a pale yellow powder.

IR (cm @ -1): 1785, 1655, 1530, 1380, 1200, 1035

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ -D ₆ -DMSO) δ: 1.36 (3H, d, J = 6Hz), 2.1-3.3 (4H, m), 3.87 (3H, s), 4.1-4.9 (2H, m), 6.89, 6.92 (both 0.5H, s), 7.13 (2H, s), 9.06, 9.08 (both) 0.5H, d, J = 8Hz).

Example 8

Preparation of 4-Nitro-benzyl-2 - [(4R) -4-benzyloxycarbonyl-amino (no-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuranecarboxylate (Compound 8) (a) Dissolve 85 mg in 3 ml dichloromethane

Compound (1) prepared in Example 1 and 41 mg of 1-hydroxybenzotriazole (HOBT). To the solution was added 62 mg of DCC and the mixture was stirred at room temperature for 30 minutes, followed by the addition of 60 mg of (4R) -4-benzyloxycarbonylamino-3-oxoxazolidinone (Journal of Medicinal Chemistry 13, 1013, 1970) and the reaction mixture was stirred at room temperature for 30 minutes. The insoluble material was separated by filtration and washed with dichloromethane. The filtrate and the washings were combined and concentrated. The concentrate was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. Elution was carried out with a 1: 1 by volume mixture of hexane and ethyl acetate. 96 mg of the title compound (8) are obtained in the form of a colorless foam. IR (cm- ¹ ): 3330, 1805, 1760 (shoulder), 1730, 1530, 1350, 1270, 1245, 1185, 1055

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.3 - 3.4 (4H, m), 4.0 - 4.4 (1H, m), 4.4 - 5.1 (2H, m) .

5.11 (2H, s), 5.36 (2H, s), 5.53, 5.59 (both 0.5, d, J = 6Hz), 7.33 (5H, s), 7, 50

7.52 (both 1H, d, J = 9Hz), 8.18 (2H, d, J = 9Hz).

Mass spectrum m / e: 499 (M ⁺ ).

(b) 85 mg of (1) and 60 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone are dissolved in 2 ml of dichloromethane. To the solution was added 77 mg of 2-chloro-1-methylpyridinium iodide and 84 μΐ triethylamine. The mixture was stirred at room temperature for 40 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and worked up as described in Example 8 (a). 31 g of the title compound (8) are obtained.

Example 9

4-Nitrobenzyl-2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-3-isoxazolidinyl] -5-oxo-216

Preparation of Tetrahydrofuran Carboxylate (Compound 9) (a) Dissolve 236 mg of dichloromethane in 20 ml.

(4S) -4-Benzyloxycarbonylamino-3-isoxazolidinone prepared according to Reference Example 4 and 365 mg of compound (1) obtained according to Example 1. To the solution was added 277 mg DCC and stirred at room temperature for 14 hours. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined and washed with aqueous sodium bicarbonate solution, then water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel, eluting with a 1: 1 by volume mixture of hexane and ethyl acetate. 297 mg of the title compound (9) are obtained in the form of a colorless foam.

IR v ^ ^a (cm ^-1): 3350, 1800,

1770-1700, 1520, 1340, 1260, 1230, 1180, 1050 NMR (90MHz, CDC1 ₃₎ He: 2.3-3.3 (4H, m), 4.1 (1H, m), 4 , 5-4.8 (2H, m),

5.11 (2H, s), 5.3 (1H, b), 5.37 (2H, s), 7.35 (5H, s), 7.53 (2H, d, J = 9Hz, m) ), 8.23 (2H, d, J = 9Hz)

Mass spectrum m / e: 499 (M ⁺ ).

(b) Dissolve 282 mg of compound (I) in 10 ml of dichloromethane and cool in a brine bath, followed by the addition of 140 μΐ triethylamine and 96 μΙ ethyl chlorocarbonate. To the mixture was added (4S) -4-benzyloxycarbonylamino-3-isoxalidinone (119 mg) and stirred in a salt-ice bath for 1 hour and then at room temperature for 1 hour. The solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic phase was washed with aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was chromatographed on silica gel, eluting with a 9: 1 by volume mixture of 1,2-dichloroethane and ethyl acetate followed by a 1: 1 by volume mixture of hexane and ethyl acetate. 73 mg of the title compound are obtained.

(c) Dissolve 155 mg of (1) and 119 mg of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone in 5 ml of dichloromethane. To the solution was added 2 drops of a 47% solution of boron trifluoride diethyl ether in ether and 2 g of molecular sieve (3A). The mixture was allowed to stand at room temperature for 2 days. The molecular sieve was removed from the reaction mixture, washed with cold aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel using a 5: 1 by volume mixture of 1,2-dichloroethane and ethyl acetate. 12.5 mg of the title compound (9) are obtained.

-16197742

Example 10 Preparation of 1-Methyl-2-oxoglutarate (Compound 10)

27.93 g of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofuranecarboxylic acid as described in Journal of Organic Chemistry 6, 878 (1941) are dissolved in 100 ml of Ν, Ν-dimethylformamide. is prepared as described. To the solution was added 4.0 g of sodium hydride as a 60% oil suspension, 28.4 g of methyl iodide was added and the reaction mixture was kept at room temperature for 4 hours. To the mixture was added 14.2 g of methyl iodide and stirring was continued for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the precipitated crystals were filtered off and washed with ether. Methyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofuran carboxylate (27.25 g) was obtained as colorless crystals, m.p. 134-134,5 ° C.

IR (cm -1): 3295, 1780, 1758, 1700, 1540, 1308, 1196, 1049.

To the above compound (10.0 g) was added 30% hydrobromic acid (20 ml) and the mixture was stirred for 30 minutes. The reaction mixture was washed twice by decantation with 500 mL of a 9: 1 mixture of hexane and diethyl ether under ice-cooling. Water was added to the resulting solution and the mixture was extracted four times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 2.95 g of the title compound (10) are obtained in the form of colorless crystals, m.p. 54.5-55.0 ° C.

IR spectrum? ™ '(cm ^-1): 3430, 1750, 1735 1710, 1275, 1255, 1225, 1080 NMR (90MHz, _CDCl3)?: 2.60-

3.27 (4H, m), 3.88 (3H, s), 8.20 (1H, bs) Calculated for C ₆ H ₈ O ₅ : C, 45.01; H, 5; 04%; Found: C, 44.92; H, 4.92. ¹¹

Example 11 Preparation of 1- (4-Nitrobenzyl) -2-oxoglutarate (Compound 1)

838 mg of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofuranecarboxylic acid were dissolved in 5 ml of Ν, Ν-dimethylformamide. To the solution was added 120 mg of sodium hydride as a 60% oily suspension. 648 mg of 4-nitrobenzyl bromide are added and the mixture is stirred at room temperature for 2.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography. Elution was carried out with a 1: 1 by volume mixture of hexane and ethyl acetate. 687 mg of 4-nitrobenzyl-2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofuranecarboxylate are obtained in the form of colorless crystals, m.p. 127-127.5 ° C. IR (cm @ ^-1 ): 3310, 1780, 1759, 1728, 1520, 1345, 1185, 1042.

2.07 g of the title compound were obtained as described in Example 10 to give 1.14 g of Compound (1) having the same physical constants as Compound (1) prepared in Example 1.

Example 12

Preparation of methyl 2- (4R) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 12) (a) 8 ml of dichloro 74 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone, 50 mg of Example 10, 96 mg of 2-chloro-1-methylpyridinium iodide and , 5 mg of dihydropyridopyrimidone. The solution was stirred at room temperature under nitrogen for 15 hours. Ethyl acetate was added to the solution, the insoluble material was filtered off and the filtrate was evaporated to dryness. The resulting concentrate was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (1: 1). 40.1 mg of the title compound (12) are obtained. IR (cm ^-1 ): 3375, 1805, 1740, 1525

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.20 -

40 (4H, m), 3.75 (3H, s), 4.15 (1H, m),

75 (2H, m), 5.13 (2H, s), 5.45 (1H, bd),

7.34 (5H, s).

(b) 82 mg thiphenylphosphine and 70 mg 2,2'-dipyridyl disulfide are dissolved in 8 ml dichloromethane. The solution was stirred at room temperature under a stream of nitrogen for 5 minutes, then 290 mg of silver chloride and 154 mg of

3.4-Dihydro-2H-pyrido [1,2-a] pyrimidin-2-one and the mixture was stirred for 5 minutes. To the mixture was added (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone (74 mg) and compound (10) (50 mg). The reaction mixture was stirred at room temperature

After stirring for 7.5 hours, it was worked up as described in Example 12 (a). 69.6 mg of the title compound (12) are obtained.

(c) Dissolve 74 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone, 50 mg of compound (10), 50 mg of 3,4-dihydro-5H-pyrido [1,2- a] pyrimidin-2-one and 90 mg triphenylphosphine. The mixture was stirred at room temperature under a nitrogen atmosphere. 100 μΙ of carbon tetrachloride was added and the mixture was stirred for 6 hours and worked up as described in Example 12 (a). 46 mg of the title compound (12) are obtained.

(d) Dissolve 74 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone, 50 mg of 10 and 52 mg in 10 mL of dichloromethane.

3,4-dihydro-2H-pyrido [1,2-a] pyrimidin-2-one.

-17197742

To the solution was added 80 μΐ of diphenylphosphoryl azide at room temperature with stirring under a stream of nitrogen and the reaction was allowed to proceed for 20 hours. The reaction mixture was concentrated and the concentrate was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 30 mg of the title compound (12) are obtained.

(e) Dissolve 74 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone, 50 mg of compound (10) and 94 mg of 1-ethoxycarbonyl-2-ethoxy-1 in 8 ml of dichloromethane. , 2-dihydroquinoline. The solution is stirred under a stream of nitrogen for 18 hours and worked up according to the above procedure (d). 111 mg of the title compound (12) are obtained.

Example 13

Preparation of Methyl 2-Chloro-5-oxo-2-tetrahydrofuranecarboxylate (Compound 13) (a) A mixture of (10) (80 mg) from Example 10, 131 mg triphenylphosphine and 5 ml carbon tetrachloride under a stream of nitrogen After refluxing for 4 hours, the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with hexane: ethyl acetate (1: 2). 46 mg of the title compound are obtained in the form of colorless crystals, m.p. 50.5-51.0 ° C.

IR spectrum ν max (cm ^-1 ): 1820, 1750, 1175, 1160, 1100, 1075

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.40-3.23 (4H, m), 3.90 (3H, s)

Elemental analysis for C ₆ H ₇ ClO ₄ : Calculated: C = 40.36%, H = 3.95%; Found: C, 40.35; H, 3.94.

(b) Dissolve 1.0 g of 10 in dichloromethane (10 mL). To the solution was added 911 μΐ thionyl chloride and a drop of N, N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated. The concentrate was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 2). 985 mg of the title compound (13) are obtained.

Example 14

Preparation of Methyl 2 - [(4R) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 12) Dissolved in DMF (236 ml). mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution was added 326 mg of cesium carbonate. After stirring at room temperature for 20 minutes, 179 mg of Example 13 (13) is added and the mixture is stirred for 2 hours. Dilute brine was added to the reaction mixture. The mixture was extracted with diethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 101 mg of the title compound (12) are obtained, which have the same IR and NMR spectra of the compound (12) prepared according to Example 12.

Example 15

Preparation of 4-Nitrobenzyl-2-chloro-5-oxo-2-tetrahydrofuranecarboxylate (Compound 15): Dissolve 0.40 g in 1,2-dichloroethane.

Compound (1) prepared according to Example 1. To the solution was added 0.88 ml of thionyl chloride. The mixture was refluxed for 10 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography. Elution was carried out with a 3: 1 by volume mixture of hexane and ethyl acetate. 0.36 g of the title compound (15) are obtained in the form of a colorless oil.

IR (cm ^-1 ): 1815, 1760, 1520, 1340, 1160, 1080

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ 2.8 (4H, m), 5.43 (2H, s), 7.60 (2H, d, J = 9Hz), 8.30 (2H, d, J = 9 Hz)

Mass Spec m / e: 301, 299 (M ⁺ ).

Example 16

Preparation of 4-Nitrobenzyl 2 - [(4R) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 8) in dichloromethane (4R) -4-Benzyloxycarbonylamino-3-isoxazolidinone (60 mg) was dissolved in methane. Under ice-cooling, 0.08 ml of diisopropylethylamine and 90 mg of compound 15 obtained in Example 15 are added. The mixture was stirred under ice-cooling for 15 minutes and then at room temperature for 30 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel, eluting with 11 volumes of hexane: ethyl acetate, to give 71 mg of compound (8) as a colorless foam. nt prepared with (8).

Example 17

Sodium 2 -] (4R) -4- [2- (2-amino-4'-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl-5 Preparation of -oxo-2-tetrahydrofurancarboxylate (Compound 17) in a mixture of ml of ethyl acetate and 7.5 ml of phosphate buffer, pH 7.0

Compound 8 prepared according to Example 8. Palladium on carbon (220 mg, 10%) was added to the solution and the mixture was stirred under a stream of hydrogen under ice-cooling for 90 minutes. The catalyst was filtered off and washed with water

-18197742 was combined, the aqueous phase was separated and 5 mL of tetrahydrofuran was added. To the resulting mixture was added, under ice-cooling and stirring, 110 mg of sodium bicarbonate and 195 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride. . The reaction mixture is stirred for 30 minutes and then 110 mg of sodium N-methyldithiocarbamate are added. The mixture was stirred at room temperature for 30 minutes. The tetrahydrofuran was evaporated under reduced pressure. The residue was washed with ethyl acetate and chromatographed on an HP-20 column. The water eluted fractions were lyophilized to give 107 mg of the title compound as a white powder.

IR spectrum ν £ 8ϊ (cm ^-1 ): 1175, 1720, 1650, 1530, 1380, 1190, 1035

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 2.6-3.5 (4H, m), 4.23 (3H, s), 4.6 (1H, m), 5.0 (1H, m), 5.4 (1H, m), 7.28 (1H, s).

Found: C, 36.37; H, 3.71; N, 15.15. Calculated for C ₁₄ H ₁₄ N ₅ NaO ₈ SX X1.5H ₂ O: C, 36.37; Found: C, 36.29; H, 3.58; N, 15.04.

Example 18

Preparation of 4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 9) in dichloromethane dissolved in 118 mg

(4S) -4-Benzyloxycarbonyl-mino-3-isoxazolidinone prepared according to Reference Example 4. Triethylamine (0.14 mL) and Compound (1) (160 mg) prepared in Example 1 (1 mL) in dichloromethane were added to the solution under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, then washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was chromatographed on silica gel, eluting with a 1: 1 by volume mixture of hexane and ethyl acetate. 135 mg of the title compound (9) are obtained in the form of a colorless foam. The product was identical to the compound (9) prepared in Example 9 according to IR and NMR.

Example 19

Sodium [(4S) -4- [2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran Preparation of Carboxylate (Compound 19) In a mixture of ml of ethyl acetate and 6 ml of phosphate buffer, pH 7.0, 125 mg.

Compound 9 prepared according to Example 9. To the solution was added 125 mg of 10% palladium on carbon and the mixture was stirred under ice-cooling under a stream of hydrogen for 1 hour. The catalyst is filtered off and washed with water. The filtrate and the washings were combined, the aqueous phase separated and 4 mL of tetrahydrofuran added. To the mixture was added, under ice-cooling and stirring, 63 mg of sodium bicarbonate and 102 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride. After stirring for 20 minutes, 57 mg of sodium N-methyldithiocarbamate are added and the mixture is stirred at room temperature for 40 minutes. The tetrahydrofuran was evaporated under reduced pressure and the residue was washed with ethyl acetate and purified by column chromatography on an HP-20. The water-eluted fractions were lyophilized to give 70 mg of the title compound (19) as a white powder. The IR and NMR spectra of the above compound were consistent with those of the corresponding (4R) compound prepared in Example 17.

Elemental analysis for C _l4 H _l4 N NaOgSX ₆ <1.5 H ₂ O: Calcd: C = 36.37%, H 3.71%, N = 15.15% Found: C = 36.59%; H = 3.85%, N = 15.31%

Example 20 Preparation of 1-Benzyl-2-oxo-glutarate (Compound 20) 2.92 g of 2-oxo-glutaric acid are dissolved in ml of anhydrous N, N-dimethylformamide. To the solution was added 3.63 g of dicyclohexylamine and 2.61 ml of benzyl bromide. The mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the precipitated crystals were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography, eluting with 50:50: 1 hexane: ethyl acetate: acetic acid. 3.20 g of the title compound (20) are obtained, which are recrystallized from a mixture of diethyl ether and hexane. Colorless prism crystals melting point 51-52 ° C.

^T R spectrum (.lambda.max. Cm @ ^-1 ): 1740, 1705, 1270, 1090, 1040

MR spectrum (90 MHz, CDCl ₃ ) δ: 2.67 (2H, t, J = 6Hz), 2.97 = 2H, m), 5.26 (2H, s), 7.35 (5H, s), 8.9 (1H, b).

Elemental analysis results for C, ₂ Hi ₂ O ₅ :

Calculated: C, 61.01; H, 5.12;

Found: C, 61.02; H, 5.12.

Example 21 Preparation of 1- (4-nitrobenzyl) -4-methyl-2-oxoglutarate (Compound 21) in anhydrous N, N-dimethylformamide (0.74 g). oxo-glutaric acid. To the solution was added dicyclohexylamine (0.94 mL) and 4-nitrobenzyl chloride (1.0 g). It's your mixture! and stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction mixture. The precipitated Crystals are filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate = 1: 1 → 1; : 3 by volume. 0.66 g of the title compound (21) is obtained in the form of a pale yellow oil.

-19197742

IR ν ^ ^α (cm ^-1): 1780-1700,

1520, 1345, 1220, 1170

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.32 (3H, d, J = 6Hz), 2.2-3.3 (3H, m), 5.38 (2H, s), δ, 0 (1H, b), 7.55 (2H, d, J = 9Hz),

8.22 (2H, d, J = 9Hz).

Example 22

Preparation of 4-nitrobenzyl-2-chloro-4-methyl-5-oxo-2-tetrahydrofuranecarboxylate (Compound 22) Dissolve 0.13 g in 1,2-dichloroethane per ml.

Compound 21 prepared according to Example 21 is added and 0.13 ml of thionyl chloride is added. The mixture was refluxed for 90 minutes. The solvent was evaporated and the residue was purified by silica gel column chromatography. Elution was carried out with a 3: 1 by volume mixture of hexane and ethyl acetate. 0.11 g of the title compound (22) is obtained in the form of a colorless oil. IR spectrum νίί, βί · (cm ^-1 ): 1810, 1755,

1600, 1520, 1345, 1165, 1070, 1010 Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.35 (1.5H, d, J = 6Hz), 1.47 (1.5H, d, J = 6 Hz),

2.3-3.5 (3H, m), 5.42 (2H, s), 7.59 (2H, d, J = 9Hz), 8.25 (2H, d, J = 9Hz).

Example 23

Preparation of 4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -4-methyl-5-oxo-24-tetrahydrofuran carboxylate (Compound 23). Dissolve 118 mg in 1,2 ml dichloroethane

(4S) -4-Benzyloxycarbonylamino-3-isoxazolidinone prepared according to Reference Example 4 and 150 mg of Compound 21 prepared according to Example 21. To the solution was added 160 mg of DCC and the mixture was stirred at room temperature for 90 minutes. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined and washed with aqueous sodium bicarbonate solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate = 3: 2 (v / v). 152 mg of the title compound (23) are obtained in the form of a colorless oil. IR v'Í, ^ ^a (cm ^-1): 1795, 1760-

1700, 1520, 1450, 1345, 1260, 1180, 1080, 1010 NMR (90MHz, CDC1 ₃₎ δ: 1.27 (3H, d, J = 6Hz), 2.0 (1H, m); 2.7-3.5 (2H, m), 4.1 (1H, m), 4.7 (2H, m), 5.10 (2H, s),

5.35 (2H, s), 7.33 (5H, s), 7.55 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz)

Mass spectrum m / e: 513 (M ⁺ ).

Example 24 Preparation of Compound 23 Dissolve 55 mg in dichloromethane

(4S) -4-Benzyloxycarbonylamino-3-isoxazolidinone prepared according to Reference Example 4. To the solution, under ice-cooling and stirring, were added triethylamine (0.07 mL) and Compound (22) (80 mg, Example 22) dissolved in 1.5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour, then washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 2). 78 mg of the title compound are obtained in the form of a colorless oil. The IR and NMR spectra of the product were consistent with those of the compound of Example 23 prepared in Example 23.

Example 25

Sodium 2 - [(4S) -4- [2- (2-amino-4-thiazolyl (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -4-methyl Preparation of -5-oxo-2-tetrahydrofuran carboxylate (Compound 25) was dissolved in a mixture of ml of ethyl acetate and 7.5 ml of phosphate buffer, pH 7.0.

Compound 23 prepared according to Example 23. To the solution was added 225 mg of 10% palladium-on-carbon and the mixture was stirred under ice-cooling under a stream of hydrogen for 75 minutes. The catalyst is filtered off and washed with water. The filtrate and the washings were combined and the aqueous layer was separated and 5 ml of tetrahydrofuran was added. Under ice-cooling and stirring, 110 mg of sodium bicarbonate and 180 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride are added. The reaction mixture was stirred for 30 minutes, N-methyldithiocarbamate (100 mg) was added and the mixture was stirred at room temperature for 45 minutes. The tetrahydrofuran was evaporated under reduced pressure and the residue was washed with ethyl acetate and purified on an HP-20 column. The water-eluted fractions were lyophilized to give 106 mg of the title compound (25) as a white powder.

IR spectra ν * αζ (cm ^-1 ): 1775, 1720, 1660, 1530, 1380, 1200, 1030

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 1.4 (3H, m),

2.3 (1H, m), 2.9-3.7 (3H, m), 4.12 (3H, s),

4.5 (1H, m), 4.9 to 5.5 (2H, m), 7.17 (1H, s) Elemental Analysis for C ₁₅ H _t6 NaO _g N _s H ₂ SX 0 Calc'd:

date; C, 38.55; H, 3.88; N, 14.98. Found: C, 38.56; H, 3.89; N, 14.66.

Example 26

Preparation of methyl 2-6-bromo-2,5-dlhydro-5-oxo-2-furancarboxylate (Compound 26) Dissolve 184 mg of methyl 5-acetoxy-2-furancarboxylate in dichloromethane. A solution of bromine (0.045 ml) in dichloromethane (1 ml) was added gradually. The reaction mixture was stirred at room temperature for 30 minutes and then the solvent and the resulting acetyl bromide were evaporated under reduced pressure. 220 mg of the title compound (26) are obtained in the form of a pale yellow oil. IR (cm ^-1 ): 1805, 1760,

1435, 1265, 1210, 1105, 880

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.88 (3H, s), 6.27 (1H, d, J = 6Hz), 7.8 (1H, d, J = 6Hz).

Example 27

Preparation of methyl 2-chloro-2,5-dihydro-5-oxo-2-furan carboxylate (Compound 27) Dissolve 184 mg of methyl 5-acetoxy-2-furancarboxylate in 4 ml of dichloromethane. To the solution was added 1.5 mL of a 2 molar solution of carbon tetrachloride. The mixture was stirred at room temperature for 30 minutes. The solvent and the by-product acetyl chloride were evaporated under reduced pressure. 176 mg of the title compound (27) are obtained in the form of a colorless oil.

IR v (i, ^{s m} (cm ^-1): 1810, 1760,

1440, 1270, 1210, 1100, 880 NMR (90MHz, CDC1 ₃₎ δ: 3.90 (3H, s), 6.13 (1H, d, J = 6Hz), 7.60 (1H, d, J = 6 Hz)

Example 28

Preparation of Benzyl 2-chloro-2,5-dihydro-5-oxofurancarboxylate (Compound 28) In a mixture of acetic acid (10 ml) and acetic anhydride (10 ml) was dissolved 10.1 g of 2-furancarboxylic acid. While stirring, 4.55 g of chlorine gas were introduced while maintaining the internal temperature at 7 ° C. After standing at room temperature for 40 hours, the solvent was evaporated and the hot fractions were distilled off at a bath temperature of 17 ° C and a pressure of 6.45 Pa. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 6: 1). 2.6 g of benzyl 5-acetoxy-2-furancarboxylate are obtained in the form of a colorless oil.

IR (cm ^-1 ): 1770, 1700, 1520, 1480, 1300, 1205, 1140, 1020 NMR (90 MHz, CDCl ₃ ) δ: 2.28 (3H, s), 5.30 (2H) , s), 6.07 (1H, d, J = 3Hz),

7.19 (1H, d, J = 3Hz), 7.37 (5H, s) Mass Spectrum m / e: 260 (M ⁺ ).

Dissolve 260 mg of the above compound in dichloromethane (ml). To the solution was added 1.4 mL of a 2 molar solution of carbon tetrachloride and the mixture was stirred at room temperature for 30 minutes. The solvent and the by-product acetyl chloride were evaporated under reduced pressure. 250 mg of the title compound (28) are obtained in the form of a colorless oil.

IR (cm- ¹ ): 1810, 1760, 1210, 1100, 1060, 880

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 5.30 (2H, s), 6.27 (1H, d, J = 6Hz), 7.40 (5H, s), 7.58 (1H, d, J = 6 Hz).

Example 29

Methyl 2 - [(4R) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2,5-dihydro-2-furancarboxylate [Compound 29] (4R) -4-Benzyloxycarbonylamino-3-isoxazolidinone (240 mg) was dissolved in dichloromethane. To the solution was added 0.25 mL of triethylamine and 220 mg of Example 26 (26 mg) in dichloromethane (2 mL) under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1 + 1: 1). 150 mg of the title compound (29) are obtained in the form of a pale yellow oil.

IR spectrum ν max ^Z / ^O (cm ^-1 ): 3350, 1810,

1770-1710, 1530, 1260, 1080, 1040, 960, 900 NMR (90MHz, _CDCl3) δ: 3.85 (3H, s), 4.2 (1H, m), 4.8 (2H , m), 5.11 (2H,

s), 5.4 (1H, b), 6.32 (1H, d, J = 6Hz), 7.35 (5H, s), 7.60 (1H, d, J = 6Hz). Mass Spectrum m / e: 376 (M ⁺ ) τρ Example 30

Preparation of Methyl 2 - [(4R) -4-phenylacetamido-3-oxo-2-isoxazilidinyl] -5-oxo-2,5-dihydro-2-furancarboxylate (Compound 30)

110 mg of (4R) -4-phenylacetamido-3-isoxazolyl dinone are suspended in 8 ml of dichloromethane. To the suspension was added 0.14 ml of triethylamine and 106 mg of Example 27 (27) in 2 ml of dichloromethane under ice-cooling. The ring reakció40 ^{mixture was} stirred at room temperature for 40 minutes, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by column chromatography on silica gel, eluting with 2: 3 hexane: ethyl acetate. 78 mg of the title compound 30 are obtained in the form of a colorless oil.

IR Spectrum (cm ^-1 ): 3300, 1800, 1750, 1660, 1530, 1260, 1080, 1040, 900 NMR (90 MHz, CDCl ₃ ) δ: 3.59 (2H, s) ), 3.83 (3H, s), 4.1 (1H, m), 4.8 (2H, m), 6.5 (1H, b), 6.30 (1H, d), 7.30 (5H, s),

7.53 (0.5H, d, J = 6Hz), 7.60 (0.5H, d, J ==6Hz)

Mass spectrum m / e: 360 (M ⁺ ).

(b) Dissolve 220 mg of (4R) -4-phenylacetamido-3-isoxazolidinone in 3 ml of anhydrous N, N-dimethylformamide. To the solution was added, while cooling with ice, 60 mg of sodium αθhydride as a suspension in 50% mineral oil, and 220 mg of Example 26 (26) dissolved in 0.5 ml of Ν, Ν-dimethylformamide. The reaction mixture was stirred under ice-cooling for 69 minutes and then poured into a mixture of ethyl acetate and water.

-21197742

The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate (2: 1? 2: 3). 32 mg of the title compound (30) are obtained in the form of a colorless oil.

Example 31

Preparation of Methyl 2 - [(4R) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate (Compound 31) Dissolve in tetrahydrofuran (30 mg)

Compound 30 prepared according to Example 30. To the solution was added 30 mg of 10% palladium on carbon and the mixture was stirred at room temperature under a stream of hydrogen for 30 minutes. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate and the washings were combined and the solvent was evaporated. The residue was purified by column chromatography on silica gel, eluting with 2: 3 hexane: ethyl acetate. 24 mg of the title compound 31 are obtained in the form of a colorless oil.

IR (cm ^-1 ): 3300, 1800, 1750, 1660, 1530, 1270, 1190, 1050 Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.3-

3.3 (4H, m), 3.57 (2H, s), 3.82 (1.5H, w),

3.84 (1.5H, s), 4.1 (1H, m), 4.8 (2H, m),

6.2 (0.5H, b), 6.4 (0.5H, b), 7.30 (5H, s) Mass Spectrum m / e: 362 (M ⁺ ).

Example 32

Benzyl 2 - [(4R) -4-phenylacetamido-3-oxo-2-isoxazolidinyl | Preparation of -5-oxo-2,5-dihydro-2-furancarboxylate (Compound 32) Dissolve 220 mg of (4R) -4-phenylacetamido-3-isoxazolidinone in anhydrous N, N-dimethylformamide. Sodium borohydride (60 mg) was added as a 50% suspension in mineral oil with ice-cooling and stirring. The reaction mixture was stirred for 10 minutes. The mixture was cooled to -10 ° C and 250 mg (28 mg) prepared in Example 28 (0.7 ml) in anhydrous Ν, Ν-dimethylformamide were added with stirring. The reaction mixture was stirred at the above temperature for 45 minutes and then poured into a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 2: 1 by volume mixture of hexane and ethyl acetate. 87 mg of the title compound 32 are obtained in the form of a colorless foam.

IR v ^ ^{a (cm-1):} 3300, 1800, 1760, 1660, 1530, 1260, 1080, 1035, 900 NMR (90MHz, CDC1 ₃₎ His: 3.59 (2H, s), 4 , 0 (1H, m), 5.25 (1H, s), 5.27 (1H, s), 6.1 (1H, b), 6.27 (1H, d, J = 6Hz), 22

7.3 (10H, s), 7.50 (0.5H, d, J = 6Hz), 7.57; 0.5H, d, J = 6Hz).

Mass spectrum m / e: 436 (M ⁺ ).

Example 33

Preparation of sodium 2 - [(4R) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 33) in ml of ethyl acetate and 5 ml of phosphate buffer ( (7.0), 68 mg (32) of Example 32 was dissolved. Palladium on carbon (70 mg, 10%) was added and the mixture was stirred under ice-cooling under a stream of hydrogen for 2 hours. The catalyst is filtered off and washed with water. The filtrate and the washings were combined and concentrated. The concentrate was chromatographed on an HP-20 column, lyophilizing the fractions eluted with 5% ethanol to give 41 mg of the title compound 33 as a white powder. IR (cm ^-1 ): 3400, 1775, 1720, 1650, 1530, 1370, 1185, 1110, 1020, 965, 900 NMR (90 MHz, D ₂ O) δ: 2.5-3.5 (4H, m), 3.83 (2H, s), 4.3-5.3 (3H, m),

7.53 (5H, s).

Example 34 Preparation of 1- (4-nitrobenzyl) -2-oxo-3-phenylthioglutarate (Compound 34) is suspended in dichloromethane (ml)

2.25 g of 3-bromo-2-oxoglutaric acid. To the suspension was added 1.0 ml of thiophenol under ice-cooling and stirring, followed by addition of 4.15 ml of triethylamine. The reaction mixture was stirred at room temperature for 45 minutes and then the solvent was evaporated. The residue was partitioned between ethyl acetate and 1 ^N hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.28 g of 2-oxo-3-phenyl-thioglutaric acid as a pale yellow oil. IR (cm- ¹ ): 3000 (b), 1720, 1470, 1440, 1400, 1280, 1200

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.87 (2H, d, J = 8Hz), 4.73 (1H, t, J = 8Hz),

7.40 (5H, s), 9.4 (2H, b).

To a solution of 2.28 g of the title compound in 18 ml of N, N-dimethylformamide is added 1.5 g of 4-nitrobenzyl bromide under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 15 hours and then diluted with ethyl acetate. The precipitated crystals are filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate = 1: 2 → 1: 3 (v / v).

2.25 g of the title compound (34) are obtained in the form of colorless prismic crystals, m.p. 119-120 ° C.

IR spectrum ν "(cm ^-1 ): 1745, 1730, 1700, 1520, 1440, 1350, 1280

-2 243

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.85 (2H, d, J = 8 Hz), 4.7 (1H, m), 5.43 (2H, s),

6.7 (1H, b), 7.35 (5H, s), 7.60 (2H, d, J = 9Hz) Elemental analysis for C ₁₈ H ₁₅ NO ₇ S:

Calculated: C, 55.52; H, 3.88; N, 3.60; Found: C, 55.49; H, 3.90; N, 3.50.

Example 35

Preparation of 4-Nitrobenzyl-2-chloro-3-phenylthio-5-oxo-2-tetrahydrofuranecarboxylate (Compound 35) Dissolve 145 ml in dichloromethane

Compound 34 prepared according to Example 34. To the solution was added 0.30 mL of thionyl chloride. The mixture was refluxed for 4 hours. The solvent was distilled off and the residue was purified by Florisilen column chromatography. Elution was carried out with a 3: 1 by volume mixture of hexane and ethyl acetate. 116 mg of the title compound 35 are obtained in the form of a colorless oil.

IR v ^ ^a (cm ^-1): 1825, 1770, 1525, 1350, 1290, 1090

NMR (90MHz, CDC1 ₈₎ δ: 2.71 (1H, dd, J = 3, 18Hz), 3.37 (1H, dd, J = 8, 18 Hz), 4.27 (1H, dd, J = 3.8 Hz). 5.37 (2H, ABq, J = 13, 22Hz), 7.35 (5H, m), 7.57 (2ft, d, J = 9Hz), 8.23 (2H, d, J = 9) Hz) Mass spectrum m / e: 407, 409 (M ⁺ ).

Example 36

4-Nitrobenzyl-2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl | Preparation of -5-oxo-3-phenylthio-2-tetrahydrofuran carboxylate (Compound 36)

177 mg of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone and 380 mg of 34 prepared in Example 34 are dissolved in 7.5 ml of dichloromethane. 210 mg of DCC was added to the solution and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined, washed with aqueous sodium bicarbonate solution, water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel, eluting with 5: 3 hexane: ethyl acetate. 185 mg of the title compound (36) are obtained in the form of a colorless oil. IR ν ^ ^α (cm ^-1): 3350, 1810, 1760, 1730, 1525, 1350, 1250, 1055

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.5 - 3.4 (2H, m), 4.1 (1H, m), 4.4 - 5.0 (3H, m), 5.10 (2H, s), 5.3 (1H, b), 5.35 (2H, s), 7.33 (5H, s), 7.5 (7H, m), 8.2 (2H, m).

EXAMPLE 36 Preparation of Compound 36 Dissolve 48 mg of (4S) -4-zyloxycarbonyl-amino-3-isoxazolidinone in dichloromethane. The solution was treated with 0.055 mL of triethylamine and 110 mg with ice-cooling and stirring

A solution of the compound (35) prepared in Example 35 in dichloromethane was added. The reaction mixture was stirred at room temperature for 30 minutes, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 3). 23 mg of the title compound (36) are obtained in the form of a colorless oil having the same IR and NMR spectra as in Example 36 (36).

Example 38

Preparation of Sodium 2 - [(4S) * 4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-3-phenylthio-2-tetrahydrofuranecarboxylate (Compound 38) Dissolve 70 mg of ethyl acetate in 3 ml of phosphate buffer, pH 7.0.

Compound 36 prepared according to Example 36. To the solution was added 140 mg of 10% palladium on carbon and the mixture was stirred at room temperature under a stream of hydrogen for 2.5 hours. The catalyst is filtered off and washed with water. The filtrate and the washings are combined. The aqueous phase was separated and concentrated. The concentrate was purified by chromatography on an HP-20 column. The fractions eluted with 30% ethanol were lyophilized to give 20 mg of the title compound (38) as a white powder. IR (cm ^-1 ): 1780, 1710, 1650, 1530, 1380, 1240

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 2.7-3.5 (2H, m), 3.7-5.3 (4H, m), 5.20 (2H, s),

7.5 (10H, b).

Example 39 Preparation of 1- (4-nitrobenzene) -3-ethylthio-2-oxoglutarate (Compound 39)

1.00 g of 3-bromo-2-oxoglutaric acid are suspended in 20 ml of dichloromethane. Ethane thiol (0.33 mL) followed by triethylamine (1.83 mL) was added to the suspension under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give 0.82 g of 3-ethylthio-2-oxoglutaric acid as a pale yellow oil.

IR v ^ ¹ (cm ^-1); 3000 (b), 1720, 1400, 1250

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 8Hz), 2.55 (2H, q, J = 8Hz), 3.0 (2H, b), δ , 4 (1H, b), 8.9 (2H, b).

0.82 g of the title compound is dissolved in 8 ml of N, N-dimethylformamide. Under ice-cooling and stirring, 0.65 ml of dicyclohexylamine and 0.70 g of 4-nitrobenzyl bromide are added. The reaction mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate. The precipitated crystals are filtered off. The residue is refined

The residue was purified by column chromatography on toluene (23197742) eluting with hexane: ethyl acetate (3: 2). 0.61 g of the title compound (39) is obtained in the form of colorless crystals. Recrystallization from isopropyl ether gave colorless prismic crystals, m.p. 100-101 ° C. .

IR (ν max (cm ^-1 ): 1745, 1720, 1700, 1530, 1350, 1255)

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.18 (3H, t, J = 8Hz), 2.48 (2H, q, J = 8Hz), 2.95 (2H, m), 4 , 3 (1H, b), 5.41 (2H, s), 7.0 (1H, b,), 7.57 (2H, d, J = 9Hz), 8.25 (2H, d, J) = 9 Hz)

Elemental analysis results for C _I4 H _I6 NO ₇ S:

Calc'd: C, 49.26; H, 4.43; N, 4.10%; Found: C, 49.32; H, 4.33; N, 3.99.

Example 40

Preparation of 4-Nitrobenzyl-2-chloro-3-ethylthio-5-oxo-2-tetrahydrofuranecarboxylate (Compound 40) In a solution of 1,2-dichloroethane (170 mg) was dissolved ). To the solution was added 0.30 mL of thionyl chloride. The mixture was refluxed for 3.5 hours. The solvent was evaporated and the residue was purified by column chromatography on Florisilen (Floridin Inc., USA), eluting with 3: 1 hexane: ethyl acetate. 79 mg of the title compound (40) are obtained in the form of a colorless oil.

IR v '^ ^a (cm ^-1): 1820, 1770,

1610, 1530, 1355, 1290, 1145, 1090 NMR (90MHz, CDC1 ₃₎ δ: 1.15 (3H, t, J = 7Hz), 2.7 (3H, m), 3.37 ( 1H, dd, J = 9, 18 Hz), 3.95 (1H, dd, J = 4 ₍ 9 Hz),

5.43 (2H, s), 7.60 (2H, d, J = 9Hz), 8.25 (2H, d, J = 9Hz).

Mass spectrum m / e: 359, 361 (M ⁺ ).

Example 41 Preparation of 1- (tert-Butyl) -2-oxoglutarate (Compound 41)

Dissolve 5.0 g in 100 ml of dichloromethane

5-oxo-2-tetrahydrofuran carboxylic acid. At -60 ° C, add 0.3 ml of concentrated sulfuric acid and then about 50 ml of isobutene. The reaction mixture was allowed to stand at room temperature overnight in a sealed vessel and then poured into cold aqueous sodium bicarbonate solution. The dichloromethane layer was separated, washed with water and dried over anhydrous sodium sulfate, then concentrated to give tert-butyl 5-oxo-2-tetrahydrofuran carboxylate as a colorless oil.

IR ^ν ζ _{^"β4 α} (cm ^-1): 1760

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl ₃ ) δ: 1.50 (9H, s), 2.4 (4H, m), 4.8 (1H, m).

The above compound was dissolved in 50 ml of anhydrous ethanol. Sodium methylate (100 mg) was added to the solution with ice-cooling and stirring. The reaction mixture was stirred under ice-cooling for 24 hours and then concentrated. The concentrate was poured into a mixture of ethyl acetate and aqueous ammonium chloride solution. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 8.2 g of 1- tert -butyl-5-methyl-2-hydroxy-glutarate as a residue in colorless crystalline form. The material was recrystallized to give colorless prism crystals, m.p. 36-37 ° C.

IR (cm ^-1 ): 3450, 1735, 1260, 1230, 1160, 1110

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.7-2.6 (4H, m), 2.87 (1H, d, J

3 = 5 Hz), 3.63 (3H, s), 4.1 (1H, m).

Elemental analysis results for C _I0 Hi ₈ O ₅ :

Found: C, 55.03; H, 8.31; Found: C, 54.60; H, 8.35.

Dissolve 0.39 g of oxalyl chloride in dichloromethane (ml). To the solution was added 0.60 mL of dimethyl sulfoxide in 4 mL of dichloromethane at -70 ° C under nitrogen, with stirring. To the mixture was added 0.95 of the above 1- (tert-butyl) -5-methyl-2-hydroxyglutarate,

Dissolved in 3.5 ml of dichloromethane. The reaction mixture was stirred at -70 ° C for 15 minutes and then triethylamine (3.0 mL) was added. The temperature of the reaction mixture was raised to -40 ° C, poured into ice water and extracted with dichloromethane. The extract was washed with water, dilute acid and water again and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 5: 1 by volume mixture of hexane and ethyl acetate. 0.60 g of 1-tert-butyl-5-methyl-2-oxoglutarate is obtained in the form of a pale yellow oil.

⁴⁰ IR (cm ^-1 ): 1730, 1370, 1295, 1260, 1200, 1160, 1080

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.57 (9H, s), 2.63 (2H, t, J = 6Hz), 3.10 (2H, s,

J = 6Hz), 3.69 (3H, s).

108 mg of the above compound are dissolved in a mixture of 1 ml of tetrahydrofuran and 1 ml of water. To the solution was added 0.4 ml of 1N sodium hydroxide solution with ice-cooling and stirring. The reaction mixture was stirred under ice-cooling for 45 minutes and then poured into a mixture of water and ethyl acetate. The aqueous phase was separated, adjusted to pH 4 with 1 N hydrochloric acid and extracted with ethyl acetate. The extract is aqueous salt.

solution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue purified by column chromatography on silica gel, eluting with hexane: ethyl acetate = 3: 2 → 1: 2 (v / v). 26 mg of the title compound (41) are obtained in colorless crystals, m.p. 76-77 ° C. IR (cm ^-1 ): 1740, 1700, 1280, 1250, 1160, 1080

NMR (90MHz, _CDCl3) δ: 1.55 ⁰⁵ (ΕΉ, m), 2.58 to 3.05 (4H, m), 8.10 (1H, bs).

-24197742

Example 42

Preparation of diphenylmethyl 2-oxoglutarate (Compound 42)

Starting from 2.93 g of 2-oxoglutaric acid, 4.75 g of diphenylmethyl bromide and 3.63 g of dicyclohexylamine, 3.2 g of the title compound 42 are obtained, following the procedure of Example 1 (a). m.p. 107-109 ° C.

IR ν «« (cm): 1730, 1710 NMR (60MHz, CDC1 ₃₎ δ: 2,58- 3,17 (4H, m), 6.99 (1H, s), 7, 31-7.54 (10 H, m)

Elemental analysis results for C ₁₈ H ₁₆ O ₅ :

Calculated: C, 69.22; H, 5.16; Found: C, 69.30; H, 5.18.

Example 43

Tablets are prepared the following compo- nensekből: Example 4 Compound (4) 300 mg cornstarch 50 mg lactose 28 mg hydroxypropylcellulose L 20 mg magnesium stearate _

400 mg per tablet Adults take 4-8 tablets daily, 3 times a day after meals

Example 44

A tablet is prepared from the following components:

Example 25 Compound 25 300 mg corn starch 50 mg lactose 28 mg hydroxypropyl cellulose L 20 mg magnesium stearate 2 mg 400 mg per tablet

Adults are given 4-8 tablets daily, after meals, 3 times daily.

Example 45

4-Nitrobenzyl-2 - [(4S) -4- (4-nitrobenzyloxycarbonylamino) -3-oxo-2-isoxazolidinyl] -5-oxo-3-ethylthio-2- Preparation of tetrahydrofuran carboxylate (Compound 45) (a) 140 mg of (4S) -4- (4-nitrobenzyloxycarbonylamino) -3-isoxazolidinone prepared in Reference Example 5 and 200 mg of Example 39. Prepared compound (39) was suspended in dichloromethane (6 ml). To the suspension was added 120 mg of DCC and the mixture was stirred at room temperature for 14 hours. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined, washed with aqueous sodium bicarbonate solution, water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 70 mg of the title compound are obtained in the form of a pale yellow oil.

IR vl ££ ^a (cm ^-1): 3330, 1805, 1750, 1625, 1520, 1350

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.15 (3H, t, J = 7Hz), 2.45-3.40 (3H, m), 4.0-5.0 (5H, m) ), 5.20 (2H, s), 5.37 (2H, s), 5.9 (1H, b), 7.55 (4H, m), 8.20 (4H, d, J = 7Hz) (b) 140 mg of (4S) -4- (4-nitrobenzyloxycarbonylamino) -3-isoxazolidinone prepared in Reference Example 5 and 200 mg of compound (39) obtained in Example 39 in 10 'dichloromethane. in methane. 160 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline were added to the suspension. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 165 mg of the title compound (45) are obtained in the form of a pale yellow oil. The IR and NMR spectra of the compound are identical to those of the compound prepared according to process (a) above.

Example 46

Sodium {(4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -3-ethylthio Preparation of -5-oxo-2-tetrahydrofuran carboxylate (Compound 46) In a mixture of 5 ml of ethyl acetate and 5 ml of phosphate buffer, pH 7.0, 60 mg of compound 45 obtained according to example 45 is dissolved. To the Kz solution was added 150 mg of 10% palladium on carbon and the mixture was stirred under ice-cooling under a stream of hydrogen for 4 hours. The catalyst is filtered off and washed with water. The filtrate and the washings were combined, the aqueous phase was separated and THF (3 mL) was added. Under ice-cooling and stirring, 30 mg of sodium bicarbonate and 40 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride are added. After stirring for 30 minutes, N-methyldithiocarbamate (30 mg) was added. The mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was evaporated under reduced pressure, the cone concentrate washed with ethyl acetate and purified by column chromatography on an HP-20 resin. The fraction eluted with 5% ethanol was lyophilized to give 8 mg of the title compound as a pale yellow powder.

IR (cm ^-1 ): 1780, 1720, 1660, 1530, 1380, 1030

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ Q) δ: 1.40 (3H, t, J = 7Hz), 2.7-3.9 (4H, m), 4.17 (3H, s),

4.4-5.5 (4H, m); 7.23 (1H, s).

Example 47 Preparation of 1-Diphenylmethyl-2-oxo-3-phenyl-thioglutarate (Compound 47)

-25197742

6.7 g of crude 2-oxo-3-phenylthioglutaric acid prepared in Example 4 are dissolved in 30 ml of N, N-dimethylformamide. Dicyclohexylamine (4.0 mL) and diphenylmethyl bromide (4.0 g) were added to the solution with stirring at room temperature. The reaction mixture was stirred at room temperature for 15 hours and then diluted with ethyl acetate. The precipitated crystals are filtered off and the filtrate is washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1 * 1: 1). 3.2 g of the title compound (47) are obtained in the form of pale yellow crystals. Recrystallization from ethyl acetate-hexane gave colorless needles, m.p. 98-100 ° C.

IR spectrum 1740, 1205, 1180

Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl ₃ ) δ: 2.85 (2H, d, J = 8Hz), 4.70 (1H, t, J = 8Hz), 7.05 (1H, s), δ , 3 (15H, m).

Example 48

Preparation of diphenylmethyl 2-chloro-3-phenylthio-5-tetrahydrofurancarboxylate (Compound 48)

0.5 g of compound 47 prepared according to example 47 is dissolved in 10 ml of 1,2-dichloroethane. To the solution was added 0.4 ml of thionyl chloride. The reaction mixture was refluxed for 2 hours. The solvent was evaporated and the residue was purified by Florisilen column chromatography. Elution was carried out with a 5: 1 by volume mixture of hexane and ethyl acetate. 0.30 g of the title compound (48) is obtained in the form of a colorless oil.

IR v ^ ^{a (cm-1):} 1820, 1760, 1380, 1080

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.70 (1H, dd, J = 3 and 18 Hz), 3.29 (1H, dd, J = 8 and 18 Hz), 4.20 (1H, dd) , J = 3 and 8Hz), 7.10 (10H, s), 7.4 (15H, m).

Example 49

Preparation of diphenylmethyl 2-chloro-5-oxo-2,5-dihydrofurancarboxylate (compound 49)

0.30 g of compound (48) obtained in Example 48 is dissolved in 10 ml of dichloromethane. To the solution was added 150 mg of 3-chloroperbenzoic acid. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was washed with aqueous sodium bicarbonate solution, then water, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dissolved in toluene (6 ml) and the solution was heated at 60 ° C for 30 minutes and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1). 0.15 g of the title compound (49) is obtained in the form of colorless crystals. Recrystallization from ethyl acetate-hexane gave 26 colorless needles, m.p. 99-101 ° C.

IR spectrum 1810, 1760, 1740,

1260

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ 6.27 (1H, d, J = 6Hz), 6.90 (1H, s), 7.33 (10H, s), 7.58 (1H, d, J = 6 Hz).

Example 50

Diphenylmethyl 2 - [(4S) -4-phenylacetamido-3-. -oxo-2-isoxazolidinyl] -5-oxo-3-phenylthio-2-tetrahydrofuran carboxylate (Compound 50) (a) 110 mg of (4S) -4-phenylacetamido-3-isoxazolidinone and 252 mg of the compound of Example 47 prepared in Example 47 are suspended in 10 ml of dichloromethane. 145 mg of DCC was added to the suspension. The mixture was stirred at room temperature for 2 hours. The precipitated crystals were filtered off and washed with dichloromethane. The filtrate and washings were combined, washed with aqueous sodium bicarbonate solution, then water, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1? 3: 2) to give 60 mg of the title compound (50) as a colorless oil. IR (cm @ ^-1 ). : 3330, 1810, 1750, 1670

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.4-3.3 (2H, m), 3.50 (1H, s), 3.53 (1H, s), 3.7-5.0 (4H, m), 6.2 (1H, m), 6.9 (0.5H, s), 7.0 (0.5H, s), 7.3 (20H, m).

(b) 110 mg (4S) -4-phenylacetamido-3-isoxazolidinone and 252 mg in 10 ml of dichloromethane

Compound (47) prepared according to Example 47 was suspended. 148 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline were added to the suspension. The reaction mixture was stirred at room temperature for 14 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1 + 3: 2). 45 mg of the title compound (50) are obtained in the form of a pale yellow oil having 1 H-NMR spectral data identical to that of the product of process (a).

Example 51

Preparation of diphenylmethyl 2 - [(4S) -4-phenylacetamido-2-isoxazolidinyl] -5-oxo-2,5-dihydro-2-furancarboxylate (Compound 51) (a) 35 mg. 4S) -4-Phenylacetamido-3-isoxazolidinone and 50 mg of diphenylmethyl 2-chloro-5-oxo-2,5-dihydro-2-furancarboxylate prepared in Example 49 in 2.5 mL of dichloromethane slurry and 0.025 ml of triethylamine are added to the suspension with ice-cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (26197742) eluting with hexane: ethyl acetate (1: 1). 56 mg of the title compound (51) are obtained in the form of colorless crystals. Recrystallization from dichloromethane / diethyl ether gave colorless prismic crystals, m.p. 168-169 ° C (with decomposition).

IR spectrum (cm -1): 3300, 1800, 1750,

1670, 1250 10

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.57 (2H, s), 3.9 (1H, m), 4.7 (2H, m), 6.0 (1H, m),

6.27 (1H, d, J = 6Hz), 6.90 (1H, bs), 7.3 (15H, s), 7.57 (1H, d, J = 6Hz).

(b) 60 mg (50) of Example 50 (50) is dissolved in 3 ml of dichloromethane. To the solution was added 20 mg of 3-chloroperbenzoic acid.

The reaction mixture was stirred at room temperature for 30 minutes. The mixture was washed with aqueous sodium bicarbonate then water, and dried over anhydrous sodium sulfate.

The solvent was evaporated and the residue was dissolved in toluene (1 mL). The solution was heated at 80 ° C for 30 minutes and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1). 21 mg of the title compound (51) are obtained in the form of colorless crystals having the same IR and NMR spectra as the product obtained according to process (a) above.

Example 52

4-Nitrobenzyl-2 - [(4S *, 5R *) - 4-benzyloxy]

Preparation of Carbonylamino-5-methoxycarbonyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarboxylate (Compound 52) Dissolve in dichloromethane (89 mg)

Prepared according to Reference Example 7 (4S *, 40)

5R *) -4-Benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone and 93 mg of 1- (4-nitrobenzyl) -2-oxo-glutarate. To the solution was added 68 mg of DCC and the mixture was stirred at room temperature for 30 minutes. The insoluble material was filtered off and washed with dichloromethane, and the filtrate and washings were combined and concentrated. The concentrate was purified by column chromatography on silica gel eluting with hexane: ethyl acetate = 2: 3 (50% v / v). 104 mg of the title compound are obtained in the form of a white foam.

IR (cm ^-1 ): 3320, 1805,

1770-1710, 1525, 1350, 1240, 1180, 1050 55

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.3 - 3.3 (4H, m), 3.75 (3H, s), 4.5 - 5.1 (2H, m), 5.10 (2H, s), 5.33 (2H, s), 5.94 (1H, d, J = 7Hz),

7.31 (5H, s), 7.49, 7.52 (both 1H, d,

J = 7 Hz), 8.17 (2H, s, J = 8 Hz). βθ

Example 53

Sodium 2 - ((4S *, 5R *) - 4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5-methoxycarbonyl-3 Preparation of -oxo-2-isoxazolidinyl-15H, 5-oxo-2-tetrahydrofuran carboxylate (Compound 53) In a mixture of mL of ethyl acetate and 3 mL of water, 104 mg of compound 52 obtained according to Example 52 was dissolved. Palladium on carbon (100 mg, 5%) was added to the solution, the mixture was stirred at room temperature under a hydrogen stream for 45 minutes, the catalyst was filtered and washed with water, the filtrate and washings were combined and the aqueous phase was added with 10 mL of THF. and 81 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride and aqueous sodium bicarbonate solution were added with stirring. At about 7.0, the reaction was run for 30 minutes and then 62 mg of sodium N-methyldithiocarbamate was added and The mixture was stirred at room temperature for 1 hour and the tetrahydrofuran was evaporated under reduced pressure. The concentrated solution was washed with diethyl 1-acetate and purified by column chromatography on XAD-2 resin. The fractions eluted with water and 5% ethanol were combined and lyophilized. 24 mg of the title compound are obtained. IR spectrum ν $ " _χ (cm ^-1 ): 1780, 1760-1730, 1665, 1530, '1040

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 2.3-3.3 (4H, m), 3.79, 3.82 (both, 1.5H, s), 3.S1 (3H, s) ), 4.9-5.6 (2H, m), 6.90 (1H, s).

Example 54

4-Nitrobenzyl-2 - [(4S *, 5S *) - 4-benzyloxycarbonylamino-5-methoxycarbonyl-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran- Preparation of Carboxylate (Compound 54): Dissolve 69 mg in dichloromethane

(4S *, 5S *) - 4-Oenzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone prepared in Reference Example 8 and 60 mg of 1- (4-nitrobenzyl; -2-oxo-glutarate) To the solution was added 71 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was allowed to stand for 18 hours, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with hexane / ethyl acetate. acetate 1:. 1 by volume mixture of (54) 114 mg of the title compound was obtained as a white foam: IR v ^l t% f ^{a (cm-1).} 3360, 1805,

1770-1720, 1525, 1350, 1240, 1180, 1060 NMR (90MHz, CDC1 ₃₎ δ: 2,3-

3.4 (4H, m), 3.63 (3H, s), 5.0-5.5 (2H, m), 5.09 (2H, s), 5.34 (2H, s), δ , 83, 6.02 (both 0.5H, d, J = 6Hz), 7.31 (5H, s), 7.50, 8.17 (both 2H, d, J = 9Hz).

Example 55

Sodium 2 - {(4S *, 5S *) - 4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5-methoxycarbonyl-3 -oxo-2-isoxazolidiryl) -5-oxo-2-tetrahydrofuran carboxylate (Compound 55)

114 mg (54) of the product of Example 54 (54)

Starting from -27197742, following the procedure of Example 53, 50 mg of the title compound (55) are obtained.

IR (cm ^-1 ): 1780, 1775, 1750, 1740, 1660, 1530, 1380, 1200, 1040 NMR (90 MHz, D ₂ O) δ: 2.3-3.3 (4H, m ), 3.68, 3.71 (both 1.5H, s),

3.93 (3H, s), 4.9-5.6 (2H, m), 6.92 (1H, s).

Example 56

4-Nitrobenzyl-2- (4-benzyloxycarbonylamino-5-carbamoyl-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuranecarboxylate [Compound 56] production

Dissolve 150 mg of 4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone in 2.4 ml of concentrated aqueous ammonia,

In the form of a mixture of 4,5-cis and trans derivatives. The solution was allowed to stand at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. Diethyl ether was added to the concentrate to give 138 mg of 4-benzyloxycarbonylamino-5-carbamoyl-3-isoxazolidinone in crystalline form. IR ^(cm): 3325, 1730-1670, 1530, 1260th

131 mg of the above compound and 131 mg of 1- (4-nitrobenzyl) -2-oxoglutarate are suspended in 10 ml of dichloromethane. To the slurry was added 141 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was vigorously stirred at room temperature for 2.5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography, eluting with ethyl acetate. 166 mg of the title compound (56) are obtained in the form of a colorless oil.

IR ^(cm-1): 3330, 1800,

1750 (shoulder), 1730-1680, 1525, 1350 NMR (90MHz, CDC1 ₃₎ δ: 2,3-

3.4 (4H, m), 4.5-5.2 (2H, m), 5.05 (2H, s), 5.34 (2H, s), 6.4-7.1 (3H, bs), 7.28 (5H, s),

7.3-8.3 (4 H, m).

Example 57

Sodium 2- {4- [2- (2-amino-4-thiazolyl- (Z) - (methoxyimino) acetamido] -5-carbamoyl-3-oxo-2-isoxazolidinyl-5-oxo-2- tetrahydrofuran carboxylate (Compound 57)

Starting from 166 mg of compound 56, following the procedure of Example 53, 64 mg of the title compound 57 are obtained in the form of a light brown powder.

IR (cm @ ^-1 ): 1780, 1690, 1650, 1490, 1200, 1040

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 2.3-3.3 (4H, m), 3.98 (3H, s), 4.9-5.5 (2H, m), δ 95, 7.00 (both 0.5H, s).

Example 58 Preparation of 1-Pivaloyloxymethyl-2-oxoglutarate (Compound 58) Dissolved in ml, Ν-dimethylformamide (ml)

2.93 g of 2-oxoglutaric acid and 3.48 ml of N, N-diisopropylethylamine. To the solution was added 3.13 g of sodium iodide and 3.02 ml of chloromethyl pivaloate. The mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate. The precipitated crystals are filtered off. The filtrate is concentrated to dryness under reduced pressure. Ethyl acetate was added to the concentrate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 1: 1 mixture of dichloromethane and ethyl acetate. 1.52 g of the title compound (58) are obtained in the form of an oil.

IR ν '^ ^α (cm ^-1): 2970, 1750, 1710, NMR (90MHz, CDC1 ₃₎ 6: 1.24 (9H, s), 2.67 to 3.19' (4H , m), 5.89 (2H, s).

Example 59

Preparation of Pivaloyloxymethyl 2- [5-phenyl-4- (2-methyleneacetamido) -3-oxo-2-isoxazole idinite] -5-oxo-2-tetrahydrofuran carboxylate (Compound 59)

100 mg of 5-phenyl-4- (2-thienylacetamido) -3-isoxazolitinone prepared in Reference Example 9 and 127 mg of compound 58 were treated as described in Example 2 to give 129 mg of the title compound 59, a colorless foam. form.

IR (cm ^-1 ): 3300, 1800, 1780, 1750, 1655

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.20 (9H, s), 2.33-3.20 (4H, m), 3.20 (1H, s), 3 23 (1H, s) , 5.66-5.96 (3H, m), 6.50-6.63 (1H, m), 6.73-7.00 (1H, m), 7.03-7.43 (6H, m).

MS m / e 545 (M ⁺ 1).

Example 60

Preparation of Pivaloyloxymethyl 2- [5-phenyl-4- (2-phenylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate (Compound 60)

330 mg of 5-phenyl-4- (2-phenylacetamido) -3-isoxazolidinone prepared in Reference Example 10 and 435 mg of compound (58)

Following the procedure of Example 2, 320 mg of the title compound 60 are obtained in the form of a light brown foam.

IR spectrum ν 211 (cm ^-1 ): 1800, 1740, 1650-1660.

? N 4R-NMR (90MHz, _CDCl3) δ: 1.15 (9H, s), 2.30-3.00 (4H, m), 3.27, 3.30; 3.45, 3.51 (2H, each s), 5.21-5.39 (1H, m), 5.69-5.81 (2H, m), 6.69-7.00 (1H, m), 7.03-7.36 (10H, m)

Mass spectrum m / e: 539 (M ⁺ +1).

Example 61

Dimethylphenyl 2- {4- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5-phenyl-3-oxo-2-isoxazolidinyl ) -5-oxo-2-tetrahydrofuran carboxylate (Compound 61)

220 mg of 4- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-1 methoxyimino) acetamido] -5-phenyl-3-isoxa-28197742 zolidinone prepared in Reference Example 11; From 215 mg of compound (42) a

Example 2 gave 170 mg of the title compound 61 as a colorless foam.

IR (cm ^-1 ): 3300, 2930, 1800, δ

1730, 1690, 1620, 1450, 695

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.33-

2.83 (4H, m), 4.00 (3H, s), 4.19 (2H, bs),

6.96, 7.00 (1H, both s), 7.21-7.33 (15H, m), 7.73 (1H, s). 10

Example 62 Preparation of 1- (4-Nitrobenzyl) -4-phenyl-2-oxoglutarate (Compound 62) was dissolved in Ν, Ν-dimethylformamide (ml).

4.26 g of 4-phenyl-2-oxoglutaric acid. Dicyclohexylamine (2.67 ml) and 4-nitrobenzyl bromide (2.9 g) were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and the precipitated crystals were collected by filtration. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was chromatographed on silica gel. Elution is carried out with a 2: 1 → 1: 1 by volume mixture of hexane and ethyl acetate.

2.89 g of the title compound (62) are obtained in the form of pale yellow crystals. Recrystallization from ethyl acetate-hexane gave pale yellow prismic crystals, m.p. 149-150 ° C.

IR (cm ^-1 ): 1760, 170, 1710,

1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.5-

4.5 (3H, m), 5.40 (2H, s), 7.30 (5H, s), 7.68 35 (2H, d, J = 9Hz), 8.24 (2H, d, J = 9 Hz).

Example 63

Preparation of 4-Nitrobenzyl-2-chloro-4-phenyl-5-oxo-2-tetrahydrofuranecarboxylate (Compound 63) 40 ml of 1,2-dichloroethane were dissolved in 100 mg of the compound prepared in Example 62 (62). compound.

To the solution was added 0.1 ml of thionyl chloride and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was chromatographed on Florisil, eluting with a 2: 1 by volume mixture of hexane and ethyl acetate. 63 mg of the title compound are obtained in the form of a pale yellow crystalline solid.

IR v '^ ^a (cm ^-1): 1820, 1760, 1610 NMR (90MHz, CDC1 ₃₎ delta: 3.08 (1H, dd, J = 14 and 22 Hz), 3.20 ( 1H, dd, J = 8 and 22Hz), 4.33 (1Ή, dd, J = 8 and 14Hz), 5.44 55 (2H, s), 7.34 (5H, m), 7.57 ( 2H, d, J = 9Hz),

8.25 (2H, d, J = 9Hz).

Example 64

4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -4-phenyl-5-oxo-2-tetrahydrofuranecarboxylate [( Compound 64]

A mixture of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone (220 mg) in dichloromethane (20 mL) was dissolved in compound (62) (400 mg). To the solution was added 250 mg of DCC dissolved in 5 ml of dichloromethane. The mixture was stirred at room temperature for 2.5 hours. The precipitated crystals were filtered off and the filtrate was washed with aqueous sodium bicarbonate followed by water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel eluting with hexane: ethyl acetate (3: 1 to 2: 1). 325 mg of the title compound 64 are obtained in the form of a pale yellow oil. IR Spectrum? (cm ^-1 ): 1790, 1700—

1780, 1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.3—

5.1 (4H, m), 5.37 (2H, m), 7.33 (10H, s),

7.52 (2H, db, J = 10 Hz), 8.18, 8.20 (2H, both d, J = 10 Hz)

Mass Spectrum m / e 575 (M ⁺ ).

Example 65 Preparation of Compound 64

280 mg of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone is suspended in 6 ml of dichloromethane. The suspension was treated with 0.36 ml of triethylamine and 490 mg under ice-cooling and stirring

A solution of compound (63) prepared in Example 63 in dichloromethane was added. The reaction mixture was stirred at room temperature for 30 minutes, then washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel, eluting with 3: 1 hexane: ethyl acetate. 470 mg of the title compound 64 are obtained in the form of a colorless oil. The IR and NMR data of this product are consistent with the corresponding data for Example 64, prepared according to Example 64.

Example 66

Sodium 2 - [(4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl-4-phenyl Preparation of -5-oxo-2-tetra-tetrahydrofuran carboxylate (Compound 66): In a mixture of mL of ethyl acetate and 15 mL of phosphate buffer, pH 7.0, 432 mg of compound 65 obtained in Example 65 is dissolved in 400 mg. After addition of a palladium-on-carbon catalyst, the solution was stirred under a stream of hydrogen under ice-cooling for 1.5 hours. (2-Chloroacetamido-4-thiazolyl) - (Z) -methoxyiminoacetyl chloride hydrochloride (266 mg) was added to the mixture under ice-cooling and stirred for 30 minutes under ice-cooling. The tetrahydrofuran is evaporated and the aqueous phase is washed with ethyl acetate. of tetrahydrofuran (17 ml) and sodium N-methylthiocarbamate ( ¹⁷ mg) were added at room temperature for 30 minutes.

-29197742 stir. The tetrahydrofuran was evaporated under reduced pressure. The concentrate was washed with ethyl acetate and purified by column chromatography on an HP-20 resin. The fractions eluted with water / ethanol (5: 1) were lyophilized to give 220 mg of the title compound (66).

IR spectrum ν £ (cm -1): 1780, 1720, 1650 NMR (90 MHz, D ₂ O) δ: 2.3-4.0 (3H, m), 4.23 (3H, s) ), 4.5-5.5 (3H, m),

7.26 (1H, s).

Example 67 Preparation of 1- (4-nitrobenzyl) -3,3-dimethyl-2-oxoglutarate (Compound 67) was dissolved in 0.43 M aqueous sodium hydroxide solution. 57 g of 3,3-dimethyl-4-oxopentanoic acid. Under ice-cooling and stirring, 20 ml of a 1.15 M aqueous potassium permanganate solution are added. After stirring for 4 hours under ice-cooling, aqueous sodium bisulfite solution was added. The precipitate was filtered off. The filtrate was adjusted to pH 1 with 6N hydrochloric acid and then ethyl acetate. extracted. The extract was washed with water and dried, and the solvent was evaporated. 1.73 g of 3,3-dimethyl-2-oxoglutaric acid are obtained in the form of a colorless oil.

The resulting oil was dissolved in N, N-dimethylformamide (15 mL). To the solution was added dicyclohexylamine (1.08 mL) and 4-nitrobenzyl bromide (1.18 g). The mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and the precipitated crystals were filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on silica gel. Elution was carried out with a 2: 1 by volume mixture of hexane and ethyl acetate. 1.30 g of the title compound (67) are obtained in the form of colorless crystals. The material was recrystallized from ethyl acetate to give colorless prismic crystals, m.p. 134-135 ° C.

IR spectrum ν max (cm ^-1 ): 1750, 1600 NMR (90 MHz, d ₆ -DMSO) δ: 1.10 (6H, s), 2.4-2.6 (2H, b), δ , 37 (2H, s), 7.68 (2H, d, J = 9Hz), 8.25 (2H, d, J = 9Hz).

Example 68

4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -3,3-dimethyl-5-oxo-2-tetrahydrofuran carboxylate [(68) Preparation of Compound (67): Dissolve (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone (436 mg) in dichloromethane (ml) and compound (67) obtained in Example 67 (600 mg). A solution of DCC (495 mg) in dichloromethane (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The precipitated crystals are filtered off and the filtrate is concentrated. The precipitated crystals were filtered off and the filtrate was diluted with ethyl acetate. The solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a silica gel column, eluting with a mixture of hexane and ethyl acetate. 133 mg of the title compound (68) are obtained in the form of a colorless oil. IR ^(cm-1): 1820, 1720, 1620 NMR (90MHz, CDC1 ₃₎ δ: 1.06 (3H, s), 1.40 (3H, s), 2.46 (1H, d, J = 18Hz), 2.64 (1H, d, J = 18Hz), 5.14 (2H, s), 5.29 (1H, d, J = 14Hz), 5.36 (1H , d, J = 14 Hz),

7.37 (5H, s), 7.54 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz)

Mass spectrum m / e: 527 (M ⁺ ).

Example 69

Sodium 2 - {(4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamethyl] -3-oxo-2-isoxazolidinyl-3, Preparation of 3-dimethyl-5-oxo-2-tetrahydrofuran carboxylate (Compound 69)

In a mixture of 4.5 ml of ethyl acetate and 6.5 ml of phosphate buffer solution, pH 7.0, 187 mg of the compound of Example 68 (68) is dissolved. Palladium on carbon (190 mg, 10%) was added to the solution and the mixture was stirred under a stream of hydrogen for 1.5 hours. The catalyst is filtered off and washed with water. The filtrate and washings were combined and the aqueous phase separated. 6.5 ml of tetrahydrofuran and 85 mg of sodium bicarbonate are added. To the mixture was added 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride (126 mg) with stirring and ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and the tetrahydrofuran was evaporated. The aqueous phase is washed with ethyl acetate, 6.5 ml of tetrahydrofuran and then 82 mg of sodium N-methyldithiocarbamate are added. The mixture was stirred at room temperature for 30 minutes. The tetrahydrofuran was evaporated and the concentrate was washed with ethyl acetate and purified by column chromatography on an HP-20 resin. The fractions eluted with water / ethanol (20: 1) were lyophilized to give 15 mg of the title compound (69) as a white powder.

IR (cm ^-1 ): 1770 (b), 1650 NMR (90 MHz, D ₂ O) δ: 1.40 (3H,

s), 1.64 (3H, s), 2.5-3.5 (2H, m), 4.20 (3H,

s), 4.5-5.5 (3H, m), 7.23 (1H, s). Mass spectrum m / e: 464 (M ⁺ +1).

Example 70 Preparation of 1- (4-nitrobenzyl) -3- (2-acetamidoethylthio) -2-oxoglutarate (Compound 70)

1.0 g of 3-bromo-2-oxoglutaric acid is suspended in 20 ml of dichloromethane. The suspension was stirred under ice-cooling and 0.5 g

Acetamidoethane thiol (2) was added followed by triethylamine (1.83 mL). The reaction mixture was stirred at room temperature for 1 hour and then the solvent was evaporated. Ethyl acetate and water were added to the residue. The aqueous phase was separated, adjusted to pH 1-2 with 1 N hydrochloric acid and extracted with ethyl acetate. The

The extract -30197742 was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 0.67 g of 3- (2-acetamidoethylthio) -2-oxoglutaric acid as a pale yellow oil.

Under stirring and ice-cooling, 0.32 ml of dicyclohexylamine and 0.34 g of 4-nitrobenzyl bromide were added thereto. The reaction mixture was stirred at room temperature for 15 hours and then diluted with ethyl acetate. The precipitated Crystals are filtered off and the filtrate is washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / acetic acid = 100: 3). 0.4 g of the title compound (70) is obtained in the form of a pale yellow oil.

IR viral £ $ 5 ° C (cm ^-1): 3350, 1730 (b), 1640 (b), 1525, 1375, 1350, 1250 NMR (90MHz, CDC1 ₃₎ 6: 1.95 ( 3H, s), 2.67 (2H, t, J = 6Hz), 2.9 (2H, b),

3.43 (2H, dd, J = 6, 12 Hz), 4.3 (1H, b), 5.43 (2H, s), 6.2 (1H, b), 7.58 (2H, d) , J = 9 Hz),

8.27 (2H, d, J = 9Hz).

Example 71

4-Nitrobenzyl 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -3- (2-acetamidoethylthio) -5-oxo-2-tetrahydrofuran carboxylate [ Preparation of compound (71)] in dichloromethane (ml) 48 mg of (4S) -4-phenylacetamido-3-isoxazolidinone and 95 mg of compound (70) prepared in Example 70 are suspended. To the suspension was added 71 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. The mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography, eluting with ethyl acetate. 75 mg of the title compound are obtained in the form of a colorless oil. IR ν ^ ^α (cm ^-1): 3300, 1800, 1750, 1650, 1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.93 (3H, s), 3.04 (2H, t, J = 7Hz), 3.40 (2H, t, J = 7Hz), δ , 5-5.4 (10H, m), 6.4 (1H, b),

7.28 (5H, s), 7.50 (2H, d, J = 9Hz), 8.0-8.3 (2H, m).

Mass spectrum m / e: 600 (M ⁺ ).

Example 72

Sodium 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -3- (2-acetamidoethylthio) -5-oxo-2-tetrahydrofuran carboxylate [Compound 72 ] A mixture of mL (71) of Example 71 (168 mg) was dissolved in a mixture of mL of ethyl acetate and 4 mL of phosphate buffer, pH 7.0. To the solution was added 170 mg of 10% palladium-on-carbon palladium on carbon and the mixture was stirred under a stream of hydrogen under ice-cooling for 1.5 hours and then at room temperature for 0.5 hours. The catalyst is filtered off and washed with water. The filtrate and washings were combined, the aqueous phase separated and concentrated under reduced pressure. The concentrate was purified by column chromatography on an HP-20 resin, eluting with a 10: 1 mixture of water and ethanol. The resulting fractions were lyophilized to give 40 mg of the title compound (72) as a white powder.

IR & £ v (cm ^-1): 1780, 1720, 1650 NMR (90 MHz, D ₂ O) δ: 2.23 (3H, ski, 2.8-3.8 (6H, m) , 3.91 (2H, s), 4.0-5.4 (4H, m), 7.60 (5H, s).

Example 73 Preparation of 1- (4-nitrobenzyl) -4-benzyl-2-oxoglutarate (Compound 73)

To a solution of 0.98 ml of diisopropylamine in 13 ml of anhydrous tetrahydrofuran is added 4.29 ml of a 1.5 M solution of n-butyllithium in hexane under nitrogen atmosphere at -78 ° C with stirring. After stirring for 15 minutes, dimethyl 2-oxoglutarate dimethylacetal (1.18 g) in anhydrous tetrahydrofuran (7 ml) was added over 5 minutes, and the mixture was stirred for 15 minutes. A solution of benzyl bromide (0.76 ml) and hexamethylphosphoramide (0.28 ml) in dry tetrahydrofuran (7 ml) was added over 5 minutes. The reaction mixture was stirred at -78 ° C for 30 minutes. The temperature of the mixture was raised to -20 ° C over 2 hours with stirring, then an aqueous saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1 → 2: 1). 1.64 g of dimethyl 4-benzyl-2-oxoglutarate dimethylacetal are obtained in the form of a pale yellow oil.

IR (cm ^-1 ): 1740, 1600 NMR (90 MHz, CDCl ₃ ) δ: 2.2-3.0 (5H, m), 3.07 (3H, s), 3.17 ( 3H, s), 3.57 (3H, s), 3.68 (3H, s), 7.0-7.4 (5H, m).

The above product is dissolved in 10 ml of methanol, 15 ml of a 3.5 M aqueous potassium hydroxide solution are added and the mixture is stirred at room temperature for 3.5 hours and then the methanol is evaporated. The reaction mixture was adjusted to pH 1 with 6N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 1.43 g of 4-benzyl-2-oxoglutaric acid dimethylacetal are obtained as a yellow oil.

The oily product was dissolved in tetrahydrofuran (40 mL). To the solution was added 40 ml of 1 N hydrochloric acid and the mixture was stirred for 30 minutes. The tetrahydrofuran was evaporated and the aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with brine and then with water.

Dry over sodium sulfate. The solvent was evaporated to give 1.40 g of 4-benzyl-2-oxoglutaric acid as a yellow oil.

The resulting oil was dissolved in 10 ml of N, N-dimethylformamide. To the solution was added dicyclohexylamine (0.83 mL) and 4-nitrobenzyl bromide (0.90 g). The mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture. The precipitated crystals are filtered off, the filtrate is washed with water and dried over anhydrous magnesium sulfate, and the solvent is evaporated. The residue was purified by column chromatography on silica gel, eluting with 2: 1 hexane: ethyl acetate. 1.35 g of the title compound 73 are obtained in the form of a colorless oil.

IR spectrum? (cm ^-1 ): 3700-3200,

3150-3000, 1760 (b), 1600 NMR (90MHz, CDC1 ₃₎ δ: 2,5-

3.4 (5H, m), 5.30 (2H, s), 7.0-7.4 (5H, m), 7.45 (2H, d, J = 9Hz), 8.18 (2H) , d, J = 9 Hz) Mass spectrum m / e: 371 (M ⁺ ).

Example 74

Preparation of 4-Nitrobenzyl-4-benzyl-2-chloro-5-oxo-2-tetrahydrofuranecarboxylate (Compound 74) In 1,2-dichloroethane (ml) was dissolved 475 mg of compound 73 prepared according to Example 73. . The solution is refluxed for 5 hours · The solvent is evaporated and the residue is purified by Florisilen column chromatography eluting with 5: 1 hexane: ethyl acetate. 370 mg of the title compound (74) are obtained in the form of a pale yellow oil. IR v ^ ^a (cm ^-1): 1810, 1760,

1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.3-3.6 (5H, m), 5.37 (2H, s), 7.0-7.5 (5H, m),

7.52 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz) Mass spectrum m / e: 389.391 (M ⁺ ).

Example 75

4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -4-benzyl-5-oxo-2-tetrahydrofuranecarboxylate (Compound 75) ] (286 mg) of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone and 540 mg of compound 73 obtained in Example 73 are dissolved in dichloromethane. To the solution was added 325 mg of DCC dissolved in 2 ml of dichloromethane and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, the precipitated crystals were filtered off, the filtrate was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel, eluting with 2: 1 hexane: ethyl acetate. 553 mg of the title compound (75) are obtained in the form of a pale yellow oil.

V'iSÍÍ ^one IR (cm ^-1): 1790, 1780-1700, 1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.6-

3.5 (5H, m), 3.9-4.3 (1H, m), 4.4-4.9 (2H, m), 5.10 (2H, s), 5.27 (2H, s), 5.36 (1H, b), 7.0-7.6 (12H, m).

Mass spectrum m / e: 589 (M ⁺ ).

Example 76 Preparation of compound (75): Dissolve (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone (55 mg) in triethylamine (0.07 ml) in dichloromethane. To the solution was added 100 mg of the compound prepared in Example 74 (100 mg) under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes and then ethyl acetate (25 mL) was added. The mixture was washed with water, aqueous sodium bicarbonate solution and water again, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1). 70 mg of the title compound (75) are obtained in the form of a pale yellow oil. The IR and NMR spectra of the product were identical to those of compound 75 prepared according to Example 75.

Example 77

Sodium 2-j (4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl Preparation of 4-Benzyl-5-oxo-2-tetrahydrofuranecarboxylate (Compound 77) In a mixture of ml of ethyl acetate and 12 ml of phosphate buffer, pH 7.0, 318 mg of compound 75 obtained in Example 75 is dissolved. . To the solution was added 318 mg of 10% palladium on carbon and the mixture was stirred under a stream of hydrogen under ice-cooling for 1.5 hours. The catalyst was filtered off and the filtrate was washed with ethyl acetate. 12 ml of tetrahydrofuran and 130 mg of sodium bicarbonate are added to the aqueous phase. 2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride (191 mg) was added under ice-cooling and stirring. The mixture was stirred under ice-cooling for 30 minutes. The tetrahydrofuran was distilled off and the aqueous layer was washed with ethyl acetate. 12 ml of tetrahydrofuran and 125 mg of sodium N-methyldithiocarbamate are added to the aqueous phase. The mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was evaporated under reduced pressure, the concentrate was washed with ethyl acetate and purified by column chromatography on an HP-20 resin. The fractions eluted with water / ethanol (5: 1) were lyophilized to give 110 mg of the title compound (77) as a white powder.

IR (cm ^-1 ): 1780, 1730, 1650 NMR (90 MHz, D ₂ O) δ: 2.6-3.8

-32197742 (5Η, m), 4.18 (3H, s), 4.2-5.1 (2H, m),

5.4 (1H, m), 7.21 (1H, s), 7.57 (5H, s).

Example 78 Preparation of 1- (4-Nitrobenzyl) -4-methoxymethyl-2-oxo-glycol (Compound 78)

12.5 ml of a solution of 2.85 ml of diisopropylamine in 30 ml of anhydrous tetrahydrofuran

A 1.5 M solution of n-butyllithium in hexane was added at -78 ° C under a nitrogen atmosphere. The mixture was stirred for 15 minutes. To the solution was added 3.45 g of dimethyl 2-oxoglutarate dimethylacetal dissolved in 15 ml of anhydrous tetrahydrofuran for 10 minutes. under. After stirring for 15 minutes, 1.32 ml of chloromethyl methyl ether and 1.36 ml of hexamethylphosphoramide, dissolved in anhydrous tetrahydrofuran, were added over 10 minutes. The temperature of the reaction mixture was raised to -20 ° C over 30 minutes and stirred at the above temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (2: 1). 2.28 g of dimethyl 4-methoxymethyl-2-oxoglutarate dimethylacetal are obtained in the form of a pale yellow oil.

IR v '^ ^a (cm ^-1): 1750

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.02 (1H, dd, J = 5, 15 Hz), 2.35 (1H, dd, J = 9, 15 Hz), 2.75 (1H, m), 3.23 (6H, s), 3.28 (3H, s), 3.44 (1H, dd, J = 5Hz), 3.46 (1H, d, J = 6Hz), 3 , 67 (3H, s), 3.77 (3H, s).

To a solution of the above compound (560 mg) in methanol (4 mL) was added potassium hydroxide solution (1.8 mL, 1.8 M). The mixture was stirred at room temperature for 3 hours. The methanol was evaporated and the aqueous phase was washed with ether, adjusted to pH 1 with 6N hydrochloric acid and saturated with sodium chloride, and then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 471 mg of 4-methoxymethyl-2-oxoglutaric acid dimethibacetal as a yellow oil.

The product was dissolved in tetrahydrofuran (10 mL), 1N hydrochloric acid (10 mL) was added and the mixture was stirred at room temperature for 4 days. The tetrahydrofuran was evaporated and the aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 397 mg of 4-methoxymethyl-2-oxoglutaric acid as a colorless oil.

355 mg of the above oil product are dissolved in 3 ml of N, N-dimethylformamide. To the solution were added 0.30 ml of dicyclohexylamine and 323 mg of 4-nitro64

Benzyl bromide was added and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture. The precipitated crystals are filtered off, the filtrate is washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 2: 1 by volume mixture of hexane and ethyl acetate. 293 mg of the title compound (78) are obtained as a yellow oil.

IR spectrum δ Si (cm ^-1 ): 1750 (b), 1600 NMR (90 MHz, CDCl ₃ ) δ: 3.05 (3H, m), 3.48 (3H, s), 3.6-. 3.9 (2H, m), 5.37 (2H, s), 7.52 (2H, d, J = 9Hz), 8.21 (2H, d, J = 8Hz).

Example 79

Preparation of 4-nitrobenzyl (2-chloro-4-methoxymethyl-5-oxo-2-tetrahydrofuranecarboxylate (Compound 79))

340 mg of Example 78 (78) was dissolved in 14 ml of 1,2-dichloroethane. Thionyl chloride (0.34 mL) was added and the mixture was refluxed for 5 hours. The solvent was evaporated and the residue was purified by Florisilene column chromatography eluting with 5: 1 hexane: ethyl acetate. 152 mg of the title compound (79) are obtained in the form of a colorless oil.

IR spectra (cm ^-1): 1810, 1760 NMR (90MHz, CDC1 ₃₎ 6: 2,8-

3.4 (3H, m), 3.28 (3H, s), 3.7 (2H, m), 5.40 (2H, s), 7.57 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz).

Example 80

4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -4-methoxymethyl-5-oxo-2-tetrahydrofuranecarboxylate [ Preparation of Compound 80] Dissolve 121 mg of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone in 200 ml of dichloromethane and 200 mg of compound 78 prepared in Example 78. To the solution was added 137 mg of DCC dissolved in 1 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours and then ethyl acetate was added. The precipitated crystals are filtered off, the filtrate is washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (2: 1 hexane: ethyl acetate). 216 mg of the title compound 80 are obtained in the form of a pale yellow oil.

IR spectrum (cm ^-1 ): 1790, 1770—

1700, 1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.4 - 2.8 (2H, m), 3.0 - 3.4 (4H, m), 3.5 - 3.7 (2H, m) , 3.0-4.4 (1H, m), 4.5-4.9 (2H, m), 5.10 (2H, s), 5.34 (2H, s), 5.5 (1H , b), 7.33 (5H, s), 7.50 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz).

-33197742

Example 81 Preparation of Compound 80 mg (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone is suspended in 2 ml of dichloromethane. To the suspension was 0.12 ml of triethylamine and 152 mg under ice-cooling and stirring

A solution of the compound (79) prepared in Example 79 in dichloromethane (1 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with 2: 1 hexane: ethyl acetate. 175 mg of the title compound 80 are obtained having the same IR and NMR spectra

With the appropriate spectra of the compound of Example 80 (80).

Example 82

Sodium 2-y (4S) -4-] 2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl) -4- Preparation of methoxymethyl 5-oxo-2-tetrahydrofuran carboxylate (Compound 82) In a mixture of mL of ethyl acetate and 7 mL of phosphate buffer, pH 7.0, 216 mg of compound 80 obtained according to Example 80 was dissolved. To the solution was added 216 mg of 10% palladium on carbon and the mixture was stirred under ice-cooling under a stream of hydrogen for 1.5 hours. The catalyst is filtered off and washed with water. The filtrate and washings were combined, the aqueous phase was separated, and tetrahydrofuran (9 mL) and sodium bicarbonate (95 mg) were added. 2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride (141 mg) was added under ice-cooling and stirring, and the reaction mixture was stirred under ice-cooling for 30 minutes. After stirring, the tetrahydrofuran was evaporated and the aqueous phase was washed with ethyl acetate. To the aqueous phase was added tetrahydrofuran (9 mL) and sodium N-methyldithiocarbamate (93 mg), and the mixture was stirred at room temperature for 30 minutes. The tetrahydrofuran was evaporated under reduced pressure. The resulting concentrate was washed with ethyl acetate and purified by chromatography on HP-20 resin. Elution was carried out with a mixture of water and ethanol (100: 5 by volume). The eluted fractions were lyophilized to give 140 mg of the title compound 82 as a white powder.

IR (cm ^-1 ): 1780, 1720, 1660 NMR (90 MHz, D ₂ O) δ: 2.6-3.5 (3H, m), 3.54, 3.55 (3H total) , each s)

3.8-4.2 (2H, m), 4.19 (3H, s), 4.4-5.6 (3H, m), 7.23 (1H, s).

Example 83

Preparation of 5-Phenylamino-4,5-dioxopentanoic acid (Compound 83)

To a solution of 1.46 g of 2-oxoglutaric acid in 20 ml of acetonitrile was added 2.06 g of DCC and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 930 mg of aniline and stirred at room temperature for 5 hours. The resulting white precipitate was filtered off. To the filtrate was added ethyl acetate (40 mL) and extracted with aqueous sodium bicarbonate (30 mL). The pH of the extract was adjusted to 3.0 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 2).

390 mg of the title compound 83 are obtained in the form of colorless crystals, m.p. 92-193 ° C.

IR spectrum:? (cm ^-1 ): 3340, 1700, 1690, 1600, 1540, 1450, 1320

NMR (90MHz, CDCl ₃ -d ₆ -DMSO) δ: 2.42 to 2.70 (2H, m), 2.90 to 3.32 (2H, m), ^'7, 01-7, 90 (5 H, m).

Example 84

Preparation of 5-pyrrolidyl-4,5-dioxopentanoic acid (Compound 84)

Starting from 584 mg of 2-oxoglutaric acid and 284 mg of pyrroidine, as described in Example 83, 412 mg of the title compound 84 are obtained in the form of colorless crystals, m.p. 101-102 ° C.

IR (cm ^-1 ): 2970, 1730, 1710, 1600, 1390, 1330, 1210, 1170 Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.81 -

2.06 (4H, m), 2.65-2.84 (2H, m), 3.08-3.27 (2H, m), 3.43-3.80 (4H, m), δ, 60-9.01 (1H, m).

Example 85

Preparation of 5- (n-Propyl) amino-4,5-dioxopentanoic acid (Compound 85)

Starting from 1.46 g of 2-oxoglutaric acid and 0.828 ml of n-propylamine, the title compound (85) is obtained in the form of pale yellow crystals (496 mg), m.p. 79-81 ° C. IR spectra (cm ^-1 ): 3250, 2960, 1730, 1690, 1660, 1530, 1440, 1400 NMR (90 MHz, CDCl ₃ ) δ: 0.81 -

1.19 (3H, t, J = 6Hz), 1.36-1.75 (2H, m),

2.58-2.72 (2H, m), 3.12-3.34 (4H, m), 6.79-7.03 (1H, m), 7.91-8.37 (1H, m) ).

Example 86. Preparation of N-Phenyl-2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-tetrahydrofuran-2-carboxamide (Compound 86) was dissolved in acetonitrile (400 mL). mg

5Q (4S) -4-Benzyloxycarbonylamino-3-isoxazolidinone, prepared according to Reference Example 4, and 372 mg of compound (83). To the solution was added 416 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure agent ^ö

-34197742 and the residue was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (1: 1). 124 mg of the title compound (96) are obtained in the form of colorless crystals. IR v ^ _x ^(cm-1): 3320, 1800, 1730, 1690, 1530, 1250, 1180, 1050

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl3) δ: 2,373.54 (4H, m), 4.01-4.29 (1Η, m), 4.52-4.79 (2H, m), 5.10 (2H, s), 5.51-5.70 (1H, m), 7.09-7.60 (10H, m), 8.31-8.44 (1H, m).

Example 87 Preparation of 1- {2 - [(4S) -4-Benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuranecarbonyl} pyrrolidine (Compound 37)

Starting from 400 mg of (4S) -4-benzyloxycarbonylamino-3-isoxazolidinone and 335 mg of compound 84 as described in Example 86, 72 mg of the title compound 87 are obtained in the form of a colorless oil. IR spectrum v'1%? (cm -1): 3320, 1800, 1730, 1640, 1530, 1250, 1180, 1020

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.62 - 2.01 (4H, m), 2.39 - 3.26 (4H, m), 3.38 - 3.70 (4H, m) , 4.02-4.29 (1H, m), 4.51-4.80 (2t, m), 5.10 (2H, s), 5.79-6.20 (1H, m), 7 , 15-7.42 (5H, m).

Example 88 Preparation of 1- {2 - [(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuranecarbonyl] pyrrolidine (Compound 88) 380 mg of (4S) -4- (2-thienylacetamido) -3-isoxazolidinone and 368 mg of (84) are dissolved in acetonitrile. 458 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline are added and the mixture is stirred at room temperature for 23 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate: acetic acid (6: 3: 0.1), then ethyl acetate: acetic acid (10: 0.1). 80 mg of the title compound (88) are obtained in the form of a colorless oil. IR (cm ^-1 ): 3270, 1790, 1720, 1680, 1540, 1180, 1040

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.73-2.01 (4H, m), 2.41-3.11 (4H, m), 3.40-3.71 (4H, m) , 3.76, 3.78 (2H, each s), 4.10-

4.29 (1H, m), 4.53-4.99 (2H, m), 6.88-7.28 (3H, m).

Example 89

Preparation of N- (n-Propyl) -2 - [(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-tetrahydrofuran-2-carboxamide (Compound 89)

Starting from 120 mg of (4S) -4- (2-thienylacetamido) -3-isoxazolidinone and 99 mg of compound 85 as described in Example 86, 30 mg of the title compound 89 are obtained in the form of a colorless oil.

IR v ^'of ££ (cm ^-1): 3270, 1800, 1720, 1680, 1540, 1180, 1040

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 0.81-1.00 (3H, m), 1.38-1.68 (2H, m), 2.25-3.42 (6H, m) , 3.70-4.09 (1H, m), 3.77 (2H, s), 4.59-4.98 (2H, m), 6.87-7.29 (3H, m).

example

Preparation of N-Phenyl-2 - [(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl] -5-oxo-tetrahydro-furan-2-carboxamide (Compound 90) in ml of ethyl acetate 124 mg of compound 86 are dissolved. To the solution was added 124 mg of 10% palladium on carbon. The mixture was stirred under a stream of hydrogen at 0 ° C for 2 hours. The catalyst is filtered off. To the filtrate was added 0.12 ml of Ν, Ν-dimethylacetamide and 45 ml of 2-thienylacetyl chloride. The mixture was stirred at 0 ° C for 30 minutes. The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 2: 3 hexane: ethyl acetate. . 3300, 1800, 1730, 1690, 1540, 1180, 1040 (compound 90 as a colorless oil IR spectrum? ^ ^'Of (cm ^-1) 23 mg of

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.37-

3.46 (4H, m), 3.81-4.08 (1H, m), 3.80 (2H, s), 4.57-5.01 (2H, m), 6.58-6, 83 (1H, m), 6.83-7.61 (8H, m), 8.41-8.62 (1H, m).

Example 91 Preparation of 1- (tert-Butyl) -2-oxo-glutarate (Compound 41) (a) 1.46 g of 2-oxo-glutaric acid was dissolved in 10 ml of N, N-dimethylformamide. 21 g of triethylamine. To the solution was added 1.64 g of tert-butyl bromide and the mixture was stirred at 70 ° C for 5 hours. The reaction mixture was poured into saturated brine and extracted twice with ethyl acetate. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 1: 1 mixture of dichloromethane and ethyl acetate. 144 mg of the title compound are obtained in crystalline form. The IR, NMR and melting points of the product are consistent with the corresponding data for the compound (41) prepared in Example 41.

(b) Dissolve 1.46 g of 2-oxoglutaric acid in a mixture of 5 ml of acetonitrile and 10 ml of tert-butanol. To the solution was added 2.06 g of DCC and 50 mg of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 2 days. The reaction mixture was worked up as described in process (a) to give 150 mg of the title compound (4l) in crystalline form.

-35197742

Example 92 Preparation of 1- (2-Trimethylsilyl) ethyl-2-oxo-glutarate (Compound 92) 1.46 g of 2-oxo-glutaric acid are dissolved in acetonitrile. To the solution was added 2.06 g of DCC and the mixture was stirred at room temperature for 30 minutes. 1.42 ml of 2-trimethylsilylethanol and 50 mg of 4-dimethylaminopyridine were added and the mixture was stirred at room temperature.

Stir for 3.5 hours. The precipitated crystals are filtered off and the filtrate is evaporated to dryness. The concentrate was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (1: 1). 646 mg of the title compound (92) are obtained in the form of an oil.

IR (cm ^-1 ): 1730, 1420, 1250, 1080, 1030, 840

Nuclear Magnetic Resonance Spectrum (100 MHz, CDCl ₃ ) δ: 0.80-1.20 (2H, m), 2.50-2.85 (2H, m), 2.98-3.20 (2H, m) , 4.16-4.44 (2 H, m).

Example 93 Preparation of 1- (4-Nitrobenzyl) -4-methoxy-2-oxoglutarate (Compound 93)

Dissolve 10 g in 300 ml of dichloromethane

4-hydroxy-2-cyclopentenone. 25.7 g of dihydropyran and 0.5 g of p-toluenesulfonic acid are added and the mixture is stirred at room temperature for 45 minutes. The reaction mixture was poured into aqueous sodium bicarbonate solution. The organic phase was separated. The aqueous phase was further extracted with dichloromethane. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 7: 3). 17.4 g of 4- (2-tetrahydropyranyl) oxy-2-cyclopentenone are obtained in the form of an oil.

IR v ^ ^a (cm ^-1): 2900, 1720 NMR (90MHz, CDC1 ₃₎ δ: 1,40- 2,03 (6H, m), 2.27-2.60 (2H, m), 3.63-4.00 (2H, m), 4.63-4.78 (1H, m), 4.78-5.05 (1H, m), 6.18 (1H, d, J = 6 Hz), 7.63 (1H, dd, J = 6, 1.5 Hz).

15.0 g of the above oil product are dissolved in 170 ml of methanol. To the solution was added 3.11 g of cerium (III) chloride time. After stirring at room temperature for 45 minutes, sodium borohydride (1.17 g) was added portionwise over 20 minutes with stirring. The reaction mixture was concentrated to about half volume under reduced pressure, saturated aqueous brine was added and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with 2: 3 hexane: ethyl acetate. 13.2 g of 4- (2-tetrahydropyranyl) oxy-2-cyclopentenol are obtained in the form of an oil.

IR ν '^ ^α (cm ^-1): 3500, 2950, 1100 NMR (90MHz, CDC1 ₃₎ δ: 1.33- 1.87 (6H, m), 2.45 to 2.84 ( 2H, m), 3.30-3.57 (1H, m), 3.66-4.06 (1H, m), 4.48-4.75 (3H, m), 6.00 (2H, s).

10.3 g of the above product are dissolved in 20 ml of tetrahydrofuran. The solution was added dropwise over 3 minutes to a suspension of sodium hydride (3.36 g, 40% in oil) in tetrahydrofuran (100 mL) under ice-cooling. After stirring at room temperature for 30 minutes, 16 g of methyl iodide are added. The mixture was stirred for 4 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 4). 9.7 g of 1-methoxy-4- (2-tetrahydropyranyl) oxy-2-cyclopenten are obtained in the form of an oil.

IR spectra (cm ^-1 ): 2950, 1100 NMR (90 MHz, CDCl ₃ ) δ: 1.39-1.86 (6H, m), 2.46-2.89 (2H) , m), 3.33 (3H, s) 3.33-3.63 (1H, m), 3.73-4.03 (1H, m), 4.20-4.39 (1H, m) , 4.49-4.79 (2H, m), 6.00 (2H, s).

8.0 g of the product obtained above are dissolved in 250 ml of dichloromethane. Ozone was bubbled into the solution at -78 ° C. After 1 hour, the excess ozone gas was expelled with nitrogen and 12.5 g of dimethylsulfide was added. The mixture was stirred at 0 ° C for 2 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in 125 ml of ethanol. To the solution was added 17 g of silver nitrate and 19 g of sodium hydroxide in 125 ml of water, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered off and the filtrate was neutralized with 35% hydrochloric acid and then concentrated. The concentrate was suspended in methanol and diazomethane was added to the suspension for methylation. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with 2: 1 hexane: ethyl acetate. 7.5 g of dimethyl 2-methoxy-4- (2-tetrahydropyranyl) oxyglutarate are obtained in the form of an oil. IR spectrum v '%,? (cm ^-1 ): 2950, 1740, 1200, Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.21 (2H, dd, J = 12, 3 Hz), 3.30, 3.36 (3H, each s), 3.65, 3.69, 3.70, 3.71 (6H, each s), 4.42 (1H, t, J = 6Hz), 4.59-4.79 (1H, m).

7.5 g of the above product are dissolved in 60 ml of methanol. To the solution was added 2.5 mL of 5% hydrochloric acid. The mixture was stirred at room temperature 36197742 for 30 minutes, then neutralized with aqueous sodium bicarbonate solution and concentrated under reduced pressure. The concentrate was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and then concentrated. The concentrate was dissolved in 50 ml of acetone. To the solution was added 8N Jones reagent until the reaction mixture turned orange, then stirred at 150 ° C for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate = 3: 2 (v / v). 3.2 g of dimethyl 4-methoxy-2-oxoglutarate are obtained in the form of an oil. IR v '^ ^a (cm ^-1): 2950, 1740 NMR (90MHz, CDC1 ₃₎ δ: 3.25 (2H, d, J = 6Hz), 3.43 (3H, s) , 3.76, 3.89 (3H, each s), 4.29 (1H, t, J = 6Hz).

The above product (1.66 g) was dissolved in a mixture of methanol (30 ml) and water (6 ml). Lithium hydroxide (820 g) was added portionwise under ice-cooling and stirred for 20 minutes. Water (10 mL) was added, neutralized with 35% HCl, and the methanol was evaporated under reduced pressure. The reaction mixture was adjusted to pH 1 with 35% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. 1.42 g of 4-methoxy-2-oxoglutaric acid are obtained as an oily residue.

IR v '^ ^a (cm ^-1): 2950, 1730,

1450-, 1260

Nuclear Magnetic Resonance Spectrum (90 MHz, d ₆ -DMSO) δ: 3.28 (2H, d, J = 5Hz), 3.33 (3H, s), 4.20 (1H, t, J = 6Hz) .

mg of the product obtained above is dissolved in 10 ml of Ν, Ν-dimethylformamide and 522 mg of dicyclohexylamine are added. The solution was stirred at room temperature for 30 minutes, 4-nitrobenzyl bromide (622 mg) was added and stirred at 40 ° C for 1 hour. The precipitated crystals are filtered off. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. 896 mg of the title compound (93) are obtained in the form of an oil.

IR spectrum? X ' ⁰ ' (cm ^-1 ): 1735, 1707, 1530, 1345, 1275, 1085

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.30 (2H, d, J = 6Hz), 4.30 (1H, t, J = 6Hz), 5.3 (2H, s), δ , 6.2 8.2 (2H, both d, J = 8Hz)

Example 94

4-Nitrobenzyl 2 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -4-methoxy-5-oxo-2-tetrahydrofuran-carboxylate (Compound 94) ]

896 mg of compound (93) in 10 ml of dichloro72

dissolved in methane. 680 mg of (4S) -1-benzyloxycarbonylamino-3-isoxazolidinone and 593 mg of DCC are added and the mixture is stirred at room temperature for 1 hour. The precipitated crystals are filtered off and the solvent is evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 2). 723 mg of the title compound 94 are obtained in the form of an oil.

IR spectrum λ (cm ^-1 ) 2930, 1800, 1720, 1520

NMR (90MHz, _CDCl3) δ: 3,263,40 (1H, m), 3.51, 3.56 (3H, each s), 3.66-3.80 (IH, m), 4 10-4.33 (2H, m), 4.59-4.89 (2H, m), 5.10 (2H, s), 5.33 (2H, s), 7.33 (5H, s) , 7.50, 8.23 (2H, both d, J = 7.5 Hz).

Example 95

Sodium 2-j (4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -4- Preparation of methoxy-5-oxo-2-tetrahydrofuran carboxylate (Compound 95)

Starting from 290 mg of compound 94, following the procedure of Example 4, 73 mg of the title compound 95 are obtained in the form of a white powder.

IR spectrum ν (cm ^-1 ): 1780, 1720, 1660, 1530, 1020

Nuclear Magnetic Resonance Spectrum (100 MHz, D ₂ O) δ: 3.02-3.20, 3.36-3.64 (total 2H, m), 3.38, 3.86 (total 3H, each s), 4.00 (3H, s), 7.02 (1H, s) beam spectrum m / e: 466 (M ⁺ +1).

Example 96

Preparation of Sodium 2 - [(4S) -4- (2-thienylacetamido) -3-oxo-2-isoxazolidinyl] -4-methoxy-5-oxo-2-tetrahydrofuran carboxylate (Compound 96)

Starting from 190 mg (94), as in Example 3, 37 mg of the title compound 96 are obtained in the form of a white powder.

IR (cm ^-1 ): 1780, 1720, 1650, 1540

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 3.06-3.72 (2H, m), 3.66 (2H, s), 3.46, 4.00 (3H in total, each s), 4.17-4.56 (2H, m), 4.60-5.26 (2H, m), 7.06-7.26 (2H, m), 7.43-7.56 UH, m) .

Mass spectrum m / e: 407 (M ⁺ +1).

Example 97 Preparation of 1- (4-nitrobenzyl) -2-carboxy-α-oxophenylacetate (Compound 97) In tetrahydrofuran (388 mg), 2-carboxy-α-oxo-phenylacetic acid was dissolved and the 495 mg of DCC was added to the solution. The mixture was stirred at room temperature for 30 minutes. The precipitate was filtered off. 306 mg of 4-nitrobenzyl alcohol are added to the filtrate and the mixture is refluxed for 3 hours. The solvent was evaporated and the residue 37

The residue was purified by column chromatography on silica gel (37197742) eluting with hexane: ethyl acetate (2: 1? 0: 1, v / v). 112 mg of the title compound (97) are obtained in the form of colorless crystals, m.p. 165-167 ° C.

IR (cm '): 3450, 1760, 1750, 1345, 1260

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 5.30 (2H, s), 8.01-7.40 (4H, m), 7.42 (2H, d, J = 9Hz), δ , 18 (2H, d, J = 9Hz).

Example 98

Preparation of 4-nitrobenzyl-3-chloro-1,3-dihydro-1-oxo-isobenzofuran-3-carboxylate (Compound 98) In dichloroethane (580 mg) was dissolved in 97 ml and 0.58 ml was added. of thionyl chloride. The mixture was refluxed for 1 hour. The solvent was evaporated and the residue was treated with isopropyl ether. 500 mg of the title compound (98) are obtained in the form of colorless crystals, m.p. 132-134 ° C.

IR spectrum ν max (cm ^-1 ): 1795, 1770, 1620, 1550, 1265, 1255, 1040.

Example 99

4-Nitrobenzyl 3 - [(4S) -4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl] -1,3-dihydro-1-oxoisobenzofuran-3-carboxylate [(99 Preparation of Compound (II) in dichloromethane (ml) Dissolve 236 mg (4S) -4-zyloxycarbonylamino-3-isoxazolidinone and 347 mg (98). Triethylamine (0.14 mL) was added to the solution under ice-cooling, and the mixture was stirred for 30 minutes. The solvent was evaporated and ethyl acetate was added to the residue, which was washed with water and then with brine. The organic phase is dried and the solvent is evaporated. The residue was purified by Florisilen column chromatography eluting with hexane: ethyl acetate (2: 1 → 1: 1). 350 mg of the title compound are obtained in the form of a pale yellow oil.

IR spectrum ν '# (cm ^-1 ): 3340, 1785 -

1720, 1520, 1345, 1250

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.96 -

4.35 (2H, m), 4.85-4.42 (1H, m), 5.10 (2H, s),

5.35 (2H, s), 5.6 (1H, b), 7.30 (5H, s), 7.48 (2H, d, J = 9Hz), 7.55-8.00 (4H, m) ), 8.19 (2H, d, J = 9Hz).

Mass Spectrum m / e 547 (M ⁺ ).

Example 100

Sodium 3 - ((4S) -4- [2- (2-amino-4-thiazolyl)

Preparation of (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazole idinyl] -1,3-dihydro-1-oxoisobenzofuran-3-carboxylate (Compound 100) in ethyl ethyl 350 mg of compound (99) are dissolved in a mixture of acetate and 5 ml of phosphate buffer solution (pH 7.0). 350 mg of 10% palladium on carbon were added to the solution. The mixture was stirred under a stream of hydrogen under ice-cooling for 2 hours. The catalyst is filtered off and washed with water. The filtrate and the washings were combined and the aqueous phase separated. To the aqueous phase were added 15 ml of tetrahydrofuran and 161 mg of sodium bicarbonate. 213 mg of 2-chloroacetamido-4,4-azolyl- (Z) -2-methoxyiminoacetyl chloride were added with stirring and ice-cooling. The mixture was stirred under ice-cooling for an additional 30 minutes and then 99 mg of sodium N-methyldithiocarbamate was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with diethyl ether, the aqueous phase was concentrated and the residue was purified by XAD-II column chromatography. The fractions eluted with 20% ethanol were lyophilized to give 65 mg of the title compound (100) as a white powder.

IR (cm- ¹ ): 1760, 1660, 1530, 1385

NMR (90 MHz, _DMSO-d6) δ: 3.85 (3H, s), 4.70 to 4.20 (2H, m), 4.70 to 5.10 (1H, m), 7 , 02 (1H, s), 7.1 (2H, b), 7.35-7.90 (4H, m), 9.10 (1H, d, J = 8Hz).

Example 101 Preparation of 1- (4-Nitrobenzyl) -2-oxo-4-phenylthioglutarate (Compound 101) In anhydrous tetrahydrofuran, 1.71 ml of diisopropylamine was dissolved. 7.49 ml of a 1.6 M solution of n-butyllithium in hexane are added under stirring at -78 ° C under nitrogen. After stirring for 15 minutes, dimethyl 2-oxoglutarate dimethylacetal (2.06 g), dissolved in anhydrous tetrahydrofuran (5 ml), was added over 5 minutes, and the mixture was stirred for 15 minutes. A solution of 2.81 g of phenylbenzene thiosulfonate and 0.81 ml of hexamethylphosphoramide in 5 ml of anhydrous tetrahydrofuran is then added over 13 minutes and the mixture is stirred at -78 ° C for 30 minutes. The temperature of the reaction mixture was raised to -50 ° C with stirring over 1 h, then an aqueous saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 2: 1 by volume mixture of hexane and ethyl acetate. 3.02 g of dimethyl 2-oxo-4-phenylthioglutarate dimethylacetal are obtained in the form of a pale yellow oil. IR Spectrum (cm ^-1 ): 1740, 1600 NMR Spectrum (90 MHz, CDCl ₃ ) δ: 2.26 (1H, dd, J = 5.8 Hz), 2.63 (1H, dd, J = 5.8Hz), 3.23 (6H, s), 3.62 (3H, s), 3.73 (1H, m), 3.73 (3H, s), 7.2-7.6 (5H, m).

The above compound was also prepared as described above using phenyl disulfide instead of phenylbenzene thiosulfonate.

3.02 g of the compound obtained above are dissolved in 25 ml of methanol. 25 ml of 1.8 M solution are added to the solution

Aqueous potassium hydroxide solution (-38197742) was added under ice-cooling and stirring at a rate to ensure homogeneity of the reaction mixture. The methanol was evaporated. The aqueous phase was adjusted to pH 1 with 6N hydrochloric acid, then saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated.

2.85 g of 2-oxo-4-phenylthioglutaric acid dimethylacetal are obtained as a yellow oil.

To a solution of 2.76 g of the oily product obtained above in 40 ml of tetrahydrofuran is added 40 ml of 1N hydrochloric acid. The mixture was heated at 50 ° C

Stir for 7.6 hours. The tetrahydrofuran was evaporated and the aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. 2.25 g of 2-oxo-4-phenylthioglutaric acid are obtained in the form of a yellow oil.

To a solution of the above oil (2.05 g) in dimethylformamide (20 ml) was added dicyclohexylamine (0.96 ml) and 4-nitrobenzyl bromide (1.05 g). The mixture was stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture and the precipitated crystals were filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, eluting with hexane: ethyl acetate = 3: 1 (v / v). 883 mg of the title compound 101 are obtained in the form of a pale yellow oil.

IR (cm ^-1 ): 3600-2500,

1800-1700, 1600

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 3.03 (2H, m), 4.12 (1H, t, J = 9Hz), 5.30 (1H, m),

5.33 (2H, s), 7.2-7.7 (5H, m), 7.48 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz).

Example 102

4-Nitrobenzyl-2-j (4S) - [4- (4-nitro-benzyloxy-carbonyl) amino] -3-oxo-2-isoxazolidinyl ^l l-5-oxo-4-phenyl-thio Preparation of 2-Tetrahydrofurancarboxylate (Compound 102) In dichloromethane, 180 mg of (4S) -4- (4-nitrobenzyloxycarbonylamino) -3-isoxazolidinone and 260 mg of compound (10) are suspended. To the suspension was added 206 ml of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was stirred at room temperature for 3.5 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with a 2: 1 + 1: 1 by volume mixture of hexane and ethyl acetate. 253 mg of the title compound (102) are obtained in the form of a pale yellow oil.

IR v ^ ^u (cm ^-1): 3370, 1790,

1870-1700, 1600, 1520, 1340 NMR (90MHz, _CDCl3) δ: 2.43 (1H, dd, J = 9, 16Hz), 3.3-3.7 (1H, m); 4.21 (2H, t, J = 9Hz), 4.4-5.0 (2H, m),

5.20 (2H, s), 5.28, 5.35 (total 2H, all 76 one s, 2: 1), 5.52 (1H, m), 7.2-7.7 (5H, m) .

7.46 (4H, d, J = 9Hz), 8.18 (4H, d, J = 9Hz). Mass spectrum m / e: 652 (M ⁺ ).

Example 103

Sodium 2 - {(4S) -4- [2- (2-amino-4-thiazolyl (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl} -4-phenyl Preparation of thio-5-oxo-2-tetrahydrofuran carboxylate (Compound 103) In a mixture of ml of ethyl acetate and 9 ml of phosphate buffer, pH 7.0, 230 mg of 102. was dissolved in 230 mg of 10% metal. The mixture was stirred under ice-cooling under ice-cooling for 1 hour and then at room temperature for a further 1 hour. The catalyst was filtered off and washed with water. 89 mg of sodium bicarbonate and 152 mg of 2-chloroacetamido-4-thiazolyl (Z) -2-methoxyiminoacetyl chloride hydrochloride are added under ice-cooling and stirring. the reaction mixture was stirred under ice-cooling for 30 minutes and then 82 mg of sodium N-methyldithiocarbamate was added, and the mixture was stirred at room temperature for 1 hour, the tetraK drofuran was evaporated and the aqueous phase was washed with ethyl acetate and purified by column chromatography on HP-20 resin. The fractions eluted with 10% efanol were lyophilized to give 26 mg of the title compound 103 as a pale yellow powder.

IR spectrum ν max (cm ^-1 ): 1780, 1720, 1660 NMR (90 MHz, D ₂ O) δ: 2.73 (1H, dd, J = 9, 15 Hz), 3.0- 4.1 (2H, m), 4.20 (2H, s), 4.3-4.8 (2H, m), 5.1-5.6 (1H, m), 7.20, 7, 22 (1H total, each s), 7.5—

7.9 (5 H, m).

Example 104

Preparation of 4-Nitrobenzyl 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-3-phenylthio-2-tetrahydrofuran carboxylate (Compound 104)

(4S) -4-Phenylacetamido-3-isoxazolidinone (227 mg) and 1- (4-nitrobenzyl) -2-oxo-3-phenylthioglycerate (405 mg) were suspended in dichloromethane (5 mL). A solution of DCC (278 mg) in dichloromethane (2.5 mL) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added ethyl acetate and the precipitate was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1 + 1: 1). 288 mg of the title compound (104) are obtained in the form of a pale yellow oil.

IR £ ^j virus (cm ^-1): 3350, 1810, 1760, 1670, 1600, 1520, 1350

-39197742

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.64 (1H, dd, J = 6, 18 Hz), 3.22 (1H, dd, J = 9, 18 Hz), 3.60 (2H, s), 3.8-4.2 (1H, m), 4.3-5.1 (3H, m), 5.2-5.5 (2H, m), 6.0-6.3 ( 1H, m), 7.1-7.7 (10H, m), 7.52 (2H, d, J = 9Hz), 8.18 (2H, d, J = 9Hz).

Example 105

Preparation of Sodium 2 - [(4 S) -4-phenylacetylamino-3-oxo-2-isoxazolidinyl] -5-oxo-3-phenylthio-2-tetrahydrofuranecarboxylate (Compound 105)

To a solution of compound (104) (280 mg) in ethyl acetate (7 ml) was added phosphate buffer solution (pH 7.0) (11 ml) and palladium on carbon (280 mg, 10%) was added. The reaction mixture was stirred under a stream of hydrogen under ice-cooling for 1 hour and then at room temperature for an additional 30 minutes. The catalyst is filtered off and washed with water. Combine the filtrate and the washings. The aqueous phase was separated and washed with ethyl acetate and purified by column chromatography on HP-20 resin. The fractions eluted with 30% ethanol were lyophilized to give 75 mg of the title compound 105 as a white powder.

IR (cm ^-1 ): 1790, 1720, 1660

Nuclear Magnetic Resonance Spectrum (90 MHz, D ₂ O) δ: 2.95 (1H, dd, J = 6, 19 Hz), 3.53 (1H, dd, J = 9, 19 Hz), 3.88 (2H , s), 4.0-5.4 (4H, m), 7.4-7.9 (5H, m), 7.58 (5H, s).

Example 106

Preparation of 4-Nitrobenzyl-2-chloro-4- (phenylthio) -5-oxo-2-tetrahydrofuran carboxylate (Compound 106)

To a solution of compound (101) (315 mg) in 1,2-dichloroethane (13 mL) was added thionyl chloride (0.33 mL). The mixture was refluxed for 2 hours. The solvent was evaporated and the residue was purified by Florisilene column chromatography (eluent: hexane: ethyl acetate = 2: 1). 170 mg of the title compound 106 are obtained in the form of a light brown oil. IR v ^ ^{a (cm-1):} 1810, 1760, 1600, 1520, 1320

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.83 (1H, dd, J = 11, 15 Hz), 3.14 (1H, dd, J = 9, 15 Hz), 4.23 (1H, dd, J = 9, 11Hz), 5.34 (2H, s), 7.2-7.7 (5H, m), 7.50 (2H, d, J = 9Hz), 8.24 ( 2H, d, J = 9Hz)

Mass spectrum m / e: 409, 407 (M ⁺ ).

Example 107

Preparation of 4-Nitrobenzyl 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-4-phenylthio-2-tetrahydrofuran carboxylate (Compound 107). (a) 265 mg of (4S) -4-phenylacetamido-3-isoxazolidinone and 165 mg of 1- (4-nitrobenzyl) -2-oxo-4-phenylthioglutarate are suspended in 6 ml of dichloromethane. 219 g of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline are added to the suspension and the mixture is stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with 2: 1 + 1: 1 hexane: ethyl acetate. 200 mg of the title compound (107) are obtained in the form of a colorless oil. IR v ^ ^{a (cm):} 33Ö0, 1790, 1760, 670, 1600, 1520, 1350

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 2.40 (1H, dd, J = 9.15 Hz), 2.7-3.5 (1H, m), 3.55 (2H, s), 3.6-4.4 (2H, m), 4.5-5.0 (2H, m), 5.28 (2H, b), 6.25 (1H, m), 7.1-7, Δ 1.12H, m), 8.17 (2H, d, J = 9Hz).

(b) Dissolve 76 mg of (4S) -4-phenylacetamido-3-isoxazolidinone and C in 11 ml triethylamine in 2.5 ml dichloromethane. A solution of 155 mg of compound 106 in 1 ml of dichloromethane is added under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (2: 1? 1: 1). 56 mg of the title compound are obtained in the form of a pale yellow oil. The IR and NMR spectra of the compound are consistent with the corresponding data for compound (107) prepared according to method (a).

Example 108

Preparation of Sodium 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl] -5-oxo-4-phenylthio-2-tetrahydrofuran carboxylate (Compound 108)

To a solution of compound (107) (250 mg) in ethyl acetate (7 mL) was added phosphate buffer solution (pH 7.0) (10 mL) and palladium on carbon (250 mg, 10%). The mixture was stirred under a stream of hydrogen under ice-cooling for 1 hour and then at room temperature for an additional 30 minutes. The catalyst is filtered off and washed with water. The filtrate and the washings were combined, the aqueous phase separated, washed with ethyl acetate and purified by column chromatography on HP-20 resin. The fractions eluted with 30% ethanol were lyophilized to give 80 mg of the title compound (108) as a white powder.

IR (cm ^-1 ): 1790, 1730, 1660 NMR (90 MHz, D ₂ O) δ: 2.6-2.9 (1H, m), 3.1-3.8 (1H, m) ), 3.86 (2H, s), 4.1-5.3 (4H, m), 7.57-7.67 (10H, m).

Example 109

4-Nitrobenzyl 2 - [(4S) -5-acetoxymethyl-4- (tert-butoxy) carbonylamino-3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate [ (Compound 109)] To a mixture of tert-butanol (30 ml) and water (30 ml) was added 4.30 g of (2S) -2- (tert-butoxy) carbonylamino-3-butenoic acid as described in [Journal of Drganic Chemistry 45, 4817]. (1980)]. The

O-benzylhydroxylamine hydrochloride (3.75 g) was added to the mixture, followed by 1-ethyl-3- (3-dimethyl, aminopropyl) carbodiimide hydrochloride (4.50 g) in 5 portions. , Every 10 minutes while maintaining the pH at 4.2.

After stirring at room temperature for 1 hour, the t-butanol was evaporated and the residue was extracted with diethyl ether. The organic layer was washed with 1 N potassium hydrogen sulfate, 0.5 π sodium bicarbonate followed by saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. 5.12 g of (2S) -O-benzyl-2- (tert-butoxy) carbonylamino-3-butenylhydroxamate are obtained.

IR (cm ^-1 ): 3330, 2980, 1680, 1670, 1528

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.40 (9H, s), 4.50-4.80 (1H, m), 4.90 (2H, s), 5.20-5.45 (3H, m), 5.66-6.10 (1H, m), 7.35 (5H, s), 8.80-9.10 (1H, m).

2.50 g of the compound obtained above are dissolved in 20 ml of toluene and 2.81 g of m-chloroperbenzoic acid are added. The mixture was stirred at 35 ° C for 8 hours. The mixture was cooled to 0 ° C and the excess m-chloroperbenzoic acid was quenched by the addition of sodium bisulfite solution. Ethyl acetate (50 mL) and 0.5N sodium bicarbonate (50 mL) were added and the mixture was stirred for 1 hour. The ethyl acetate layer was separated, washed with 0.5 N sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with 2: 3 → 1: 2 hexane: diethyl ether. 473 mg of (A) diastereomer and 1.433 g of (2S) -O-benzyl-2- (tert-butoxy) carbonylamino-3,4-epoxy-butenehydroxamate are obtained.

(A) IR spectrum (cm ^-1 ): 3330, 3260, 1680, 1670, 1530

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 2.82 (2H, d, H = 3Hz), 2.90-3.10 (1H, dd, J = 3 , 7.5 Hz), 3.75 (1H, dd, J = 6.6,

7.5 Hz), 4.93 (2H, s), 5.60 (1H, d, J = 6.6 Hz),

7.40 (5H, s).

(B) Infrared absorption spectrum ^'u (cm ^-1): 3330, 3250, 1680, 1670, 1540

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 2.53-2.83 (2H, m), 3.23-3.50 (1H, m), 4.30 -4.50 (1 H, bs), 4.92 (2H, s), 5.47 (1H, d, J = 8Hz), 7.40 (5H, s).

914 mg of diastereomer B obtained above are dissolved in 15 ml of methanol. Palladium on carbon (150 mg, 5%) and pyridine (20 mg) were added to the solution, and the mixture was stirred at room temperature under a stream of hydrogen for 30 minutes. The catalyst was filtered off, and 184 mg of sodium methoxide was added to the filtrate and the mixture was stirred at room temperature for 4 hours. The methanol was evaporated under reduced pressure to a residue of 4 ml

r. potassium bisulfate was added and the mixture was extracted four times with ethyl acetate: tert-butanol (4: 1). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with hexane: ethyl acetate: methanol (4: 8: 1). 59i mg of (4S) -4-tert-butoxycarbonylamino-5-hydroxymethyl-3-isoxazolidinone is obtained.

IR (cm ^-1 ): 3360, 1720, 1700, 1535

Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl ₃ ) δ: 1.49 (9H, s), 3.92 (1H, dd, J = 13, 16 Hz), 4.27-

4.40 (1H, m), 4.60-4.73 (1H, m), 5.63-5.70 (1H, m).

116 mg of the compound obtained above are dissolved in 1.5 ml of dichloromethane. To the solution was added 65 mg of Ν, Ν-diisopropylethylamine followed by 53 mg of chloromethyl methyl sulfide in 1.5 ml of dichloromethane and the mixture was stirred for 30 minutes.

The reaction mixture was stirred at room temperature overnight and the excess chloromethyl methyl sulfide was evaporated. The residue was dissolved in ethyl acetate and the organic phase was dried over water and then with saturated aqueous sodium sulfate. The residue was purified by flash column chromatography on silica gel, eluting with 5: 6 hexane: ethyl acetate. 55 mg of (4S) -4-tert-butoxycarbonylamino-5-hydroxymethyl-2-methylthiomethyl-3-isoxazolidinone are obtained. IR ^(cm-1): 3360, 1715, 1655, 1530

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 2.25 (3H, s), 3.40-3.65 (1H, bs), 3.35-4.05 (2H, m), 4.17-4.40 (1H, m), 4.63 (1H, dd, J = 6, 12Hz), 5.43 (1H, d, J = 6Hz).

mg of the compound obtained above is dissolved in 1 ml of dichloroethane. Triethylamine (101 mg) and acetic anhydride (102 mg) were added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 3: 2). 43 mg of (4S) -5-acetoxymethyl-4-tert-butoxycarbonylamino-2-methylthiomethyl-3-isoxazolidinone are obtained. Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.13 (3H, s), 2.27 (3H, s), 4.23-4.75 (4H, s) ), 4.67 (2H, s), 5.30 (1H, d, J = 4Hz).

To a solution of the above product (0.5 mg) in tetrahydrofuran-water (0.5 ml) was added 2,6-lutidine and 85 mg of silver nitrate, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated copper sulfate solution, then washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The ma41

The residue was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 2: 3). 20 mg of (4S) -5-acetoxymethyl-4-tert-butoxycarbonylamino-2-hydroxymethyl-3-isoxazolidinone and (4S) -5-acetoxymethyl-4-tert. butoxycarbonylamino-3-isoxazolidinone.

To the above product was added 1 ml of ethanol and 1 ml of saturated sodium bisulfite solution, and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered off and the filtrate was extracted with ethyl acetate / tert-butanol (4: 1). The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated, chloroform is added to the residue, the precipitate is filtered off and the filtrate is concentrated under reduced pressure. 15 mg of (4S) -5-acetoxymethyl-4-tert-butoxycarbonylamino-3-isoxazolidinone are obtained.

IR aquatic ^-1): 3380, 2920, 1735, 1720, 1500

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.10 (3H, s), 4.20-4.70 (4H, m), 5.13-5.45 (1H, bs).

Dissolve 1 mg of the above product in 1 ml of dichloromethane. To the solution was added 1- (4-nitrobenzyl) -2-oxoglutarate (15 mg) and DCC (11 mg) at 0 ° C, and the mixture was stirred.

After 1 minute, the reaction mixture was brought to room temperature and stirred for 40 minutes. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (2: 1 hexane: ethyl acetate). 10 mg of the title compound (109) are obtained. IR (cm ^-1 ): 3430, 2920, 1805, 1745, 1720, 1600, 1520, 1500

Nuclear Magnetic Resonance Spectrum (90 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 2.10 (3H, s), 2.30-3.20 (4H, m), 3.95-4.85 (4H, m), 5.05 (1H, d, J = 6Hz), 5.37 (2H, s), 7.57 (2H, d, J = 9Hz), 8.23 (2H, d) , J = 9 Hz).

Claims (6)

PATENT CLAIMS l. A process for the preparation of a compound of formula (I) - R 1 is a group of formula (a) wherein R ¹³ is C 1 -C 4 alkyl substituted with phenyl or thienyl, or C 1 -C 6 alkoxy optionally substituted with phenyl or nitrophenyl, or in the latter formula R ²⁰ is amino or [halo]; Thiazolyl substituted with (C1-C4) -alkyl-carbonylamino; R ²¹ is C 1-4 alkyl, R ² is a group of formula (p) wherein R ⁴⁷ is a C 1-4 alkyl group optionally substituted with a nitrophenyl group or a C 1-6 alkylcarbonyloxy group or two phenyl groups, or a group of formula (q) wherein R ⁴⁸ is phenyl or C 1-5 alkyl; and R ⁴⁹ is hydrogen, or R ⁴⁸ and R ^{49 taken} together with the nitrogen to which they are attached form pyrrolidinyl, R ³ is hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyloxy (C 1-4) alkyl, C 1-4 alkoxycarbonyl, phenyl or carbamoyl, R 0 is hydrogen, C 1-4 alkyl, phenylthio, or C 1-4 alkylthio optionally substituted with (C 1-4) alkylcarbonylamino; R @ 4 is hydrogen or C1 -C4 alkyl, R ⁷ is hydrogen, C 1-4 alkyl, phenyl, phenyl (C 1-4) alkyl, (C 1-4) alkoxy (C 1-4) alkyl, C 1-4 alkoxy or phenylthio, R ⁸ is hydrogen, or R ⁵ and R ^{7 form} a second carbon-carbon bond, or R ⁵ , R ⁶ , R ⁷ and R ⁸ together with the furan ring form a 1,3-dihydroisobenzofuranyl group and their base salts, characterized in that (a) a compound of the formula (III) is R ¹ and R ³ are as defined in the preamble, with a compound of formula (IV) R ² , R ⁵ , R ⁷ , R ⁷ and R ⁸ are as defined in the preceding claims, and Y is hydrogen or a leaving group, or (b) to produce a compound of formula (I) wherein: R ² is a group of formula (p): a compound of formula (II): wherein R ² is R ² , R ⁵ , R ⁷ , R ⁷ and R ⁸ are as defined herein, or a reactive derivative thereof, with a compound of formula (III): R ¹ and R ³ are as defined in the scope of this invention and, if desired, (i) to form a compound of formula I wherein R ³ and R ⁷ are hydrogen, a -42197742 A compound of formula (I) wherein R ⁵ and R ⁷ together represent a second carbon-carbon bond, are reduced, or 5 (ii) is transaminated in a compound of formula (I) with an acylamino group at R ¹ , and / or (iii) The ester of formula I is converted to a salt with a base. 10 (Priority 30/04/85). Process b) according to claim 1, wherein sodium 2 - [(4S, 5R) -4- (2-thienylacetamido) -5-methyl-3-oxo-2-isoxazolidinyl] -5-oxo-2- tetrahydrofuran carboxylate, sodium 2 - {(4S, 5R) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -5- methyl 3-oxo-2-isoxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate, 20-sodium 2-j (4S, 5S) -4- [2- (2-amino-4-thiazolyl) - (Z ) -2- (methoxyimino) acetamido] -5-methyl-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuranecarboxylate, sodium 2 - {(4R) -4- [2- (2-Amino-4-thiazole () - 25 - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl} -5-oxo-2-tetrahydrofuran carboxylate. sodium 2 - ((4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2- -isoxazolidinyl] -5-oxo-2-tetrahydrofuran carbonate, or sodium (4S) -4-] 2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) - acetamido] -3-oxo-2-isoxazolidinyl] -4-methyl-5-oxo-2-tetrahydrofuranecarboxylate, characterized in that the appropriately substituted starting materials of the formulas II and III are used. (Priority 30/04/85). Process b) according to claim 1, comprising 40 sodium 2 - {(4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] - 3-Oxo-2-isoxazolidinyl {-3- (ethylthio) -5-oxo-2-tetrahydrofuranecarboxylate, Sodium 2 - ((4S) -4- [2- (2-amino-4-thiazolyl)) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -4-phenyl-2-tetrahydrofuranecarboxylate, sodium 2-j (4S) -4- [2- ( 2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2- 50 -isoxazolidinyl] -3,3-dimethyl-5-oxo-2-tetrahydrofuran carboxylate, sodium 2 - [(4S) -4-phenylacetamido-3-oxo-2-isoxazolidinyl) -3- {2-acetamido -ethylthio) -5-oxo-2-tetrahydrofuran carboxylate, 55-sodium 2 - ((4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxy) imino) -acetamido] -3-oxo-284 isoxazolidinyl] -4-benzo-1-tetrahydrofuran carboxylate or sodium 2 -] (4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxy) -imino) -acetamido] -3-oxo-2-isoxazolidinyl) -4- (methoxymethyl) -5-oxo-2-tetrahydrofuran carboxylate, characterized in that the appropriately substituted compounds (II) and (III) starting materials. (Priority: December 16, 1985) Process a) according to claim 1, comprising sodium 2 - ((4R) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido) -3 -oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran carboxylate, sodium 2 - ((4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2 - (methoxyimino) acetamido] -3-oxo-2-yl: oxazolidinyl] -5-oxo-2-tetrahydrofuran carboxylate, or sodium 2 -] (4S) - (2- (2-amino- 4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl] -4-methyl-5-oxo-2-tetrahydrofuranecarbonyl, characterized in that substituted compounds of formulas (III) and (IV) (Priority: 30.04.1985). Process a) according to claim 1, wherein sodium 2 - [(4S) -4- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3 -oxo-2-isoxazolidinyl) -4-phenyl-5-oxo-2-tetrahydrofuran carboxylate, sodium 2-] (4S) -4- [2- (2-amino-4-thiazolyl) - (Z) - 2- (methoxyimino) acetamido] -3-oxoisoxazole idinyl] -4-benzyl-5? -2-tetra-hydrofuranecarboxylate, or sodium 2 - {(4S) -4- (2- (2-Amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido] -3-oxo-2-isoxazolidinyl} -4- (methoxymethyl) -5-oxo-2-tetrahydro ' for the preparation of rofuran carboxylate. characterized in that the appropriately substituted compounds of the formulas (III) and (IV) are used. (Priority: December 16, 1985). 6. A process for the preparation of a pharmaceutical composition comprising the steps of: A compound of formula (I) according to claim 1, obtained by process a) or b) R ¹ , R ² , R ^J , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in claim 1 with the proviso that at least one of R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ or a pharmaceutically acceptable salt thereof, in admixture with carriers and / or other excipients commonly used in the manufacture of a medicament for the preparation of a medicament. (Priority 30/04/85).