KR900004398B1 - Monosulpactam Intermediates for Manufacturing and Manufacturing Method Thereof - Google Patents

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Description

Monosulpactam Intermediates for Manufacturing and Manufacturing Method Thereof

The present invention relates to compounds having antibacterial activity and pharmacologically acceptable salts thereof, represented by the following structural formula (I).

Symbols described in the above formula (I) and throughout the present specification are defined as follows. R 'and R2 are the same or different from each other and are each hydrogen or an alkyl group, or R' and R2 together are-(CH ₂ ) n-, where n is 2,3,4,5 or 6, and R₃ and R _{4, which} is the same as or different from each other, is hydrogen or an alkyl group having 1 to 3 carbon atoms, respectively.

The term "alkyl" is a straight and branched chain group unless otherwise defined. As such groups, groups having 1 to 10 carbon atoms are suitable.

Compounds according to the invention together with inorganic and organic bases form basic salts, which salts fall within the scope of the invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts and salts with organic bases such as dicyclohexylamine, benzatin, N-methyl-di-glucamine, hydramine, and the like.

Compounds of the invention are represented by acids. However, they also exist as zwitterions (internal salts) and are also included in the "pharmacologically acceptable salts", which are included within the scope of the present invention.

Β-lactams of the formula (I) and pharmacologically acceptable salts thereof have activity against gram positive and gram negative bacteria. The compounds of the present invention are used in the treatment of bacterial hepatitis (including urinary tract infections and respiratory infections) in mammals, for example livestock (dogs, cats, cattle, horses, etc.) and humans.

To treat mammalian bacterial infections, the compounds of the present invention were administered at a dose of about 1.4-300 mg / kg / day, suitably about 14-100 mg / kg / day, to a mammalian animal in need thereof. In order to use the β-lactam according to the present invention, all the administration modes conventionally used for delivering penicillin and cephalosporin to the site of infection, such as oral, intravenous, intramuscular administration and suppository administration, are used. It was.

The compound according to the present invention is represented by the following structural formula (II)

Wherein A 'is a carboxyl protecting group. Carboxyl protecting groups are known in the art and are used to prevent the carboxyl groups from participating in the following reactions. Examples of groups used to protect carboxyl groups are described in US Pat. No. 4,144,333, filed March 13, 1979. As the protecting group, t-butyl, diphenylmethyl and phenylmethyl groups are suitable.

Carboxylic protecting groups can be removed using methods well known in the art that vary depending on the particular protecting group. For example, when the protecting group is a t-butyl group, it uses trifluoroacetic acid, dichloromethane and anisole, trifluoroacetic acid and thioanisole, or trimethylsilyl iodide and acid scanbinder, For example, it can be removed using N-methyl-N- (trimethylsilyl) trifluoroacetamide. If the protecting group is a diphenylmethyl group, it can be removed using trifluoroacetic acid, dichloromethane and anisole. If the protecting group is a phenylmethyl group, it uses trifluoroacetic acid and thioanisole, or trimethylsilyliodide and an acid scanbinder, for example N-methyl-N- (trimethylsilyl) trifluoroacetamide Can be removed. The compounds of formula (II) are new and these compounds form an important part of the present invention.

The compound of formula (II) is reacted with 2-amino-4-thiazolylglyoxylic acid (or a derivative thereof protected with an amino group) to give the following formula (III)

(Wherein A ₂ is hydrogen or an amino protecting group) to obtain a compound. Amino protecting groups are well known in the art and they are used to prevent the amino groups from participating in the following reactions. Examples of amino protecting groups include aromatic acyl groups (e.g. p-nitrobenzyl and p-tert-butylbenzoyl groups), aliphatic acyl groups (e.g. formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl And trifluoroacetyl groups), esterified carboxyl groups (eg methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, β, β , β-trichloroethoxy carbonyl, benzyloxy carbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbon Carbonyl, isobornyloxycarbonyl and phenyloxycarbonyl groups), methylene groups [eg, (hexahydro-1H-azin-1-yl) methylene groups], sulfonyl groups (eg 2-amino-2-carboxyethylsulfo Amino-protecting groups (eg, trityl, 2-nitrophenylthio, Di- or trialkylsilyl, benzyl and p-nitrobenzyl groups). Carboxylic acids of formula III are novel compounds, which form an important part of the present invention.

The carboxylic acid of the formula (III) is represented by the formula (IV)

By coupling with β-lactam of Structural Formula (V)

The corresponding compound represented by is obtained. The reaction proceeded very easily when the carboxylic acid was active. Active forms of carboxylic acids are well known in the art, and examples include acid halides, acid anhydrides (including mixed anhydrides), active acid amides and active acid esters. From the compound of the above formula (V), using a method known in the art, the borage was removed to obtain the corresponding product of the formula (I).

As another method, the compound of formula II is represented by the following formula

By reacting with glyoxylic acid of, the corresponding compound of formula (V) can be obtained, and the protecting group can be removed from the compound to obtain the corresponding product of formula (I).

As another method, the compound of formula (I) is removed from the compound of formula (II) by using a method known in the art to remove the protecting group

It can be prepared by obtaining a product of. The compounds of formula (VII) are novel and these compounds form an important part of the present invention.

The compound of formula (VII) was reacted with the compound of formula (VI), and optionally the protecting group was removed to obtain the compound of formula (I).

Β-lactam of formula (IV) is initially represented by the following formula

Wherein A ₃ is an amino protecting group, preferably t-butoxycarbonyl or benzyloxycarbonyl group, and the compound represented by the following structural formula (IX)

A ₄ -O-NH ₂

(Wherein A ₄ is a protecting group such as benzyl, trityl or pivaloyl group) by coupling with O-protective hydroxylamine represented by the following structural formula (X)

It can be prepared by obtaining the corresponding compound represented by. The reactant coupling agent, for example '-ethyl-3- (dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide or dicyclohexylcarbodiimide N-hydroxybenzotriazole was carried out in the presence.

The compound of formula (X) is represented by the following structural formula (XI)

Wherein m is 0,1,2 or 3, and is reacted with a pyridine (optionally substituted) -sulfur trioxide complex to give the following structural formula (XII)

The corresponding compound of was obtained. The sulfonation reaction can be carried out in an organic solvent such as pyridine, mono-, di- or trimethylpyridine, dichloromethane, 1,2-dichloroethane, acetonitrile, diethylformamide or dioxane.

The compound of formula (XII) is cyclized by treatment with a base to give the following formula (XIII)

The corresponding compound of was obtained. The base is suitably an inorganic base, for example an alkali metal carbonate, and the reaction can be carried out in a mixture of water and an organic solvent (eg ethyl acetate, ethyl butyl ketone, pyridine or mono-, di- or trimethylpyridine). have.

From the compound of formula (XIII), protecting group A ₄ is removed using techniques known in the art to give the following formula (XIV)

The corresponding compound of was obtained. For example, when A ₄ is a benzyl group, protecting group removal can be accomplished by catalytic hydrogenation. When A ₄ is a pivaloyl group, protecting group removal can be accomplished by treatment with a base such as sodium sulfide or sodium hydroxide. When A ₄ is a trityl group, protecting group removal can be achieved by treatment with an aqueous 80% acetic acid solution.

The compound of formula (XIV) was treated with pyridine (optionally substituted) -sulfur trioxide complex of formula (XI) to give the following formula (XV)

The pyridinium salt of the corresponding compound of was obtained. The reaction can be carried out in a solvent such as pyridine (optionally substituted), dichloroethane or 1,2-dichloroethane. Conventional techniques (eg, ion-exchange resins) can be used to convert the pyridinium salts formed above to other salts and free acids.

The compound of formula (IV) wherein A ₂ is hydrogen can be obtained by removing the protecting group of the corresponding compound of formula (XV). The protecting group removal method used depends on the specific protecting group. For example, when the protecting group is a t-butoxycarbonyl group, trifluoroacetic acid can be used to remove the amino-protecting group. When the protecting group is a benzyloxycarbonyl group, a catalytic hydrogenation reaction can be used.

Β-lactam of formula (IV) can also be prepared using the method described in US Pat. No. 4,337,197, filed June 29, 1982. In addition, the compounds of formula (VI) can be prepared using the acylation techniques described in the patent.

과 반응 (알돌 축합)시키고, 이어서 카르복실 보호기를 제거시키는 것이다.The amino acids of the structural formulas are known or can be obtained using methods known in the art [eg, J. Org. Chem., 44, page 3967 (1979), J. Org. Chem., 46, 2809 (1981), Z. Chem., 10, 393 (1970), Tetrahedron, 39, 2085 (1983), Liebigs Annalender Chem. , 763, page 1 (1972), Synthesis, page 216 (1979), Bul1. Chem. Soc. Japan, 39, page 2287 (1966)], the above methods are suitable ketones that protect protected glycine (both amino and carboxyl groups are protected).

Reaction (aldol condensation), followed by removal of the carboxyl protecting group.

The compound of formula (II) wherein "A" is a t-butyl group and R 3 and R are each hydrogen is the following formula (XVI)

Compounds of can be prepared by treating with hydrazine or methylhydrazine. Compounds of formula (XVI) wherein A 'is a t-butyl group are known (see Belgium Patent 866,422), and by means known in the art, the t-butyl group is removed and a replacement protecting group such as diphenylmethyl or phenylmethyl groups It can be substituted with.

Compound of formula (II) is represented by formula (XVII)

It can be prepared from ketones or aldehydes. The compound of formula (XVII) is reacted with α-haloacetate ester (eg ethyl chloroacetate) in the presence of a strong salt such as potassium t-butoxide, and then the resulting glycidic ester is hydrolyzed [J.0rg. Chem. 26, page 3176 (1961)], the following structural formula (XVIII)

The salt of the corresponding compound represented by is obtained.

As another method, the compound of formula (XVIII) may be represented by the following formula (XIX)

The salt of the compound was treated with aqueous hydrogen peroxide solution in the presence of sodium tungstate catalyst [J.0rg. Chem., 50, page 1979 (1985).

The presence of a base of a compound of formula (XVIII) in a solvent (e.g. water, water / dioxane, water / dimethylsulfoxide, water / ethanol, ethanol, dimethylformamide or diethylsulfoxide) Treated with acetoneoxyl, benzaldehyde oxime, p-methoxybenzaldehyde oxime or t-butyl N-hydroxycarbamate

Wherein A ₅ is isopropylidene, benzylidene or p-methoxybenzylidene, or "A ₅ = N-" is a t-butoxycarbonylamino group. When A ₅ is an isopropylidene, benzylidene or p-methoxybenzylidene group, the compound of formula (XX) is taken off using a mineral acid in the presence of water, and this is replaced by a technique known in the art. Can be converted to a compound having a replacement protecting group (ie, A ₅ is a phthaloyl group or “A ₅ = N group” is a t-butoxycarbonylamide group). When "A ₅ = N-" is a t-butoxycarbonylamino group, converting the compound of formula (XX) to a compound having a replacement protecting group uses trifluoroacetic acid and anisole to remove the protecting group, which It can be accomplished by substitution with a replacement protecting group by techniques known in the art.

A compound of formula (XX) (or a compound corresponding thereto having a different protecting group) is esterified using a carboxyl protecting group A 'to give the following formula (XXI)

The corresponding compound of was obtained.

Compounds of formula (XXI) are dehydrated using any one of a number of techniques known in the art, to give formula (XXII)

The corresponding compound of was obtained. For example, dehydration can be achieved by treating the compound of formula (XXI) with methanesulfonyl chloride in the presence of at least 2 equivalents of trimethylamine. Alternatively, the compound of formula (XXI) is treated with methanesulfonyl chloride in the presence of at least one equivalent of triethylamine, and then the corresponding mesylate is isolated and finally an inorganic base in an organic solvent such as dimethylformamide. (Example: potassium carbonate) to remove the compound to obtain a compound of formula (XXII). Alternatively, compounds of formula (XXI) were converted to compounds of formula (XXII) using reagents such as thionyl chloride / pyridine, phosgene / pyridine or diethylaminosulfurtrifluoride / pyridine.

The protecting group was selectively removed from the compound of formula (XXII) using techniques known in the art to obtain the target compound of formula (II). Alternatively, a protecting group removal technique known in the art may be used to convert the compound of formula (XXII) to the corresponding compound of formula (VII).

In the above synthetic method for preparing a compound of formula (II) or formula (III), from the compound of formula (XVIII) wherein R ₄ is in the trans position relative to the carboxyl moiety, R ₄ is the cis of the carboxyl moiety. It is possible to produce compounds of general formula (I) in position.

As another method, the following structural formula (XXIII)

From the amino acid of, a compound of formula (II) or formula (VII) wherein one of R 3 and R VII is hydrogen and the other is an alkyl group having from 1 to 3 carbon atoms can be prepared.

The compound of formula (XXIII) is converted to the corresponding benzyl ether using conventional methods to give formula (XXIV)

Was obtained.

The compound of formula (XXIV) is reacted with nitrous acid in the presence of bromine ions to give structure (XXV)

The corresponding compound of was obtained.

Compound of formula (XXV) is esterified using t-butyl group by a conventional method to formulate (XXVI)

The corresponding compound of was obtained.

The compound of formula (XXVI) is reacted with N-hypoxyphthalimide in dimethylformamide in the presence of a base such as potassium carbonate to give the following formula (XXVII)

Was obtained. This was hydrolyzed to remove the benzyl protecting group, followed by dehydration to give the following structural formula (XXVIII)

Was obtained.

By a method known in the art, the t-butyl group of the compound of formula (XXVIII) is substituted with a replacement protecting group such as a diphenylmethyl group to give the following formula (XXIX)

Was obtained.

The compound of formula (XXIX) was treated with hydrazine or methylhydrazine to obtain the corresponding compound of formula (II) wherein A 'is a diphenylethyl group. Standard protecting group removal and protecting group introduction methods were used to convert this compound to other compounds of formulas (II) and (VII).

As another method, the compound of formula (XXVI) is treated with t-butyl-N-hydroxycarbamate in a solvent such as dimethylformamide in the presence of a base such as sodium hydride to give the following formula (XXX)

Can be converted to the corresponding compound.

The benzyl protecting group was removed from the compound of formula (XXX) by hydrogenolysis, and then dehydrated to give formula (XXXI).

Was obtained. Using standard protecting group removal and protecting group introduction methods, compounds of formula (XXXI) can be converted to compounds of formula (II), which can be readily converted to the corresponding compounds of formula (VII).

Using this method, the following geometric formula (XXXII)

From the compound having the following structural formula (XXXIII)

A compound having

Alternatively, the following structural formula (XXXIV)

Wherein one of R 3 and R ′ is hydrogen and the other is an alkyl group having from 1 to 3 carbon atoms, and is used in the preparation of the compound of formula (XVI) and described in Belgian Patent No. 866,422 It can be converted to the compound of formula (XXVIII) by a similar method.

The compound having the structure of formula (XXXIV) in which R 'is in the seaswitch with respect to the carboxyl group is converted to the compound of structure (XXXIII) in which R ₄ is in the seaswitch with respect to the carboxyl group.

기를 가지며, R₃ 및 R.가 상이할 경우, syn 또는 abti 이성질체로 존재하거나, 또는, 이를 이성질체들의 혼합물로 존재한다. 이러한 이성질체들 모두가 본 발명의 범위 안에 포함된다.The compound of formula (I) has at least one chiral central carbon atom (at the 3-position of the β-lactam nucleus) to which an amino or acylamino substituent is attached. The present invention relates to such β-lactams wherein the stereochemistry at the 3-position chiral center of the β-lactam nucleus is identical to the arrangement at the 6-position carbon atom of natural penicillin (eg penicillin G). The compound of formula (I)

And when R 3 and R. are different, exist as syn or abti isomers, or as mixtures of isomers. All such isomers are included within the scope of the present invention.

을 가지며, 그리하여, syn 또는 anti 이성질체로 존재하거나, 또는 이들 이성질체들의 혼합물로 존재한다. 이러한 이성질체 형태 모두가 본 발명의 범위 안에 포함된다. 그러나, 일반적으로, 구조식(I)의 화합물의 syn 이성질체가 가장 큰 활성을 갖는다.Compound of formula (I) is an imino substituent

And thus exist as syn or anti isomers or as a mixture of these isomers. All such isomeric forms are included within the scope of the present invention. However, in general, the syn isomer of the compound of formula (I) has the greatest activity.

Hereinafter, the present invention will be described in more detail by the following examples.

Example 1

(±)-(Z) -2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-diethyl-2-oxo-1- (sulfooxy) -3- Azetidinyl] amino-2-oxoethylylene] amide] oxy] -2-propenoic acid

A) 2-[(1,3-dioxo-2H-isoindol-2-yl) oxy] -2-propenoic acid 2-[(l, 3-dioxo-2H-isoindol-2-yl) oxy A solution of 1.75 g (5.7 mmol) of 2-propenic acid and t-butyl ester in 10 ml of methylene chloride and 10 ml of anisole was treated with 5 ml of trifluoroacetic acid. After stirring overnight at room temperature, toluene was added thereto, and the reaction mixture was then concentrated in vacuo. The perfusion was treated twice with hexane to give 1.54 g of the title compound.

B) 2-[(1,3-dioxo-2H-isoindol-2-yl) oxy] -2-propenoic acid, diphenylmethyl ester 2-[(1,3-dioxo-2H-isoindole- 2-yl) oxy] -2-propenoic acid 1.54 g (4.8 mmol) was dissolved in 25 ml of acetonitrile, and thereto was added dropwise a solution of 1.17 g (5.94 mmol) / acetonitrile 50 ml of diphenyldiazomethane. After addition of about 1.1 equivalents of diphenyldiazomethane, measurement by tlc showed no starting material remaining. A small amount of acetic acid was added to decompose excess diphenyldiomethane. The reaction solution was concentrated to give a residue, the residue was dissolved in ethyl acetate, then washed with 1N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give a solid. This solid was treated with hexane to give 1.9 g of the title compound.

C) 2-amino-α [[[[1- (diphenylmethoxy) carbonyl] -ethenyloxy] imino-4-thiazole acetic acid

0.8 g (2 mmol) of 2-[(1,3-dioxo-2H-isoindol-2-yl) oxy] -2-propenoic acid and diphenylmethyl ester were dissolved in 50 ml of methylene chloride under an argon atmosphere at 0 ° C. To the resulting solution was added 100 mg of hydrazine hydrate (2 mmol in 1 ml of anhydrous ethanol). The reaction mixture was slowly warmed at 0 ° C. to room temperature for at least 1 hour and then further stirred at room temperature for 2 hours. The white precipitate was filtered off and the solution was diluted with diethyl ether and it was filtered again. The volatiles were removed from the filtrate to afford 2-aminooxy-2-propenic acid as a residue. 2-aminooxy-2-propene acid was dissolved in 6 ml of ethanol and 4 ml of water, and 0.31 g (1.8 mmol) of 2-aminothiazole-4-glyoxylic acid was added to this solution. The mixture was stirred at room temperature for 17 hours and then measured by tlc, indicating that the reaction was incomplete. To this was further added ethanol and water and a small amount of dimethylformamide was added to dissolve the reaction. The mixture was stirred for 72 hours and then measured by tlc, indicating no 2-aminooxy-2-propenoic acid remained. Evaporation gave the crude title compound, which was chromatographed with HP20 column using acetonitrile / water gradient (0-80%) as eluent. The fraction containing the product is concentrated to remove acetonitrile. The resulting aqueous slurry solution was filtered to afford the title compound as a precipitate. After drying the precipitate overnight in vacuo, 167 mg of the title compound was obtained.

D) N- (t-butyloxycarbonyl) -N ^2- (phenylmethoxy) -D, L-3-hydroxyvalineamide

A solution in which 24.84 g (106.6 mmol) of Nt-butyloxycarbonal-D, L-3-hygisivalin and 16.33 g (106.6 mmol) of hygioxybenzotriazole hydrate were dissolved in 500 ml of dry tetrahydrofuran to -10 ° C. Cool and add 22 g (106.6 mmol) of dicyclohexylcarbodiimide to it. The mixture was stirred for 1 hour under a nitrogen atmosphere of 0 ° C. Then, a solution of 13.13 g (106.6 mmol) of 0-benzylhydroxysilamine dissolved in 250 ml of dry tetrahydrofuran was added to the activated ester mixture for at least 15 minutes, and the resulting mixture was stirred for 1 hour under a nitrogen atmosphere of 0 ° C. Was stirred. The insoluble material was filtered off and the filtrate was evaporated in vacuo to give a foam. This foam was extracted with ethyl acetate and the more insoluble material was filtered off. The filtrate was washed twice with 5% sodium bicarbonate solution. The organic phase was dried using sodium sulfate and evaporated to give a syrup, which was crystallized using 130 ml of isopropyl ether to give 24.7 g of the title compound. Melting point: 76 ° C-78 ° C.

E) Round 500 ml of 8.08 ml (0.10 mole) of N- (t-butyloxycarbonyl) -N ^2- (phenylethoxy) -D, L-3- (sulfooxy) valineamide and pyridinium salt dry The flask was placed in a bottom flask and cooled to -10 ° C under a nitrogen atmosphere. 15.6 ml (0.10 mol) of trimethylsilyl chlorosulfonate was added dropwise with vigorous stirring using a magnetic stirrer, and then the reaction mixture, which was very thick due to precipitation of the product, was stirred at 0 ° C. for 0.5 hour. Chlorotrimethylsilane was removed in vacuo to give 15 g of pyridine-sulfur trioxide complex.

16.92 g (50 mmol) of N- (t-butyloxycarbonyl) N ^2- (phenylmethoxy) -D and L-3-hydroxyvalinamide are dissolved in 200 ml of dry pyridine, and the pyridine-sulfur trioxide complex 9.87 g (62.5 mmol) was added. The mixture was stirred for 2 hours under a nitrogen atmosphere of 55 ° C. Another portion of 790 mg (5 mmol) of the pyridine-sulfur trioxide complex was added thereto and the stirring was continued for 1 hour or more. The reaction mixture was stripped in vacuo to yield an oil. The oil was stripped three times with acetonitrile in vacuo to give a foamy crude compound. Yield was quantitative.

F) (±) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl-1- (phenylmethoxy) -2-azetidinone

A flask containing about 50 mmol of crude N- (t-butyloxycarbonyl (N ^2- (phenylmethoxy) -D, L-3- (sulfooxy) -valinamide, pyridinium salt) was placed in an empty bath, and To 400 ml of ethyl acetate and then a solution of 42.8 g (0.31 mol) of potassium carbonate dissolved in 90 ml of water was added with vigorous stirring The resulting mixture was refluxed under nitrogen atmosphere and stirred vigorously for 2 hours. After cooling to room temperature, each phase was separated The aqueous phase was extracted using ethyl acetate (200 ml × 2 times), then all organic phases were combined, dried using sodium sulphate and evaporated in vacuo. Was dissolved in 125 ml of ethyl acetate / hexane and quickly filtered through a Mallinkrodt SilicAR CC-7 350 ml pad (10 cm) using 40% ethyl acetate / hexane 3-4 L. The filtrate was evaporated in vacuo. 12.2 g of a solid was crystallized using 50 ml of isopropyl ether to obtain 7.15 g of the title compound (melting point: 110 ° C). G) (±) -3-[(t-butyloxycarbonyl) amino -1-hydroxy-4,4-dimethyl-2-azetidinone (±) -3-[(t-butyloxycarbonyl) amino-4,4-dimethyl-1- (phenylmethoxy) -2- 8.07 g (25 mmol) of azetidinone was hydrogenated at room temperature and atmospheric pressure in 40 ml of methanol using 0.6 g of 10% charcoal based palladium as a catalyst for 2 hours The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. This gave 5.78 g of the title compound in the solid phase.

H) (±) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl-2-oxo-1-azetidinylsulfate, tetrabutylammonium salt chlorosulfonic acid 12.27 g (0.105 mol)- At 40 ° C., a solution dissolved in 210 ml of dichloromethane under argon atmosphere was treated dropwise with 20.5 g (0.26 mol) of pyridine for at least 10 minutes. The mixture was stirred at 0 ° C. for at least 10 minutes and then at 25 ° C. for 10 minutes. To this was added a slurry of (±) -3-[(t-butyloxycarbonyl) amino] -1-hixishi 4,4-dimethyl-2-azetidinone in 20 ml of dichloromethane, and the mixture was 25 deg. Stirred for 3.5 h. This almost uniform solution was then treated with 250 ml of water and 17 g (0.05 mol) of hydrogen tetrabutylammonium sulfate. This mixture was mixed well and the organic phase was separated and then dried using sodium sulfate. Evaporation in vacuo gave a foam, which was further purified by dissolving in ethyl acetate, removing insoluble material and evaporating to give 30 g of the title compound on the foam.

I) (±) -3-amino-4,4-dimethyl-2-oxo-1-azetidinylsulfate (±) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl- 30 g (0.05 mol) of 2-oxo-1-azetidinylsulfate and tetrabutylammonium salt were added dropwise at -5 ° C in a solution of 125 ml of dichloromethane and 10 ml of anisole under argon atmosphere for 10 minutes. Treatment. After stirring the mixture at -5 ° C to 0 ° C for 2.5 hours, the mixture was diluted with 50 ml of ethyl acetate and then filtered. The solid was washed with dichloromethane and then ethyl acetate and dried in vacuo to give 9.4 g of the title compound as a white granular solid.

(J) (±)-(Z) -2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo-1- (sulfooxy)- 3-azetidinyl] amino-2-oxoethylideneamino] oxy] 2-propenoic acid, diphenylmethyl ester, 2-amino-α-[[[[1- (diphenyl) at -30 ° C under argon atmosphere. To a solution of 167 mg (0.4 mmol) ethoxy) carbonyl] ethenyloxy] amino] -4-thiazole-acetic acid and 56 μ1 (1.0 equiv) of triethyl amine was added 107 mg (0.4 mmol) of diphenyl chlorophosphate. The reaction mixture was stirred at -30 [deg.] C. for 1 hour to obtain mixed anhydride. 126 mg (0.6 mmol) of (±) -3-amino-4,4-dimethyl-2-oxo-1-azetidinyl sulfate were dissolved in dimethylformamide at 0 ° C., this solution and triethylamine 71 μ1 (0.85) Equivalent) was added simultaneously to the mixed anhydride solution at -30 ° C. The reaction mixture was stirred at −30 ° C. for 0.5 h and then slowly warmed to 0 ° C. for 1 h. The reaction mixture was concentrated in vacuo, then dissolved in acetone / water and adjusted to pH 6.5 with 1N potassium bicarbonate. This was eluted with 30% acetone / water as eluent in the Dowex AG (50 (K +) column, the appropriate fractions were combined and concentrated, and the remaining aqueous solution was added to an HP20 column.The column was eluted with water. And eluted with acetone / water gradient eluent (0-100%) The appropriate fractions were combined and lyophilized to afford the title compound, which was all used in the next step.

K) (±)-(Z) -2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo-1- (sulfooxy) -3 -Azetidinyl] amino-2-oxoethylidene] anino] oxy] -2-propenoic acid.

(±)-(Z) -2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-diethyl-2-oxo-1- (sulfooxy) -3- 10 ml of methylene chloride and 10 ml of anisole were added to a flask containing azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-propenoic acid and diphenylmethyl ester. After cooling the mixture to -5 [deg.] C., 8 ml of trifluoroacetic acid was added thereto, and the reaction mixture was then stirred for 45 minutes under an argon atmosphere of -5 [deg.] To 0V. Toluene was added thereto and the reaction mixture was evaporated to give a residue. Water and hexane were added to this residue, and each layer was separated. The aqueous layer was adjusted to pH 2.5 with 10% potassium bicarbonate. HP20 columns were used to elute first as water and then as acetone / water gradient eluent as eluent. Appropriate fractions were combined and lyophilized to afford the title compound as a white solid.

¹ H- (NMR (1: 1D ₂ O / CD ₃ CN): ∂1.57 (s, 3H); l.75 (s, 3H): 5.09 (s, 1H); 5.75 (d, J = 2.3Hz, 1H): 5.86 (d, J2.3 Hz, 1H): 7.42 (s, 1H).

Example 2

[3S (Z)]-2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo-1- (sulfooxy) -3-azeti Diyl] amino] -2-oxoethylideneamino] oxy] -2-propenic acid

A) 2-[(1,3-dioxo-2H-isoindol-2-yl) -oxy] -2-propenoic acid

49.9 g (0.173 mol) of 2-[(1,3-dioxo-2H-isoindol-2-yl) -oxy] -2-propenoic acid and t-butyl ester were dissolved in 300 ml of methylene chloride and 150 ml of anisole. The solution was treated with 300 ml of trifluoroacetic acid. After stirring the mixture overnight at room temperature, 800 ml of dry toluene was added thereto, and the reaction mixture was then concentrated in vacuo. The residue was treated twice with hexane to give 39.6 g of the title compound.

B) 2-[(1,3-dioxo-2H-isoindol-2-yl) oxy] -2-propenic acid, diphenylmethyl ester

39.6 g (0.17 mole) of 2-[(1,3-dioxo-2H-isoindol-2-yl) oxy] -2-propenoic acid are dissolved in 800 ml of acetonitrile, and a diphenyldiazomethane solution ( A solution of 43.4 g, 0.224 mol / acetonitrile) was added dropwise at 0 ° C. over 3 hours. The reaction solution was doubled to obtain a solid, which was treated with hexane. The resulting solid was dissolved in dichloroethane and filtered through a pad of silica gel (Kieselge 1 60). Hexane was added to the filtrate to give 47.7 g of the title compound.

C) 2-amino-α-[[[[1- (diphenylmethoxy) carbonyl] ethenyl] oxy] amino-4-thiazole acetic acid 2-[(1,3-dioxo-2H-isoindole -2-yl) oxy] -2-propenoic acid and 6.07 g (15.2 mmol) of diphenylmethyl ester were dissolved in 375 ml of methylene chloride in an argon atmosphere at 0 ° C., 0.76 g (15.2 mmol) of hydrazine hydrate in 4 ml of absolute ethanol. ) Was added. After 1 hour at 0 ° C., the mixture was evaporated at + 10 ° C., dried and treated with ethyl ether. This was filtered and the filtrate was concentrated to give 2-aminooxy-2-propenic acid and diphenylmethyl ester as residue. This compound was then treated with a solution of 2.61 g (15.2 mmol) of 2-amino-4-thiazoleglyoxylic acid dissolved in 50 ml of dimethylformamide at 20 ° C. followed by 5 ml of water. The reaction was stirred at 20 ° C. for 20 hours, then cooled and diluted with 250 ml of water. The resulting gum was stirred to give a granular solid, which was filtered off, washed with water, and then dried by azeotroping with acetonitrile. This dry solid was slurried with 100 ml of acetonitrile and then filtered and finally washed with acetonitrile, ethyl ether and hexane. Drying in air gave 1.97 g of the title compound.

D) N- (t-butyloxycarbonyl) -L-3-hygesivaline), α-methylbenzylamine salt.

A solution obtained by dissolving 7.02 g (30 mmol) of Nt-butyloxycarbonyl-D, L-3-higeshivaline in 250 ml of ethyl ether was dissolved in 3.63 g (30 mmol) of S-(-)-α-methylbenzylamine. Treated. After 8 hours, the resulting solids were filtered off. Recrystallization three times with acetonitrile gave 5.80 g of the title compound. Melting Point: l46。-147 ℃

[α] _D = -4.5 ° (c = 2.0, methanol)

E) 204.6 g (0.577 mol) of N- (t-butyloxycarbonyl) -L-3-hyoxysivalin N- (t-butyloxycarbonyl) -L-3-hygishivaline, α-methylbenzylamine salt ), 3 l of ethyl acetate, and 1 g of water dissolved in a mixture of 100 g of potassium bisulfate and 150 g of sodium chloride, and after separating the layers, the organic phase was washed with water and dried using magnesium sulfate. The organic solution was concentrated and treated with 800 ml of hexane to give 136 g of the title compound.

Melting Point: 120 ° -121 ℃

]_D=+7.81°[

] _D = + 7.81 °

F) N- (t-butyloxycarbonyl) -N ^2- (phenylmethoxy) -L-3-hydroxyvalinamide

Reaction was carried out by D of Example 1, but instead of N- (t-butyloxycarbonyl) -D, L-3-hydroxyvaline, N- (t-butyloxy carbonyl) -L-3-hydride Roxyvaline was used to obtain the title compound.

G) (3S) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl-1- (phenylmethoxy) -2-azetidinone

A solution of 296 ml (3.0 mol) of 2-methylpyridine dissolved in -2700 ml of methyl isobutyl ketone under an argon atmosphere was treated dropwise with 80 ml (1.2 mol) of chlorosulfonic acid for at least 30 minutes. After addition, the temperature of this mixture was brought to 25 ° C. for at least 30 minutes and held at this temperature for 30 minutes further. 338.4 g (1.0 mol) of N- (t-butyloxycarbonyl) -N ^2- (phenylmethoxy) -L-3-hydroxyvaline amido were added to this slurry, and the stirring was continued for 2 hours. To this mixture was added 800 ml of betyl isobutyl ketone, 1222 g (4.0 mol) of K ₂ B ₄ O ₇ .4H ₂ O, and 2700 ml of water, and the mixture was heated to 70 ° C. To this mixture was added dropwise at least 45 minutes with heating 1000 ml (2 mol) of 2N potassium hydroxide, and then the mixture was further heated for 55 minutes. Each layer was separated and the aqueous phase was extracted using 500 ml of methyl isobutyl ketone. The combined organic layers were cooled to 0 ° C. and washed with 3 l of cooled 20% potassium bisulfate and 1 l of ice water, followed by the addition of a solution of 50 g sodium bicarbonate and 100 g sodium chloride dissolved in 1 l water. The organic layer was dried using sodium sulfate and concentrated in vacuo. The residue was crystallized using 1.75 L / of isopropyl ether to give 161 g of the title compound.

Melting Point: 121 ° -122 ℃

]_D=+21.06°(c=2.55, CH₂CL₂)[

] _D = + 21.06 ° (c = 2.55, CH ₂ CL ₂ )

H) (3S) -3-[(t-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone

14.77 g (0.0461 mol) of (3S) -3-[(t-butyloxycarbonyl) amino-4,4-dimethyl-1- (phenylmethoxy) -2-azetidinone was added to 15 ml of ethanol and 85 ml of ethyl acetate. The dissolved solution was hydrogenated for 1.5 hours at 1 atmosphere using 0.75 g of a 5% carbon-based palladium catalyst. The reaction mixture was filtered and concentrated to give a white solid. This solid was recrystallized using ethyl acetate to give 8.82 g of the title compound.

Melting Point: 148 ° -149 ℃

]_D=+31°(C=1, 에틸 아세테이트)[

_D = + 31 ° (C = 1, ethyl acetate)

I) (3S) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl-2-oxo-1-azetidinyl sulfate, tetrabutyl ammonium salt

The reaction was carried out by the method of Example 1, except for (±) -3-[(t-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone (3S ) -3-[(t-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone to give the title compound on the foam.

J) (3S) -3-amino-4,4-dimethyl-2-oxo-1-azetidinylsulfate

The reaction was carried out by the method of Example 1, except that (±) -3-[(t-butyloxycarbonyl) amino] -4,4-dimethyl-2-oxo-1-azetidinyl sulfate, tetrabutylammonium salt Instead, (3S) -3-[(t-butyloxycarbonyl) amino-4,4-dimethyl-2-oxo-1-azetidinyl sulfate, tetrabutylammonium salt was used to obtain the title compound. A small amount of sample was recrystallized using ethanol / water to afford the title compound as a crystalline solid.

Melting Point: 140 ° -142 ° C (Decomposition)

]_D= 74.8°(c =1, H₂O)[

_D = 74.8 ° (c = 1, H ₂ O)

K) [3S (Z)]-2-[[[-(2-amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo-1- (sulfooxy) -3-ase Thidinyl] amino-2-oxoethylidene] amino] oxy] -2-propenic acid, diphenylmethyl ester, tetrabutylammonium salt at -30 ° C under a argon atmosphere, 2-amino-α-[[[1- 0.902 g (3.36 mmol) diphenyl chlorophosphate in a solution of 1.423 g (3.36 mmol) of (diphenylmethoxy) carbonylvinethenyloxy] amino] -4-thiazole acetic acid and 0.404 g (3.88 mmol) of tmeethylamine. Was added. The reaction mixture was stirred at −30 ° C. for 1 hour to give mixed anhydride. 0.706 g (3.36 mmol) of (3S) -3-amino-4,4-diethyl-2-oxo-1-azetidinyl sulfate was dissolved in 4 ml of dimethylformamide at 0 ° C, and this solution and triethylamine 0.404 g (3.88 mmol) was added simultaneously to the mixed anhydride solution at -30 ° C. The reaction mixture was slowly warmed to 0 ° C. for 1 hour. The reaction mixture was treated with 0.338 g (3.36 mmol) of triethylamine and then concentrated in vacuo. The residue was treated with water to give a gum, which was separated from the aqueous layer and washed again with water. The gum was dissolved in 100 ml of methyllian chloride and shaken by adding a solution of 1.l4 g (3.36 mmol) of hydrogen tetrabutylammonium sulfate dissolved in 30 ml of water. The organic phase was separated, washed three times with water, dried with sodium sulfate and evaporated to give a foam. The foam was dissolved in 30 ml of methylene hydrate and diluted to 120 ml by addition of ethyl acetate. This was crystallized to give 1.73 g of the title compound as a white solid.

Melting Point: 170 ° -172 ℃

L) [3S (Z)]-2-[[[1- (2-Amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo-1- (sulfooxy) -3- Azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-propenoic acid

[3S (Z)]-2-[[[1- (2-amino4-thiazolyl) -2-[[4,4-diethyl-2-oxo-1- (sulfooxy) -3-azeti Diylamino] -2-oxoethylritene] aminooxy] -2-propenic acid, diphenylmethyl ester, 2.l7 g (2.54 mmol) of tetrabutylammonium salt was dissolved in 24 ml of methylene chloride and 1 ml of anisole at -12 ° C. The solution was treated with 8 ml of trifluoroacetic acid and the reaction mixture was stirred at −10 ° C. under argon atmosphere for 1 hour. The mixture was treated dropwise using 60 ml of ethyl acetate and the resulting slurry was stirred for 20 minutes, then filtered and washed with ethyl acetate and hexanes. After drying in air, the solid was slurried at 50C with 50 ml of water to form crystals within minutes. After crystallization, the solution was filtered, the solid was washed with water and dried in vacuo to give 0.9 g of the title compound.

Melting Point: 140 ° -70 ° C (Decomposition)

Example 3

(±)-(Z)-[[[1- (2-amino-4-thiazolyl) -2-oxo-2-[[2-oxo-1- (sulfooxy) -1-azaspiro [3.3] Hept-3-yl] amino] ethylidene] amino] oxy] -2 -propenoic acid

A) N- (t-butoxycarbonyl) -α- (1-hexicyclocyclo) -glycine, benzyl ester

A solution of 9.7 ml (70 mmol) of diisopropylamine dissolved in 150 ml of dry tetrahydrofuran at −40 ° C. under argon atmosphere was treated with 39 ml (64.5 mmol) of l.71 N n-butyliridium in hexane, This pale yellow solution was stirred at −40 ° C. for 20 minutes. The solution was cooled to -78 deg. C, and a solution obtained by dissolving N- (t-butoxycarbonyl) glycine and 7.95 g (30 mmol) of benzyl ester in 30 ml of dry tetrahydrofuran was added dropwise at least 5 minutes. A yellow solution was obtained, which had some turbidity after 20 minutes. After 0.5 hour, a solution in which 2.42 g (2.0 ml, 34.5 mmol) of cyclobutanone was dissolved in 30 ml of tetrahydrofuran was added thereto. The resulting yellowish turbid mixture was stirred at −78 ° C. for 15 minutes and then left in an empty bath at 0 ° C. for 2 hours. After 1 hour at -25 ° C, the solution became clear and dark purple at -15 ° C. This was stirred at 0 ° C. for 0.5 hour and then treated with 3.96 g (66 mmol) of glacial acetic acid in 15 ml of tetrahydrofuran to give a pale yellow cloudy mixture. It was poured into 500 ml of cold water and extracted twice with ethyl acetate. The extract was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine, dried using sodium sulfate and evaporated to give a dark oil. This oil was chromatographed using hexane / ethyl acetate (2: 1) as an eluent, 800 ml of LPS-1, and the product fractions (Rf = 0.29) were combined to obtain 7.8 g of an oily product.

B) N- (t-butoxycarbonyl) -α- (1-hexicyclocyclo) -glycine

7.8 g (23.3 mmol) of N- (t-butoxycarbonyl) -α- (1-hygecycyclobutyl) -glycine and benzyl ester were obtained by using 1.0 g of 10% charcoal based palladium catalyst in 150 ml of anhydrous ethanol. Hydrogenation was carried out for 4 hours at 1 atm. The catalyst was filtered off and the solvent was evaporated in vacuo. Benzene was added thereto and evaporated twice to obtain 5.0 g of a hard foamy product.

C) N- (benzyloxy) -N ^2- (t-butoxycarbonyl) -α- (1-hexicyclocyclo) glycineamide

5.0 g (20.4 mmol) of N- (t-butoxycarbonyl) -α- (1-hexicyclocyclo) glycine were dissolved in 150 ml of dry tetrahydrofuran under argon atmosphere. To this was added 3.12 g (20.4 mmol) of hydroxybenzotriazole hydrate and the mixture was cooled to 0 ° C. and then treated with 4.20 g (20.4 mmol) of dicyclohexylcarbodiimide. After 1.75 hours at 0 ° C., an O-benzylhydrylsilamine solution dissolved in 15 ml of tetrahydrofuran was added thereto, and the mixture was stirred at 0 ° -25 ° C. for 17 hours. The tetrahydrofuran mixture was cooled to −10 ° C. for 20 minutes and the resulting breakdown was filtered and then washed with dry tetrahydrofuran. The filtrate was evaporated and the residue was dissolved in ethyl acetate, washed quickly with 2% potassium bisulfate, 5% brine, sodium bicarbonate and brine, then dried over sodium sulfate and evaporated to give a foam. This was treated with isopropyl ether to obtain 4.69 g of a color solid product.

Melting point: 95 ° -97 ° C.

D) 1- (benzyloxy) -3- [t-butoxycarbonyl) amino-2-oxo-1-azaspiro [3.3] heptane

3.50 g (10 mmol) N- (benzyloxy) -N ^2- (t-butoxycarbonyl) -α- (1-hydroxycyclobutyl) glycinamide in 200 ml of dry detrahydrofuran at 0 ° C under argon atmosphere Was treated with 2.4 ml (15 mmol) of diethylazodicarboxylate, followed by 10 minutes or more with a solution of 5.2 g (20 mmol) of triphenylphosphine in 500 ml of tetrahydrofuran, and the mixture was heated to 0 deg. Stirred for 1 h. 0.52 g (2 mmol) of triphenylphosphine was added because yellow persisted. After 15 minutes, it was evaporated in vacuo to give an oil. The oil was treated with 100 ml of hexane / ethyl acetate (2: 1) to obtain a white solid, which was filtered off. The filtrate was chromatographed with LPS-1800 ml to obtain a product fraction contaminated with impurities eluted at similar rates [(Rf = 0.8 in eluent hexane / ethyl acetate (1: 1)] Removal was carried out using isopropyl ether to give 1.07 g of product as a white solid.

Melting point 156 ° -157 ° C.

E) 3-[(t-butoxycarbonyl) amino-2-oxo-1- (sulfooxy) -1-azaspiro [3.3] heptane, 1 sodium salt

1.07 g (3.22 millibols) of 1- (benzyloxy) -3-[(t-butoxycarbonyl) amino-2-oxo-1-azaspiro [3.3] heptane in 10 ml of anhydrous ethanol under 1 atm, 0.4 g of charcoal based palladium catalyst was hydrogenated at 25 ° C. for 3 hours. The catalyst was filtered off, and the solvent was removed in vacuo at 10 ° C. to obtain a solid. This was dissolved in 19 ml of dry pyridine and treated with 1.44 g (9 mmol) of pyridine-trioxide in 25 ° C. and argon atmosphere. After 4 hours, the volatiles were removed in vacuo, the residue was dissolved in water and the pH (5.40) was adjusted to 6.45 using dilute sodium bicarbonate. Water was used as the eluent to elute the product within 300 ml by passing through a 40 ml Dowex AG50 (K +) column. It was freeze-dried to obtain a white solid, which was eluted with water using an HP-20 column and then chromatographed by eluting with acetone (20%) with increasing gradient. The resulting fractions were lyophilized to yield 0.75 g of a white powder product.

F) 3-amino-2-oxo-1- (sulfooxy) -1-azaspiro [3.3] heptane

0.3 g (0.87 mmol) of 3-[(t-butoxycarbonyl) amino-2-oxo-1- (sulfooxy) -1-azaspiro [3.3] heptane, 1 sodium salt at -10 deg. Was slurried in 2.5 ml of dry dichloromethane and 1.0 ml of anisole and then treated with 4.0 ml of trifluoroacetic acid. After 0.5 hour, a solid formed. After 1.5 hours, 4 ml of dry toluene was added thereto and the mixture was evaporated in vacuo to give 3-amino-2-oxo-1- (sulfooxy) -1-azaspiro [3.3] heptane as a solid, which was Treated twice with hexane and dried for 1 hour in 25 ° C. vacuum.

G) (±)-(Z) [[[1- (2-amino-4-thiazolyl) -2-oxo-2-[[2-oxo-1- (sulfooxy) -1-azaspiro [3.3 ] Hept-3-yl] aminoethylidene] amino] oxy] -2-propenic acid, diphenylmethyl ester, tetrabutyl ammonium salt

The reaction is carried out according to Method K of Example 2, except for (3S) -3-amino-4,4-dimethyl-2-oxo-1-azetidinyl sulfate, 3-amino-2-oxo-1- (Sulfooxy) -1-azaspiro [3.3] heptane was used to obtain the title compound.

H) (±)-(Z)-[[[1- (2-amino-4-thiazolyl) -2-oxo-2-[[2-oxo-1- (sulfooxy) -1-azaspiro [ 3. 3] hept-3yl] ethylidene] amino] amide] oxy-2 -propane

The reaction was carried out by the method L of Example 2, except that [3S (Z)]-2-[[[1- (2-amino-4-thiazolyl) -2-[[4,4-dimethyl-2-oxo -1- (sulfooxy) -3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-propenoic acid, diphenylmethyl ester, tetrabutylammonium salt, instead of (±)-( Z)-[[[1- (2-amino-4-thiazolyl) -2-oxo-2-[[2-oxo-1- (sulfooxy) -1-azaspiro [3.3] hept-3-yl ] Amino] ethylidene] amino] oxo] -2-propenic acid, diphenylmethyl ester, tetrabutylammonium salt, and HP-20 resin was not recrystallized using precipitate and water precipitated from ethyl acetate diluent. Chromatography to obtain the title compound. Melting Point: 170 ° -200 ° C (Decomposition)

Claims (5)

Compound represented by the following structural formula

Wherein A 'is hydrogen or a carboxyl protecting group, and R 3 and R' are the same or different from each other and are hydrogen or an alkyl group having 1 to 3 carbon atoms, respectively. The compound according to claim 1, wherein the compound is a compound represented by the following structural formula.

Wherein R ₃ and R ₄ are the same as or different from each other, and are each hydrogen or an alkyl group having 1 to 3 carbon atoms. Structural formula

A structural formula characterized by reacting a compound of hydrazine or methyl hydrazine with

Process for producing a compound represented by the formula A 'is a carboxyl protecting group. Structural formula

Structural formula characterized in that the protecting group of the compound represented by

In the above formula, A 'is a carboxyl protecting group, A ₅ is isopropylidene, benzylidene, or p-methoxybenzylidene, or A ₅ = N is t-butoxycarbonylamino group , R 3 and R VII are the same or different from each other and are hydrogen or an alkyl group having 1 to 3 carbon atoms, respectively. Structural formula

Structural formula characterized in that the protecting group of the compound represented by

Method for producing a compound represented by the formula A 'is a carboxyl protecting group, R 3 and R' are the same or different from each other, each hydrogen or an alkyl group having 1 to 3 carbon atoms.