JPS5850981B2 - Amidoketsugouoyuusuru Kagobutsuno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION In the present invention, when producing a compound having an amide bond by reacting a compound having a carboxy group with a compound having an NH that can be acylated, R1 is an organic residue, R2 is the formula -N=(wherein, R3
is lower alkoxycarbonyl group or carbamoyl group)
, a succinimide group, a benzotriazolyl group or an oxobenzotriazinyl group optionally substituted with a group selected from halogen, nitro, or vinyl, respectively). The present invention relates to a method for producing a compound having an amide bond, which is characterized in that it is used as a condensing agent.

This invention provides a novel method for producing compounds having an amide bond using sulfonic acid esters (I) as a condensing agent.

When a compound having a carboxy group and a compound having an NH that can be acylated are reacted using sulfonic acid esters (I) as a condensing agent, an amide is produced in high yield and in a relatively short time.

Sulfonic acid esters (I) are generally stable crystals and are not easily hydrolyzed even when they come into contact with water. Also, unlike other condensing agents, there is no risk of causing rashes or burns, and they are very easy to handle. Furthermore, when used as a condensing agent, the amidation reaction proceeds quickly under mild conditions, with little risk of side reactions, and is useful for the synthesis of unstable and difficult-to-synthesize compounds. This method is also suitable for direct reaction between the two without first activating the carboxy group of a compound having a carboxyl group or activating the NH of a compound having an NH that can be acylated as in conventional methods. It has excellent features such as:

In this invention, N which can be acylated with a carboxy group
When H belongs to different molecules, it also includes cases where it has side groups in one molecule, and when it has side groups in one molecule, the side groups react within the molecule to form an amide bond. These cases are also included within the scope of the present invention.

The compounds having a carboxyl group used in this reaction include all compounds having one or more carboxyl groups in the molecule, and specifically include saturated or unsaturated compounds,
It includes all linear, branched or cyclic, substituted or unsubstituted aliphatic, aromatic and heterocyclic compounds.

In addition, in this invention, the compound having NH that can be acylated includes all of ammonia, primary amines, and secondary amine compounds, and specifically includes ammonia and saturated or unsaturated, chain, branched, or cyclic compounds. It includes all primary or secondary amine compounds containing substituted or unsubstituted aliphatic, aromatic, or heterocycles in the molecule, and in the heterocycle, NH is present as a heteroatom in the ring. You can leave it there.

In a compound containing a carboxyl group and NH in one molecule, when the side groups bond within the molecule to form an amide bond, the carboxyl group and NH are separated by at least two or more carbon atoms. The order of addition of the sulfonic acid ester (I) used as a condensing agent in this reaction is not particularly limited, and for example, the sulfonic acid ester (I) is added to a metal compound having a carboxy group, and then A method of adding a compound having an NH that can be acylated, a method of adding a sulfonic acid ester (I) to a compound having an NH that can be acylated, and then adding a compound having a carboxyl group, and a method of adding the above three at the same time. This reaction can be carried out by any method such as the addition method, but when a compound having a carboxy group is reacted with a compound having an NH side group that can be acylated with a carboxy group in one molecule, It is preferable to first add the sulfonic acid ester (I) to a compound having a carboxy group, and then add a compound having an NH side group that can be acylated with the carboxy group in one molecule.

Among the sulfonic acid esters (I) used as condensing agents in this invention, for example, l-methanesulfonyloxy-1
, 2.3-benzotriazole can be produced by reacting methanesulfonyl chloride with 1-hydroxy-1,2,3-benzotriazole in the presence of a base, and other compounds can be produced in the same manner. can.

Sulfonic acid esters are represented by the above general formula (I),
More specifically, the organic residue in R1 means any substituted or unsubstituted aliphatic hydrocarbon residue, substituted or unsubstituted aryl group, or substituted or unsubstituted heterocyclic residue; The aliphatic hydrocarbon residue in the substituted aliphatic hydrocarbon residue is a saturated or unsaturated aliphatic hydrocarbon residue, which may have a side chain or be cyclic, and more specifically, for example,
Alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, vinyl, 2-propenyl, 1-isopropenyl,
Alkenyl such as 3-butenyl, 2-methyl-2-propenyl, alkynyl such as ethynyl, 2-propynyl, cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, shifrob7:-)L/, cyclopentenyl , cycloalkenyl such as cyclohexenyl, bicycloalkyl such as 1,7.7-t-limethylbicyclo[2,2,1]heptyl, cycloalkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, etc. Alkyl-alkyl, cycloalkyl-alkeni/L/ such as 2-cyclohexylvinyl, 3-cyclohexyl-2-propenyl, cycloalkenyl-alkyl such as cyclopropenylmethyl, 2-cyclobutenylethyl, cyclohexenylmethyl, 2- C'70hexenylvinyl, 3-
Cycloalkenyl-alkenyl such as cyclohexenyl-2-(2-methylpropenyl), 7,7-dimethylbicyclo[2,2,1]heptylmethyl, 7,7-dimethyl-2-bicycloC2,2,1] Examples include bicycloalkyl-alkyl such as butylethyl.

These aliphatic hydrocarbon residues may have one or more substituents at their positions, such as alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, etc. Methylthio, ethylthio,
Alkylthio such as propylthio and isopropylthio, amine, mercapto, halogen such as nitro, cyano, chloro, fluoro, frome, oxo, carboxy, sulfo,
Hydroxy, hydroxyamino, mono(or di)methylamino, mono(or di)ethylamino, mono(
Also included are all groups that do not adversely affect this reaction, such as mono(or di)alkylamino groups such as di)propylamino and mono(or di)isopropylamine, aryl groups, acyl groups, and heterocyclic groups.

Here, examples of aryl include phenyl, xylyl, tolyl, naphthyl, etc. Furthermore, these aryl groups have one or more substituents at any position that do not adversely affect this reaction. It may have more than that.

Aryls having such substituents include, for example, 4-
Methoxyphenyl, 4-methylthiophenyl, 4-aminophenyl, α-aminonaphthyl, 2-amino-3゛-
Hydroxyphenyl, 4-mercaptophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl, 4-sulfophenyl, 4-hydroxyphenyl, 4-hydroxyaminophenyl, 4-dimethylaminophenyl, etc. can be mentioned.

Furthermore, the acyl in the substituent of an aliphatic hydrocarbon residue means a group obtained by removing a hydroxy group from an organic carboxylic acid or an organic sulfonic acid, and more specifically includes an aliphatic acyl, an acyl containing an aromatic ring, or a heterocycle. It means everything about Asil.

Furthermore, the aliphatic acyl is saturated or unsaturated alkanoyl or saturated or unsaturated alkanesulfonyl, which may have a side chain or be cyclic, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, pivaloyl. , acryloyl, crotonoyl, 2-methylacryloyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclohebutylcarbonyl, succinyl, cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexylsulfonyl, cyclohebutylpropionyl, dihydrobenzoyl, 2,4. 6-Cyclohebtatrienylacetyl, dihydrophenylacetyl, methanesulfonyl, exonsulfonyl, fropanesulfonyl, methanesulfonyl, vinylsulfonyl, allylsulfonyl, ethynylsulfonyl, cyclofurobylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohe xylsulfonyl, etc., and the carbon atom of the alkyl part of these saturated or unsaturated alkanoyls may be replaced with an oxygen atom or a sulfur atom; examples of such groups include methoxyacetyl, methylthioacetyl, etc. , 2-propenylthioacetyl, cyclohexylthioacetyl, cyclohexyloxyacetyl, dihydrophenoxyacetyl, dihydrophenylthioacetyl, and the like.

Acyls containing aromatic rings include benzoyl, toluoyl, naphthoyl, α-methylnaphthoyl, 7-taloyl,
Aroyl such as tetrahydro-7toyl, aralkayl such as phenylacetyl, phenylpropionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, tetrahydronaphthylacetyl, arylsulfonyl such as pencenesulfonyl, naphthylsulfonyl, P-toluenesulfonyl, etc. and aralkylsulfonyl such as benzylsulfonyl and 7enethylsulfonyl, and the carbon atom of the alkyl part of this aralkayl may be replaced with an oxygen atom or a sulfur atom, such groups include, for example, phenoxyacetyl, phenyl Thioacetyl, 2-phenoxypropionyl, 2
-Phenoxybutyryl and the like.

Furthermore, acyl containing a heterocycle includes saturated or unsaturated heteromonocyclic or heteropolycyclic residues containing at least one or more oxygen atom, sulfur atom, nitrogen atom, or other heteroatoms, such as chenyl, benzothenyl, furyl, etc. , pyranyl, 5,6-sihydro-2H-pyranyl, isobenzofuranyl, chromenyl, xanthenyl, 2H-
Pyrrolyl, 3H-pyrrolyl, pyridyl, imidazolyl,
Pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolyl, indolyl, invaleryl, quinolyl, isoquinolyl, isoxazolyl, inthiazolyl, oxadiazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, piperidinyl, piperazinyl,
Heterocyclic carbonyl and heterocyclic sulfonyl containing heterocycles such as diazolyl, triacylyl, oxasilyl, thiazolyl, thiadiazolyl, tetrazolyl, penzoxasilyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, cytononyl, etc. and acetyl, propionylbutyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, acryloyl having as a substituent a group such as the above heterocycle or heterocycle-substituted oxy, heterocycle-substituted thio, or heterocycle-substituted amine or N-alkylheterocycle-substituted amino. , crotonoyl, 2-methylacryloyl and other alkanoyls, such as IH (or 2H)-tetrazolylacetyltetrazolylpropionyl, chenylacetyl, chenylpropionyl, furylacetyl,
Examples include piperazinyl acetyl, pyrrolidinyl acetyl, pyrrolidinylpropionyl, pyridylpropionyl, thiadiazolyl acetyl, benzothiazolylacetyl, cytononylacetyl, oxacylylacetylbenzoxacylylacetyl, etc. The carbon atom of the alkyl moiety of the alkanoyl as a substituent may be replaced with an oxygen atom or a sulfur atom, and examples of such groups include pyridyloxyacetyl, tetrazolylthioacetyl, and the like.

Furthermore, these aliphatic acyls, acyls containing an aromatic ring, or acyls containing a heterocycle may have one or more substituents at any position, and such substituents include methyl, ethyl, Alkyl such as propyl, isopropyl, aldanyl such as -propenyl, 2-7'penyl, cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy,
Alkylthio such as methylthioethylthio, propylthio, isopropylthio, aryl such as phenyl, xylyl, tolyl, aralkyl such as benzyl, phenethyl, amino, mercapto, nitro, cyano, chlor, fluoro,
Halogen, carboxysulfo, hydroxy, etc.
Mono(or di)alkylamino groups such as hydroxyamino, mono(or di)methylamino, mono(or di)ethylamino, mono(or di)propylamino, mono(or di)isopropylamino, etc. have an adverse effect on this reaction. All substituents not provided are included.

Examples of aliphatic acyl, aromatic-containing acyl, or heterocyclic-containing acyl having such a substituent include chloroacetyl, chloromethylsulfonyl, cyanoacetyl,
2-chloropropionyl, trifluoroacetyl, α-
Aminophenylacetyl, α-hydroxyphenylacetyl, P-hydroxyphenylacetyl, 2-amino-
2-(5,6-sihydro-2H-pyran-3-yl)acetyl, 2-amino-2-(P-hydroxyphenyl)
Acetyl, 2,6-simethoxybenzoyl, α-hydroxychenylacetyl, 3-phenyl-5-methyl-4
-Oxasilylcarbonyl, 3-(210lophenyl)
-5-methyl-4-oxasilylcarbonyl, 3-(2
, 6-dichlorophenyl)-5-methyl-4-oxasilylcarbonyl, 3-(2-chloro-6-fluorophenyl)-5-methyl-4-oxasilylcarbonyl, and the like.

Furthermore, the heterocyclic group in the substituent of the aliphatic hydrocarbon residue contains at least one oxygen, nitrogen, sulfur atom, or other heteroatom, or contains one or more of these atoms, whether the same or different. It includes an aliphatic or aromatic heteromonocyclic group or a heteropolycyclic group.

For example, pyrrolidinyl, piperazinyl, piperidyl, piperidino, homopiperidyl, furyl, chenyl, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, quinolyl,
isoquinolyl, benzimidazolyl, pentuchenyl,
Benzothiazolyl, benzothiazolinyl, indolyl,
isoindolyl, benzoxasilyl, thiazolyl, thiadiazolyl, thiatriazolyl, morpholino, oxasilyl, benzoxasilyl, isoxazolyl, oxadiazolyl, oxatriazolyl, triazolyl, tetrazolyl, cytononyl, etc., and these heterocyclic groups have substituents such as methyl, ethyl Alkyl groups such as methoxy,
Alkoxy groups such as ethoxy, halogens such as fluoro, chloro, brome, oxo, amino groups, nitro groups, aryl groups such as phenyl, tolyl, xylyl, chlorophenyl,
Examples include cases in which the substituent has one or more same or different substituents that do not adversely affect this reaction, such as a substituted aryl group such as nitrophenyl, or an aralkyl group such as benzyl or phenethyl.

When the substituent of the above aliphatic hydrocarbon residue is a free amino group, hydroxy group, mercapto group, carboxy group, or sulfo group, or when the substituent of the above aliphatic hydrocarbon residue is an aryl group, an acyl group, When an amine group, hydroxy group, mercapto group, carboxy group and sulfo group are present in the heterocyclic group, such amine group, hydroxy group, mercapto group, carboxy group and sulfo group are protected with a protecting group. These cases are also included within the scope of this invention.

Here, the protecting group for the amine group includes all the groups that can be normally used as an amine protecting group, and includes, for example, aliphatic acyl as exemplified as the acyl in the substituent of the aliphatic hydrocarbon residue, and aromatic rings. Acyl or heterocyclic-containing acyl groups and groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertiary phthoxycarbonyl, benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, and amino groups protected with two carboxy groups For example, when an amino group is combined with phthalic acid to form an imide, all the protecting groups for hydroxy and mercapto groups that can be used as protecting groups for hydroxy and mercapto groups can be used. In addition to aliphatic acyl, acyl containing an aromatic ring, or acyl containing a heterocyclic ring, as exemplified as the acyl group in the substituent of the aliphatic hydrocarbon residue, methyl, ethyl, propyl, phenyl,
Examples include groups such as tolyl, xylyl, benzyl, phenethyl, methoxymethyl, etc. Protecting groups for carboxy and sulfo groups include all groups that can be used as normal protecting groups for carboxy and sulfo groups, such as carboxy and the hydrogen of the hydroxyl group of the sulfo group is methyl, ethyl, propyl, isopropyl, butyl, benzyl, P-nitrobenzyl, benzoylmethyl, acetylmethyl, P-nitrobenzoylmethyl, P-bromobenzoylmethyl, P-methanesulfonylbenzoylmethyl ,
Esters substituted with trichloroethyl, tribromoethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, etc., or hydroxyl groups of carboxy and sulfo groups substituted with amine, mono(or di)methylamine, mono(or di) ethylamino, mono(
Alternatively, examples include amides substituted with di)propylamino, mono(or di)isopropylamino, and the like.

Further, examples of the aryl group in the substituted or unsubstituted aryl group in the organic residue of R1 include the groups exemplified as the aryl group in the substituent of the aliphatic hydrocarbon residue; In addition to the groups exemplified as substituents for hydrocarbon residues, alkenyl such as vinyl, ■-proveni/L', 2-phrobenyl, ethynyl,
Examples include alkynyl such as 2-7'lopynyl, cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

When these substituents are free amine groups, hydroxy groups, mercapto groups, carboxy groups, and sulfo groups, or when amino groups, hydroxy groups, mercapto groups, and carboxy groups are present in the aryl groups, acyl groups, and heterocyclic groups of the substituents. When a sulfo group and a sulfo group are present, the cases where these groups are protected with a protecting group are also included in the scope of the present invention, and the protecting group is exemplified as a protecting group for these groups in the aliphatic hydrocarbon residue. Examples include groups such as:

In addition, examples of the heterocyclic residue in the substituted or unsubstituted heterocyclic residue in the organic residue of R1 include oxygen, nitrogen, sulfur atoms, etc. as exemplified as the heterocyclic group in the substituent of the aliphatic hydrocarbon residue. contains at least one heteroatom of
Examples of substituents include aliphatic or aromatic heteromonocyclic groups or heteropolycyclic groups containing more than 1,000 methyl,
Examples include alkyl such as ethyl and furobyl, alkenyl such as vinyl, 1-propenyl, and 2-propenyl, alkynyl such as ethynyl and 2-propynyl, and cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

When these substituents are free amine groups, hydroxy groups, mercapto groups, carboxy groups, and sulfo groups, or when amino groups, hydroxy groups, mercapto groups, and carboxy groups are present in the aryl groups, acyl groups, and heterocyclic groups of the substituents. When a sulfo group and a sulfo group are present, the scope of the present invention also includes the case where these groups are protected with a protecting group, and examples of the protecting group include those exemplified as protecting groups for these groups in the aliphatic hydrocarbon residues mentioned above. Examples include protecting groups such as those described above.

CN / In the general formula (I), the lower alkoxycarbonyl group in R3 of the group represented by the formula -N-\R3 in R2 includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, imbutoxycarbonyl, butoxycarbonyl. , imbutoxycarbonyl, and the like.

Examples of the halogen substituent for the benzotriazolyl group of R2 include chloro, fluoro, and bromine.

Representative fi sulfonic acid esters (I) include 2-
Methanesulfonyloxyimino-2-cyanoacetic acid ethyl ester, 2-methanesulfonyloxyimino-2-cyanoacetamide, N-methanesulfonyloxysuccinimide, l-methanesulfonyloxy-1,2,3-
Benzotriazole, 1-methanesulfonyloxy-6
-nitro 1.2.3-benzotriazole, 1-(D
L-10-kan7arsulfonyloxy) -L2,3
-Benzotriazole, 1-(DL-10-camphorsulfonyloxy)-6-chloro-1,2,3-benzotriazole to 1-(DL-10-camphorsulfonyloxy)-6-nitro 1.2. 3-penztriazole, 1-benzylsulfonyloxy-1,2,3
-benzotriazole, 1-(β-styrenesulfonyloxy) -1,2,3-benzotriazole, 1-methanesulfonyloxy-4-riOD-1,2,3-/<
Sotriazole, 1-methanesulfonyloxy-6-
Chloro-1,2,3-penztriazole, 2-(P-
Toluenesulfonyloxyimino)-2-cyanoacetic acid ethyl ester, l-pensenesulfonyloxy-1,2
, 3-penztriazole, ■-pensenesulfonyloxy-6-nitro-1,2゜3-penztriazole,
1-benzenesulfonyloxy-6-chloro-1,2,
3-benzotriazole, 1-(P-)luenesulfonyloxy) -1,2,3-penztriazole, 1-
(P-,)luenesulfonyloxy)-6-nitro-1
,2,3-benzotriazole, 1=(P-chlorobenzenesulfonyloxy)-1,2,3-benzotriazole, 1-(P-chlorobenzenesulfonyloxy)-
6-chloro-1,2,3-penztriazole, 1-(
P-nitropencenesulfonyloxy) -1,2,3
-benzotriasheet, ■-mesitylenesulfonyloxy-1.2.3-benz) IJ asole, 1-(3-
(pyridylsulfonyloxy)-1°2.3-benzotria sheets and the like.

The reaction of this invention is usually carried out in a solvent, and the solvents include ethyl acetate, chloroform, dimethylformamide,
Dichloromethane, tetrahydrofuran, acetone, water, etc. are used, but any other solvent that does not participate in this reaction can be used, and these solvents may be used in combination.

Additionally, this reaction is usually carried out using sodium hydroxide, if necessary.
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate, Inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium acetate,
Alkali metal acetate such as potassium acetate, trimethylamine, triethylamine, triethanolamine N.

It is carried out in the presence of an organic base such as N-dimethylaniline, N,N-dimethylbenzylamine, N,N'-dimethylpiperazine, N-methylmorpholine, pyridine, quinoline, etc., and these bases are used in combination. You can also do that.

Although the reaction temperature is not particularly limited, it is usually carried out under water cooling or at room temperature.

The product thus obtained is isolated and collected by conventional methods.

Next, this invention will be explained by examples.

Example 1 Acetic acid 0.3f? and triethylamine 0.7f111
is dissolved in ethyl acetate, 1.1f of ethyl ester of 2-methanesulfonyloxyimino-2-cyanoacetic acid is added to this solution at room temperature, and the mixture is stirred for 40 minutes.

Next, 0.51 g of aniline was added to this solution, and after stirring for 2 hours, the reaction solution was thoroughly washed with water, IN-sodium bicarbonate solution, water, and 1N-hydrochloric acid, and dried over magnesium sulfate.

After drying, the solvent is distilled off to obtain acetanilide 0.6S' in the form of flaky crystals with an mp95 of 105°C.

When ice crystals are recrystallized from water, the temperature becomes mp104 108°C.

Example 2 To a solution of 0.3 r of acetic acid, 0.7 of triethylamine, and 0.59 of aniline dissolved in 10 of ethyl acetate, l-
Add 1.05 r of methanesulfonyloxy-1,2,3-benzotriazole and stir at room temperature for 1 hour.

- After standing overnight, the reaction solution is extracted with ethyl acetate, the extract is washed with water, and then dried over magnesium sulfate.

After drying, when the solvent is distilled off, acetanilide 0.7 f
get.

When Motoichi is recrystallized from water, the temperature becomes mpllo-112°C.

Example 3 1H-tetrazole-1-acetic acid 1,281 and triethylamine 14- were combined with ethyl acetate 10- and chloroform 5-
7727! To this solution was added 2.21 g of ethyl ester of 2-methanesulfonyloxyimino-2-cyanoacetic acid, and the mixture was stirred at room temperature for 2 hours.
Add 95r and stir for an additional 2 hours.

Next, water was added to this solution and left overnight, and the precipitated crystals were collected with E and recrystallized from chloroform to give rnp 19.
2-(IH-tetrazole-1 at 2-193°C (decomposition)
-yl)acetanilide 0.31 is obtained.

In addition, from the mother liquor roughly mp190-191℃ (decomposition) 2
．． -(IH-tetrazol-1-yl)acetanilide 0.41 is obtained.

Elemental analysis: C, HoON.

Calculated values: C53,19, H4,46, N34.47 Experimental values: C5292, H4,26, N34.07 Example 4 1.28 g of 1H-tetrazole-1-acetic acid, 1.4 m of triethylamine and 0.953 F of aniline was dissolved in 10 d of ethyl acetate, and the ethyl ester of 2-methanesulfonyloxyimino-2-cyanoacetic acid 2 was added to this solution at room temperature.
．． Add 21 and stir at room temperature for 2.5 hours.

Next, water was added to this solution and left overnight, and the precipitated crystals were treated with r and recrystallized from chloroform to give mp192.
2-(1H-tetrazol-1-yl)acetanilide 1.75f at 193°C (decomposed) is obtained.

Example 5 N-benzyloxycarbonyl-L-7'loline 125
and L-leucine ethyl ester hydrochloride 1. or
was suspended in 10 ml of chloroform, then 1.10 g of N-methylmorpholine was added and dissolved. To this solution was added 11 g of ethyl ester of 2-methanesulfonyloxyimino-2-cyanoacetic acid, and the mixture was stirred at room temperature for 16 hours. .

After the reaction, ethyl acetate is added to the reaction mixture for extraction, and the extract is washed with water, 1N aqueous sodium bicarbonate solution, water, 1N hydrochloric acid, and water in this order, and dried over magnesium sulfate.

After drying, the solvent was distilled off and the residue was crystallized by adding petroleum ether to obtain 14 g of ethyl ester of N-(N-benzyloxycarbonyl-L-7''loryl)-ri-leucine with a mp of 65-67°C. .

Elemental analysis: C, H3,0, N2 Calculated values: C64,59, H7,74, H7,18 Experimental values: C64,68, H7,88, H7,20 Example 6 N-benzyloxycarbonyl-L-proline 1.25
S' and L-leucine ethyl ester hydrochloride 1.0
2 was suspended in 10 rrll of chloroform, and then 1.40 ml of triethylamine was added to dissolve it. To this solution was added 1.11 ml of ethyl ester of 2-methanesulfonyloxyimino-2-cyanoacetic acid, and the mixture was stirred at room temperature for 16 hours.

After the reaction, ethyl acetate is added to the reaction solution for extraction, and the extract is washed with water, IN aqueous sodium bicarbonate solution, water, IN hydrochloric acid, and water in this order, and dried over magnesium sulfate.

After drying, the solvent is distilled off, and petroleum ether is added to the residue for crystallization to obtain 0.8P of ethyl ester of N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine with a mp of 55-67°C.

Example 7 N-benzyloxycarbonyl-L-florin 1, 2
5 f and L-leucine ethyl ester hydrochloride 1.
After suspending 01 in 107 ml of chloroform and dissolving it by adding 1.40 yd of triethylamine, add 1.071 yd of 1-methanesulfonyloxy-1,2,3-benzotriazole to this solution and stir at room temperature for 16 hours. .

After the reaction, ethyl acetate was added to the reaction solution for extraction.
Wash with hydrochloric acid and water in that order, and dry with magnesium sulfate.

After drying, the solvent is distilled off, and the residue is crystallized by adding petroleum ether to obtain 1.45f of N-(N-benzyloxycarbonyl-L-7'loryl)-ri-leucine ethyl ester with a mp of 6566°C.

Example 8 N-benzyloxycarbonyl-L-7'loline 1, 2
5 r and L-leucine ethyl ester hydrochloride 1.
02 was suspended in 10 rnl of chloroform, then 1.4-triethylamine was added to dissolve it. To this solution was added 1st ethyl ester of 2-(P-toluenesulfonyloxyimino)-2-cyanoacetic acid, and the mixture was stirred at room temperature for 16 hours. Stir.

After the reaction, ethyl acetate is added to the reaction mixture for extraction, and the extract is washed successively with water, 1N sodium bicarbonate aqueous solution, water, 1N hydrochloric acid, and water, and dried over magnesium sulfate.

After drying, the solvent was distilled off, and the residual oil (1,6y) was dissolved in chloroform, and then subjected to silica gel column chromatography using chloroform as a developing solvent. After concentrating the first fraction, ether and petroleum were added to the residue. When crystallized by adding ether, N-(
Ethyl ester of N-benzyloxycarbonyl-L-prolyl-leucine 80rn& is obtained.

This product was fixed by the standard sample and infrared absorption spectrum.

Example 9 1.73 g of N-benzyloxycarbonyl-8-benzyl L-cysteine and 0.70 g of hydrochloride of glycine ethyl ester were dissolved in 12 TL of dimethylformamide, and 1.4011 L of triethylamine was added to this solution followed by 2-methanesulfonyloxyimino. Add 1.1 g of ethyl ester of -2-cyanoacetic acid.

After standing at room temperature for 14 hours, water and ethyl acetate were added to the reaction solution for extraction, and the extract was washed successively with water, IN-hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then water, and dried over magnesium sulfate.

After drying, the solvent was distilled off, ethanol and petroleum ether were added to the residue to crystallize it, and when it was taken out of the oven and dried, it gave mp9
N-(N-benzyloxycarbonyl-8 at 3-95°C
0.5 g of ethyl ester of -benzyl-L-cysteinyl)glycine is obtained.

This product was identified using the standard specimen and infrared absorption spectrum.

Example 10 1.73 g of N-benzyloxycarbonyl-8-benzyl-L-cysteine and 0.709 g of glycine ethyl ester hydrochloride were suspended in 20 TL of chloroform, and 1.4 ml of triethylamine was added to dissolve the solution. 1-methanesulfonyloxy-1,2 under stirring with water cooling.
, 1.07 g of 3-penztriazole were added, and after stirring for 2 hours, the mixture was heated overnight.

After water and ethyl acetate are added to the reaction mixture for extraction, the extract is washed successively with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and water, and dried over magnesium sulfate.

After drying, the solvent was distilled off, and petroleum ether was added to the resulting residue to crystallize it.
-benzyloxycarbonyl-8-benzyl-L-cysteinyl) ethyl ester of chrysin 1.259 is obtained.

This product was identified using the standard specimen and infrared absorption spectrum.

Example 11 2-methoxy-4-amino-5-chlorobenzoic acid 1.0
．． 9 and 1-methanesulfonyloxy-1゜2.3-
Benzotriazole 1.07f! Chloroform 157
0.7 of triethylamine suspended in rLl and stirred with water cooling.
ml dropwise to make a clear solution.

Then, 0.69 g of 2-(diethylamino)ethylamine was added to this solution at room temperature, stirred, and left at room temperature for 18 hours.

After standing, the solvent was distilled off, water and a 1N aqueous sodium hydroxide solution were added, and the precipitated crystals were collected, washed with water, and dried to give N-(2-diethylaminoethyl)-2-methoxy-4 with a mp of 145-146°C. -Amino-5-chlorobenzamide O,'l is obtained.

This product was identified as the standard product by infrared absorption spectrum.

Example 12 5-chloro-2-benzothiazolinone-3-acetic acid 2.5
g and 1.4 ml of triethylamine were dissolved in 257 rL of dichloromethane, 2.2 g of 1-methanesulfonyloxy-1,2,3-benzot-IJ azole was added to this solution at room temperature, and after 10 minutes, 1-(2-hydroxy Add 1.3 g of ethyl)piperazine.

After standing at room temperature for 18 hours, the reaction solution was diluted with saturated hydrogen carbonate l-I.
Wash with Jumium aqueous solution and dry with magnesium sulfate.

After drying, ethanol and ether were added to the residue obtained by distilling off the solvent to crystallize it, which was washed with acetone and dried to give 3-44-(2
-hydroxyethyl)-1-hiheracinyl]carbonylmethyl-51c]rho-2-benzothiazolinone 1.3 g
get.

This product was identified as the standard product by infrared absorption spectrum.

Example 13 4.2 g of 2-chenylacetic acid and 4. triethylamine.
7-amino A solution of 5.6 g of cephalosporanic acid and 8.4 ml of triethylamine dissolved in 30 TL of dichloromethane was added at once at room temperature, stirred for 2 hours, and then left to stand for 20 hours.

After the reaction, add about 3TLl of triethylamine to the reaction solution,
Extracted once with 50 mA' of water and twice with 25-, and the extract was adjusted to pH 4.2 with acetic acid, then extracted with Zeolite 1-A-6.
A 5% sodium acetate-acetic acid aqueous solution 4007711 having a pH of 4.5 is passed through a column having an inner diameter of 2.5 CrrL filled with 75 TL of resin.

The eluate is gradually acidified with 6N hydrochloric acid and extracted with 100 TL of ethyl acetate, and the extract is dried over magnesium sulfate.

After drying, the solvent was distilled off under reduced pressure, and about 50 d of ether was added to the resulting residual oil to crystallize it, which was then dried several times to give 7-(2-(
2-chenyl)acetamido)cephalosporanic acid5.
Obtain 5 g (70%).

Motoichi was identified as a specimen by infrared absorption spectrum.

Example 14 1.5 g of N-benzyloxycarbonyl-L-phenylalanine and 0.7 TL of triethylamine were dissolved in 20 yd of anhydrous tetrahydrofuran, and 1-methanesulfonyloxy-1,2,3-benzol was added to this solution at room temperature.
-IJ Add 1.10 g of azole and stir for 1 hour, then add 3.0 ml of 28% aqueous ammonia and stir for 2 hours.

-After standing overnight, the solvent was distilled off under reduced pressure, water was added to the residue, the crystals were crushed, the crystals were crushed, washed with water, and then dried. 1.15 g of L-phenylalanine amide is obtained.

Motoichi was identified as a specimen by infrared absorption spectrum.

Example 15 N-benzyloxycarbonyl-L-/”) 1.25
．． ! Li' and L-valine ethyl ester hydrochloride 1
．． 08g of dichlormecne was dissolved in 15TfLl, and 1.54ml of triethylamine was added to this solution under ice cooling, followed by 1-
After adding 1.079 g of methanesulfonyloxy-1,2,3-benzotriazole, the mixture was allowed to stand at room temperature for 72 hours.

After the reaction, ethyl acetate and water were added to the reaction solution and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off to give N-(N-benzyloxycarbonyl-L-valyl).
-1.70 g of ethyl ester of L-valine is obtained.

When Motoichi is washed with petroleum ether, mp 93-93.5
Obtain 1.50 g of powder at °C.

Example 16 3.0 g of N-benzyloxycarbonyl-L-phenylalanine and the hydrochloride of the methyl ester of L-isoleucine 1. s2g was dissolved in 30ml of anhydrous dichloromethane, and 2.807d of triethylamine was added to this solution under stirring while cooling with water.
Then, 2.1 sg of 1-methanesulfonyloxy-1,2,3-benzotriazole was added, and the mixture was stirred at room temperature for 40 hours.

After the reaction, the solvent was distilled off, ethyl acetate was added to the residue for extraction, and the extract was washed five times with water, a saturated aqueous sodium bicarbonate solution, water, 2N hydrochloric acid, and water in that order, and then washed with magnesium sulfate. dry.

After drying, the solvent is distilled off to form a crystalline powder of N(N-benzyloxycarbonyl-L-
3.46 g of methyl ester of (phenylalanyl)-L-isoleucine are obtained.

Example 17 N-benzyloxycarbonyl-L-7'loline 1.2
5. ii', L-serine methyl ester hydrochloride 0.7
8g and 1.4Q1rLl of triethylamine were dissolved in 20TLl of anhydrous chloroform, and 1-benzenesulfonyloxy-6-chloro-1,2
, 1.5 g of 3-benzotriazole were added and stirred for 1 hour.

- After standing overnight, ethyl acetate and water are added to the reaction mixture, extracted with ethyl acetate, washed and dried.

After drying, the solvent was distilled off, and the remaining oil was left to crystallize. Ether and petroleum ether were added to the crystals, and the crystals were taken in an oven to give N -(N-penzyloxycarbonyl) with a mp of 97-100°C. 1.5 g of methyl ester of L-L-7'loryl)-L-serine is obtained.

Example 18 N-(N-benzyloxycarbonylglycyl)-L-
Phenylalanine 0.9 & Chrysin ethyl ester hydrochloride 0.35g and triethylamine 0.70T
L1 was dissolved in 10 TL of anhydrous chloroform, and 0.55 g of 1-methanesulfonyloxy-1,2,3-benzotriazole was added to this solution at room temperature, followed by stirring for 1 hour.

- After standing overnight, ethyl acetate and water are added to the reaction mixture and extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium bicarbonate solution, water, 1N hydrochloric acid and water in this order, and dried over magnesium sulfate.

After drying, the solvent is distilled off and the resulting crude crystals are recrystallized from 2% ethanol to give N-(N-(
0.80 g of ethyl ester of N-penzyloxycarbonylchrysyl)-L-phenylalanyl)chrysin is obtained.

Example 19 N-benzyloxycarbonyl-L-valine 1.26.
91 Glycine ethyl ester hydrochloride 0.70 g and triethylamine 1.40 TLl were dissolved in anhydrous chloroform 1
0TfLl, 1.05 g of 1-methanesulfonyloxy-1,2,3-benzo-IJ azole was added to this solution while stirring under water cooling, and the mixture was stirred at room temperature for 20 hours.

After the reaction, ethyl acetate and water are added to the reaction solution, extracted with ethyl acetate, and the extract is washed and dried.

After drying, when the solvent is distilled off, N-
1.1 g of hydrochloride of ethyl ester of (N-benzyloxycarbonyl-L-valyl)chrysin is obtained.

Example 2O NG-tertiary butoxycarbonyl-NG-nitro-L-
1.60 g of arginine and 2.22 g of p-toluenesulfonate of L-tyrosine benzyl ester were dissolved in 20 TL of anhydrous chloroform, and 1.4 OmA' of triethylamine was added to this solution, followed by 1-methanesulfonyloxy-1
, 2,3-penztriazole 1.05g was added, and 20
Stir at room temperature for an hour.

After the reaction, ethyl acetate and water are added to the reaction solution, and extracted with ethyl acetate. The extract is washed sequentially with water, saturated aqueous sodium bicarbonate solution, water, citric acid aqueous solution, and water, and dried over magnesium sulfate.

After drying, the solvent was distilled off, and 2.2 g of the resulting residue was dissolved in chloroform, and then subjected to chromatography using 20 g of silica gel and eluted with chloroform to obtain an amorphous powder of N-(NG-tertiary butoxycarbonyl- 2.0.9 Benzyl ester of NG-nitro-L-arginyl)-L-tyrosine was obtained.

Elemental analysis: C2□H3608N6・'/2H20 Calculated values: C55,75, H6,41, N14.47 Experimental values: C
55,95, H6,41, N14.14 Example 21 1.21 g of dihydrochloride of methyl ester of L-histidine
was suspended in 20 ml of chloroform, 1.407 d of triethylamine, 1.4 d of N-benzyloxycarbonyl-L-glutamine (Bi') and 0.70 ml of triethylamine were added thereto, and after stirring for a while, 1-methanesulfonyloxy-1,2 , 3-benzotriazole (1.0'l) and stirred for 1 hour.

After standing overnight, the solvent was distilled off, and the residue was dissolved in water.
Then, 1N aqueous sodium hydrogen carbonate solution was added and cooled.
Collect the gel-like product and wash with water.

The mixed product is heated with a small amount of water, then cooled and the precipitate is removed to obtain 1.25 g of N-(N-benzyloxycarbonyl-L-glutaminyl)-L-histidine methyl ester with a mp of 186-188°C. .

Elemental analysis: C2oH2506N5 Calculated values: C55,67, H5,84, N16.24 Experimental values: C55,53, H5,81, N16.22 Example
22 2.3 g of 2-methoxy-5-sulfamoylbenzoic acid and 1.41 rLl of triethylamine were dissolved in 20Tll of anhydrous tetrahydrofuran, and then 2.2 g of 1-methanesulfonyloxy-1,2,3-benzotriazole was added to this solution at room temperature. After stirring for 20 minutes, 1.3 g of 1-ethyl-2-aminomethylpyrrolidine was added, generating heat and precipitating an oily substance.

After stirring for 1 hour, the solvent was distilled off, the residual oil was dissolved in IN-hydrochloric acid, and then washed twice with ethyl acetate.

After distilling off the remaining ethyl acetate under reduced pressure, the aqueous layer is made alkaline by adding ammonia water, and the precipitate is separated, washed with dilute ammonia water, and dried.
2.2 g of 1-ethyl-2-(2-methoxy-5-sulfamoylbenzamidomethyl)pyrrolidine are obtained.

Example 23 1-n-butanesulfonyloxy-6-chloro-1,2
, 1.47 g of 3-benzotriazole, 1.409 g of N-benzyloxycarbonyl-L-glutamine and 0.7 ml of triethylamine were added to 10 ml of anhydrous acetonitrile.
It crystallizes when added to a solution in 1 rLl at room temperature.

After 30 minutes, P- of L-tyrosine benzyl ester was added to this.
2.2 g of 1-luenesulfonate and 0.7 ml of triethylamine were added to 20 ml of anhydrous acetonitrile! When a solution dissolved in is added and stirring is continued, the crystals gradually dissolve to form a homogeneous solution, and when stirring is continued for a further 3 hours, a gel-like substance is precipitated.

After standing overnight, water was added to the reaction solution to dissolve it, concentrated under reduced pressure, water and ethyl acetate were added to the residue, and filtration resulted in m
1.275 g of benzyl ester of N-(N-benzyloxycarbonyl-L-glutaminyl)-L-tyrosine at p 165-170°C are obtained.

The ethyl acetate layer of the filtrate was washed with IN hydrochloric acid, an aqueous sodium bicarbonate solution, and water in that order, dried over magnesium sulfate, and the solvent was distilled off to obtain the target compound of mp 164-1676C.
．． Obtain 642g.

If you recrystallize Honjima from methanol, mp173-174
°C.

Example 24 125 g of N-benzyloxycarbonyl-L-proline
, L-leucine ethyl ester hydrochloride 1.00g, N
-1.10 yd of methylmorpholine to 101 yd of chloroform
1.20 g of 4-oxo-3,4-dihydro-3-methanesulfonyloxy-1,2,3-benzotriazine is added to this solution and left overnight.

Water and ethyl acetate are added to the reaction solution, and after extraction with ethyl acetate, the extract is washed and dried.

After drying, - when the solvent is distilled off, the N-
(N-benzyloxycarbonyl-L-prolyl)-ri-leucine ethyl ester 1. : Get 1.

Example 25 4.6 g of N-(N-benzyloxycarbonyl-L-7'loryl)-ri-leucine, 1.8 g of hydrochloride of glycine ethyl ester and 1.78 ml of triethylamine
4.25 g of 1-(p-toluenesulfonyloxy)-6-nitro-1,2,3-benzotriazole was added to a solution of 40 mL of anhydrous chloroform while cooling with ice water, and the mixture was stirred for 1 hour.

- After standing overnight, water and ethyl acetate were added to the reaction solution for extraction, and the extract was washed six times with 1N ammonia water containing 5% sulfur chloride, water, IN hydrochloric acid, then water, and sulfuric acid. Dry with magnesium.

After drying, the solvent was distilled off, and the residue was washed with a mixture of ether and petroleum ether to give N-(N-(N-benzyloxycarbonyl-L-prolyl)-L-leucyl) with an mp of 149 to 150°C. Ethyl ester of glycine 3.
Obtain 0g.

Example 26 N-benzyloxycarbonyl-L-proline 1.25
g, 0.78 g of L-serine methyl ester hydrochloride and 1.40 yd of triethylamine were dissolved in anhydrous chloroform 2
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2 to this solution under cooling with ice water.
, 1.72 g of 3-benzotriazole was added and left overnight.

After water and ethyl acetate are added to the reaction solution and extracted, the extract is washed and dried.

After drying, when the solvent is distilled off, N-(
N-benzyloxycarbonyl-L-prolyl)-L-
1.4 g of serine methyl ester is obtained.

Example 27 6.9 g of 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole was added to a solution of 2.4 g of benzoic acid and 2.8 TLl of triethylamine dissolved in 30 TrLl of dichloromethane. Stir for an hour.

After the reaction, dichloromethane is distilled off, and the residue is extracted with water and ethyl acetate.

The extract was washed with an aqueous sodium bicarbonate solution and then with water.
Dry with magnesium sulfate.

After drying, the solvent was distilled off to form crystals of 1-benzoyloxy-6-chloro-1,2,3-benzotriazole 4.6
get g.

When this crystal is recrystallized from ethanol, it has a mp of 132°C.

1-benzoyloxy-6-chloro-1 obtained above
, 2.75 g of 2,3-benzotriazole and 0.93 g of aniline. ! Dissolve li' in chloroform and stir for 4 hours.

After adding ethyl acetate to the reaction solution, water, IN hydrochloric acid, water,
The mixture is washed with an aqueous solution of t-IJium hydrogen carbonate and then with water, and dried with magnesium sulfate.

After drying, the solvent is distilled off, and the remaining crystals are washed with a small amount of ether and sifted to give 1.8:l of benzanilide with a mp of 158-160°C.

Example 28 1.4'l of N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)"D-glycine and 2.4'l of 7-amino-3-methyl-3-cephem-4-carboxylic acid.
2.2=hydrochloride of trichloroethyl ester], 6
6 g was suspended in 20 m of dry chloroform, and N-
Add 1.10 TL of methylmorpholine to make a homogeneous solution.

To this solution, 1.49 g of 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole was added while cooling with ice water, and the mixture was stirred at room temperature for 4 hours.

Water and ethyl acetate are added to the reaction solution to separate the layers, and the ethyl acetate layer is washed with an aqueous solution of t-IJ carbonate, water, a 5% aqueous citric acid solution, and water in this order, and then dried over magnesium sulfate.

After drying and filtration, the solvent was distilled off from the filtrate, and ether and petroleum ether were added to the residue to crystallize it. When this was dried several times, 7-[N-tertiary butoxy 2.25 g of carbonyl-2-(3-mesylaminophenyl)-D-glycinamide 3-methyl-3-cephem-4-carboxylic acid CD2,2.2-toIJ chloroethyl ester are obtained.

Example 29 N-benzyloxycarbonyl-L-7'loline1.
2! Hydrochloride of l and L-leucine ethyl ester 1.
0 g of a well-washed and dried weakly basic ion exchange resin DOWEX MWA-1 (trademark: manufactured by Dow Chemical Co.) 3.1 was added to a solution in which 20 g of dichloromethane was vertically suspended.

To this solution was added 1.72 g of 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole under ice-water cooling, and the mixture was shaken at room temperature until dissolved, and then allowed to stand for 72 hours with occasional shaking.

The reaction solution is filtered and the resin is washed several times with acetone.

Solution F and washing solution were combined and concentrated, and then the residue was dissolved in ethyl acetate.

The ethyl acetate solution is washed with an aqueous sodium bicarbonate solution and an aqueous solution of I-IJ chloride in this order, and dried over magnesium sulfate.

After drying, the solvent is distilled off, and a small amount of n-hexane is added to the obtained oil to crystallize it.
660C N-(N-benzyloxycarbonyl-L-
ProIJ, +L/)-L-leucine ethyl ester 1
．． Get 676.9.

Example 3O N-benzyloxycarbonyl-L-alanine 2.38
9 was dissolved in acetonyl)IJyl0TLl, and 1.49m of triethylamine was added to this solution under water cooling, followed by 1-(p-
'70 lobenzenesulfonyloxy) = 6-chloro-I
When 3.96 g of H-benzotriazole was added and stirred for 30 minutes, white crystals were precipitated.

After stirring for 3 hours and 15 minutes, about 50-chloroforme was added to the reaction solution.
to make the solution homogeneous.

To this solution is added a suspension prepared by suspending 3.96 g of 3.5-dibenzyloxyphenethylamine hydrochloride in 50 TrL of acetonitrile and adding 1.49 ml of triethylamine while cooling with water to form a homogeneous solution.

After this was left to stand overnight, the solvent was distilled off, water was added to the residue and stirred, and then an aqueous sodium bicarbonate solution was added and further stirred.

Handle the crystals, wash with water, dry, and add 2201 rL of methanol.
Recrystallization from mp 143-146 °C N-
(N-benzyloxycarbonyl-L-alanyl)-3
, 3.4 g of 5-dibenzyloxyphenethylamine are obtained.

After concentrating the filtrate to 110 TLl and allowing it to stand, 1.5 g of the target substance is obtained.

Total yield 4.9g0 Example 31 N-(N-benzyloxycarbonylglycyl)-L-
712 mA of phenylalanine, 206 mA of glycine ethyl ester, and 0.16 mA' of pyridine were dissolved in dry acetonitrile 10-1, and this solution was added 1 (1) under ice-water cooling.
p-chlorobenzenesulfonyloxy)-6-chloro-
After adding 689 ml of IH-benzotriazole and stirring for 1 hour, the mixture was left to stand overnight.

The reaction solution was extracted with ethyl acetate, and after drying the extract, the solvent was distilled off, resulting in N-(N =
(N-benzyloxycarbonylglycinolyl-'L-phenylalanyl)chrysin ethyl ester 598 ml is obtained.

Example 32 3.2 g of 1-methanesulfonyloxy-IH-benzotriazole was added to a solution of 2.4 g of 2-(1,2,3-thiadiazol-3-yl)acetic acid, 30 ml of dichloromethane, and 2.1 ml of triethylamine under stirring under water cooling. Add gradually and stir for 1 hour.

This solution was added to 7-amino-3-(5-methyl-1,3,4
-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 3.4 g and triethylamine 2
．． Add at once to a solution of 8 TLl dissolved in 30 TLl of dichloromethane under water cooling and stirring.

After stirring for 30 minutes, it was left to stand for 20 hours, and then 21 ml of triethylamine was added to the reaction solution, followed by 30 ml of water! Extract once at 15 yards and twice at 15 yards.

After adding acetic acid to the extract to adjust the pH to 4.5, this solution was poured into a tube with an inner diameter of 2.5 (
The mixture was adsorbed onto a column of 5% sodium acetate and acetic acid at pH 4.5, and flushed out with a 100% aqueous solution of sodium acetate and acetic acid at pH 4.5.

This aqueous solution was gradually acidified with 6N hydrochloric acid and extracted with ethyl acetate iOOm.

After drying the extract with magnesium sulfate and activated carbon, the solvent was distilled off, and the remaining oil was crystallized by adding 50 d of ether to it.
C (decomposition) of 7-(2-(1,2,5-thiadiazol-3-yl)acetamide)-3-,(5-methyl-1
,3,4-thiadiazol-2-yl)thiomethyl-3
2.35 g of -cephem-4-carboxylic acid are obtained.

Similarly, the following condensing agents are used to obtain the same results as above.

1) 2-methanesulfonyloxyimino-2-cyanoacetamide 143-145°C.

mp 2) N-methanesulfonyloxysuccinimide m
p150-152°c.

3) 1-methanesulfonyloxy-6-nitro-1,2
, 3-benzotriazole, mpH 7-118°c.

4) 1-methanesulfonyloxy-6-chloro0-1,2
．． 3-benzotriazole, mpH 7-118°C (decomposed).

5) 1-methanesulfonyloxy-4-chloro-1,2
, 3-benzotriazole, mp71-74°C86)
1-(DL-10-camphorsulfonyloxy)-1
,2,3-benzotriazole, mp146-148°
C0 7) 1-(DL-10-camphorsulfonyloxy)
-6-nitro-1,2,3-benzotriazole, m
p 157-159°C.

8) 1-(DL-10-camphorsulfonyloxy)
-6-chloro-1,2,3-benzotriazole, mp
151-153°C.

9) 1-Benzylsulfonyloxy-1,2,3-benzotriazole, mp 65-67°c.

10) 1-benzenesulfonyloxy-1,2,3
-benzotriazole, mp 83-84°C11)
1-benzenesulfonyloxy-6-nitro-1,
2,3-benzotriazole, mp124°C812)
1-(p-1 luenesulfonyloxy)-1,2,3-
Benzotriazole, mp 85-86°C.

13) 1-(p-1-ruenesulfonyloxy)-6-
Nitro-1,2,3-benzotria-sil, mp1
44℃.

14) 1-(p-chlorobenzenesulfonyloxy)-1,2,3-benzotriazole, mp94-9
5℃.

15) 1-(pichlorobenzenesulfonyloxy-6
-Chloro-1,2,3-benzotriazole.

mp 125-127°c.

16) 1-(1)-tritrobenzenesulfonyloxy)
-1,2,3-benzotriazole, mp119.5~
121.5℃.

17) 1-(3-pyridylsulfonyloxy)-1,2
,3-benzotriazole, mp 98°C618)
1-mesitylenesulfonyloxy-1,2,3-benzotriazole, 130-131°C0p 19) 1-(β-styrenesulfonyloxy)-1,2
, 3-benzotriazole, mpH 7-118°c.

20) 1-(n-butanesulfonyloxy)-1,2°3-benzotriazole, oil.

Infrared absorption spectrum (liquid film) 1395.1175 (m' 21) 1-benzylsulfonyloxy-6-chloro-1,2,3-benzotriazole, mp 126.
5-127.5°c.

22) 1-(p-toluenesulfonyloxy)-6-chloro-1,2,3-benzotriazole, mp94-9
6°c.

23) 4-oxo-3,4-dihydro-3-benzenesulfonyloxy-1,2,3-benzotriazine.

mpH 7-118°c.

24) 1-methanesulfonyloxy-6-vinyl-
1,2,3-benzotriazole, mp129-129
．． 5°c.

25) 1-(p-vinylbenzenesulfonyloxy)-
6-pinyl-1,2,3-benzotriazole, mp
85-87°C.

26) 1-(p-chlorobenzenesulfonyloxy)-6-pinyl-1.2.3-benzotriazole, m
p125°C0 27) 1-(p-Toluenesulfonyloxy)-6-pinyl-1.2.3-benzotriazole.

mp90-91°C.

Claims (1)

[Claims] 1 N that can be acylated with a compound having a carboxy group
When reacting with a compound having H to produce a compound having an amide bond, the general formula % formula % [In the formula, Ro is an organic residue, R2 is the formula -N-'\R3 (In the formula, R3 is a lower benzo) which may be substituted with a group selected from alkoxycarbonyl group or carbamoyl group), succinimide group, halogen, nitro or vinyl, respectively. 1. A method for producing a compound having an amide bond, which comprises using the sulfonic acid ester shown below as a condensing agent.