WO1998045290A1

WO1998045290A1 - 2-aminothiazoleacetamide derivatives

Info

Publication number: WO1998045290A1
Application number: PCT/JP1997/001170
Authority: WO
Inventors: Fumiaki Iwasaki; Herman Petersen; Keiji Terao; Shohei Tani
Original assignee: Tokuyama Corporation
Priority date: 1997-04-04
Filing date: 1997-04-04
Publication date: 1998-10-15

Abstract

2-Aminothiazoleacetic acid derivatives of general formula (I), wherein R1, X and Y are each a specified organic group. These compounds are particularly useful for the acylation of some cephalosporin antibiotics.

Description

Specification

2-aminothiazole amide derivative Technical field

The present invention relates to a novel 2-aminothiazoleacetic acid amide derivative. These derivatives are useful as intermediates in the synthesis of pharmaceuticals, especially cephalosporin antibiotics. Background art

The following formula (Π)

In the above formula, R ³ is a protecting group for a hydrogen atom or an amino group, and Ζ is a group

,.

C or C = N-OR ⁴

Η

(Where R ⁴ is a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group, an aryl group or a hydroxyl group protecting group). The thiazolecarboxylic acid derivative represented by is an intermediate for the production of pharmaceuticals, for example, It is an important compound used in the side chain (formation of an acyl group) of antibiotics such as cefm. The above compound is combined with a / 3-lactam compound such as a 7-aminocephalosporanic acid derivative by an amidation reaction to form a basic skeleton of an antibiotic. At this time, the thiazolecarboxylic acid derivative represented by the above formula (II) is converted into a more reactive derivative (hereinafter referred to as a reactive derivative) in order to facilitate the reaction with the amino group. 7-aminocephalosporanic acid It is a common method to react with a conductor.

As such a reactive derivative, the terminal carboxyl group of the thiazole carboxylic acid derivative represented by the above formula (II) is substituted with a halogen such as phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentabromide. Active compounds obtained by reacting an agent or a lower alkyl chlorocarbonate have long been proposed.

However, such reactive derivatives have high reactivity, but have a problem in stability. Therefore, conversion to the reactive derivative is performed immediately before the reaction with the 7-aminocephalosporanic acid derivative, using water-free, The reaction was performed under control under strict reaction conditions such as low temperature, and it was common to react with a 7-aminocephalosporanic acid derivative without isolation.

Therefore, development of a reactive derivative that can be isolated, is stable, and reacts with a 7-aminocephalosporanic acid derivative under mild conditions has been eagerly desired. In view of the above problem, many reactive derivatives having various characteristic groups introduced by reacting the thiazole derivative represented by the above formula (II) with a carboxyl group have been proposed. For example, Japanese Unexamined Patent Publication (Kokai) No. 3-173894 discloses a typical reactive derivative represented by the following formula (Ι Π)

(In the above formula, R ³ is a protecting group for a hydrogen atom or an amino group, R ⁴ is a protecting group for a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group, an aryl group or a hydroxyl group, A is a pyrazolyl group, Imidazolyl group, dimethylpyrazo Ryl group, benzotriazolyl group, 1-benzotriazolyloxy group, 4-nitrophenoxy group, 2,4-dinitrophenoxy group, trichlorophenoxy group, 1H-2-pyrrolidol 111, a N-succinimide group, an N-phthalimidoxy group, a 2-pyridylthiooxy group, and a 2-benzothiazolylthiooxy group. )

And the like are described.

In addition, Japanese Patent Application Laid-Open No. 2-177 describes a method for esterifying a thiazolcarboxylic acid derivative represented by the above formula (II), which includes a wide variety of compounds introduced by reaction with a carboxyl group. A triazolylthio group is described as an example of a nitrogen heterocyclic group. Further, JP-A-2-73090 discloses an ester-type reactive derivative incorporating 1-benzotriazolyloxy group, 4-nitrophenoxy group, and 2,4-dinitrophenoxy group. It has been proposed to subject it to a condensation reaction with 7 _aminocephalosporanic acid.

However, the thiazole acetic acid derivative of the formula (ΠΙ) actually used for acylation of a 7-aminocephalosboronic acid derivative in Japanese Patent Application Laid-Open No. 3-173894 is a carboxyl group at the end. Or only one reactive derivative in which the carboxyl group has been converted to an acid chloride group. There is no description that the concrete compounds of the reactive derivatives falling into the categories of the exemplified active amides, active esters and active thioesters were actually synthesized. Therefore, it is, of course, unknown at all whether or not the active amides and the like listed in the above publication can be used for acylation of 7-aminocephalosporanic acid derivatives in the same manner as acid chloride. is there. On the other hand, JP-A-2-1777 discloses a compound having a triazolylthio group (that is, an active thioester) as a reactive derivative of the thiazole carboxylic acid derivative represented by the above formula (II). However, this compound has not been actually synthesized, nor has any reaction activity for acylation been confirmed.

In addition, among the characteristic groups disclosed in JP-A-2-73090, a reactive group having a combination of an 11-benzotriazolyloxy group and a protected amino group bonded to a thiazole ring is preferred. Derivatives (active esters) have the disadvantage that the 7-aminocephalosporanic acid derivative has a low activity for the acylation.

In addition, the 1-benzotriazolyloxy group and the other groups are all soluble in water as a result of the removal of these groups when reacted with the 7-aminocephalosporanic acid derivative. Therefore, to completely remove the by-products from the reaction system, use a large amount of water, wash the reaction solution with an acidic or basic aqueous solution, or use an organic solvent soluble in water and water. It was necessary to dissolve the by-product in the mixed solution. For this reason, in the case of the above reactive derivative, when the reaction product is unstable to an acid or a base or when the solubility of the reaction product in a mixed solvent of organic solvent and water is high, by-products These reactive derivatives could not be employed because of the difficulty in separating them.

Therefore, the thiazole carboxylic acid derivative has high reactivity with 7-aminocephalosporanic acid, and has a reactivity in which a by-product generated by elimination of a characteristic group during the reaction can be easily removed even with neutral water. The development of derivatives was strongly desired. Disclosure of the invention

The present inventors have intensively studied to solve such a problem. More specifically, first, the heterocyclic compounds such as imidazole and pyrazole specifically described in the above-mentioned Japanese Patent Application Laid-Open No. 3-173894 show high solubility in water. Focusing on, a reactive derivative (an amide compound) in which a residue derived from these heterocyclic compounds was incorporated as the Y group of a 2-aminothiazoleacetic acid amide derivative represented by the above formula (I) was synthesized. However, it was found that a compound having a residue including the residue derived from the imidazole showed little reaction activity in the acylation of a 7-aminocephalosporanic acid derivative. Therefore, as a result of further studies, surprisingly, a specific 2-aminothiazoleacetic acid amide derivative having a triazolyl group as the Y group and protecting the amino group has been found to be a reactive derivative. The present inventors have found that they exhibit excellent functions, and have completed the present invention. That is, according to the present invention, the following formula (I)

In the above formula, R represents a protecting group for an amino group, and X is a group represented by.

C; or C = N—OR ²

'H'

(Where R ² represents an alkyl group, an alkenyl group, a benzyl group or an aryl group, and Y is a triazolyl group). According to the present invention, the amide derivative of the formula (I) is different from, for example, a compound derived from imidazole specifically described in JP-A-3-173894, A reactive derivative is provided which can be conveniently used as a reactant for the acylation of an aminocephalosporanic acid derivative.

Specific description of the present invention

In the above formula (I), the amino-protecting group represented by R ¹ may be any amino-protecting group commonly used in the art, which is easily removable, as far as the object of the present invention is concerned. Can be adopted without limitation. For example, an acyl group, an alkoxycarbonyl group, an alkoxyalkylcarbonyl group, an aralkyloxycarbonyl group, an aralkyl group, an alkenyl group, an alkylsulfonyl group, an alkylsulfonylalkoxycarbonyl group, an arylsulfonyl group, an arylcarbonyl group, an aralkyl carboxy group And a benzyl group.

Further, the alkyl, alkenyl and aryl groups of these groups may be substituted with a substituent. Such a substituent may be any group as long as it does not adversely affect the physical properties of the compound of the present invention, particularly the reaction activity with 7-aminocephalosboronic acid. For example, a halogen atom such as fluorine, chlorine, and iodine; a nitro group; an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, and a butyl group; a methoxy group, an ethoxy group, and a propoxy group. And alkoxy groups having 1 to 4 carbon atoms such as butoxy group, aryl groups having 6 to 10 carbon atoms such as phenyl group and naphthyl group, and arylcarbonyl groups such as benzoyl group. The number and position of these substituents are not particularly limited. Examples of the protective group having a substituent include a substituted alkoxycarbonyl group, a substituted aralkyloxycarbonyl group, and a substituted Examples include a substituted arylsulfenyl group and a substituted alkenyl group. In the above formula (I), the protecting group for the amino group represented by R ¹ will be specifically described. As the acyl group, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, a vivaloyl group A group having 1 to 5 carbon atoms, such as a group, is preferable. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxyquincarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and a t-butoxycarbonyl group. A group having 2 to 7 carbon atoms, such as a methyl group or a pentyloxycarbonyl group, is preferable. As the alkoxyalkylcarbonyl group, a group having 3 to 6 carbon atoms, such as a methoxyacetyl group or a methoxypropionyl group, is preferred. The arylalkyloxycarbonyl group is preferably a benzyloxycarbonyl group or a phenyloxy group. A group having 8 to 10 carbon atoms such as a rubonyl group is preferable, and a group having 7 to 20 carbon atoms such as a triphenylmethyl group, a benzyl group and a diphenylmethyl group is preferable as the aralkyl group. As the alkenyl group, a group having 2 to 6 carbon atoms such as a vinyl group, an aryl group, a 1-propenyl group and an isopropyl group is preferable. As the alkylsulfonyl group, a methanesulfonyl group, a propane group A group having 1 to 4 carbon atoms such as a sulfonyl group and a butanesulfonyl group is preferable, and a group having 3 to 10 carbon atoms such as a methanesulfonylethyloxycarbonyl group is preferable as the alkylsulfonylalkoxycarbonyl group. The arylsulfonyl group is preferably a group having 6 to 7 carbon atoms, such as a phenylsulfonyl group and a tolylsulfonyl group, and the arylcarbonyl group is benzoyl. , Toluoyl group, the number 7 to 1 1 group carbon atoms such as naphthoyl groups are preferred, as the § Lal Kill carbonyl group, Fuweniruasechiru group, number 8 to 9 carbon such as full We sulfonyl propionyl group Groups can be suitably mentioned.

In addition, when a substituent having a substituent is exemplified as a protecting group for an amino group, examples of the substituted alkoxycarbonyl group include a group having 3 to 4 carbon atoms such as a trichloroethoxycarbonyl group. As the carbonyl group, a group having 8 to 9 carbon atoms, such as a p-nitrobenzyloxycarbonyl group and a p-methoxybenzyloxycarbonyl group, is preferable. As the substituted arylsulfonyl group, A group having 5 to 6 carbon atoms, such as an o-dinitrophenylsulfonyl group, a 3-nitro-2-phenylpyridine sulfonyl group, or the like is preferable. Groups having 10 to 11 carbon atoms, such as -methylvinyl group, can be suitably mentioned.

Among them, particularly, from the viewpoint of easiness of elimination reaction of the protecting group and high reactivity as a reactive derivative, an acyl group such as a formyl group and acetyl, a methoxycarbonyl group, a t-butyne carbonyl group. An aralkyl group such as an alkoxycarbonyl group such as a group, a benzyl group or a triphenylmethyl group is preferably used.

In the above formula (I), as the alkyl group, alkenyl group and aryl group represented by R ² , a hydrocarbon group commonly used in the technical field is used without any limitation. When these are specifically exemplified, as the alkyl group, a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group is preferable. The alkenyl group is preferably a group having 2 to 6 carbon atoms such as a vinyl group, an aryl group, a 1-propyl group and an isopropyl group, and the aryl group is a phenyl group, a tolyl group and a xylyl group. C6 to C8 groups are preferred. Among them, an alkyl group having small steric hindrance is preferably used. be able to.

In the above formula (I), as the triazolyl group represented by Y, 1,2,41-triazolyl group and 1,2,3-triazolyl group are preferably used.

According to the above definition, specific examples of the 2-aminothiazolacetic acid amide derivative represented by the above formula (I) include, but are not limited to, 1— [2— (2_t —Butkincarbonylaminothiazole-4—yl) -1-2-Methoxyiminoacetyl] — 1,2,4-triazole, 1— [2 -— (2-t-butoxycarbonylaminothiazole-1-yl) ) — 2-Methoxymethoxyminoacetyl] — 1, 2, 3-triazole, 1-1 [2- (2-t-butoxycarbonylaminonotiazole_4-yl) acetyl] — 1, 2,, 4-triazole, 1-1 [2- (2-t-butoxycarbonylaminothiazole-41-yl) acetyl] — 1,2,3-triazole, 1-1 [2- (2-methoxycarbonylamino Thiazole-1-yl) 1-2-methoxyminoacetyl] 1,2,4-tria Zole, 1- [2- (2-Methoxycarbonylaminothiazolyl-4-yl) -12-Methoxyiminoacetyl] 1-1,2,3-Triazole, 1- [2— (2-methyl Toxylcarbonylaminothiazo-1-yl 4-acetyl) —1,2,4-triazole, 1 _ [2- (2-methoxycarbonylaminothiazole-1-41-yl) acetyl] 1,1 2,3-triazole, 1- [2- (2-formylaminothiazole-4-yl) -12-methoxyiminoacetyl] 1,2,4-triazole, 1-1 [2- (2 —Formylaminothiazol-1-yl) 1-2-Methoxyxyminacetyl] 1,1,2,3-Triazole, 1— [2— (2_ (formylaminothiazo) 1-ru 4- acetyl) acetyl] — 1,2,4-triazole, 1— [2- (2-formylaminonotiazole—4-yl) acetyl] — 1, 2, 3 — triazole, 1 _ [2— (2_tritylaminonotiazole 1-4yl) -1 2—methoxyiminoacetyl] 1-1,2,4—triazole, 1— [2— (2—tritylaminonotiazole 1) 4-yl) 1 2-Methoxyiminoacetyl] — 1,2,3-triazole, 1- [2_ (2—tritylaminothiazoyl_4_yl) acetyl] — 1,2 , 4—triazole, 1— [2— (2—tritylaminonotiazo—ru 41-yl) acetyl] _ 1,2,3—triazole, 41—2— (2—t—butoxycal Bonylaminothiazole-1-4-yl) 1-2-methoxyminoacetyl] 1-1,2,4-triazole, 2- [2_ (2-t-butoxy) 2-Luminothiazol-4-yl) -1-2-Methoxyiminoacetyl] — 1,2,3-triazole, 4 _ [2- (2-t-butoxycarbonylaminothiazole-4-yl) acetyl] 1,1, 2,4—triazole, 2— [2— (2— (t—butoxycarbonylaminonotiazole_4-yl) acetyl] -1,1,2,3-triazole, 4 _ [2— (2— Methoxycarbonylaminobutiazolyl-41-yl) 1-2-Methoxyiminoacetyl] — 1,2,4-triazole, 2- [2 -— (2-methoxycarbonylaminotinothiazole-41-yl) 1) 2-Methoxyxyminoacetyl]-1,2,3-triazole, 4- [2- (2-Methoxycarbonylaminothiazole-4-yl) acetyl] 1,2,4- Triazole, 2— [2— (2-Methoxycarbonylamino Le) Asechiru] one 1, 2, 3-preparative Riazoru, 4 one [2- (2-Horumirua Mi Nochiazo Honoré one 4-I le) one 2- main Tokishii Mi Noasechiru "one 1, 2, 4-preparative Ria Zol, 2- [2-((2-formylaminonotiazole) 4-yl) — 2—Methoxyiminoacetyl] 1,2,3_triazole, 41- [2-(2-Formylaminonothiazole) 4_yl) acetyl] ー 1,2,4—triazole, 2— [2— (2-formylaminotinothiazole 4-yl) acetyl] —1,2,3—triazole , 4_ [2— (2-trimethylaminothiazole-4_yl) -12-methoxyiminoacetyl] 1-1,2,4-triazole, 2- [2— (2-tritylaminothiazole-41-yl) 1) 2-Methoxyiminoacetyl] — 1,2,3-triazole, 4- [2- (2-tritylaminonotiazole_4_yl) acetyl] _1,2,4— Rizole, 2— [2— (2-tritylaminothiazole—4-yl) acetyl] _1,2,3—triazole The can and Ageruko.

Among these, from the viewpoint of high reaction activity, from the viewpoint of high reaction activity, 1- [2- (2t-butoxycarponylaminotinothiazo-41-yl) 1-2-methoxyminoacetyl] — 1,2,4 1-triazole, 1- [2— (2-t-butoxycarbonylaminothiazole-41-yl) 1-2-methoxymino-acetyl] —1, 2, 3-triazole, 1— [2— (2_t—butoxycarbonylaminothiazole 1-4-yl) acetyl] 1,1,4,1-triazole, 1- [2— (2—t—butoxycarbonylaminothiazole-4 —Yl) acetyl] 1,2,3—triazole, 1— [2—1 (2—formylaminothiazolyl-14-1yl) 1-2—methoxyethoxyminoacetyl ”1 1,2,4 _ Triazole, 1-1 [2-(2 _ tritylaminonotiazole _ 4 -yl) 1-2-methoxyimi Acetyl] - 1, 2, 4-preparative Riazoru, 4- [2- (2- t- butoxycarbonyl § Mi carbonothioyl 1- 2-Methoxyiminoacetyl] — 1,2,4-triazole, 2- [2- (2-t-butynecarbonylaminonotiazo 1- 4-yl) 1-2-me Toxiiminoacetyl] 1,1,2,3-triazole, 4- [2— (2-t-butoxycarbonylaminothiazol—4-yl) acetyl] 1,1,2,4-triazole , 2— [2 -— (2-t-butoxycarbonylaminothiazole—41-yl) acetyl] 1-1,2,3-triazole, 4 _ [2- (2-formylaminothiazoyl 4- 1) 2-Methoxyiminoacetyl ”1,2.4-triazole, 4- [2- (2-tritylaminothiazole-41-yl) — 2-methoxyiminoacetyl] -1,2,4-triazole Etc. can be suitably adopted.

In addition, among the compounds represented by the above formula (I), there are theoretically both syn (Z) and anti (E) isomers with respect to the oximino group, and both areomers in the present invention. Although it can be used, the syn-form is preferably used for the 7-aminocephalosporanic acid derivative because the syn-form is expected to have higher pharmacological activity. For the triazolyl group, the nitrogen atoms in the ring are the nitrogen atoms at the 1- and 4-positions for the 1,2,4-triazolyl group, and the 1- and 2-positions for the 1,2,3_triazolyl group. Since the nitrogen atoms of the two are in different environments, if each nitrogen atom is bonded to the carbon atom of the carbonyl group of the 2-aminothiazoleacetic acid derivative, it will be an isomer. As long as it has a function, it is included in the compound of the present invention.

The structure of the compound represented by the above formula (I) can be confirmed by the following means. By measuring (1) nuclear magnetic resonance spectrum (H-NMR), it is possible to know the bonding formula of the hydrogen atom present in the compound represented by the above general formula (I).

(2) By measuring the infrared absorption spectrum (IR), characteristic absorption derived from the functional group of the compound represented by the above formula (I) can be observed. In the compounds represented by the above formula (I), the absorption based on C = 0 bond near 1600~ ¹ 700 c m- 1, to observe absorption due to N_H binding Ami de group near 3,400-3,500 cm- ¹ be able to.

(3) By elemental analysis, the weight percentage of carbon, hydrogen, nitrogen, sulfur and oxygen can be calculated, and thus the composition formula can be determined.

In the present invention, the method for producing the 2-aminothiazoleacetic acid amide derivative represented by the above formula (I) is not particularly limited, but a typical production method is represented by the following formula (IV)

In the above formula, R ¹ represents an amino-protecting group, and X represents a group

, Η

: C or: C = N—OR ²

', H'

(Where R ² is an alkyl group, an alkenyl group, a benzyl group or an aryl group).

Can be produced by condensing a 2-aminothiazoleacetic acid derivative represented by the following formula with a triazole.

2-aminothiazolacetic acid derivative represented by the above formula (IV) and triazo There are no particular restrictions on the method of condensation with phenol, and there are no particular restrictions on the method using a condensing agent or the 2-aminothiazoleacetic acid derivative represented by the above formula (IV) under low-temperature, water-free conditions, with phosphorus pentachloride, After reacting with a halogenating agent such as phosphorus bromide or a halogenocarbonate lower alkyl ester, a method of reacting with triazole may be mentioned.

As the condensing agent used in this reaction, a condensing agent commonly used in an amide forming reaction can be used without any limitation. These are specifically exemplified by 1,3-dicyclohexyl carbodiimide, 1,3-diisopropyl carbodiimide, 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide, 1- (3 —Dimethylaminopropyl) 1 3 —Carpoimide compounds such as ethylcarbodimid hydrochloride, azide compounds such as diphenylphosphoryl azide and dodecylbenzenesulfonazide, and dichloromethylenedimethylimidimidium chloride Vilsmeier reagent and the like can be mentioned.

The amount of these condensing agents used is 1 equivalent of the 2-aminothiazoleacetic acid derivative represented by the above formula (IV) since the condensation reaction is an equivalent reaction between a carboxylic acid and an amine compound. The amount is not particularly limited as long as it is 1 equivalent or more, since it is not economical if the amount is too large, usually 1 to 4 equivalents, preferably 1 to 3 equivalents with respect to 1 equivalent of the 2-aminothiazoleacetic acid derivative. It is better to select from the range.

Further, as another condensation method, an acid halogenating agent and a halogenocarbonate lower alkyl ester can be used. When these are specifically exemplified, examples of the acid halogenating agent include phosphorus compounds such as phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, and phosphorus tribromide. Alkyl Examples of the ester include methyl methyl carbonate, ethyl methyl carbonate, propyl methyl carbonate, methyl bromocarbonate, ethyl bromocarbonate, propyl bromocarbonate and the like.

The use amount of these acid haematizing agents and halogenocarbonate lower alkyl esters is not particularly limited as long as it is at least 1 equivalent to 1 equivalent of the 2-aminothiazolacetic acid derivative represented by the above formula (IV). However, the amount is usually selected from the range of 1 to 4 equivalents, preferably 1 to 3 equivalents, per 1 equivalent of the 2-aminothiazolacetic acid derivative.

In the condensation reaction according to the above method, a base is generally co-present for the purpose of capturing hydrogen halide which is usually produced as a by-product. As the base to be used, any base used for such a purpose can be used without any limitation. Specific examples thereof include aliphatic triamines such as triethylamine, tripropylamine, triptylamine and ethyldiisopropylamine. Tertiary amines; aromatic tertiary amines such as pyridine, 4-N, N-dimethylaminopyridine, N, N-dimethylbenzylamine; alminates such as carbonated lime and sodium carbonate Metallic carbonates and the like can be used. The amount of the base used is not particularly limited as long as it is at least stoichiometrically used to capture the hydrogen halide generated from the acid halogenating agent and the lower alkyl ester of halogenocarbonate. It is better to select from a range of 3 equivalents of the theoretical amount.

These condensation reactions are generally performed in an organic solvent. Any organic solvent that does not inhibit the condensation reaction can be used without any particular limitation.

Specific examples of these organic solvents include methylene chloride and chlorophore. Aliphatic halides such as lum, carbon tetrachloride, 1,2-dichloroethane, etc., ethers such as tetrahedrofuran, 1,4-dioxane, and getylether; nitriles such as acetonitrile and propionitrile; Ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, propyl acetate and butyl acetate; aromatic hydrocarbons such as toluene, xylene and benzene; halogenated aromatic hydrocarbons such as chlorobenzene Hydrogens; carbonates such as dimethyl carbonate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; aliphatic hydrocarbons such as hexane and heptane; Can be. Among these organic solvents, in particular, the 2-aminothiazole acetic acid derivative represented by the above formula (II) is well dissolved and aliphatic halogens such as methylene chloride, chloroform and the like are provided in order to give a sufficient reaction rate. And ethers such as 1,4-dioxane and the like. These solvents may be used alone or in combination of two or more.

The concentration of the 2-aminothiazoleacetic acid derivative represented by the above formula (IV) in these organic solvents is not particularly limited, but if the concentration is too low, the yield per reaction is low. Therefore, it is not economical, and if the concentration is too high, it will hinder the operation such as stirring. Therefore, it is preferable to select from 0.1 to 80% by weight, more preferably from 1 to 60% by weight. .

The reaction temperature is not particularly limited because it varies depending on the type of reactants used in the condensation reaction.However, if the temperature is too high, the side reaction is promoted, and if the temperature is too low, the reaction rate is significantly reduced. 6 0. C, preferred It is better to select from the range of 60 to 50 ° C.

Since the reaction is usually inhibited by water, it is preferable to carry out the reaction in a dry state. The drying method is not particularly limited because it differs depending on the type of the reactant used for the condensation reaction.However, usually, a tube filled with a dehydrating agent such as calcium chloride is attached to the reactor, and moisture enters the reactor. The method can be carried out under an atmosphere of an inert gas such as nitrogen or argon.

Although the reaction time varies depending on the type of the 2-aminothiazole acetic acid derivative represented by the above formula (IV) and the type of the reactant used for the condensation reaction, it cannot be said unconditionally, but it is usually from 0.01 to 1%. A range of 0 hours is sufficient.

As a method for isolating and purifying the thus obtained 2-aminothiazoleacetic acid amide derivative represented by the above formula (I), a usual method is used without any limitation. Specifically, after the completion of the condensation reaction, by-products are removed as much as possible by filtration or washing with water, and then separated and purified by recrystallization or column chromatography. . According to the present invention, there can be provided a 2-aminothiazole amide derivative represented by the above formula (I), which easily reacts with a 7-aminocephalosporanic acid derivative under mild conditions. . Further, the 2-aminothiazole amide derivative of the present invention can produce by-products generated by elimination of a characteristic group upon reaction with a 7-aminocephalosboronic acid derivative with neutral water. Since it can be easily removed, there is an advantage that isolation and purification of the reaction target product is easy.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples. Example 1

In a 100 ml eggplant-shaped flask equipped with a calcium chloride tube, add (Z) -1- (2-t-butoxycarbonylaminotazoyl 4-yl) -1

2-Methoxyiminoacetic acid 3.01 g (1 Ommo 1). 0.83 g (12 mmo 1) of 1,2,4-triazole and 30 ml of methylene chloride are added. To this reaction solution, at room temperature, 2.88 g (15 mmo 1) of 1- (3-N, N-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride dissolved in 20 ml of methylene chloride was added dropwise. The mixture was stirred for 1 hour. After completion of the reaction, water was added and washed with 3 Om1, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 2.14 g of a white solid.

As a result of measuring the infrared absorption scan Bae-vector of this product, 1 756 cm- give ¹ and 1 720 cm- ¹ in the absorption based on the carbonyl group, to give the absorption based on § Mi de group 3436 cm- ^1. Its elemental analysis values were as follows: C 44.58%, H 4.70%. N 23. 73%. 018.06%, S 8.93%, and the formula C ₁₃ H ₁₆ N ₆ 0 ₄ S C Calculated for (352.37) C 44.

Good agreement with 3 1%. H 4.58%. N 23. 85%. 018. 16%. S 9. 10%.

Further, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (σ: ρρηι: tetramethylsilane reference: heavy dimethyl sulfoxide solvent) was as follows.

1. A singlet for 9 protons was shown at 53 ppm, and it was a t-butyl group proton in (a). A singlet for three protons was shown at 4.02 ppm, which was the methyl group proton in (b). 10.07 ppm pro The singlet for one ton was shown, and it was the proton of the amide in (c). A singlet for one proton was shown at 7.4 ppm, which was the proton of the thiazole ring in (d). A singlet for one proton was shown at 8.03 ppm, and it was a triazole ring proton in (e). At 9.08 ppm, a singlet for one proton was shown, indicating a proton in the triazole ring of (f).

(b) From the above results, the isolated and purified product was found to be 1-[(Z) -2- (2-t-butoxycarbonylaminothiazole-14-yl) 1-2-methoxyoximinoacetyl ] — It was confirmed to be 124-triazole. The yield of this was 60.7%.

Example 2

The same reaction as in Example 1 was carried out except that the condensing agent was changed to 13-dicyclohexylcarpoimide, and instead of washing with water, by-products were removed by filtration. As a result, 2.96 g of 1 _ [(Z) -2- (2-t-butoxycarbonylaminothiazole-41-yl) -12-methoxyiminoacetyl] _124-triazole was obtained (yield: 2.96 g). 78.1%).

Reference example 1

In a 100 ml eggplant-shaped flask equipped with a calcium chloride ring, 1 C (Z) —2— (2—t—butoxycarbonylaminoaminothiazole—41 yl) 1-2—Methoxyiminoacetyl] 1 1 2 4—triazole 0. 35 g (1 mmo 1), 0.39 g (l. 2 mmo 1) of 7-aminocephalosporanic acid t-butyl ester and 10 ml of methylene chloride were added, and the mixture was stirred at room temperature for 24 hours.

After completion of the reaction, 5 ml of water was added to the reaction solution to completely remove the by-produced 1,2,4-triazole, the methylene chloride was concentrated, and the residue was purified by silica gel column chromatography. t-Butyl 7-[(Z) -2- (2-t-butoxycarbonylaminothiazol-14_yl) —2-Methoxyiminoacetamide] -13-acetyloxymethyl-13-cepum-4 —The carboxylate was obtained in 0.41 g (yield 67.0%).

Example 3

(Z) — 2— (2-t-butoxycarbonylaminothithiazole 4-yl) 1—2—2-Methoxyiminoacetic acid and 2- (2-t-butoxycarbonylaminothiazole-4) 1) The same reaction as in Example 1 was performed except that acetic acid was used. After completion of the reaction, water was added and washed with 3 Om1, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 2.29 g of a white solid.

As a result of measuring the infrared absorption spectrum of this compound, to give the absorption based on the carbonyl group in the ^{^{l TSZ cm- 1 1 720 cm- 1}} , to give a absorption based on amino-de-group 3433 cm- ^1. Its elemental analysis values were: C 46.48%. H 5.02%. N 22.60%, 015.43%. S 10.47%, and the composition formula C ₁₂ H ₁₅ N ₅ 0 ₃ S ( The calculated values for 293.34) agreed well with C 46.59%, H 4.89%, N 22.64%. 015.52%. S 10.36%. Further, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane based: heavy dimethyl sulfoxide solvent) was as follows.

1. A singlet for 9 protons was shown at 54 ppm, which was the t-butyl group proton in (a). 3. A singlet of two protons was shown at 70 ppm, which was the methylene group proton in (b). 12. At 15 ppm, a broad singlet of one ton was shown, and it was the proton of the amide in (c). A singlet for one proton was shown at 6.7 ppm, and it was the proton of the thiazole ring in (d). A singlet for two protons is shown at 8.27 ppm, which is the proton of the triazole ring in (e).

From the above results, it was confirmed that the isolated and purified product was 4- [2- (2-t-butoxycarbonylaminothiazol-1-4-yl) acetyl] —1,2.4-triazole . Its yield was 74.0%. Example 4

The same reaction as in Example 3 was carried out except that the condensing agent was changed to 1,3-dicyclohexylcarpoimide, and by-products were removed by filtration instead of washing with water. As a result, 2.40 g (77.6%) of 4- [2- (2-t-butoxycarbonylaminothiazole-4-yl) acetyl] -1,2,4-triazole was obtained.

Reference example 2 1-[(Z) -2- (2_t-butoxycarbonylaminothiazol 1-4-yl) _2-methoxyiminoacetyl] —4-1,2 instead of 1,2,4-triazole (2-t-butoxycarbonylaminothiazole 4-yl) acetyl] The same operation as in Reference Example 1 was performed except that 1,2,4-triazole was used.

As a result, t-butyl 7-[(Z) -12- (2-t-butoxycarbonylaminothiazol-14-yl) acetamide] —3-acetyloxymethyl-13-cefum-14-carboxylate 0.40 g (70.0%) was obtained.

Example 5

The same reaction as in Example 1 was performed except that 1,2,3-triazole was used instead of 1,2,4-triazole. After the reaction was completed, 30 ml of water was added and the mixture was washed, methylene chloride was distilled off, and the residue was separated and purified using a silica gel gel ram chromatograph to obtain 2.24 g of a white solid.

As a result of measuring the infrared absorption spectrum of this product, 1 754 cm- give ¹ and 1700 cm- ¹ in the absorption based on the carbonyl group, to give the absorption based on § Mi de group 3266 cm- ^1. Its elemental analysis values were: C 44.20%, H 4.71%. N 23.87%, 018. 40%. S 8.82%, and the formula C ₁₃ H ₁₆ N ₆ 0 ₄ S The calculated values for (352. 37) were in good agreement with the calculated values of C 44.3 1%, H 4.58%, N 23. 85%, 018. 16%.

Further, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (where: p pm: tetramethylsilane based: heavy dimethyl sulfoxide solvent) was as follows. A singlet of nine protons was shown at 1.52 ppm, which was the t-butyl group proton in (a). A singlet for three protons was shown at 4,000 ppm, which was the proton of the methyl group in (b). 10. A single line for one proton was shown at lOppm, which was the proton of the amide in (c). 7.

A singlet for one proton was shown at 32 ppm, which was the proton of the thiazole ring in (d). 7.A single line for one proton is shown at 80 ppm.

It was the proton of the triazole ring of (e). 8. A singlet for one proton was shown at 8.36 ppm, which was the proton of the triazole ring in (f).

(b) From the above results, the isolated and purified product was found to be 1-[(Z) -2- (2_t-butoxycarbonylaminothiazol-4-yl) -1-2-methoxyethoxyminoacetyl] —1, 2,3-triazole was confirmed. The yield of this was 63.6%.

Example 6

The same reaction as in Example 5 was carried out except that the condensing agent was changed to 1,3-dicyclohexylcarpoimide, and instead of washing with water, by-products were removed by filtration. as a result,

1-[(Z)-2-(2 _ t -butoxycarbonylaminonotiazole

4- (yl) -1-2-methoxyiminoacetyl] _1,2,3-triazole was obtained in an amount of 2.49 g (70.7%). Reference example 3

1 — [(Z) —2— (2—t—Butoxycarbonylaminothiazolyl—41-yl) -1-2-Methoxyiminoacetyl] -1-1,2,4-Triazole instead of 1 _ [(Z) —2_ (2_t-butoxycarbonylaminothiazole-14-yl) -1-2-methoxyiminoacetyl] —Refer to Reference Example 1 except that 1,2,3-triazol was used. The same operation was performed.

As a result, t-butyl 7 — [(Z) —2— (2-t—butoxycarbonylaminothiazol-4-yl) -1-2-methoxyminoacetamide] —3-acetyloxymethyl-3-cefem-4— 0.42 g (68.8%) of the carboxylate was obtained.

Example 7

The same reaction as in Example 3 was performed except that 1,2,3-triazole was used instead of 1,2,4_triazole. After completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by a silica gel gel chromatography to obtain 2.25 g of a white solid.

As a result of measuring the infrared absorption spectrum of this compound, to give the absorption based on the carbonyl group in ¹ 758 cm- 1 720 cm- 1, to give a absorption based on amino-de-group 3439 cm- ^1. The elemental analysis value was C 46.52%, H 4.97%. N 22. 72%. 015. 48%. S 10.22%, and the composition formula was C ₁₂ H ₁₅ N ₅ 0 ₃ S. C Calculated for (293.34) C 46.

59%. H 4.89%, N 22. 64%, 015. 52%. S 10. 3

Good agreement with 6%.

Furthermore, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (σ: p pm: tetramethylsilane based: heavy dimethyl sulfoquind solvent) is as follows. Met.

A singlet for nine protons was shown at 1.52 ppm, which was the proton of the t-butyl group in (a). 3. A singlet of two protons was shown at 70 ppm, which was the methylene group proton in (b). 12. At 20 ppm, a broad singlet of one ton was shown, which was the proton of the amide in (c). 6. A singlet for one proton was shown at 72 ppm, which was the proton of the thiazole ring in (d). 7. A singlet for one proton was shown at 82 ppm, which was the proton of the triazole ring in (e). At 8.36 ppm, a singlet for one proton was shown, indicating that it was a proton in the triazole ring of (f).

From the above results, it was confirmed that the isolated and purified product was 1_ [2- (2-t-butoxycarbonylaminothiazole-14-yl) acetyl] -11,2,3-triazole. Its yield was 72.7%. Example 8

The same reaction as in Example 7 was carried out except that the condensing agent was changed to 1,3-dicyclohexylcarpoimide and by-products were removed by filtration instead of washing with water. as a result,

2.42 g (78.2%) of 1 _ [2- (2-t-butoxycarbonylaminothiazole-41-yl) acetyl] -1,2,3-triazole was obtained. Reference example 4

1-[(Z) 1 2-(2-t-butoxycarbonylaminothiazole-4-yl) 1-2-methoxyiminoacetyl] 1-1, 2-4- )-2-(2-t-Butoxycarbonylaminothiazole_4-yl) acetyl] The same operation as in Reference Example 1 was performed except that 1,1,2,3-triazole was used.

As a result, t-butyl 7_ [2- (2_t-butoxycarbonylaminonotiazole-14_yl) acetamide] -13-acetyloxymethyl-1-3-cefm-14-carboquinate was obtained. 0.42 g (73.9%) was obtained.

Example 9

(Z) — 2- (2-t-Butoxycarbonylaminothiazolyl-141-yl)-(Z) -2- (2-formino-re-amino-thiazole-41) in place of 2-Methoxyiminoacetic acid The reaction was carried out in the same manner as in Example 1 except that _2-methoxyiminoacetic acid was used. After the completion of the reaction, water was added and washed with 3 Om 1, methylene chloride was distilled off, and the residue was separated and purified by silica gel gel chromatography to obtain 1.56 g of a white solid.

As a result of measuring the infrared absorption spectrum of this compound, to give the absorption based on the carbonyl group in 1733 cm- ¹ 700 cm- 1, to give a absorption based on amino-de-group 3443 cm- ^1. Its elemental analysis values, C 38. 38%. H 3. 00%. N 29. 78%. 017. 20%. S 1 1. A 64%, formula _{_{_{_{C 9 H 8 N 6 0 3}}}} S (280.26), which is the calculated value for C 38. 57%. H 2.88%. N 29. 99%. 017. 13%. Further, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (bi: ppm: tetramethylsilane based: heavy dimethyl sulfoxide solvent) was as follows.

A singlet for a single proton was shown at 8.80 ρpm, indicating that it was a formyl-based proton in (a). A singlet for three protons was shown at 4,000 ppm, and it was a methyl group proton in (b). A singlet for one proton was shown at 12.6 ppm, which was the proton of the amide in (c). A singlet for one proton was shown at 7.18 ppm, which was the proton of the thiazole ring in (d). At 8.08 ppm, a singlet for one proton was shown, which was a proton of the triazole ring in (e). 9. A singlet for one proton was shown at 10 ppm, indicating that it was a proton in the triazole ring of (ί).

From the above results, the isolated and purified product was composed of 1-[(Ζ) -2- (2-formylaminonotiazole-14-yl) -12-methoxyiminoacetyl] -1,2,4-triazole. It was confirmed that there was. The yield was 55.8%.

Reference example 5

1-[(Ζ) —2- (2-t-Butoxycarbonylaminothiazol—4-yl) -1-2-Methoxyiminoacetyl] 1-1,2,4-Triazol [(Z) — 2 _ (2—formylaminothiazole-4 1-yl) -2-Methoxyiminoacetyl] The same operation as in Reference Example 1 was performed except that 1,1,2,4-triazole was used.

As a result, t-butyl 7 — [(Z) —2- (2-formylamino-thiazole-4-yl) -1-2-methoxyiminoacetamide] -13-acetyloquin-methyl-13-cefume 4-carboxylate 0.36 g (65.9%) was obtained.

Example 10

(Z) -2- (2-t-butoxycarbonylaminothiazoyl 4-yl)-(Z) -2- (2-tritylaminonotiazole-4-yl) instead of 2-methoxyethoxyaminoacetic acid G) The same reaction as in Example 1 was carried out except that 12-methoxyiminoacetic acid was used. After completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography. As a result, 3.77 g of a white solid was obtained.

As a result of measuring the infrared absorption spectrum of this product, absorption based on a carbonyl group was obtained at 1750 m- ¹ . Its elemental analysis values were: C 65.78%, H 4.60%, N 16.90%, 06.35%, S 6.37%, and the composition formula C ₂₇ H ₂₂ _Ne 0 ₂ S ( The calculated values for 494.57) were in good agreement with C 65. 57%, H 4.48%, N 16.99%, 06. 41%, and S 6.48%.

Further, the result of measurement of ¹ H—nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane based: heavy dimethyl sulfoxide solvent) was as follows.

7. Multiplex lines corresponding to 15 protons were shown at 7.10 to 7.33 ppm. 3. 3 ppm of protons to 70 ppm It showed a singlet, and was a methyl group proton in (b). At 9.1 pm, a singlet for one proton was shown, indicating the proton of the amide in (c). 6. A singlet for one proton was shown at 68 ppm, and it was the proton of the thiazole ring in (d). A single line for one proton was shown at 8.08 ppm, and it was a triazole ring proton in (e). 9. A single line corresponding to a single ton was shown in l Op p pm, which was a proton of the triazole ring of (f).

(b) From the above results, the isolated and purified product was found to be 1-[(Z) -2- (2-tritylaminothiazol-4-yl) -12-methoxyiminoacetyl] -1,2,4ー It was confirmed to be a triazole. Its yield was 76.2%.

Reference example 6

1-[(Z) -2- (2-t-Butoxycarbonylaminothiazole—4-yl) -1-2-Methoxyiminoacetyl] —1 — [(Z instead of 1,2,4_triazole )-2-(2-Tritylaminothiazoyl 4-yl) -12-Methoxyiminoacetyl] 1,2,4-Triazole except that triazole was used. went.

As a result, t—butyl 7— [(Z) 1 2— (2—tritylaminotchi (Azole-4-yl) -12-methoxyiminoacetamide] -13-acetyloxymethyl-13-cefm-14-carboxylate was obtained in an amount of 0.49 (64.8%).

Comparative Example 1

(Z) -2- (2_t-Butoxycarbonylaminothiazole_41-yl) Instead of (Z) _2- (2-t-Butoxycarbonylaminothiazole) instead of _2-Methoxyiminoacetic acid The reaction was carried out in the same manner as in Example 1 except that l-trityloxyaminoacetic acid was used. After the completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 3.62 g of a white solid.

When this white solid was identified, the following formula was obtained. [1- (Z) -2-1 (2-t-butoxycarbonylaminothiazol-14-yl) -12-trityloxyiminoacetyl] —1,2,4 —The substance was identified as triazole. Its yield was 62.5%.

When the same reaction as in Reference Example 1 was performed using this compound, the reaction hardly proceeded even after 24 hours. Therefore, the above compound Has no function as a reactive derivative.

Comparative Example 2

(Z) -1- (2-t-Butoxycarbonylaminothiazoyl-41-yl) Instead of (2-)-methoxyaminoacetic acid (Z) -2- (2-aminothiazole-4-1) The same reaction as in Example 1 was performed except that 2-methoxyiminoacetic acid was used. After the completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 0.25 g of a white solid.

When this white solid was identified, the following formula was obtained. [1- (Z) -2-1 (2-aminothiazo-l-ul-4_yl) -12-methoxyminoacetyl] -11,2,4-triazole Was confirmed. The yield was 10.2%.

Η

When the same reaction as in Reference Example 1 was performed using this compound, the reaction hardly proceeded even after 24 hours. Therefore, it was found that the compound did not have a function as a reactive derivative.

Comparative Example 3

The same reaction as in Example 1 was performed except that imidazole was used instead of 1,2,4-triazole. After the reaction was completed, 30 ml of water was added and the mixture was washed, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 1.69 g of a white solid. When this white solid was identified, it was found to be [(Z) —2- (2—t-butoxycarbonylaminothiazole-41-yl) -12-methoxyiminoacetyl] imidazole represented by the following formula. confirmed. The yield was 48.1%.

H

Comparative Example 4

The same reaction as in Example 1 was performed except that 1-benzotriazole was used instead of 1,2,4-triazole. After completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 1.88 g of a white solid.

When this white solid was identified, the following formula was obtained. [1- (Z) -2- (2-t-butoxycarbonylaminothiazol-l-4-yl) -12-methoxyiminoacetyl] benzotriazo The yield of this product was 54.6%.

Comparative Example 5

1. The same reaction as in Example 1 was carried out except that 1-hydroxybenzotriazole was used instead of 2,4-triazole. After the completion of the reaction, 30 ml of water was added for washing, methylene chloride was distilled off, and the residue was separated and purified by silica gel column chromatography. As a result, 3.39 g of a white solid was obtained. When this white solid was identified, the following formula was obtained. [(Z) —2- (2-t-butoxycarbonylaminothiazolyl-14_yl) -12-methoxyiminoacetyloxy] It turned out to be benzotriazole, and the yield was 81.0%.

When the same reaction as in Reference Example 1 was performed using this compound, the conversion after 24 hours was only 22.8%. Further, the reaction solution was washed by the same operation as in Reference Example 1. As a result, 20.3% of hydroxyquinbenzotriazole remained in the reaction solution.

Industrial applicability

According to the present invention, for example, as exemplified in Reference Examples 1 to 6 and Comparative Examples 1 to 5, compounds having an acylation reaction activity for a 7-aminocephalosporanic acid derivative which cannot be expected from the prior art are provided. Is done. Therefore, INDUSTRIAL APPLICABILITY The present invention can be suitably used, for example, in the pharmaceutical manufacturing industry and the like.

Claims

Range of reading

The following formula (I)

In the formula, R ¹ represents a protecting group for an amino group, and X represents a group

H

C or C = N-OR ²

H

(Here, R ² is an alkyl group, an alkenyl group, a benzyl group or an aryl group.)

And Y is a triazolyl group).

A 2-aminothiazole amide derivative represented by the formula:

2. In the general formula (I), R ¹ is an acyl group having 15 carbon atoms, an alkoxycarbonyl group having 27 carbon atoms, an alkoxyalkylcarbonyl group having 36 carbon atoms, or an aralkyl having 8 to 10 carbon atoms. Cyloxy carbonyl group, aralkyl group having 720 carbon atoms, alkenyl group having 26 carbon atoms, alkylsulfonyl group having 14 carbon atoms, alkylsulfonyl alkoxycarbonyl group having 3 10 carbon atoms, aryl group having 67 carbon atoms 1-sulfonyl group, arylcarbonyl group having 711 carbon atoms, aralkylcarbonyl group having 89 carbon atoms, substituted alkoxycarbonyl group having 34 carbon atoms, substituted aralkyloxycarbonyl group having 89 carbon atoms 2. The 2-aminothiazole monoacetic acid amide derivative according to claim 1, which is a substituted arylsulfenyl group having 56 carbon atoms or a substituted alkenyl group having 1011 carbon atoms.

3. In the general formula (I), R ¹ is a formyl group, an acetyl group, Pionyl group, butyryl group, isoptyryl group, valeryl group, bivaloyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, pentyloxycarbonyl Methoxyacetyl group, methoxypropionyl group; benzyloxycarbonyl group, phenyloxycarbonyl group; trifluoromethyl group, benzyl group, diphenylmethyl group; vinyl group, aryl group, 1-propenyl group, isopropyl group Methanesulfonyl group, propanesulfonyl group, butanesulfonyl group; methanesulfonylethyloxycarbonyl group; phenylsulfonyl group, trisulfonyl group; benzoyl group, toluoyl group, naphthyl group; Enylacetyl group, phenylpropionyl group; trifluoroquinonecarbonyl group; p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group; 0-nitrophenylsulfonyl group, 3 2. The 2-aminothiazoleacetic acid amide derivative according to claim 1, which is a 2-pyridine-2-pyridinyl group; a 2-benzoyl-1-methylvinyl group.

4. The compound according to claim 1, wherein, in the general formula (I), R ² is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a benzyl group, or an aryl group having 6 to 8 carbon atoms. —Aminothiazole amide derivatives.

5. In the general formula (I), R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group; a vinyl group, an aryl group, a 1-propenyl group or an isopropyl group; 2. The 2-aminothiazoleacetic acid amide derivative according to claim 1, which is a benzyl group; a phenyl group, a tolyl group or a xylyl group.

6. In the general formula (I), Y is a 1,2,4-triazolyl group or 2. The 2-aminothiazole amide derivative according to claim 1, wherein is a 1,2,3-triazolyl group.

7. The compound represented by the general formula (I) is represented by the following formula: 1- [2- (2-t-butoxycarbonylaminothiazole-41-yl) -12-methoxyethoxyminoacetyl] _1,2,4_triazole, 1 — [2— (2-t-butoxycarbonylaminonotiazo-41-yl) -1-2-methoxyminoacetyl] — 1, 2, 3-triazole, 1-1 [2 -— (2-t-butoxycarbo) 2-laminothiazo-l-u-yl) acetyl] 1,2,4-triazole, 1- [2- (2-t-butoxycarbonylamino-l-uti-l-u-yl) acetyl] -1, 2,3-Triazole, 1- [2— (2-Methoxycarbonylaminothiazole-41-yl) 1-2-Methoxyiminoacetyl] —1,2,4-Triazole, 1— [2 — (2—Methoxycarbonyl) Acetyl] 1,2,3-triazole, 1- [2- (2-Methoxycarbonylaminothiazole-14-yl) acetyl] 1-1,2,4-triazole, 1— [2— (2-Methoxycarbonylaminothiazole-4-yl) acetyl] 1,2,3-triazole, 1-1 [2_ (2_formylaminotinothiazole-4-yl) 1-2-methoxy 1,2-, 4-Triazole, 1- [2- (2-formylaminothiazole_4-yl) -12-methoxyiminoacetyl] —1,2,3-triazole, 1— [2- (2-formylaminothiazolyl_4-yl) acetyl] ― 1,2,4-triazole, 1-1 [2- (2-formylaminothithiazole-41-yl) acetyl ] — 1, 2, 3—triazole, 1— [2— (2—tritylaminonotiazol-4-yl) 1—2-methodine I Mi Noasechi 1], 1,2,4—triazole, 1— [2— (2—tritylaminonotiazol-1-41) 1-2—methoxyiminoacetyl] —1,2,3-triazol 1- [2— (2—tritylaminothiazol-1-yl) acetyl] —1,2,4_triazole, 1-1 [2— (2-tritylaminotinthiazole— 4- (yl) acetyl] — 1,2,3-triazole, 4- [2- (2_t-butoxycarbonylaminonotiazole-1-4-yl) -1 2-methoxyethoxyminoacetyl] 1 1,2,4-triazole, 2- [2- (2-t-butoxycarbonylaminonotiazole-14-yl) -1-2-methoxyethoxyminoacetyl] -1,2,3-triazole, 4 I [2- (2-t-Butoxycarbonylaminonotiazole 1-4-yl) acetyl]-1,2,4-triazole, 2- [2- (2-t-butoxy) Carbonyl § Mi Nochiazoru - 4 one I le) Asechiru] - 1, 2, 3-preparative Riazoru, 4 _ [2- (2-main-butoxycarbonyl § Mi Nochiazoru 4 _ I Le) -

2-Methoxyiminoacetyl] — 1,2,4-triazole, 2- [2— (2-Methoxycarbonylaminothiazole-1-yl) -1-2-methoxyiminoacetyl] — 1, 2,3_triazole, 4- [2- (2-Methoxycarbonylaminonotiazole-1-4-yl) acetyl] -1,2,4-triazole, 2- [2-(2-Methoxy Carbonylaminothiazo—Lu 4-yl) acetyl , 2,4-triazole, 2- [2- (2-formylaminonotiazole-4-yl) -1-2-methoxyminoacetyl] — 1,2,

3-triazole, 4- [2- (2-formylaminothiazole-4-yl) acetyl] -1,2,4_triazole, 2- [2- (2-formyl) Milaminothiazol-4-yl) acetyl] 1-1,2,3-Triazole, 4- [2- (2-tritylaminothiazol-1-4-yl) 1-2-Methoxyiminoacetyl] -1 , 2,4-triazole, 2— [2— (2—tritylaminonotiazole_4-yl) 1-2-methoxyiminoacetyl] —1,2,3_triazole, 4- [2 — (2—tritylaminothiazolyl 4-yl) acetyl] 1,2,4—triazole and 2— [2 _ (2—tritylaminothiazole-1-4-yl) acetyl] 1 1 ,

2. The amide derivative of 2-aminothiazoleacetic acid according to claim 1, which is selected from the group consisting of 2,3-triazole.