JPS6322570A - Production of 1-methanesulfonyloxy-6- trifluoromethyl-1h-benzotriazole and cephalosporine derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION a. Field of Industrial Application The present invention relates to a new method for producing the syn isomer of a compound of the following general formula (R).

In the formula, R represents a furyl group, a thiazolyl group, or a thiadiazolyl group, and R1 represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms.

Z is a hydrogen or halogen atom, or an alkyl, cycloalkyl, alkoxy, or alkylthio group with up to 5 carbon atoms, or an acetoxymethyl, or a carbamoyloxymethyl group, or R4 is S and N
represents a heterocycle with 5 to 6 rings containing any substituted 1 to 4 heteroatoms selected from or an acyl group with 2 to 4 carbon atoms, or a fused -Cth-5-Rg when representing a heterocycle
Jj or -CL-Rz group or group; R1 represents hydrogen, an alkyl group having 1 to 5 carbon atoms, an esteramide or an organic acid group;

M represents a hydrogen atom, an alkali, an alkaline earth metal, or an ester group; C00M5 may also represent CO, and when Z represents, C00M represents coo-.

Furthermore, a feature of the method of the present invention is that the reactive derivative obtained by treating the compound of general formula (II) with a condensing agent of general formula (III) in the presence of a base is converted into a reactive derivative of general formula (IV). ).

\OR.

In the above general formula, R1, Z and M are the same as above, R4 represents an alkyl or aryl group, X represents a halogen atom, and n represents an integer from 0 to 2. In particular, R1 can represent a 2-furyl group,! , 3-thiazol-4-yl, 2-amino-1
, 3-thiazol-4-yl group, 5-amino-1,2,
Mention may be made of 4-thiadiazol-3-yl group.

b. Prior Art In the acylation reaction of β-lactam antibiotics, acid chloride or mixed acid anhydride methods are mainly used, and organic acylation using l-hydroxysuccinimide or 1-hydroxy-IH-benzotriazole is used. A method has been developed to convert acids into reactive derivatives. Although each of these methods has its own advantages and disadvantages, the acylation reaction using 1-hydroxy-IH-benzotriazole is particularly widely used.

Problems to be Solved by the C0 Invention However, the acylation reaction using 1-hydroxy-IH-benzotriazole has the disadvantage that the reaction time is long.

For example, in German Patent No. 3,316,798 and British Patent No. 2,098,216, 1-hydroxy-IH-benzotriazole hydrate was used in a dicyclocarbodiimide process for 3 to 4 hours. It takes a long time to complete the reaction, such as by performing the acylation reaction while stirring at room temperature overnight after obtaining a reactive compound.

An object of the present invention is to provide a new and advanced method that has superior reactivity than the existing method using a condensing agent such as 1-hydroxy-IH-hensitriazole.

d.Means to solve the problem The method of the present invention can be expressed as a reaction formula as follows.

The condensing agent of general formula (III) used in the present invention is a novel substance created by the present inventors, and is a compound that is not only produced at a low cost but also stable and easy to handle. .

The reactive derivative of the compound of general formula (II) using the condensing agent of general formula (l[l) produced in the first step process of the present invention has the structure of the following general formula (V). Isolated and confirmed in the example.

As a solvent for dissolving the organic acid of general formula (II), N
, N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone are mainly used, and the reaction can generally be quantitatively completed within a few minutes at 0±5°C.

The most suitable base for neutralizing the methanesulfonic acid produced at this time is triethylamine or pyridine.

The second step of the present invention is the acylation step of the prepared reactive derivative and the compound of general formula (rV), and the reaction can be quantitatively completed within one hour at room temperature even in the absence of a base.

Examples of the solvent used to dissolve the compound of general formula (IV) include N,N-dimethylformamide, NN-dimethylacetamide, and N-methylpyrrolidone. After the reaction is completed and the solvent is removed by distillation under reduced pressure, the target compound can be isolated in a high yield by processing in a conventional manner.

e. Examples Next, the present invention will be explained in more detail with reference to Examples.

Example 1 6.8 g (33.5 m, mole) of 1-hydroxy-6-trifluoromethyl-IH-benzotriazole are suspended in 200 s 1 of water and then dissolved in an IN sodium hydroxide solution iPi36wl. Methanesulfonyl chloride under water cooling 2.8+++ 4! (36,2
m, mole) was slowly added dropwise, and then ethyl acetate was added.
) Add 20a+It and stir at room temperature for 2 hours. Separate the organic layer and dilute the aqueous layer with ethyl acetate (20+wf
x 2) and combine the organic layers. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure and crystallized from petroleum ether. ! After drying, white 1-methanesulfonyloxy-6-trifluoromethyl-I H-benzotriazole was obtained.

Yield: 8.8 g (93%) m, p, 98-100°C IR 1 maX, Br, am-'): 130
0 (S = O) NMR (DMSO-di, δ)
: 2.65 (3H1S), 7.60~7.80 (
Ill, +a), 8.0θ~8.30 (21L m)
Example 2 8.12 g (40 s, mole) of 1-hydroxy-6-trifluoromethyl-IH-hensitriazole are suspended in 501 mA of water and then dissolved in 45 m of IN sodium hydroxide solution II. Under water cooling, I)-
) Luenesulfonyl chloride 8.0g (40.3m,
After slowly dropping 1 mole of ethyl acetate,
Add 00II+1 and stir at room temperature for 1 hour. The organic layer is separated, quenched with water (50 n/! x 2 ) and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and crystallized with petroleum ether. After filtering and drying, white 1-(p-toluenesulfonyloxy)-6-1-lifluoromethyl-IH-benzotriazole was obtained.

Yield: 13.6g (95.3%) 1). 1): 99-102°C IR (A tmax, Br5On-'): 13
1ON gate R (DMSO-dk-δ): 2.3 (3+
1, S), 7.05-7.55 (4+1, ABq),
7.45-8.05 (IH, Sho), 8.05-8.2
5 (21), S) Example 3 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid 4.0 g (20s, 11ole)
was dissolved in 40 s1 of N,N-dimethylformamide and 3.1 va 1 triethylamine was added under water cooling.
After dropping (22+s, +*ole), 6.1 g of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriacy/Iz (22 m, m
ole) was added and stirred under PA for 30 minutes. The reaction solution was added to ice water, the crystals formed were filtered, and then dried under reduced pressure to give off-white (OFF-WHITE) 2-(2-amino-4-thiazolyl-2-syl-methoxyiminoacetic acid-5-). Trifluoromethyl-IH-benzotriazol-1-yl ester was obtained.

Yield: 7.3 g (95%) m, p,: 198°C (decomposition) IR (λvxax, KBr, cm-'): 18
50 (C=O)NAR(DMSO-d,,δ):3
．． 90(31), S), 6.84 (IHLS) 7.5
6-8.25 (31), m) Example 4 7-Amino-3-((2,3-cyclopenteno-1-pyridinio)methylgo-3-cephem-4-carboxylade-iodo hydrate 0. 96g (2m, mole
) was dissolved in N,N-dimethylformamide 1O1)12, and then 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid-5-trifluoromethyl-IH-benzotriiso- Ru-1-il
After adding 0.81 g (2.1 m, mole) of ester and stirring at room temperature for 1 hour, insoluble materials were removed by filtration.

The solvent was distilled off under reduced pressure (~2 imml/g) and the residue was crystallized by adding 10 ml of isopropyl alcohol, followed by stirring for 30 minutes under water cooling. After filtering and drying under reduced pressure, a soft and beautiful 7-(2-(2-amino-4
-thiazolyl)-'1-syn-(methoxyimino)acetamide] -3-((2,3-cyclopenteno-1
-pyridinio)methylgo 3-cephem-4-carboxylade iodoic acid was obtained.

Yield: 1.2g (93.4%) Rin, p: 178-181°C (decomposition) IR (λa+
axJBr, ell-'): 1785 (lactam C-
0) NMC-0) N bustling C000, δ): 2.3Q~2.
85 (21, Suga-1), 3.10-4.05 (6H, m
), 4.41(31), S), 5.21-6.23 (
4H, m), 8.1) (IHlS), 7.65-8.70 (3H, m) Example 5 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole 1.98 g (6, 8m.

mole) to N,N-diethylformamide 9mj! 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid (1.2 g
, mole) and N,N-dimethylformamide 12m
j! After dropping a clear volume of the solution, 0.9 ta 1 (6.6 m, mole) of triethylamine was slowly added. After stirring for 30 minutes under water cooling, 7-amino-1-((2°3-cyclopenteno-1-pyridinio)
2.6 g (5.4 m, mole) of 3-cephemucarboxilurade iodo acid hydrate was added, stirred at room temperature for 1 hour, and then treated in the same manner as in Example 3 and removed. white 7-(2-(2-amino-4-
3.2 g (92%) of thiazolyl)-2-syn-(methoxyimino)acetamide)-3-((2,3-cyclopenteno-1-pyridinio)methylgo-3-cephem-4-carboxylade iodide M were obtained. IR and NMR data are the same as Example 3.

In fact, Example 6 1.4 g (6,9 Il, mole) of -hydroxy-6-trifluoromethi-IH-benzotriazole was added to N.

N-dimethylformamide 0.9+1 A (6.6 m.
After adding 0.64 ml (8.3 m.mole) of methanesulfonyl chloride at the same temperature,
) and N,N-dimethylformamide 4I1)1 was gradually added dropwise. After stirring for 30 minutes under water cooling and adding 0.84 ml of triethylamine, 2-(2
-Amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid 1.2 g (6 moles) and N. N-
A clear solution of dimethylformamide 181) 1 was poured and stirred at the same temperature for 30 minutes. Thereafter, 7-amino-3-((1,2-cyclopenteno-1-pyridinio)methylcou-3-cephem-4-carboxylrad
After adding 2.8 g (5.9+m.mole) of iodo acid hydrate and stirring at room temperature for 1 hour, the same method as in Example 3 was used to obtain 7-[2-(2-amino-4- thiazolyl)2-syn-(methoxyimino)acetamido)-3- (2.

3-cyclopenteno-1-pyrinonionomethyl)-3-
Cephem-4-carboxilurade iodine 613,5
g (92%) was obtained. The results of IR and N gate R measurements are the same as in Example 3.

Example 7 2.0 g (10 m.mole) of 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid was added to N.
Dissolve in 20ml of N-dimethylacetamide,
Under ice cooling, 3.93 g (1) m. m
ole), then add 1.54 m of triethylamine.
l (1)m. mol) was gradually added dropwise. After stirring for 30 minutes at the same temperature, 7-amino-(3-
(1-Methyl-IH-tetrazol-5-yl)thiomethyl2-3-cephem-4-carboxilrad hydrochloride 3.65 g (10 m, mole) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. After putting this solution in ice water, 2
The precipitate formed was adjusted to pH 1.5 with N-hydrochloric acid solution, filtered and dried under reduced pressure to give an off-white 7-((
2-(2-amino-4-thiazole)-2-syn-methoxoimino]acetamide]-3-((1-methyl-IH-tetrazol-5-yl)thousomethyl]-3-cephemu-4-carboxylic acid was obtained.

Yield: 4.5g (90%) It? (NiBr, C1)-') :178ONM
tl(1)zo/NaHCOi, δ): 3.84 (2
1), d), 4.01 (3H, s), 4.05 (3
+1, S), 5.20 (IH, d), 5.77 (1)
1, d), 7.01 (III, S).

Example 8 2.0 g (10 m.mole) of 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid was mixed with N,
N-dimethylformamide 20m j! 3.05 g (1) of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole dissolved in water and cooled with water.
m. +aole) and then 1.54 m 1 (1) m. of triethylamine at the same temperature. mol) was added slowly. This is N. N-dimethylformamide 2Qm
4.08 g of 7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxotrian-3-yl)thiomethyl-3-cephem-4-carboxyralade hydrochloride dissolved in 12 (lom.mole
) was gradually added dropwise and stirred at room temperature for 1 hour. After the reaction is completed, N,N-dimethylformamide is removed under reduced pressure (2-m
After distilling and removing water under water cooling, adjusting to pi (4.5), saturating with NaCl, and adjusting to pi 3.o, a precipitate was formed. Ta.

After stirring for 1 hour, it was filtered and dried under reduced pressure to obtain a white 7 (
(2-(2-amino-4-thiazole)-2-syn
=methoxyimino]acetamide]-3-(2.5
-dihydro-6-hydroxy-2-methyl-5-oxotriazin-3-yl)thiomethylcou-3-cephem-
4-carboxylic acid was obtained.

Yield: 5. Qg (90%) IR (λwax. to Br, cm-'); 1780
(Lactam C=0) NMR (DgO/NallCOz,
δ): 3.20 (2+1, d), 3.62 (31],
S), 3.95 (31), S), 4.21 (2H,
d), 5, 17 (LH, d), 5.72 (III, d)
, 6.95 (ill, S), Example 9 2-(2-amino-4-thiazolyl) -2-syn-
2.0g (10m, mole) of methoxyiminoacetic acid in N
, N-dimethylformamide 20m j! Dissolved in
3.05 g of 1-methanesulfonyl off-cy 6-trifluoromethyl-I H-benzotriazole (
1) m, siole) was added, and then 1.54+wl (l1m, mole) of triethylamine was gradually added at the same temperature. This was followed by N,N-dimethylformamide (7-remino-3-(2-(5-methyl-1.2).

After 4.1 g (los+.mole) of 3,4-tetrazolyl)methyl]-3-cephemu 4-pivaloyloxymethyl)carboxillade hydrochloride was slowly added dropwise, the mixture was allowed to react at room temperature for 1 hour. After the reaction is complete, add the above solution to the water and ethyl acetate mixture under water cooling and adjust the pH.
After adjusting to 7.0, the i-layer was separated. Remove solvent under reduced pressure;
After removing it by distillation, ethyl ether was added to the residue to precipitate crystals. Filter and vacuum dry? - (2
- (2-amino-4-thiazolyl)-2-syn-methoxyiminoacetamide] -3- (2- (5-
Methyl-1.2.

3,4-tetrazolyl)methyl]-3-cephemu 4-pivaloyloxymethyl)carboxilrad (:)
Ta.

Yield: 5.3 g (90%) m. p. : 127-128℃ (decomposition) IR (NiB
", (:1)-') :1780.1743.1
675.

NMR (DMSO-d., δ): 1.17 (9H,
S), 2.46 (3+1, S), 3,55 (2H,
6s), 3.96 (31), S), 5.19 (Il
l, d), 5, 30-6. OO (5H, n), 6
．． 96 (141, s).

Example 10 2.0 g (lom.mole) of 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid was mixed with N,
1-Tosylolane-6-trifluoromethyl-l was dissolved in 20 ml of N-dimethylformamide and cooled with water.
H-benzotriazole 3.23 g (1) m. mole
), then add triethylamine 1. at the same temperature.
54m j! (1) s. siole) was added slowly.

In addition to this, N. 6-Amino-3-(2-(5-methyl-
1.2,3.4-tetrazolyl)methyltusephem-
4-Carpoquinrulate hydrochloride 3.32g (10+m
．． (1) ole) was slowly added dropwise, and the mixture was allowed to react at room temperature for 1 hour. The solvent was removed by distillation under pressure (-2 ml 1 g) and the residue was diluted with isopropyl alcohol lO
ml was added to cause crystallization, and the mixture was stirred for 30 minutes under water cooling. After filtering, drying under reduced pressure produces an off-white color 7.
-(2-(2-amino-4-thiazolyl) - 2 -
syn -methoxyiminoacetamide)-3- (
2-(5-Methyl-1.2.3.4-tetrazolyl)methyl-3-cephemu-4-carboxylrad was obtained.

Example 1) 7-(2-(2-aminothiazol-4-yl)-
2-syn-(2 L-butoxycarbonylprop-2-ofciimino)acetic acid 1.37 g (5 m.mole
) to 0MF201) 1 4! To? 0.7 m+1 (5 m.mole) of triethylamine was added dropwise to the solution. 1-Methanesulfonyl off-6-trifluoromethyl-l! under water cooling. (-benzotriazole 1.4
After adding 9g (5.3w.mole) and stirring for 30 minutes at the same temperature, D gate F10mj! 7=amino-
3-(l-pyridiniummethyl)-3-cephem-4-
Carboxilrad bishydrochloride 1.81g (5m4o
A solution containing le) was slowly added dropwise, and the mixture was allowed to react at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 20 ml of 98% formic acid was added to the residue, and after stirring at room temperature for 40 minutes, the solvent was distilled off under reduced pressure. Acetone 3Qm IH was added to the remaining solid substance to crystallize it, followed by filtration and drying under reduced pressure to give 7-(2-(2-aminothiazol-4-yl)-2-syn-(2-carpocyfur). Fu2-oxyimino)acetamide]-
:l(1-pyridiniummethyl)-3-cephem-4-
Carboxilrad bishydrochloride was obtained.

Yield: 2.72 g (88%) NMR (DtO/NaHCOs, δ): 1.45 (6
H, s), 6.26 (III, d SJ = 5.O
IIz), 5, 84 (IH., d, J = 5.0H
z), 6, 90(1)1, S), 8.05-9.05(
5H5 steel).

f. Effects of the Invention Compared to conventional acylation methods, the present invention provides the following advantages: 1) Use of low-cost methanesulfonyl chloride or tosyl chloride to produce a stable novel condensing agent of the general formula (I[[)
2) the acylation reaction can be carried out quantitatively within a few minutes without protecting the amino group; and 3) the target compound can be isolated by simple operations.

By the method according to the present invention, cephalosporin derivatives having various antibiotic effects can be obtained. In addition to the substances obtained in the examples, the following substances can be obtained by the method of the present invention.

these are,? -((2-amino-4-thiazolyl)-2
-Methoxyiminoacetamide] Cef-3-M-4-
Carboxylic acids/syn isomers, alkali or alkali metals, ammonium, salts consisting of amino organic bases and esters with degradable groups, 7=[(2-amino-4-thiazolyl)-2-methoxyiminoacetamide)-3 -((1-Methyl-1-pyrrolidinium)methyl]-3-cephemu 4-carbosyllade syn isomer.

? -((2-Flu-2-yl)-2-methoxyiminoacetamide]-3-carpomoyloxymethylcefu 3
-M-4-carboxylic acid, its syn isomer, its salt,
and esters with degradable groups, ? -((2-4-thiazolyl)-2-Ccarboxymethoxyimino)acetamide]cefu-3-M-4-carboxylic acid, N-(7-(2-(5-amino-1,2,4-thiadiazole- 3-yl)-2-ethoxyiminoacetamido)-3-cephem-3-ylmethyl]-pyridinium-
These include 4-carboxilade syn isomer and salts thereof.

Procedural amendment (September 25, 1988, own ship Kunio Ogawa, Commissioner of the Patent Office1, Indication of the case, Patent Application No. 155237 of 19882, Name of the invention l-methanesulfonyloxy-6-trifluoromethyl -IH-benzotriazole, a method for producing a cephalosporin derivative obtained using a blistering compound, and an intermediate used in the production of the derivative 3, and its relationship to the amended person's case Name of patent applicant: Korea Chemical Research Institute 4 , Agent 107 Address: 3-2-3-6 Akasaka, Minato-ku, Tokyo Contents of amendment: As shown in the attached sheet 1.
The content of the amendment (1. Intermediate containing the title of the invention) is corrected.

(2) The entire text of the specification is corrected as shown in the attached sheet.

Specification 1. Title of the invention: l-methanesulfonyloxy-6-trifluoromethyl-IH-hensitriazole, a method for producing a cephalosporin derivative obtained using the compound, and an intermediate 2 used for producing the derivative, Claims fl. Condensing agent of the following general formula (I[l) In the above formula, R
4 is an alkyl group or an aryl group.

[2] The compound of the following general formula (I[) is converted into the following general formula (
The reactive derivative obtained by reacting with the compound of I[[) is reacted with the compound of the following general formula (rV) to obtain the following general formula (1
) A method for producing the syn isomer of the compound

R represents a furyl group, a thiazolyl group, or a thiadiazolyl group, and R1 represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms.

Z is a hydrogen atom or a halogen atom, or an alkyl, cycloalkyl, alkoxy or alkylthio group having up to 5 carbon atoms, or an acetoxymethyl or carbamoyloxymethyl group, or R2 is S and N
represents a heterocycle with 5 to 6 ring members containing any substituted 1 to 4 heteroatoms selected from;
-cu, -5-R, group when representing an acyl group having ~4 carbon atoms or a fused heterocycle, or -
C1)! -R is a group or represents a hydrogen atom, an alkyl having 1 to 5 carbon atoms,
Represents an ester, organic acid, or amide group.

M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or an ester group; the C00M group may also represent C08; when Z represents, C00M represents COO-;

R4 represents an alkyl or aryl group, X represents a halogen atom, and n represents an integer from θ to 2.

(3) A syn-isomer of the following general formula (V') which is an active intermediate produced by the reaction of a 5yn-isomer represented by the following general formula (II) and a condensing agent (I[l).

\OR+ In the above formula, R represents a furyl group, thiazolyl group, thiadiazolyl group, R1 represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms, and R4 represents an alkyl group or an aryl group. represents a group.

3. Detailed Description of the Invention a. Industrial Application Field The present invention is directed to methanesulfonyl-6-trifluoromethyl-
IH-benzotriazole, a method for producing a cephalosporin derivative obtained using the compound, and the fi jJ
It relates to an intermediate used in the production of E-form.

b. Prior art In the acylation reaction of β-lactam antibiotics, acid chloride or mixed acid anhydride methods are mainly used, and 1-hydroxysuccinimide or 1-hydroxy-IH-benzotriazole is also used. A method has been developed to convert organic acids into reactive derivatives. Although each of these methods has its own advantages and disadvantages, the acylation reaction using 1-hydroxy-IH-benzotriazole is particularly popular.

C1 Problems to be Solved by the Invention However, the acylation reaction using l-hydroxy to IH-benzotriazole has the disadvantage that the reaction time is long.

For example, the methods disclosed in German Patent No. 3,316,798 and British Patent No. 2,098,216
1-Hydroxy-IH-benzotriazole hydrate was reacted with dicyclocarbodiimide method for 3 to 4 hours to obtain a reactive derivative, and the acylation reaction was carried out after stirring overnight at room temperature. It takes a long time to complete the reaction.

Therefore, the object of the present invention is to utilize the existing 1-hydroxy-
It is an object of the present invention to provide a new and advanced method which has superior reactivity than a method using a condensing agent using IH-benzotri7 pool.

d. A means for solving the problems, that is, the present invention is a new method for producing the syn isomer of a compound represented by the following general formula ([).

In the formula, R represents a furyl group, a thiazolyl group, or a thiadiazolyl group, and ze represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms.

Z is a hydrogen atom or a halogen atom, or an alkyl, cycloalkyl, alkoxy or alkylthio group having up to 5 carbon atoms, or an acetoxymethyl, or a carbamoyloxymethyl group, or any Rt selected from S and N represents a heterocycle with 5 to 6 ring members containing 1 to 4 substituted heteroatoms,
represents an acyl group having 2 to 4 carbon atoms, or a -CHt-5-Rz group when representing a fused heterocycle, or a -CHz-Rt group, or, R1 is a hydrogen atom or 1 to 5 carbon atoms; represents an alkyl, ester, organic acid, or amide group having carbon atoms.

M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or an ester group, the C00M group may represent COt, and when Z represents COO? 1 represents COO-.

Furthermore, a feature of the method of the present invention is that the reactive derivative obtained by treating the compound of general formula (II) with a condensing agent of general formula ([I) in the presence of an organic base is treated with a reactive derivative of general formula ( IV).

~, ゝOR.

In the above general formula, R+, Z and M are the same as above, R4 represents an alkyl group, preferably a methyl group or an aryl group, preferably a p-tolyl group, X represents a halogen atom, and n represents O- Representing an integer of 2, especially L
Examples of groups that can be represented include 2-furyl group, 1,
Examples include 3-thiazol-4-yl, 2-amino-1,3-thiazol-4-yl, and 5-amino-1,2,4-thiadiazol-3-yl.

The method of the present invention can be expressed as a reaction formula as follows.

The condensing agent (coupling agent) of the general formula (I[[) used in the present invention is a novel substance created by the present inventors, and is commercially available at a low price. Not only is it easily produced from lA (it is a stable and easy-to-handle compound).

When using the condensing agent of general formula (III) produced in the first stage process of the present invention, the reactive derivative of general formula (■) can be
An intermediate represented by the following general formula (V) is produced.

Examples of the reaction solvent for dissolving the organic acid of general formula (■) (wherein R and R1 have the above-mentioned meanings) include N,N-dimethylformamide, N,N-dimethylacetamide, or N- Methylpyrrolidone is mainly used and the reaction can generally be completed quantitatively within a few minutes at 0±5°C. Triethylamine or pyridine is most suitable as a base for neutralizing methanesulfonic acid produced during the reaction.

The second step of the present invention is an acylation step of the prepared reactive derivative and the compound of general formula (rV), and the reaction can be carried out within 1 hour at room temperature (about 20°C) without a base. The reaction can be completed quantitatively.

Examples of the vehicle used to dissolve the compound of general formula (IV) include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. After the reaction is completed and the solvent is removed by distillation under reduced pressure,
The target compound can be isolated in high yield by treatment using conventional methods.

The compound represented by the general formula (1) is, for example, West German Patent Publication No. 91) 12,706.413, 2,707
, No. 565, No. 2,715,385, No. 2,921,31
No. 6, No. 2,922,636, No. 3, 1) No. 8,732,
Nos. 3,137,854, 3,307, 550, 3,327,449 and European Patent <Ep.
) 71, 891 and many other patents and publications. Oximino group is syn or an
has the ti configuration, but the syn isomer is preferred.

Particularly preferred compounds represented by the general formula (1) include cefprome, cefmenoxime, ceftriaxine, cefteram, T-2588, ceftazidime, ceftizoxime,
In the form of sodium salts or esters of known products such as cefuroxime, axetil, BMY-28142 and PK-089.

Various compounds of the general formula (If) are also known, such as acid chlorides, mixed acid anhydrides, active esters and active amides.

syn-isomerism of the compound represented by general formula (1) 1
As pointed out, the body is sprayed with commonly known antibiotics. In particular, they are used as antibacterial agents in serial dilution tests at concentrations of e.g. 0.01-5 (1 wg/kHz) and in mice e.g. O.l''lOOmg/animal.

With a dosage of 1 kg, a wide range of different bacterial strains, e.g.
; Phyllococcus aureus (Staphylococ
Streptococcus pyr
ogenes), Streptoconcus faecalis (
Streptococcus faecalis), E-coli, Proteus vulgaris (
Proteus vulgaris), Proteus mirabilis
, Proteus morganii (Proteus sor.
ganii), Shigel radicenteria (Shigel
la dysenteria), Shigella sonnei, Shigella flexner
i), Alcaligenesphaecalis
Genes faecalis), Talebsiella “Klebsiella aerogenes”
es), Klebsiella rapneumoniae (Klebsi
ellalneuIIIoniae), Serra taiarcescens
, Salmonella Heidelberg (Salsonell)
a heidelberg), Salmonella typhi+sur
ius), SuJ Lemonella Enteritidis (Sa
lmonella enteritidis) and Nesseria gonorroae (Nesseria gonorrhoeae)
rhoae).

These compounds are effective as bacterially active antibiotics. For this use, the dosage will vary depending on the compound used, the mode of administration and the treatment desired. However, when given conventionally in divided doses of about 0.25 to about 3 g of the compound, generally at a dosage of 1 to 6 g per day, divided into 2 to 4 doses per day, or in a supported release form. yields satisfactory results.

-a In the formula (1), a compound in which Z is a hydrogen atom,
For example, it is used in the form of the free acid or in the form of a physiologically acceptable salt, the salt form of which has a similar active state as the free acid form. Suitable salt forms include, for example, the sodium salt form. The compounds are generally mixed with conventional pharmaceutically acceptable diluents and carriers, and optionally other excipients, and administered in the form of conventionally prepared capsules or injectable formulations.

e. Examples Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these.

Example 1 6.8 g (33.5 m, mole) of -hydroxy-6-trifluoromethi-IH-benzotriazole are suspended in 200 va 1 of water and then dissolved in 36 ml of IN sodium hydroxide solution. Methanesulfonyl chloride 2.8 m 1) (36,2+m
, a+ole) were gradually added dropwise, ethyl acetate 20IIIlβ was added, and the mixture was stirred at room temperature for 2 hours. The organic layer was separated and the aqueous layer was treated with ethyl acetate (20 mItx
2) Extract and combine the organic layers. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure and crystallized from petroleum ether. After filtering and drying, white 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole was obtained.

Yield: 8.8g (93%) 1). 1), 98-100°C IR (A tax, KBr, (J-'): 1
300 (S = O) NMR (DMSOdi, δ)
: 2.65 (3H, s), 7.60~7.8 (1
(IH, m), 8.00-8.30 (21), g+)
Example 2 8.12 g (40a+, mole) of 1-hydroxy-6-trifluoromethyl-IH-benzotriazole was added to 5++j! of water. and then dissolved in 45+w l of IN sodium hydroxide solution. Under water cooling, p-)luenesulfonyl chloride 8.0 g (40,3 s, mo
After gradually dropping ethyl acetate 10
Add 0ml and stir at room temperature for 1 hour. The organic layer is separated, washed with water (50 ml x 2), and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and crystallized with petroleum ether. After filtering and drying, white 1-(p-)luenesulfonyloxy)-6
-) Lifluoromethyl-LH-benzotriazole was obtained.

Yield: 13.6g (95.3%) Weight: 99-102°C IR (λwax, Br, Ql-'): 131
ONMR(D)IsO−dδ): 2.3(3H
,s), 7.05-7.55 (4H, ^Bq), 7.
45-8.05 (IH,, m), 8.05-8.25
(2HSg) Example 3 2-(2-amino-4-thiazolyl)' 2-5yn
-Methoxyiminoacetic acid 4.0g (20s, mole)
N, N-dimethylformamide 40s I″i
:I Dissolve 3.1 m of triethylamine under water cooling.
A! (22 m, mole) was added dropwise, and then 6.1 g of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole (22 m, mole) was added at the same temperature.
ole) and stirred for 30 minutes. The reaction solution was added to ice water, the crystals formed were filtered, and dried under reduced pressure to give pale yellowish 2-(2-amino-4-thiazolyl-2).
-syn-methoxyiminoacetic acid-5-trifluoromethyl-IH-benzotriazol-1-yl ester was obtained.

Yield: 7.3g (95%) m, p, : 198°C (decomposition) IRJ wax, KBr, eII+-,')
: 1850 (C=O)NMR (DMSO-d,,
δ): 3.90 (3H, s), 6.84 (IH, s) 7
．． 56-8.25 (31), ll1) Example 4 7-amino-3-((2,3-cyclopenteno-1-pyridino)methyl]-3-cephemu 4-carboxylate hydriodide hydride 1 .96g (2m, mole
) was dissolved in 10 ml of N,N-dimethylformamide, and then 2-(2-amino-4-thiazolyl)2-5yn-methoxyiminoacetic acid 1)-5-trifluoromethyl-IH-benzotriazole was dissolved under water cooling. Add 0.81 g (2.1 m, mole) of -1-yl ester,
After stirring at room temperature for 1 hour, insoluble materials were removed by filtration. The solvent was distilled and removed under reduced pressure (~2 mm), and the residue was crystallized by adding 10 ml of isopropyl alcohol, stirred for 30 minutes under water cooling, and then dried under reduced pressure to give a pale yellow color. 7-(2-(2)
-Amino-4-thiazolyl)-2-syn-(methoxyimino)acetamide]-3-((2,3-cyclopenteno-1-pyridino)methyl]-3-cephemu 4-carboxylate hydroiodide was obtained. Ta.

Yield: 1.2 g (93.4%)
x, KBr, cm-'): 1785 (lactam c-0
)) imR(CFiCOOD, δ): 2.30~
2.85 (2+1, m), 3. IO ~ 4.05 (61i
, l1)), 4.41 (38, s), 5.21-6
．． 23 (41), m), 8.1) (1o, S), 7
．． 65-8.70 (3 tl, m) Example 5 1-methanesulfonyloxy-6-trifluoromethyl-IH-hencytriazole 1.98 g (6.8 m).

layer o1e) with N,N-dimethylformamide 91I+1
1.2 g of 2-(2-amino-4-thiazolyl)-2-syn-methoxyimino acid 1) (
6m, mole) to N,N-dimethylformamide 12
m1! After dropping a solution dissolved in , triethylamine 0.9+ 12 (6.6 m, mole) was gradually added. After stirring for 30 minutes under water cooling, 7-amino-
2.6 g (5.4 m, mole) of 3-((2゜3-cyclopenteno-1-pyridino)methyl]-3-cephem-carboxylate hydroiodic acid hydride was added and stirred at room temperature for 1 hour. Thereafter, treatment was carried out in the same manner as in Example 3 to give pale yellowish 7-(2-(2-amino-4-thiazolyl)-2-syn-(methoxyimino)acetamide)-3-((2,3 3.2 g (92%) of -cyclopenteno-1-pyridino)methyl]-3-cephemu 4-hydroxylupoxylate hydroiodide were obtained. IR and NMR data are the same as in Example 3.

Example 6 1.4 g (7.9 m, mole) of 1-hydroxy-6-trifluoromethyl-1H-benzotriazole was added to N.

Dissolved in 13 ml of N-dimethylformamide and heated to -5°
Triethylamine 0.9 ml (6,6n+, s
After adding 0.64 ml (8,3 mymole) of methanesulfonyl chloride at the same temperature,
) and N,N-dimethylformamide 4II+1 l
The concoction liquid was gradually added dropwise. Stir for 30 minutes under water cooling,
After adding 0.84 ml of triethylamine, 2-(2
-amino-4-thiazolyl) -2-syn-methoxyiminoacetic acid 1.2g (6m, 1lole) and N,N-dimethylformamide 18ml in a clean solution. Solution a was added dropwise and stirred at the same temperature for 30 minutes. After that, 2.8 g (5.9 w, mole) of 7-amino-3-((2,3-cyclopenteno-1-pyridino)methyl]-3-cephem=4-carboxylate hydroiodic acid hydride was added, stirred at room temperature for 1 hour, and treated in the same manner as in Example 3 to obtain 7-[2-(2-amino-4-thiazolyl)
-2-syn-(methoxyimino)acetamide)-3
-(2゜3-cyclopenteno-1-pyridinomethyl)-
3-cephem-4-carboxylate hydroiodic acid 3
．． 5g (92%) was obtained. [The results of R and NMR measurements are the same as in Example 3.

Example 7 2.0 g (lon+, mole) of 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid was added to N
, dissolved in N-dimethylacetamide 20II1),
Under water cooling 1-)siloxy-6-trifluoromethyl-IH-benzotriazole 3.93 g (1) m, mo
1.54 ml of triethylamine
(1) m, mole) was gradually added dropwise. After stirring at the same temperature for 30 minutes, 7-amino-(3-(
1-Methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate hydrochloride 3
．． 65 g (lom, mole) was gradually added dropwise and stirred at room temperature for 1 hour. After putting this solution in ice water, 2N-
The precipitate formed by adjusting the pH to 1.5 with hydrochloric acid solution was filtered and dried under reduced pressure to give a pale yellowish 7-((2-
(2-amino-4-thiazole)-2-syn-methoxyimino]acetamide]-3-((1-methyl-I
H-tetrazol-5-yl)thiomethyl]-3-cephemu-4-carboxylic acid was obtained.

Yield: 4.6 g (90%) IR (KBr, clI-'): 178 ONMR (D
zO/Na) ICOs, δ): 3.84 (2+1, d
), 4.01 (3H1S), 4.05 (3B, S),
5.20 (lit, d), 5.77 (1) (, d),
7.01 (18, S).

Example 8 2-(2-amino-4-thiazolyl)-2-syn
-Methoxyiminoacetic acid 2.0g (lom, mole) with N,N-dimethylformamide 201) 14! 3.05 g of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole under water cooling.
After adding (1)m, mole), 1.54 ml of triethylamine (1)m, mole) was gradually added at the same temperature. This was treated with N,N-dimethylformamide (7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxotriazin-3-yl)).
Thiomethyl-3-cephem-4-carboxylate
4.8 g (10 m.mole) of hydrochloride was gradually added dropwise,
Stirred at room temperature for 1 hour. After the reaction was completed, N,N-dimethylformamide was distilled off under reduced pressure (2 gm II g), and the pH of the residue was adjusted to 4.5 by adding water under water cooling. After saturating with salt,
A precipitate was formed by adjusting the pH to 3.0. After stirring for 1 hour, it was filtered and dried under reduced pressure to obtain a white color ([2-(
2-Amino-4-thiazole)-2-syn-methoxyimino]acetamido)-3-(2,5-dihydro-
6-hydroxy-2-methyl-5-oxotriazine-
3-yl)thiomethyl]-3-cephemu-4-carboxylic acid was obtained.

Yield: 5. Og (90%) IR (λmax.KBr, 3-J:1780 (lactam C=O>N former ICDzO/NalICOx, δ
): 3.20 (2H, d), 3.62 (31), S
), 3.95 (3H,s), 4.21 (28,
d), 5, 17 (IH, d), 5.72 (18S d)
, 6.95 (IH, s).

Example 9 2-(2-amino-4-thiazolyl)-2-syn
-Methoxyiminoacetic acid 2.0g (10m, n+ole)
N,N. - 3.05 g of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole (dissolved in 20 l of dimethylformamide and cooled with water)
1) After adding n+, mole), 1.54+sl (l1m. mole) of triethylamine was gradually added at the same temperature. This is N. N-dimethylformamide 7-amino-3-(2-(5-methyl-1,2.

3,4-tetrazolyl)methyl]-3-cephem=4-pivaloyloxymethyl)carboxylate hydrochloride 4
．． After gradually dropping 1 g (10 m.a+ole), the mixture was allowed to react at room temperature for 1 hour. The reaction was completed after adding a mixture of water and ethyl acetate to the reaction mixture. The organic layer was separated by adjusting the pH to 7.0 under water cooling. After removing the solvent by distillation under reduced pressure, diethyl ether was added to the residue to precipitate crystals. Filter and dry under reduced pressure to obtain 7-(2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetamide)-3-(2-(5-methyl-1.2
,3.4-tetrazolyl)methyl]-3-cephemu 4
-pivaloyl oxine methyl) carboxylate was obtained.

Yield: 5.3g (90%) m, p. : 127-128℃ (decomposition) IR (KB
r, cm-'): 1780, 1743, 1
675.

N) IR (DMSO-d., δ): 1.17 (9H
, S), 2.46 (3H, s), 3,55 (2H,
6s), 3.96 (3H, S), 5.19 (III
, d), 5, 30-6. OO (5H, n), 6,9
6(1)1, s).

Example 1 2.0 g of O 2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetic acid (IOIl, n+ole) was dissolved in N,N-dimethylformamide 20+*1 and t- Tosyloxy-6-trifluoromethyl-IH-benzotriazole 3.23 g (1) m, m
ole), then add triethylamine 1 at the same temperature.
．． 54 ml (1) 1), +aole) was gradually added.

To this, 6-amino-3-(2-(5-methyl-1,2
,3,4-tetrazolyl)methyl)-cephem-4-carboxylate hydrochloride 3.33g (10m, nole
) was gradually added dropwise, and the mixture was allowed to react at room temperature for 1 hour. i
%! The solvent was distilled off under pressure (-2 Hg) and the residue was crystallized by adding 10 mA' of isopropyl alcohol and stirred for 30 minutes under water cooling. After filtering,
After drying under reduced pressure, a pale yellowish 7-(2-(2-amino-4-thiazolyl)-2-syn-methoxyiminoacetamide)-3-(2-(5-methyl-1,2,3,
4-tetrazolyl)methylgo 3-cephem-4-carboxylate was obtained.

Example 1) 7-(2-(2-aminothiazol-4-yl)2-5
1.37 g (5 m, mole) of yn -(2-t-butoxycarbonylprop-2-oximino)acetic acid was added to DI
The solution was dissolved in 7 volumes of 'll' 20III, and 0.7 ml (5 m, mole) of triethylamine was added dropwise thereto. 1.49 g of 1-methanesulfonyloxy-6-trifluoromethyl-IH-benzotriazole under water cooling
(5.3m, mole) was added and stirred at the same temperature for 30 minutes, then 7-amino-3-(
l-Pyridinium methyl)-3-cephem-4-carboxylate bishydrochloride 1.81g (5m,
) was gradually added dropwise and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and 20 ml of 98% formic acid was added to the residue, stirred at room temperature for 40 minutes, and the solvent was removed by distillation under reduced pressure. After adding 30 ml of acetone to the organic layer residue and crystallizing it, it was filtered and dried under reduced pressure. -(2-(
2-aminothiazol-4-yl) -2-5yn
-(2-carboxyprobo-2-oxyimino)acetamide]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate bishydrochloride was obtained.

Yield: 2.72 g (88%) NMR (DJ/NaHCOz, δ): 1.45 (
6H, s), 6.26 (IH, d, J = 5
．． 0Hz), 5.84 (1B, d, J
=5.0Hz), 6.90(IH,s), 8.05~9
．． 05 (5H1 Mouse).

f. Effects of the Invention The present invention provides the following advantages: 1) Compared to conventional acylation methods, the present invention utilizes methanesulfonyl chloride or tosyl chloride, which is lower in cost, to produce a stable new condensing agent of the general formula ([[I]
2) the acylation reaction can be carried out quantitatively within a few minutes without protecting the amino group, and 3) the target compound can be isolated by simple fiJ operations.

By the method of the present invention, cephalosporin derivatives having various antibiotic effects can be obtained. In addition to the substances obtained in the examples, the following substances can be obtained by the method of the present invention.

That is, 7-((2-amino-4-thiazolyl)-2
-Methoxyiminoacetamide] Cephe-3-M-4
- Carboxylic acid syn isomers, their alkali metal or alkaline earth metal salts, ammonium salts consisting of amino organic bases, and esters with degradable groups, ? -((2-Amino-4-thiazolyl)-2-methoxyiminoacetamide)-3-((1-methyl-1-virolidinium)methylgo 3-cephem-4-carboxylate syn isomer, 7-( (2-free 2-yl)-2-methoxyiminoacetamide]-3-carbamoyloxymethylcephe-3-em-4-carboxylic acid syn isomer, salts thereof, and esters with degradable groups; ?-((2-4-thiazolyl)-2-(carboxymethoxyimino)acetamidoracephe-3-em-4-carboxylic acid, N-(7-(2-(5-amino-1,2,4- Thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate syn isomer and salts thereof.

Claims (3)

[Claims] (1) Condensing agent of the following general formula (III) ▲ Numerical formula, chemical formula, table, etc. are available ▼ (III) In the above formula, R_4 is a methyl group or p-tolyl group. (2) The compound of the following general formula (II) is converted into the following general formula (III)
A method for producing a syn isomer of a compound of the following general formula (I) by reacting a reactive derivative obtained by reacting with a compound of the following general formula (IV). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( IV) R represents a furyl group, a thiazolyl group, or a thiadiazolyl group, and R_1 represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms. Z is a hydrogen or halogen atom, or an alkyl, cycloalkyl, alkoxy or alkylthio group with up to 5 carbon atoms, or an acetoxymethyl or carbamoyloxymethyl group, or any substitution in which R_2 is selected from S and N -CH_2-S-R_2 group when representing a heterocycle having 5 to 6 rings containing 1 to 4 heteroatoms, or -CH_2-R_
2 groups, or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where R_3 is hydrogen, alkyl with 1 to 5 carbon atoms, ester, organic acid, or amide group represents. M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or an ester group, and the COOM group may also represent CO_2, and Z is When representing ▼, COOM represents COO-. In the above general formula (III), R_4 represents an alkyl or allyl group. (3) A syn-isomer represented by the following general formula (V), which is an active intermediate produced by the reaction of the syn-isomer represented by the following general formula (II) and a condensing agent (III). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) In the above formula, R is a furyl group or a thiazolyl group , represents a thiadiazolyl group, and R_1 represents an alkyl, alkenyl, alkynyl, or cycloalkyl group having 6 or less carbon atoms.