JPS61186391A - Manufacture of cephem derivative - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound having the formula
cHt -3-R"(R" is a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms optionally substituted with lower alkyl)] Regarding the manufacturing method.

More particularly, it relates to a novel and advantageous method for producing cephalosporanic acid derivatives of formula (1), which is an economical method for producing compounds of formula (1).The compounds of the present invention are useful as antibacterial agents, and in particular It exhibits strong antibacterial activity against a wide range of microorganisms, such as Streptococcus, Nijiyolysia, Proteus, Shigella, Salmonella, Klebsiella, Serratia, and Neisseria.

[Prior art/problems to be solved by the invention] Semi-synthetic β
- Various methods for producing lactam antibiotics have been reported in various literature and patents. That is, various β-lactam antibiotics are
M)-Vke7-Maminocephalosporan# (7-AC
It is produced by condensing the derivative of A) to form a peptide bond to obtain the β-lactam antibiotic.

Several methods for producing the compound represented by formula (■) are also known. For example, an amino-protected organic acid represented by the formula (■°) into which an R group has been introduced (in the formula, R represents an amino-protecting group) is changed to its reactive derivative, and this reactive derivative is converted into a 7-
ACA? -Used as an acylating agent for ADCA or its derivatives. In this case, reactive derivatives such as acid halides, reactive esters, or reactive amides are usually used.

[Problem that the invention seeks to solve]

Various methods for producing acid halides of organic acids (II) and the use of these acid halides as acylating agents are disclosed in JP-A-52-102293, JP-A-53-34795, JP-A-53-68796, and JP-A-Sho. 54-52096, JP 54-157596 and British patent 1) h 20259
It is disclosed in No. 33. According to the above method, an organic acid (
rl) as thionyl chloride (SOClg), phosphorus pentachloride (PCIs), or phosphorus oxytrichloride (POC
I, ) to its acid halide, and using the halide? -ADCA.

Alternatively, 7-ACA is acylated and the protective group R of the resulting acylated compound is removed to obtain a compound represented by formula (1).

However, such a method not only requires complicated reaction conditions, but also requires a step of protecting and deprotecting an amino group, and the acid halide is unstable.

A reactive ester of organic M (II) is synthesized, and using the reactive ester, ? -ACA,? -The method for producing the compound of formula (1) by acylating ADCA or its derivatives is disclosed in JP-A-52-102293 and JP-A-54-9599.
3 and Japanese Patent Application Laid-Open No. 56-152488.

According to these methods, first, 2=pyridine thioester, 2-benzothiazole ester or 1-hydroxybenzotriazole ester of compound (II) is produced,
Using these esters, 7-ACA, ? -By acylating ADCA or a derivative thereof, the formula (I
) is being manufactured. However, when producing an ester, side reactions occur, the acylation reaction takes a long time, and the yield is low.There is also a method of producing compound (1) using an acid amide or mixed anhydride method. Those methods also have the problems mentioned above. In this method, 2-(2-aminothiazole-
After protecting the amino group of 4-yl)-2-syn-methoxyiminoacetic acid with an R group, a reactive derivative such as an acid halide or a reactive ester is prepared, followed by an acylation reaction. , the protecting group is removed.

A method using 1-hydroxybenzotriazole ester and amide of compound (n) is disclosed in JP-A-54-9559.
It is disclosed in 3. In this method, the ester of formula (VIII) and the amide of formula (VIII) are produced in approximately the same ratio.

However, the reactive ester of formula (■) is extremely unstable and decomposes into the acid of formula (rl) and l-hydroxybenzotriazole. Therefore, separating these products and using them as acylating agents is accompanied by considerable difficulties.

[Means for solving problems]

As a result of extensive research, the present inventors have found that by reacting dialkyl (or diallyl) chlorophosphate (or thiophosphate) of formula (IV) with a compound of formula (V) in the presence of a base, the compound of formula ( A compound of formula (VI) is obtained, and this compound has the formula (
II) is reacted with an organic acid represented by the formula (II) in an organic solvent to form the formula (
(2) is selectively obtained in a high yield in the form of a solvate of a solvent using a reactive amide represented by It has surprisingly and unexpectedly been found that the compound represented by formula (1) can be easily obtained in high yield by reacting with the compound represented by the formula (1).

(Thus, the object of the present invention is to react a dialkyl (or diallyl) chlorophosphate (or thiophosphate) of formula (IV) with 1-hydroxybenzothiazole of formula (V) to obtain a compound of formula (VI). and further formula (VI)
is reacted with an organic acid of formula (II) to form a compound of formula (VII).
A novel acylation method for producing a compound of formula (1) in high yield by obtaining a solvate of the reactive amide of I) and further reacting the solvate with a compound of formula (II[). It is to provide.

The formula of the method according to the present invention is as follows (IV)
(V) (■) (I) (wherein R1, R1 and R3 are the same as defined above, R
4 is lower alkyl or allyl, X is an oxygen atom or a sulfur atom, and examples of the halogen represented by R2 include bromine or chloro. ) one CI+, -5 represented by R2
-R", the 5- or 6-membered heterocycle containing 1 to 4 heteroatoms optionally substituted by lower alkyl represented by R3 is, for example, 1,2.3-
1-lyazole, 5-methyl-1,3,4-thiadiazolyl, l-methyl-IH-tetrazol-5-yl and 2
, 5-'; hydro-2-methyl-6-hydroxy-5
-oxo-as-1-riazin-3-yl and the like.

In the reaction for producing dialkyl (or diallyl) 1-hydroxybenzotriazolyl phosphate (or thiophosphate) of formula (VI), tetrahydrofuran, N, N
-dimethylformamide or N.

Preferably, a solvent such as N-dimethylacetamide is used, most preferably tetrahydrofuran. Bases such as triethylamine, trimethylamine, or pyridine can be used in this reaction, with triethylamine being most preferred.

The novel dialkyl (or diallyl) 1-hydroxybenzotriazolyl phosphates (or thiophosphates) of formula (VI) can be prepared inter alia without separation from the reaction solution.
React with the organic acid solution of I).

As the solvent for dissolving the organic acid of formula (If), it is preferable to use a solvent such as N,N-dimethylformamide or N,N-dimethylacetamide.

The reaction between the compound of formula (VI) and the organic acid of formula (If) is preferably carried out in the presence of a base. Bases such as triethylamine, trimethylamine, or pyridine may be used in this reaction. Triethylamine is the best. The reaction is carried out at room temperature for 1-2 hours on -C and then on formula (VI
A solvate of the reactive amide of II) is obtained as a precipitate.

Next, the acylation reaction is preferably carried out in a mixed solvent of an aqueous base solution and an organic solvent. Examples of the base used in this reaction include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and organic bases such as trimethylamine and triethylamine. Preferably, sodium bicarbonate is used.

The organic solvent used in this step is acetonitrile, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or the like. Acetonitrile, acetone, tetrahydrofuran, and N,N-dimethylformamide are particularly preferred organic solvents.

In the method of the invention, a compound of formula ([) is dissolved in a basic solution and an organic solvent is added thereto. To this, crystals of the solvate of reactive amide (VIII) are added, and the mixture is heated at room temperature from about 1 to
Stir for 5 hours. The reaction proceeds quantitatively. After the reaction, the organic solvent is distilled off under reduced pressure, and the pt+ of the resulting aqueous layer is adjusted to about 4.0 to separate 1-hydroxybenzotriazole produced during the reaction. After the aqueous layer is saturated with sodium chloride, ethyl acetate is slowly added to the saturated aqueous layer with stirring to adjust the pH to the isoelectric point, and the compound represented by formula (1) is obtained as a precipitate.

It is preferable to use water and organic solvent in an amount of about 10 to 30 times the amount of the compound of formula (III), and the ratio of water to organic solvent is preferably 2:1 to 1:2.

[Action/Effect]

The invention has the following advantages over known methods.

1. New dialkyl (or diallyl) of formula (VI) obtained by reacting easily available and inexpensive 1-hydroxybenzotriazole with dialkyl (or allyl) chlorophosphate (or thiophosphate) )■-Hydroxybenzotriazolyl phosphate (or thiophosphate) by using formula (V
The solvate of the reactive amide III) is obtained in high yield and purity.

2. The solvate of reactive amide (VIII) is extremely easily soluble in various organic solvents, and the acylation reaction using this solvate proceeds uniformly in a short reaction time.

3. Unlike acid halides and mixed anhydrides, solvates of reactive amide (VIII) are very stable at room temperature, and therefore solvates of reactive amide (VIII) are commercially available.

4. The method can be performed at room temperature.

5. Even if the amino group of the organic acid compound (n) is not protected, the reaction proceeds quantitatively without side reactions. Therefore, a step of protecting or deprotecting the amino group of compound (I[) is not required.

6. After the reaction is completed, the target compound can be easily separated from the reaction solution.

Therefore, these methods can be carried out with simpler manufacturing equipment than known methods and do not involve any complicated procedures.

Thus, the present invention provides a novel and economical method for producing the compound represented by formula (1).

Examples are given below, but these are solely for explaining the present invention in more detail.

〔Example〕

Example 1 Tetrahydrofuran 80m7 and triethylamine 16,
8 IIt (0.12 M) was completely dissolved in 13.5 g (0.1 M) of 1-hydroxybenzotriazole, and 15.7 m of diethyl chlorophosphate was added thereto.
l (0,1)M) was added. During the reaction, triethylamine hydrochloride formed a crystalline precipitate, and the reaction mixture was filtered and washed with 20 mZd of tetrahydrofuran. For the filtrate and washing liquid,
2-(2-aminothiazol-4-i)Ll) -'
20.1 g of 1-syn-methoxyiminoacetic acid (0,12
M) N,N-dimethylformamide (hereinafter also referred to as DMF) 100 m/solution and triethylamine 13°9
+n7 (0.1M) was applied for 10 minutes.

The reaction mixture was incubated for an additional 1 h at room temperature and then at 0-5 °C for 2 h.
The mixture was stirred for an hour to obtain a precipitate. Wash the precipitate with DMF,
After drying, 1-[α-5yn-methoxyimino-α-(2-aminothiazol-4-yl)-acetyltwobenzothiazole-3-oxide was obtained as a reactive amide.

Yield 1t14.4g, yield: 88% IR (KBr, cm-'): 1730 (amide carbonyl) NMR (DMSO-dilδ+ p
pm): 2.27 (3H,S, -N-CH3)3
．． 90 (3H,s, -0C1l+)7.07
(IH,s, thiazole-H)7.13 (2H
, S+ -NHt) 7.5-8.5 (4H, m, benzotriazole-■) 7.97 (LH, s,
H-C-) Melting point: 156-159°C (decomposition) Example 2 Tetrahydrofuran 80- and triethylamine 16,8
Completely dissolve 13.5 g (0.1 M) of 1-hydroxybenzotriazole in a mixed solution of (0.12 M) and add 20.8 m7 of diethyl chlorophosphate.
(0,1)M) was added. Triethylamine hydrochloride crystallized out during the reaction, the reaction mixture was stirred for 1 hour at room temperature, and the precipitate was filtered and washed with 20 m7 of tetrahydrofuran. 2-(2-amitthiazol-4-yl)-2-syn-methoxyiminoacetic acid to the filtrate and washing solution.
1 g (0,1M) of DMF10〇 solution and 13.9 ml (,0,1M) of triethylamine; 10
The reaction mixture was stirred for an additional hour at room temperature and then for 2 hours at 0-5° C. to obtain a precipitate. The precipitate was washed with DMF and dried to yield 1-[α-5yn-methoxyimino-α-(2-aminothiazol-4-yl)-acetyltwobenzotriazole-3-oxide as the reactive amide. .

Yield 1:36. Og, yield: 92% IR (KBr, cm-'): 1730 (amide carbonyl) NMR (DMSO-dh, δr p
pm) :2.27 (3H,S, -N-CHI)2
．． 90 (3HIS, -N-CH3)3.90 (3
H93,-0CH3) 7.07 (IO,s, thiazole-■) 7.13 (
21),s, -NHg)7.5-8.5 (4H,r
l, benzotriazole-■) 7.97 (IH,s,
H-C-) Melting point: 156-159°C (decomposition) Example 3 A reaction was carried out in the same manner as in Example 1 using DMF instead of tetrahydrofuran to produce 1-[α-5yn-methoxyimino-α-(2- A DMF solvate of aminothiazol-4-yl)-acetyl-benzotriazole-3-oxide was obtained.

Yield: 32.8g, yield: 84% The IR and NMR data were the same as in Example 1.

Example 4 A reaction was carried out in the same manner as in Example 1, using diphenylchlorophosphate 22,8@7 (0,1M)G instead of diethylchlorophosphate, and 1-(α-5yn-methoxyimino-α- A DMF solvate of (2-aminothiazol-4-yl)-acetyl-benzotriazole-3-oxide was obtained.

Yield: 35.2g, yield: 90% IR%NMR data were the same as in Example 1.

Example 5 N instead of tetrahydrofuran and DMF.

Using N-dimethylacetamide (hereinafter also referred to as DMA), a reaction was carried out in the same manner as in Example 1 to obtain 1-[α-5yn
-methoxyimino-α-(2-aminothiazole-4-
A DMA solvate of yl)-acetyl-benzotriazole-3-oxide was obtained.

Yield: 33.2 g, yield: 82% IR (Br, cm-'): 1730 (amide carbonyl.

1655 (DMA carbonyl) NMR (DMSO-di, δ+ ppm): 2.
05 (3H,s, CHi-C-)2.30 (3H
,s, -N-CHi)2.95 (3H,s, -N
-CFIi)3.95 (3H,s, -0CHz)7
．． 10 (IH,s, thiazole-■) 7.20 (2
H, s, -NHz)? , 4 8.4 (4L +w, benzotriazole-H) Melting point: 157-160°C (decomposition) Example 6 Using DMF instead of tetrahydrofuran, Example 2
The reaction was carried out in the same manner as above to obtain 1-(α-5yn-methoxyimino-α-(2-aminothiazole-3-oxide).

Yield N: 34.4g, yield: 88% IR%NMR data were the same as Example 2.

Example 7 A reaction was carried out in the same manner as in Example 2 using diphenylchlorothiophosphate instead of diethylchlorothiophosphate, and 1-(α-5yn-methoxyimino-α
A DMF solvate of -(2-aminothiazol-4-yl)-acetyl-benzotriazole-3-oxide was obtained.

Yield: 36.4g, Yield: 93% The IR and NMR data were the same as in Example 2.

Example 8 A reaction was carried out in the same manner as in Example 2 using DMA instead of tetrahydrofuran and DMF, and 1-[α-5y
n-methoxyimino-α-(2-aminothiazole-4
A DMA solvate of -yl)-acetyl-benzotriazole-3-oxide was obtained.

I R (KBr, cm-1): 1730 (amide carbonyl.

1655 (DMA carbonyl) NMR(DMSO-d&, δ+ I'l"I'
) '2.05 (3H,s, CH3-C-)2.30
(3L 5l-N-CI(ri2.95 (3H,s,
-N-CHs)3.95 (3H,s, -0CHi
)7.10 (LH,S,thiazole-H)7.20
(2't1.s, -NHZ)7.4-8.4 <4
H, m, benzotriazole-) melting point: 157-16
0°C (decomposition) Example 9 Add 7- to a mixture of 100 mj of water and 200 mj of acetonitrile
5.4 g of amitusephalosboranic acid was added.

2.4 g of sodium bicarbonate was added to this mixture and stirred for 10 minutes at room temperature to completely dissolve. 1-(α-5yn-methoxyimino- produced in Example 1) was added to the resulting mixture.
6.40 g of a DMF solvate of α-(2-aminothiazol-4-yl)-acetylgobenzotriazole-3-oxide was added, and the mixture was stirred at room temperature for 4 hours to complete the reaction. Acetonitrile was removed from the mixture under reduced pressure. The solution was cooled to 0-5°C, adjusted to pH 4.0 with 2N hydrochloric acid, and stirred for 1 hour to form a precipitate. After filtering the mixture, the filtrate was saturated with sodium chloride, 120 eLl of ethyl acetate was added thereto, and 2N
-Adjust the pH to 2.5 with hydrochloric acid. A pale yellow precipitate was formed. After stirring for 1 hour, filter and dry. −(
(2-(2aminothiazol-4-yl)-2-syn
-methoxyimino]acetamide]cephalosporanic acid (
cefotaxime) was obtained.

Yield: s, ssg, yield: 95% IR (KBr, cm-'): 1780 (β-
lactam carbonyl) N M R (DzO/NaHCOs, δ+ ppm)
:2.08 (3H,s, -C-CH3)3.53
(2H, d, Ct-H) 4.02 (3H, s, -0CHi) 4.84 (
2)! , d, 3-CHg-)5.20 (IH,
d, C, -H) 5.82 (LH, d, C1-
H) 6.97 (18,s, thiazole-H) Example IO The reaction was carried out in the same manner as in Example 9 using an equimolar amount of tetrahydrofuran instead of acetonitrile to produce 7-((2-(2
-aminothiazol-4-yl)-2-syn-methoxyimino]acetamido]cephalosporanic acid was obtained.

Yield: 8.44g, Yield: 93% The IR and NMR data were the same as in Example 9.

Example 1) Using an equimolar amount of acetone instead of acetonitrile,
The reaction was carried out in the same manner as in Example 9 to obtain 7-[[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamide]cephalosporanic acid.

Yield: 8.26g, yield: 91% toyvotysp-ht, +1Wrum
o) -aT<m This Example 12 5.44 g of 7-aminocephalosboranic acid was added to a mixed solution of 100% of water and 40% of DMF. 2.4 g of sodium bicarbonate was added to this mixture, stirred for 10 minutes at room temperature to dissolve, and cooled to below 10°C. Add 1-[α-
5yn-methoxyimino-α-(2-7minothiazol-4-yl)-acetylgobenzotriazole-3-
DMF solvate of oxide7.87 g DMF
The 40-solution was stirred for 10 minutes and stirred at room temperature for 4 hours to complete the reaction. The DMF layer was diluted with 150-ethyl acetate.
After extraction twice, the aqueous layer was saturated with sodium chloride. The solution was cooled to 5° C., the pH was adjusted to 4.0 with 2N hydrochloric acid, and insoluble impurities were filtered off. The pH was further adjusted to 2.5 with 2N hydrochloric acid to obtain a pale yellow precipitate.

The mixture was stirred for 1 hour and filtered. Wash the obtained precipitate with water and dry it. -((2-(2-aminothiazole-
4-yl)-2-syn-methoxyimino)acetamide]cephalosporanic acid was obtained.

Yield near, 98g - Yield: 88% The rR and NMR data were the same as in Example 9.

Example 13 A reaction was carried out in the same manner as in Example 12 using an equimolar amount of DMA instead of DMF. -((2-(2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamide]cephalosporanic acid was obtained.

Yield: 1.96g, Yield: 88% The IR and NMR data were the same as in Example 9.

Example 14 Using 8.10 g of the DMF solvate prepared in Example 5, a reaction was carried out for 3 hours in the same manner as in Example 9 to obtain 7-((2
-(2-aminothiazol-4-yl)-2-syn-
Methoxyimino]acetamido]cephalosporanic acid was obtained.

Yield: 8.92g, Yield: 98% The IR and NMR data were the same as in Example 9.

Example 15 328 g of 7-amino (3-(1-methyl-IH-tetrazol-5-yl))]thiomethyl-3-cephemu-4-carboxylic acid was added to 35-g of water, and 2.0 g of sodium bicarbonate was added thereto. The mixture was stirred at room temperature for 20 minutes to dissolve, and 40 m7 of acetonitrile was added to it, and 10
Cooled to ℃. 1- produced in Example 1 was added to this mixture.
4.68 g of DMF solvate of (α-5yn-methoxyimino-α-(2-aminothiazol-4-yl)-acetyl]-benzotriazole-3-oxide was added.

After stirring the mixture at room temperature for 5 hours, the mixture dissolved and the reaction was complete. An additional 40@l of water was added to the aqueous layer obtained by distilling acetonitrile under reduced pressure. The pH of the mixture was adjusted to 3.8 with 2N hydrochloric acid, stirred for 1 hour, and the precipitate was filtered off. The filtrate was saturated with sodium chloride and the pH of the mixture was adjusted to 2.7 with 2N hydrochloric acid to obtain a precipitate.

The mixture was stirred at 5°C for 2 hours, then filtered and dried. -((2-(2-aminothiazol-4-yl)-2
-syn-methoxyimino)acetamide)-3-((1
-Methyl-IHtetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (cefmenoxi
me) was obtained.

Yield: 4.65 g, yield 291% l R (KBr, cod-'): 1780 (β
-Lactam NMR (DzO/NaHC(1+, δ): 3.84
(2H, d, C2-H).

4.01 (3H, S, -0CH3).

4.05 (3H,s, =N-CH3),
-5,20 (IL d, C, -H).

5.77 (1■, d, Ct-Fl).

7,01 (I If, s, thiazole-■) Example 16 Using ethyl acetate 4o- in place of acetonitrile, the reaction was carried out in the same manner as in Example 15, and 7-[[2-(2-aminothiazole-4 -yl)-2-syn-methoxy
[mino]acetamido)-3-((1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4
-carboxylic acid was obtained.

Yield: 4.60g, Yield: 90% The IR and NMR data were the same as in Example 15.

Example 17 The same reaction as in Example 15 was carried out using 4.05 g of the DMA solvate prepared in Example 5 instead of the DMF solvate.
Do you do time? -((2-(2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamide)-3
-((1-Methyl-LH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.

Yield i1: 4.97g, yield: 94% The IR and NMR data were the same as in Example 15.

Example 18 7-amino-3-2,5-dihydro-2-methyl-6- was added to a mixed solvent of 40-water and 30+n7-tetrahydrofuran.
Hydroxy-5-oxo-as-)'Jazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid 3.7
Add 1g and further add 2.79g of sodium bicarbonate,
A clear solution with a pH of 8.0-8.2 was obtained. 1- for this
After adding 4.68 g of DMF solvate of [α-5yn-methoxyimino-α-(2-aminothiazol-4-yl)-acetyl]-benzotriazole-3-oxide and stirring the mixture at 5°C for 1 hour. Then, the temperature was raised to 25° C. and stirred for an additional 5 hours. Tetrahydrofuran was removed from the solution under reduced pressure, and 30% of water was added thereto. Add this solution to 2N
- The pH was adjusted to 4.2 with hydrochloric acid, stirred for 30 minutes, and the resulting insoluble material was filtered off. The filtrate was saturated with sodium chloride, and the pH was adjusted to 2.9 to 3.0 with 2N hydrochloric acid to obtain a precipitate. The mixture was stirred for 2 hours while maintaining po, filtered and dried to give 7-([2-(2-aminothiazole-4
-yl)-2-syn-methoxyimino]acetamide)
-3-((2,5-dihydro-2-methyl-6-hydroxy-5-oxo-aS-)riazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (ceft
riaxone) was obtained.

Yield: 4.70 g, yield: 85% IR (KBr, cm −'): 1780 (β
-lactam carbonyl) NMR (DtO/Na+ICO3, δ): 3.20
(2H, d, C, -H).

3.62 (3M, s, =N-CHz)3.
95 (3H, s, -OCH*).

4.21 (2H, d, -5-CI+□-).

5.17 (LH, d, C6-H).

5.72 (LH, d, Ct-H).

6.95 (IH, s, thiazole-H) Example 19 A7Tonitrile 40 m instead of tetrahydrofuran
The reaction was carried out in the same manner as in Example 18 using 7-[[2-(
2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamide]-3-((2,5-dihydro-2-methyl-6-hydroxy-5oxo-as-riazin-3-yl)thiomethyl2 3-cephem-4-carboxylic acid was obtained.

Yield: 4.50g, Yield: 81% The IR and NMR data were the same as in Example 18.

Example 20 Using 4.05 g of the DMA solvate produced in Example 5, the same reaction as in Example 18 was carried out for 4 hours to obtain 7-([2-(2-
aminothiazol-4-yl)-2-syn-methoxyimino]acetamide)-3-((2,5-dihydro-6
-Hydroxy-2-methyl-5-oxo-aS-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.

Yield N: 5.27g, yield: 91% The IR and NMR data were the same as in Example 18.

Example 21 7- to a mixed solvent of 20- water and 20- tetrahydrofuran
1.88 g of amino-3-cephem-4-carboxylic acid was added, followed by 2.0 g of sodium bicarbonate. 3.91 g of DMF solvate of 1-(α-5yn-methoxyimino-α-(2-aminothiazol-4-yl)-acetyl-benzotriazole-3-oxide) was added to the solution cooled to 5°C for 10 minutes. and stirred the mixture at 5℃ for 1 hour.
Time, 25 years - 71 meals A J ma 9 賎 倦倦 1 battle - 2 L elm V - 2 tl was distilled off from the solution under reduced pressure, and water 15 @ was added to it.
1 was added and the mixture was cooled to 5°C. This solution contains 2N
- The pH was adjusted to 4.2 with hydrochloric acid and the resulting insoluble material was filtered off after stirring for 30 minutes. The filtrate was saturated with sodium chloride and the pH was adjusted to 2.8 with 2N-hydrochloric acid to obtain a precipitate.

The mixture was stirred in a water bath for 2 hours while maintaining the pH and filtered. The precipitate was washed alternately with saturated sodium chloride and cold water and dried to give 7-((2-(2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamide]-3-cephem-4 -carboxylic acid was obtained.

Yield: 3.48 g, Yield: 91% T RCKBr, cm-'): 17B0.169
5.1655N MR (DMSO-d, δ): 3.60 (2H, broad, C, -El).

3.84 (3H, s, -0CRs).

5.12 (IH, d, Ct-H).

5.84 (18, d, Ct-H).

6.52 (IH,s, 3-H) 6.76 (18,s, thiazole-H) 7.26 (
2)1. Broad, -NHz)9.65 (II
(,d, -Nll-Co) Example 22 A reaction was carried out in the same manner as in Example 21 using 20 m7 of acetone instead of tetrahydrofuran, and 7-[[2-(2-aminothiazol-4-yl)-2-syn -methoxyimino]acetamide]-3-cephem-4-carboxylic acid was obtained.

Yield: 3.40g, Yield: 90% The IR and NMR data were the same as in Example 21.

Example 23 Using 4.05 g of DMA solvate produced in Example 5,
The same reaction as in Example 21 was carried out for 3 hours, and 7-((2-2
-aminothiazol-4-yl)-syn-methoxyimino]acetamide]-3-cephem-4-carboxylic acid was obtained.

Yield: 5.21g, yield: 94% The IR and NMR data were the same as in Example 21.

Claims (5)

[Claims] (1) Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^4 is lower alkyl or allyl, and X is an oxygen atom or a sulfur atom.) V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) Reacts with 1-hydroxybenzotriazole represented by the general formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (Formula (in which R^4 and The compound represented by and formula (II)
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) React with the compound represented by formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) is obtained, and further Formula (III) is a solvate of the reactive amide of formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R^1 is a hydrogen atom or an alkali metal, R^2
is a hydrogen atom, methyl, halogen, acetoxymethyl or -CH_2-S-R^3 (R^3 is a 5- or 6-membered hetero atom containing 1 to 4 heteroatoms which may be optionally substituted with lower primary alkyl) is acetoxymethyl of the formula (I ring)].
): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A method for producing a cephem derivative, characterized by producing a compound represented by (in the formula, R^1 and R^2 have the same meanings as above) . (2) Claim (1) wherein the reaction between the compound of formula (VI) and the compound of formula (V) is carried out in tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide. Method described. (3) The method according to claim (1) or (2), wherein the reaction is carried out in the presence of an organic amine such as trimethylamine, triethylamine or pyridine. (4) The solvate of the reactive amide of formula (VIII) is N,N-
A method according to claim 1, which is prepared from a solvent selected from the group consisting of dimethylformamide and N,N-dimethylacetamide. (5) Acylation is carried out at room temperature in a mixed solvent with water and an organic solvent selected from the group consisting of acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof. The method according to claim (1), which is carried out in