JPH0158189B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides cefamycin C, i.e., 7β-(D-5-amino-5
-Carboxyvaleramide-7α-methoxy-3
Using a compound in which the amino group at the 7-position side chain of -cefem-4-carboxylic acid is protected, the 3-position is converted into an S-heterocycle, and the carboxyl group is induced into a phenacyl ester with or without a halogen atom as a raw material, 7 The present invention relates to a method for converting a position side chain into a desired acyl group.

The conventional method for such a method is a method of acyl exchange using zeolite as a catalyst (Japanese Patent Application Laid-Open No. 1989-1999).
105687), a method of acyl exchange after silylation (Japanese Patent Application Laid-open No. 85386, 1983), and a method of silylation or a method that does not use a catalyst, as described in Japanese Patent Application Laid-Open No. 1982-
There are issues such as No. 20723. When producing a more effective antibacterial agent or its intermediate by performing acyl exchange using such a method, the yield becomes an industrial problem. The present inventors based on the fact that the yield of cefamycin derivatives is greatly affected by the type of protecting group for the amino group in the 7-position side chain, the type of substituent at the 3-position, and the type of the protecting group for the carboxyl group at the 4-position. As a result of various studies on this combination, we found that the protecting group for the amino group in the 7-position side chain is an electron-withdrawing group, the 3-position is a heterocyclic S-methyl group, and the carboxylic acid in the 7-position side chain and The inventors have completed the present invention by discovering that the acyl exchange reaction proceeds in an extremely high yield when the protecting group for the position carboxylic acid is a phenacyl ester with or without a halogen atom. That is, the present invention has the general formula In the formula, R ¹ represents a benzenesulfonylamino group, R ² represents a hydrogen atom or a halogen atom,
R ³ represents a 1-methyl-1H-tetrazol-5-yl group. ) in a halogenated hydrocarbon solvent A compound represented by the formula R ⁴ -X () (wherein R ⁴ represents a chloroacetyl group or a cyanomethylthioacetyl group, and X represents a halogen atom) General formula characterized by reaction with The present invention relates to a method for producing a cefamycin derivative represented by the formula (wherein R ² , R ³ and R ⁴ have the same meanings as described above).

The compound having the general formula () used as a raw material of the present invention protects the amino group of the 7-position side chain of cefamycin C, converts the 3-position carbamoyloxymethyl group to a heterocyclic thiomethyl group, and protects the 7-position side chain amino group of cefamycin C. It is obtained by converting the carboxyl group of the chain and the carboxyl group at the 4-position into a phenacyl ester with or without a halogen atom. By using the method of the present invention, it is possible to successively convert the 3- and 7-positions of cefamycin C obtained by culturing microorganisms into the desired group, and it is possible to produce a compound with stronger antibacterial activity. This provides an industrially extremely useful method.

In the method of the present invention, the 7-position acyl group exchange reaction can be easily carried out by bringing the compound having the above general formula () into contact with the compound having the above general formula () in a halogenated hydrocarbon solvent. . Examples of such halogenated hydrocarbon solvents include dichloromethane, chloroform, and trichlene, and 1,2-dichloroethane is most preferred. Examples of the halogen atom represented by x in the general formula () include chlorine and bromine. The amount of carboxylic acid halide () used is 1 to 10 molar ratio to the compound (), but 5
~10 molar ratios are preferred. Reaction temperature is usually 50-100℃
It is ℃. The progress of the reaction can be followed by thin layer chromatography. The time required for the reaction is several tens of minutes to 10 hours.

Note that this acyl exchange reaction can be suitably carried out in the presence of a deoxidizing agent, and examples of the deoxidizing agent used here include propylene oxide, butylene oxide, styrene oxide, phenyl glycidyl ether, etc. .

The target compound having the general formula () obtained by this reaction can be collected by a conventional method. Distill the solvent from the reaction mixture and add isopropyl ether to the residue and collect it as a powder, or
Alternatively, it can be purified and collected by chromatography.

The compound represented by the general formula () obtained by the method of the present invention can be obtained by reacting zinc with a mineral acid or a sulfonic acid in an inert solvent. (In the formula, R ³ and R ⁴ have the same meanings as described above.) A cefamycin derivative and its pharmacologically acceptable salt can be produced, and the compound () has excellent antibacterial activity. It is a compound useful as a medicine.

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

Example 1 (a) 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7-α-methoxy-3-carbamoyloxymethyl-3-
Cefem-4-carboxylic acid 70g (purity 85%) to 1-methyl-5-mercaptotetrazole 175
g, add 12 ml of water and 3 ml of acetone, and bring the internal temperature to 65~
Heat and stir at 75°C for 20 minutes. At this time, water and acetone are distilled off little by little by reducing the pressure from time to time. Next, add 200 ml of water and 500 ml of ethyl acetate, adjust the pH of the aqueous layer to 1.5 with hydrochloric acid, add 50 g of common salt, stir well, separate the ethyl acetate layer, and remove 100 ml of the aqueous layer.
Extract twice with ethyl acetate, combine with the previous ethyl acetate layer, and concentrate to dryness under reduced pressure. Add 1.6 liters of isopropyl ether to this and stir well. The candy-like substance will turn into powder, which will be collected and washed with isopropyl ether. Dissolve this in 500ml of ethanol and dicyclohexylamine 43.2
g and left in an ice water bath for 1 hour to precipitate white crystals. After collecting, washing with ethanol, and drying, 76.4 g of 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-3 -Cefem-4-carboxylic acid didicyclohexylamine salt was obtained. This mother liquor was further concentrated to dryness, a small amount of ethanol was added, and when it was left to stand for several days (about 6 days), more crystals were precipitated, so it was collected and dried in the same manner to obtain 8.2 g of the same crystals. Total yield: 84.6 g, yield: 83.0% 1 g of the crystals thus obtained was dissolved in 5 ml of methanol, concentrated under reduced pressure until it became syrupy, added with 5 ml of ethanol, and left to stand, yielding a pure product. .

Melting point 143-145℃ (decomposition) Elemental analysis C ₂₃ H ₂₇ N ₇ O ₉ S ₃・2C ₁₂ H ₂₃ N Experimental value C; 55.94, H; 7.45, N; 12.39, S; 9.33 Calculated value C; 56.21, H ;7.33, N; 12.56, S; 9.58 (b) 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl) Thiomethyl-3-cephem-4-
10 g of carboxylic acid di-dicyclohexylamine salt [96% purity (by HPLC)] was added to phenacyl bromide in 50 ml of dimethylformamide.
Add 4.4g little by little to the dissolved solution at 0-5℃ (10 minutes), then stir at room temperature for 30 minutes, add 200ml of ethyl acetate to remove insoluble matter (di-cyclohexylamine hydrobromide). Wash with a small amount of ethyl acetate, and wash the ethyl acetate layer twice with 50 ml of water. The ethyl acetate layer was concentrated under reduced pressure to yield 9.2 g of the corresponding diphenacyl ester as a foamy solid.

nmr δ ppm (CDCl ₃ ) 1.50 to 2.95 (multiplet 7H) 3.43 (singlet 3H) 3.58 (broad singlet 2H) 3.78 (singlet 3H) 4.38 (singlet 2H) 5.00 (singlet 1H) 5.07 (singlet 2H) 5.45 (Broad singlet 2H) 6.0 - 6.15 (Double line 1H) 7.22 - 8.02 (Multiple line 15H) 200 ml of 1,2-dichloroethane and 10.0 ml of monochloroacetyl chloride were added to this and refluxed for 4 hours with stirring. Then, the solvent was distilled off under reduced pressure,
Add 100ml of isopropyl ether to the residue, stir well, and collect the resulting powdery substance.
11.04g of 7β-monochloroacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
A crude product of 5-ylthiomethyl)-3-cephem-4-carboxylic acid phenacyl ester was obtained.
Purity: 44.7%, purity conversion yield: 93% This was subjected to silica gel column chromatography to yield benzene: ethyl acetate 3:
A pure product was obtained by developing and separating and purifying the product in step 1.

nmr δppm (CDCl ₃ ) 3.57 (3H) Singlet 3.68 (2H) 〃 3.92 (3H) 〃 4.13 (2H) 〃 4.50 (2H) 〃 (Bloat) 5.08 (1H) 〃 5.55 (2H) 〃 7.25~8.07 (5H) ) Multiplet Example 2 Same as Example 1, 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)
-7α-methoxy-3-(1-methyl-1H-tetrazol)-5-yl)thiomethyl-3-cephem-4-carboxylic acid di-dicyclohexylamine salt was synthesized from 10 g of its diphenacyl ester,
Using 8.5 g of cyanomethylthioacetyl chloride instead of monochloroacetyl chloride and refluxing with stirring for 6 hours, the same procedure was performed.
12.1g of 7β-cyanomethylthioacetamide-7α-
Methoxy-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-
A crude product of carboxylic acid phenacyl ester was obtained. Purity: 38.0% Purity conversion yield: 78.0% This was applied to silica gel column chromatography and developed and separated and purified with chloroform:ethyl acetate 2:1 to obtain a pure product.

nmr δppm (heavy acetone) 3.53 (3H) Singlet 3.60 (2H) Singlet 3.73 (4H) Multiplet 3.96 (3H) Singlet 4.50 (2H) Broad Singlet 5.15 (1H) Singlet 5.63 (2H) Singlet 7.46 ~8.2 (5H) Multiplet 8.58 (1H) Broad Singlet reference example 1 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid phenacyl ester (purity by HPLC)
Add 20 ml of acetone and 2 ml of water to 1.0 g of 88.7%) to dissolve, and cool to -30°C. Add 5.0ml of monoethyl sulfate and 1.0g of zinc powder to this and bring to -30°~
Stir at −25°C for 2.5 hours. Next, add 50 ml of water and 50 ml of ethyl acetate, shake well, and separate the ethyl acetate layer. The aqueous layer was extracted twice with 30 ml of ethyl acetate, combined with the previous ethyl acetate layer, washed with saturated brine, and the solvent was distilled off under reduced pressure, yielding 0.847 g of 7β-cyanomethylthioacetamide-7α-methoxy. -3
-(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid was obtained. (Purity by HPLC 73.7%) Purity conversion yield 88.0% nmr spectrum δppm (heavy acetone) 3.50 (singlet, 3H) 3.60 (singlet, 2H) 3.5 - 3.7 (quartet, 2H) 3.70 (singlet, 2H) ) 3.90 (singlet, 3H) 4.3 to 4.6 (quartet, 2H) 5.10 (singlet, 1H) Reference example 2 7β-Chloracetamide-7α-methoxy-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cepheme-4-carboxylic acid phenacyl ester (purity 90.1% by HPLC) 1.0 g was dissolved with 20 ml of acetone and 1 ml of water. By reacting with monoethyl sulfuric acid and zinc powder and treating in the same manner as above, 0.857 g of 7β-chloroacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4- A carboxylic acid was obtained.
(Purity by HPLC 70.3%) Purity equivalent yield 85% nmr spectrum δppm (heavy acetone) 3.5 (singlet, 3H) 3.67 (singlet, 2H) 3.98 (singlet, 3H) 4.42 (broad singlet, 2H) 5.08 (single line, 1H)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a benzenesulfonylamino group, R ² represents a hydrogen atom or a halogen atom,
R ³ represents a 1-methyl-1H-tetrazol-5-yl group. ) in a halogenated hydrocarbon solvent with a compound ^represented by the general formula R ⁴ A general formula characterized by A method for producing a cefamycin derivative represented by the formula (wherein R ² , R ³ and R ⁴ have the same meanings as defined above).