DK146627B - METHOD FOR PREPARING 7-AMINO-CEPHALOSPORANIC ACID - Google Patents

Description

in 146627

The present invention relates to a particular process for the preparation of 7-amino-cephalosporanoic acid (7-ACA), characterized in that a heavy metal complex of cephalosporin C is treated with a silylating agent, in which the silyl ester formed in a manner known per se. is transferred into an imide halide with an imide halide forming agent, the imide halide is transferred into an imino ether by an alcohol and the imino ether double bond is cleaved.

For example, from the disclosure of French Patent No. 1,394,820, it is known to prepare 7-ACA by transferring an imide halide of an N-protected cephalosporin C diester of the formula

Hall

ICE

y-ch- (ch2) 3-c = n- | -j / \ τ C = 0 __N. -CHO-0-C0CH,

I </ T

OR I

C = 0

OR

wherein Y represents a protected amino group and OR represents a leaving-ester group, in a corresponding imino ether, e.g. a low alkyl imino ether, solvolize the imino ether and optionally hydrolyzing a formed 7-ACA ester to the free acid.

Surprisingly, it has been found that 7-ACA can be advantageously prepared by treating a heavy metal complex, e.g.

In a zinc complex, of cephalosporin C with a silylating agent, transfer the thus-prepared diester with an imide halide-forming agent into an imide halide, transfer this by an alcohol into an imino ether and cleave the imino ether double bond.

The formation of the imide halide is carried out in a manner known per se, e.g. as disclosed in the specification to French Patent No. 1,394,820, by reacting with imide halide-forming agents such as acid halides, especially acid chlorides derived from phosphorus, sulfur, carbon or their oxygen acids, e.g. with phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride, pyrocatechylphosphorus trichloride, but primarily with phosphorus pentachloride. The reaction is preferably carried out in inert organic solvents and in the presence of tertiary amines, e.g. triethylamine, quinoline or preferably pyridine or dimethylaniline.

The imide halide group is preferably transferred by treatment with a lower alkanol, especially methanol, in an imino ether group. For example, the double bond in the imino ether is cleaved. by treatment with water, for example at a pH of about 0 to about 15 4, preferably at a pH of approx. 2nd

These processes can be carried out in a manner known per se, e.g. as disclosed in the specification of French patent no.

1394820. The formation of the imino ether is carried out in the absence of water.

The process of the invention presents extremely valuable opportunities for a simple process execution on a large scale, scale. Conveniently, the process can be carried out by precipitating cephalosporin C from crystalline zinc complex from fermentation solutions and treating this product directly with a silylating agent without further purification. In this way, optionally after filtration, an almost colorless clear solution is obtained, which can be used immediately to prepare the imide halide. In the same reaction medium, the formation of the imino ether and its solvolysis to 7-ACA are also carried out. From the solution, 7-ACA crystallizes directly, preferably at a pH of 3-4. The 7-ACA product is so pure (thin layer chromatography only one substance is found) that it can be used directly for the acylation of the 7-amino group, 3 146627

The silyl ester groups have the formula

R 1 - R 2 - S 1 -O-R 3 wherein R 1, R 2 and R 2 are the same or different and mean alkyl, especially lower alkyl, e.g. methyl, aryl, e.g. phenyl, or aralkyl, e.g. benzyl or wherein one of the groups R 1, R 2 or R 3 means another cephalosporin C heavy metal complex and the other groups have the meanings given above. Preferably, R 1, R 2 and R 2 are methyl and one of the groups R 1, R 2 or R 2 represents the cephalosporin C-zinc complex and the other groups mean methyl.

The introduction of the silyl ester groups and optionally the N-silyl protecting group is carried out, for example, with a compound of the formula

R \

R0-Si-X

2 /

R3 X

Wherein R 1, R 2 and are the same or different and represent alkyl, aryl or aralkyl, and X represents halogen, e.g. chlorine, or wherein one of the groups R chlorine, the other groups have the above meanings, and X means halogen, e.g. chloro. For example, the zinc-20 complex of cephalosporin C is reacted with trimethylchlorosilane. The introduction of a silyl ester group in which one of the groups R 1, R 2 and R 3 means a cephalosporin C heavy metal complex and the others means methyl, is carried out e.g. by reacting the cephalosporin C heavy metal complex, e.g. the zinc complex, with dimethyldichlorosilane. For introduction of the silylester group, one may also react with hexamethylsilazane or N-trimethylsilyldiethylamine or with bis-trimethylsilylacetamide or trimethylsilyl-N-methylacetamide. The reactions are carried out in the absence of alcohol and in the absence of such quantities of water which cannot be consumed by excess of the silylating agent in an inert organic solvent, e.g. a hydrocarbon such as benzene or toluene, preferably in a chlorinated hydrocarbon such as chloroform or methylene chloride, in ethers such as tetrahydrofuran or ethylene glycol dimethyl ether, or in nitriles such as acetonitrile, preferably at room temperature or slightly elevated temperature (up to 60 ° C ).

The preparation of a heavy metal complex, e.g. The zinc complex, of cephalosporin C, is described in DK patent no.

126,657.

The process according to the invention is further illustrated by the following examples.

For the thin layer chromatography (on silica gel) the following systems are used.

System 101A: n-butanol-pyridine glacial water (42-24-4-30) System 110: ethyl acetate-n-butanol-pyridine glacial water (42: 21: 21: 6: 10).

Example 1.

10 g approx. 80% of the cephalosporin C-zinc complex is suspended in 700 ml of absolute methylene chloride. To the suspension, 20, with thorough stirring, 8.38 ml of absolute pyridine and 19.1 ml of trimethyl chlorosilane are added and heated to 30 ° C. Over 30 minutes, a clear, light yellow solution is formed. After stirring for a total of 2 hours at 30 ° C, the solution is cooled to room temperature and 22.7 ml of absolute pyridine is added. Then the mixture is cooled in a carbon dioxide ethanol bath to below -20 ° C and 185 ml of 8% phosphorus pentachloride solution in absolute methylene chloride is added so that the internal temperature of the mixture rises to -15 to -10 ° C. The reaction is continued for 10 minutes at approx. -12 ° C, whereby the light-30 yellow solution gradually turns slightly reddish brown. After cooling again to below -20 ° C, 230 ml of absolute methanol are added to the mixture, keeping the internal temperature of the mixture below -10 ° C with good cooling. Thereby, the reaction mixture is partially decolorized, which is stirred for 30 minutes at -10 ° C, then heated to room temperature and left for 30 minutes for further reaction.

Then, with stirring, 25 ml of 50% aqueous formic acid is added and the reaction mixture is filtered immediately with the addition of Hyflo (diatomaceous earth). By the addition of triethylamine (about 16 ml), the pH is raised to 2.0. Pra a pH of approx. 1.5, the secretion of microcrystalline lineal 7-amino-cephalosporanoic acid begins. The suspension is easily stirred for 45 minutes at room temperature. Then the pH is increased by adding 34 ml of triethylamine to 3.3. The suspension is left for 2 hours in an ice bath and filtered. The precipitate is washed with methylene chloride and ether, dried under water jet vacuum, pulverized and dried in high vacuum. The product gives the following value in the UV spectrum in 0.1 N sodium hydrogen carbonate solution: λ = 263 ιημ (ε = 7800).

ΙΠαΧ [α] + = 110 ° + 1 (c = 1% in 0.5 Ν NaHCO 3 solution). In the thin layer chromatogram on silica gel, Κ ^ 101Α ~ ° '30,

Rf = 0.25 (with iodine as indicator). Yield: 75%, purity: 94%.

Example 2.

4,785 g of anhydrous cephalosporin C-zinc complex (10.0 mmol) is suspended in 300 ml of absolute methylene chloride and 4.02 ml of absolute pyridine and 9.25 ml of trimethylchlorosilane are added. The reaction is carried out under dry nitrogen and intensive stirring for 2 hours at 30 ° C.

To the almost colorless reaction solution is added 10.1 ml of absolute pyridine, then cooled to below -20 ° C, and 65.6 ml of 10% solution of phosphorus pentachloride in methylene chloride is added portionwise as the internal temperature of the mixture does not rise. above -10 ° C. The milky solution is stirred for 40 minutes at ca. -12 ° C. After cooling again to -20 ° C, 120 ml of absolute methanol is added portionwise, increasing the internal temperature to -10 ° C. The reaction is continued for 30 minutes at this temperature and for another 30 minutes at 25 ° C.

For hydrolysis, 15 ml of 50% aqueous formic acid is added and the pH of the suspension is raised by adding triethyl axinine (9 ml) from ca. 0.2 to 2.0. The mixture is stirred for 45 minutes at room temperature to form a strong precipitate of fine, almost white material. By adding 19.6 ml of triethylamine the pH is adjusted to 3.35. The reaction mixture is left for 90 minutes in an ice bath, whereby the fine precipitated material is deposited. The precipitate is filtered off with suction and washed with methylene chloride. The crude product is washed several times on the filter with water, then with methanol and finally with ether, then dried in a vacuum desiccator (1.98 g). The 7-ACA product has a purity of 90.5%.

(λ = 263 my fe = 7500]).

max 1

Example 3

3.54 g approx. 91.5% of the cephalosporin C-zinc complex is suspended in 200 ml of absolute methylene chloride, to which 3.94 ml of absolute pyridine and 3.12 ml of dimethyldichlorosilane are added (n = 1.404). After stirring for 2 hours at 30 ° C, the clear, lemon-yellow solution is cooled to below -20 ° C and 8.16 ml of absolute pyridine are added, followed by the addition of 65.5 ml of 8% solution of phosphorus pentachloride in absolute methylene chloride.

After 40 minutes at -12 ° C, the solution is cooled again to ca. -20. Then 90 ml of absolute methanol is added, the internal temperature not exceeding -10 ° C. The golden-yellow solution is stirred for a further 30 minutes at -10 ° C and then for 30 minutes at room temperature. 25 ml of 25% aqueous formic acid is added and the pH is adjusted from 1.35 to 2.0 by the addition of 3.4 ml of triethylamine. As a result, a sharp haze emerges. The suspension is stirred for 45 minutes at room temperature, after which the pH is raised to 3.35 by the addition of 15.7 ml of triethylamine. After 30 90 minutes of cooling in an ice bath, the fine bottom drop is washed which is washed on the filter plate with methylene chloride, methanol and ether. After drying in a vacuum desiccator, 1,422 g of white product is obtained, which according to the UV extinction at 263 microns has a purity of 99.5%. (UV:, = 263 my c max 35 (ε = 8250), λ. = 223 my (ε = 4800) in 0.1 Ν NaHCO -, - ορ- Q11H · 3 solution).

Claims (3)

Example 4. 2.40 g approx. 73% of the cephalosporin C-zinc complex is suspended in 250 ml of absolute methylene chloride. After the addition of 2.42 ml of absolute pyridine and 5.28 ml of trimethyl chlorosilane, the suspension is stirred for 2 hours at 30 ° C to give a colorless, almost clear solution. To this solution = 5.44 ml of absolute pyridine is added. After cooling the solution to below -20 ° C, 44.4 ml of 8% solution of phosphorus pentachloride in methylene chloride is added and stirred for 40 minutes at -12 ° C. After cooling again to below -20 ° C, 56 ml of absolute methanol is added dropwise. The reaction is continued for 30 minutes at -10 ° C and for another 30 minutes at room temperature. The resulting cloudy solution is filtered after the addition of 12 ml of 25% aqueous formic acid and the pH-15 is raised from 1.3 to 2.0, to which is required the addition of 5.6 ml of triethylamine. The resulting suspension is stirred for 45 minutes at room temperature. Then the pH is adjusted to 3.25 by the addition of triethylamine (8.5 ml). The reaction mixture is cooled for 90 minutes in an ice bath and then filtered. The residue is washed thoroughly with methanol. The nearly colorless precipitate is washed with methylene chloride and ether and dried in vacuo. 0.75 g of 7-ACA is obtained with a purity of 94%. UV spectrum (in 0.1 N NaHCO 3 solution): λ = 264 microns (ε = 8000), λ. = 222 me (ε = 4300). max min 25 PATENT REQUIREMENTS Process for the preparation of 7-amino-cephalosporanic acid, characterized in that a heavy metal complex of cephalosporin C is treated with a silylating agent and the silyl ester formed in a known manner is transferred in an imide halide with an imide halide-forming agent. , the imide halide is transferred into an imino ether by an alcohol and the imino ether double bond is cleaved.