DE2721731C2 - Process for the preparation of an N-protected cephalosporin C-diester - Google Patents

Description

HOOc-CH (CH ₂ ) JCONH

R,

CH ₂ OCOCH ₃ COOH

in which Ri and R _{2 have} the meaning given above, in liquid sulfur dioxide in the presence of pyridine or triethylamine in the temperature range from - 1O ⁰ C to -5 ⁰ C with an · * ο esterifying agent of the general formula (II)

R ₃ -X

in which Rj has the same meaning as before has indicated, and X represents a halogen or a conventional organic sulfonyloxy group.

The invention relates to a process for the preparation of an N-protected cephalosporin C-diester.

Usually, when converting an amido group of a cephalosporin compound to a Iminohalide group or an iminoether group protect the carboxylic acid in the 4-position. to silylation and esterification are known for this purpose.

The silylation process is not a technically worthwhile process because securing agents are expensive and the conversion reaction of an amido group into a silyl derivative of cephalosporin-C in cim Iminohalide group and an iminoether group are made at low temperatures of -50 to -40 ° C must be in order to avoid the elimination of the silyl protecting group (Japanese patent application Sho-49-45878 / 1974).

If an ester is used which is more stable than the silyl derivative used, the reaction does not have to be carried out at such low temperatures. If, however, the esterification is carried out in the presence of a base using an alkyl halide, part or the greater part of an ^{I 3} -cephalosporin ester isomerized to a zP-cephalosporin ester in the course of the reaction. In order to convert the zP ester back to indent ester in this case, the mixture of isomers must be oxidized with a peroxide, such as m-chloroperbenzoic acid, and then reduced with phosphorus trichloride (Cephalosporins and Penicillins, Chemistry and Biology, EH Flynn, Academic Press, New York and London, 1972, pp. 174-151) or the separation and purification must necessarily be carried out to isolate the zP-ester by column chromatography. From the

There are others in the same publication on pp. 172-173 Esterification processes are known in which no isomerization of the double bond occurs. The esterifying agents include phenyldiazomethane and Diphenyldiazomethane proposed. From DE-OS 23 35 083 the esterification of N-protected Cephalosporin esters known, the reaction taking place with an amine and a nitrosating agent.

Furthermore, a method is known in which an equivalent amount of a base to an equimolar ι ο Mixture of cephalosporin and a Haiogenmethylester supplied at such a rate how the rate of formation of an acid anion becomes equal to that of the ester in order to avoid the side reaction, at which ^ -ester is formed, to avoid '5 (Japanese Provisional Patent Application Sho-51-16687 / 1976). All of these processes are complicated in operation, give low yields, or need; expensive reagents.

The object of the invention is to develop an esterification process 2 " to show ren, in which no isomerization of a double bond takes place. That in the claim specified procedure solves this problem.

It is known that liquid sulfur dioxide is a good solvent and that numerous organic solvents can be used Can carry out syntheses in liquid sulfur dioxide (Synthesis 1971, 639-645). But it was by no means closed expect that by the process according to the invention in the reaction in liquid sulfur dioxide a unwanted isomerization can be completely prevented.

The invention is carried out by adding an N-protected cephalosporin-C of formula (I) and a Esterifying agent with the form! (II) Dissolves in liquid sulfur dioxide and at a temperature of - 10 refluxed to -5 ° C for several hours in the presence of certain bases.

Usual protective groups for a Amino group of the cephalosporin-C can be used, e.g. B. an acetyl group, a propionyl group or a Butyryl group, an aroyl group such as a benzoyl group, a p-chlorobenzoyl group or a p-nitrobenzoyl group, an alkoxycarbonyl group such as an ethoxycarbonyl group, t-butoxycarbonyl group or t-amyloxycarbonyl group, a haloalkoxycarbonyl group, such as a 2-chloroethoxycarbonyl group or 2-bromoethoxycarbonyl group, an alkoxyalkoxycarbonyl group, such as a 2-methoxyethoxycarbonyl group or 2- (n-butoxy) ethoxycarbonyl group, an aralkoxycarbonyl group, such as benzoyloxycarbonyl group, p-methoxybenzoylcarbonyl group, p-ethoxybenzyloxycarbonyl group or p-chlorobenzoyloxycarbonyl group, a substituted aryl group such as a 2,4-dinitrophenyl group, 2,4,6-trinitrophenyl group, 2,4-dinitro-6-methoxyphenyl group, 4-cyanophenyl-5 · -> group or 4-carbomethoxyphenyl group, an arylsulfonyl group, such as a benzenesulfonyl group or tosyl group, or an arylsulfenyl group such as a o-nitrophenylsulfenyl group.

As a ring which can be formed by Ri and _R2, to a phthaloyl a Tetrabromphthaloylgruppe or Tetrachlorphthaloylgruppe out of the question.

R ₃ denotes a t-butyl, p-nitrophenylmethyl, benzhydryl, di (p-nitro) benzhydryl, di (p-methoxy) benzhydryl, benzyloxymethyl, benzylthiomethyl, phenacyl, acetoxymethyl, Pivaloyloxymethyl, benzoyloxymethyl or A-benzoyloxyethyl group. As X, in the formula (II) R3-X, a halogen atom, for example a ChIo, bromine or iodine atom, can be used, and a methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy group can be used as the sulfonyloxy group.

Triethylamine or pyridine are used as bases.

The esters obtained by the present process do not contain any zP-cephalosporin ester.

The inventive method is suitable for industrial production because it is not only completely is considerably superior to the known processes in terms of yield and procedure, but because liquid sulfur dioxide is also very cheap. The products of the process are intermediate products in can be further processed in a known manner.

example 1

Dibenzhydryl ester of N-phthaloylcephalosporin-C

(A) N-phthaloylcephalosporin-C

To 80 ml of an aqueous solution containing 4.4 g (10 mmol) of cephalosporin-C was added 3.5 g of sodium bicarbonate to adjust the pH to 7.0 to 7.3. To the solution, 35 ml of acetone was added, and then further dropwise with stirring 50 ml of acetone solution containing 3 g of N-ethoxyphthalimide. After the dropwise addition, the mixture was ^{stirred at 20 °} C. for 1/2 hour. The mixture was diluted with 150 ml of water and the resulting solution was washed twice with 10 ml of ethyl acetate. After adjusting the pH of the aqueous solution to 2 using 2η hydrochloric acid, the solution was extracted three times with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate and the solvent was removed with evaporation, the N-phthaloylcephalosporin-C being contained as an oil.

(B) N-phthaloylcephalosporin-C-benzhydryl ester

5.78 g of N-phthaloylcephalosporin-C obtained according to (A) were obtained in 50 ml of liquid sulfur dioxide was, and 6.05 g (30 mmol) -chlorodiphenylmethane dissolved. Under gentle reflux at -5 ° C were to 3.5 ml (25 mmol) of triethylamine were added dropwise to the mixture in the course of 10 minutes. To Completion of the addition and an additional 4.5 hours of reflux became the liquid sulfur dioxide removed by evaporation to give an oily substance. The substance was dissolved in chloroform up dissolved to form a 200 ml solution, which was then washed with water under acidic conditions and then with a saturated aqueous solution of sodium bicarbonate and a saturated one aqueous solution of sodium chloride. The chloroform layer was poured over anhydrous magnesium sulfate dried and evaporated to dryness, removing the chloroform. The solid residue was recrystallized from ethyl acetate to give 4.65 g of the diester. In thin layer chromatography a single spot was observed. NMR only shows the presence of zP-ester.

The yield is 50.2%.

Elemental analysis: CsoH ^ jNj
Calculated (%): C 68.31,
Found (%): C 68.15,

OioS = 873.33 H 4.93, N 4.90, H 4.99, N 4.96,

S 3.65 S 3.70

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 100 MHzI ppm (Hz):

1.66 / 2.23 (-CH ₂ CH ₂ CH ₂ -, !!!),
1.93 (CH ₃ CO-, s),
3.16 / 3.36 (-SCH ₂ , AB, J = 18.5), 4.69 / 4.95 (-CH ₂ O-, A / B, J = 14), 4.83 (H- 6, d, J = 5), 4.91 (thien. CH, t, J = 6.5),
5, / 3 (H-7, dd, J = 8.5,5),
6.58 (-NH-, d, J = 8.5),
6.85 (ester -OCH <, s),

7.15 / 7.21 / 2.28 (20 arom. H, m), 7.67, 7.33 (4 arom. H, m)

Example 2 N-phthaloylcephalosporin-C-dibenzhydryl ester

Starting from an aqueous solution containing 4.4 g of cephalosporin-C, according to method (A) of Example 1 an oil of N-phthaloylcephalosporin-C obtain. Then 9.88 g of A-bromodiphenylmethane were added reacted as an esterifying agent with the oil thus obtained analogously to Example IB, 7.1 g of des N-phthaioylcephalosporin-C-dibenzhydryl ester. The compound showed a single spot on thin layer chromatography.

The NMR spectrum only showed the presence of the zi ester.

35

Example 3

N-benzoylcephalosporin-C-dibenzyhydryl ester (A) N-Benzoylcephalosporin-C

A saturated solution was added to 100 ml of an aqueous solution containing 4.15 g (40 mmol) of cephalosporin-C aqueous solution of sodium bicarbonate was added to adjust the pH to 7.0 to 7.3. To the mix 100 ml of acetone were added and then 2.1 g (15 mmol) of benzoyl chloride in 21 ml of acetone was added. After the addition was complete, the reaction mixture was stirred at the same temperature for 1 hour During the reaction, an aqueous solution of sodium bicarbonate was added to bring the pH to 7.0 hold to ~ 7.3.

After the acetone was distilled off under reduced pressure, the residue was added twice with 10 ml portions Washed ethyl acetate. The aqueous layer was adjusted to pH 3.3 and twice with 20 ml portions Washed benzene and, after adjusting the pH to 2.0, extracted three times with 20 ml portions of benzene. The extract was dried over magnesium sulfate and the solvent was distilled off, leaving 4.38 g N-Benzoylcephalosporin-C was obtained in a yield of 84.3%.

(B) N-Benzoylcephalosporin-C-Dibenzhydryl ester

The oil containing 10 mmol of N-benzoylcephalosporin-C obtained after the step (A) and 6.05 g (30 mmol) of Λ-chlorodiphenylmethane were dissolved in 100 ml of liquid sulfur dioxide, and the mixture was slightly at -5 ° C held under reflux. During the reflux treatment, 3.5 ml (25 mmol) of triethylamine were added dropwise over 10 minutes. After the addition, the mixture was refluxed for 5.5 hours and then the liquid sulfur dioxide was removed by evaporation to give an oil. This oil was dissolved in 200 ml of ethyl acetate and washed with acidic water, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution successively to remove the basic compounds. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness to give a solid which was then washed with ether to give 1.11 g of the diester. This solid showed a single spot on thin layer chromatography and the NMR spectrum did not show any presence of the A ¹ compound.

Claims (1)

Claim:
Process for the preparation of an N-protected cephalosporin-C-diester of the general formula (III) R ₃ OOCCH (CHj) ₃ CONH CH ₂ OCOCH ₃ COOR ₃ where Ri is a customary amino protective group and R2 is a hydrogen atom or R, and R ₂ together with the nitrogen atom is a phthaloyl, tetrachloro or tetrabromophthaloyl group and R _{3 is} a tert-butyl group, a p-nitrophenyl methyl group, a benzhydryl group, a di- (p -nitro) benzhydryl group, a di (p-methoxy) -benzhydrylgruppe, a benzyloxymethyl group, a benzylthiomethyl group, phenacyl group, an acetoxymethyl group, a pivaloyloxymethyl group, a benzoyloxymethyl group or an Benzoyloxyäihylgruppe, characterized in that an N-protected cephalosporin C of the general formula (I)