DE2221070C2 - Process for the preparation of 7-amino-cheph-3-em-4-carboxylic acid - Google Patents

Description

by protecting the carboxyl groups of 7- (4'-carboxybutan-amido) -ceph-3-em-4-carboxylic acid, Reaction with phosphorus pentachloride in the presence of a base in an inert organic solvent, subsequent addition of an alkanol with 1 to 6 carbon atoms or alkanediol with 2 to 4 Carbon atoms and treatment of the reaction mixture under acidic conditions, thereby characterized in that the carboxyl groups by forming a mixed anhydride with Acetic acid, chloroacetic acid, dichloroacetic acid, methyl or ethyloxalic acid protects.

The invention relates to the method characterized by the claim.

Cephalosporin C [(6R, 7R) -3-acetoxymethyl-7- (D-5-amino-5-carboxypentanamido) -ceph-3-em-4-carbon-
acid] can be entacy-Iated to the corresponding 7-aminocephalosporin N-entacy-Iated by various methods with varying degrees of success and benefits; however, N-deacylation has posed many difficulties, and there is a need for alternative methods that provide advantages. The cephalosporin compound having a 7- (4-carboxybutanamido) group can be easily obtained from cephalosporin-C by the method of Belgian patent 7 36 934, and this compound has a pleasant feature. While cephalosporin C has both acidic (carboxyl) and basic (amine) functional groups, the corresponding compound with a 7- (4-carboxybutanamido) group only has acidic functions.

A method for the N-deacylation of a 7-acylamidocephalosporin compound is the so-called imide halide technique, which consists in creating the 7-acylamido compound with an agent, ζ Β. Phosphorus pentachloride which is believed to form an imide halide, converts, the product of this reaction by reaction ■ Riit converts an alcohol into a product of which it is believed to be an imino ether, and the latter cleaves e.g. B. by hydrolysis, to form the desired 7-amino compound. Although the exact nature of the intermediates is unknown referred to herein, for convenience, as imide halides and imino ethers.

To do such a method successfully on the cephalosporin compound with a 7- (4-carboxybutanamido) group it is necessary to first add the carboxyl group in the 4-position and the Carboxyl group in the 7-side chain to protect, otherwise this with the imide-halide-forming compound can react. In general, such a process requires at least one separate step to remove the protecting group for the carboxyl group at the end of the reaction sequence, and there is that Risk of damage to other parts of the cephalosporin, such as the O-lactam ring.

It has now been found that both of the above-mentioned carboxyl groups are effective by formation of a double anhydride by converting 2 molecules of acetic acid, chloroacetic acid, dichloroacetic acid

acid, methyl or ethyloxalic acid with one molecule of the cephalosporin can be protected. The protection of the carboxyl groups is not applied to this only achieved in economic form, but has the additional important advantage that no final Step for splitting off the 4-carboxyl group at the end of the iminohalide process is necessary because the desired 4-carboxyl group of 7-aminocephalosporin is conveniently regenerated by the alcoholysis and / or hydrolysis steps. This method has a significant advantage over the use of silyl derivatives, which is that Silylating agents are expensive compared to about acetyl chloride, which is used to form the double mixed Acetic acid cephalosporin anhydride can be used.

The formation of the double mixed anhydride can be caused by reaction of the cephalosporin compound can be achieved with the corresponding acid halide.

The formation of the double mixed anhydride can easily be achieved in an inert solvent under essentially anhydrous conditions (e.g., less than 0.02% H ₂ O) by reacting the 7- (4-carboxybutanamido) -cephalosporanic acid with the acid halide in the presence of a base. The base is preferably used in excess. Suitable bases include tertiary amines such as quinoline, pyridine; N, N-dimethylaniline, Ν, Ν-diethylaniline or triethylamine. A salt of cephalosporin can also be assumed.

If essentially anhydrous conditions are not met, there is excess acid halide required to react with the contained water.

Bases forming iminoether-to Imidhalogenid- and steps are required, may be conveniently added in the full amount at this time, and it can in this way up to 15 m molar equivalents per equivalent of cephalosporin can be used.

The solvent should preferably be chosen so that it is also suitable for the subsequent implementation the iminohalide reactions is suitable. Suitable solvents, which are preferably free from alcohol, thus include halogenated hydrocarbons, e.g. B. methylene chloride, 1,2-dichloroethane or chloroform or cyclic or acyclic ethers, e.g. B. tetrahydrofuran, dioxane, diethyl ether or diisopropyl ether or aromatic hydrocarbons, e.g. B. benzene or toluene. Chloroform and methylene chloride are special preferred, either alone or mixed with other solvents.

The anhydride may be at a temperature above -100 ° C, preferably be carried out -50 to + 4O ⁰ C _1, for example at from -10 ° to +20 ⁰ C, preferably at room temperature.

The invention will now be described in more detail with reference to the imide halide technique.

Imide halide-forming compound

Phosphorus pentachloride is used as the imide halide-forming compound, advantageously in finely divided form Shape, ζ. B. with a grain size of 1.68 mm.

A) Reaction of phosphorus pentachloride with
the double anhydride

This reaction should be carried out in the presence of a base, preferably an organic base will. Suitable organic bases, which preferably have a pKa of 4 to 6, include tertiary amines such as Pyridine, N, N-dimethylaniline, Ν, Ν-diethylaniline, quino-Hn, Dimethylacetamide or dimethylformamide or mixtures thereof. If in the previous Implementation of an excess of base is used, so it is usually not necessary to use additional base of the present implementation.

A mixture of phosphorus pentachloride and the base may, if desired, be brought into contact with the anhydride. The reaction is preferably carried out in an inert organic solvent as described above.

Phosphorus pentachloride can and can be added to the anhydride in molar excess up to a 10 mole excess can be used. It is not economical to use a large excess and it is preferably carried out in molar proportions of 1: 1 to 1: 3.

The temperature for the reaction of the phosphorus pentachloride with the anhydride can -100 °, eg -50 ° to +50 ⁰ C, are. It may be advantageous to operate at temperatures from -30 to +30 ⁰ C, and is preferably carried out at -30 ° C to +10 ^0.

Imino ether-forming compound

10

15th

20th

30th

45

50

The imino ether-forming compound is an alkanol with 1 to 6 carbon atoms, for example methanol, Ethanol, n-propanol, n-butanol, isopropanol or Isobutanol, preferably methanol or a diol of the general formula

HO-R ² -OH

(wherein R ^{2 is} a divalent alkylene group having 2, 3 or 4 carbon atoms in the carbon chain connecting the two oxygen atoms). Suitable diols include ethylene glycol, propane-1,2- and -1,3-diol, butane-1,2-; -1,3-; -1,4- and -2,3-diol. A preferred diol is butane-1,3-diol.

B) Implementation with the imino ether-forming
link

The product of step A can be reacted with the iminoether-forming compound, the The course of the reaction is followed, for example, by thin-layer or paper chromatography or polarimetry will.

The imino ether-forming compound can be used in a substantially molar excess, ζ. B. up to 75 and even 100 moles can be used over the cephalosporin compound. Although the imino-ether-forming Compound can be added to the reaction solution, it is preferred to add the reaction solution to the Add imino ether-forming compound, as this allows better control of the reaction system.

The temperature for reaction with the iminoether-forming compound can be above -100 °, e.g. B. -50 ° to + 20 ⁰ C, be. The optimum temperature will depend, at least to some extent, on the reactants used, and it is generally preferred to carry out this step at temperatures of from -50 ° to -10 ° C.

C) Aqueous treatment

To complete stage B, the reaction mixture is preferably with water or with brought into contact with an aqueous medium, optionally with an aqueous solution of an acid. This Step is not essential as the anhydride group can also be alcoholysed, e.g. B. with methanol.

The reaction with water can be at a temperature of -25 ° to +50 ⁰ C, preferably be carried out -13 ° to + 30 ° C.

Under the acidic conditions that prevail in both stages B and C, alcoholysis or Hydrolysis of the anhydride and imino ether brought to completion, and the 7-aminocephalosporin-4-carboxylic acid gets formed. The amino compound can be conveniently added by changing the pH on its isoelectric point, d. H. about 3.5, can be obtained. This can be done by titration with aqueous ammonia be achieved.

The 7-amino compound can be used as an acid addition salt be isolated, e.g. B. as hydronitrate or hydrocarbon sulfonate, such as p-toluenesulfonate or Methanesulfonate.

The following examples serve to illustrate the invention.

Unless otherwise stated, solutions were dried over anhydrous magnesium sulfate and evaporated in vacuo. Solids were dried in the presence of phosphorus pentoxide at 20 to 30 ° at 1 mm. Rotation values were measured at temperatures between 18 ° and 23 °. The dry chloroform and methylene chloride solvents were recovered by distillation over phosphorus pentoxide. The proton magnetic resonance spectra were recorded on a Varian HAlOO at 100 MHz. The values for the coupling constants are not listed. The yields of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid were corrected on the basis that pure material had an X _{m! Ix} of 264 nm (E \ "° _m 302) in aqueous solution of pH 6-7.

example 1

a) bis (acetyl anhydride) of (6R, 7R) -3-acetoxy-

methyl-7- (4-carboxybutanamido) -ceph-3-em-

4-carboxylic acid

A suspension of 3.86 g (10 mmol) (6R, 7R) -3-acetoxymethyl-7- (4-carboxybutanamido) -ceph-3-em-4-carboxylic acid in 50 ml dry chloroform was with 2.8 ml (20 mmol) of triethylamine treated to form a clear solution which was cooled to 0-5 °. 1.43 ml (20 mmol) of acetyl chloride were carefully added and the solution was stirred in an ice bath for 1 hour. The pale yellow solution was washed with 2 × 50 ml of cold buffer, pH 7.3, and with 50 ml of water, then dried and evaporated to give 4.36 g (93%) of the title compound as a white solid, mp 92 to 93 °; [<x] _D + 68.2 ° (c 1.07;

CHCI3), K _max . 267 nm (E ] * 142), v _max . (CHBr ₃ ) 3415 (NH), 1818 and 1740 (anhydride), 1782 (azetidin-2-one), 1740 (acetate), 1687 and 1502 cm- '(amide), v (CDCl ₃ ) 3.26 (1 -Proton doublet, J 10 Hz; NH), 4.10 (1-proto-

35

nen double doublet, | 10 and 5 Hz; C ₇ -H), 4.79 and 5.10 (2 proton AB-quartet, J 14 Hz; C ₃ -CH ₂ OAc), 4.99 (1 proton doublet, J 5 Hz; C ₆ -H), 6.33 and 6.55 (2-proton AB-quartet,] 18 Hz; C ₂ -CH ₂ ), 7.42 and 7.59 (two 2-proton multiples; C ₂ 'and C ₄ 'CH ₂ ), 7.70 and 7.78 (two 3-proton singlets; anhydride acetyl] CH ₃ ), 7.90 (3-proton singlet; C-acetoxy) and 792 (2-proton multiplet ; C ₃ '—CH ₂ ) -

b) (6R, 7R) -3-acetoxymethyl] -7-aminoceph-3-em-4-carboxylic acid

2.35 g (5 mmol) of the bis (acetyl anhydride) of (6R, 7R) -3-acetoxymethyl-7- (4'-carboxybutanamido) -ceph-3-em-4-carboxylic acid were added to 60 ml of dry methylene chloride cooled to -15 ° C in a nitrogen atmosphere; 1.43 ml (12 mmoles) of quinoline followed by 2.4 g (12 mmoles) of phosphorus pentachloride were added. The suspension obtained was stirred for 2 hours at -15 °, then 12 ml of methanol were added, as a result of which the temperature rose to + 10 °. The solution was stirred at -15 ° for 30 minutes and 20 ml of water were added. The mixture was allowed to warm to + 20 ° while stirring for 30 minutes. The phases were separated and the chloroform phase was back-extracted twice with water (2 × 5 ml). The aqueous phases were combined and the pH was adjusted from 0.8 to 3.6 with ammonia (0.880). After cooling the suspension for 30 minutes, the solid was filtered off, washed with 5 ml of water, 5 ml of methanol and 10 ml of methylene chloride and dried in vacuo, 0.843 g (62%) of (6R, 7R) -3-acetoxymethyl-7-aminoceph- 3-em-4-carboxylic acid gave; X _max . 264 nm (E ! 1302).

Example 2

Table 1 below contains various forms of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid from (6R, 7R) -3-acetoxymethyl-7- (4'-carboxybutanamido) -ceph-3-em-4-carboxylic acid conditions applied via the in situ prepared bis (acetyl anhydride).

ίο The implementations were made according to the following general method carried out

In the formation of the mixed anhydride, 4 drops of dimethylformamide were added to reactions that are shown in on a 5 mmole scale and 8 drops on a 10 mmole scale. The whole The reaction was carried out under an atmosphere of dry nitrogen.

After the addition of the phosphorus pentachloride (which probably forms an iminochloride), an alcohol was added to the solution. The product was isolated by separating off the aqueous phase, back-extracting the organic phase with water and combining the aqueous phases. The pH was adjusted from the final pH to 3.6 with 0.880 ammonia. The resulting suspension was cooled to about 5 ° for 30 minutes and filtered. The solid was washed with water, methanol and methylene chloride and dried in vacuo to give (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid. The yields have been corrected assuming that in a pH 6 buffer, E \ " _m at 264 nm of authentic material is 302.

1
1
S. Tabollo G base Acetyl Solution time Imino chloride at - 15 ° Time Iminoather at -15 ° hydrolysis Time Final pH Corrected E \ K) OO * ¹ "S ti UI ühlofitl middle -20 ° yield K) S. CmMoI) CmMoI) (ml) (Min.) PGl ₅ base (Min.) alcohol Time H ₂ O (Min.) % K) f Anhydride formation at 20 ° "- ⁴ ^ Jj; Chlnolln 44 CHCl, 60 CmMoI) CmMoI) 120 (ml) (Min.) (ml) 30th 0.5 288 O scale (34) (120) Quinoline 22nd CH ₂ CI ₂ 30th 23.2 Quinoline 120 MeOH 30th 40 30th 0.5 67.3 296 O CmMoI) (17) (38) (34) (24) k PhNMe ₂ 22nd CHCl, 45 11.6 Quinoline 120 MeOH 30th 20th 30th 0.3 69.3 302 f to (17) (38) (17) (12) f Chlnolln 22nd CHCl) 30th 11.6 PhNMe ₂ 120 MeOH 30th 20th 30th 0.7 59.1 285 y 5 (17) (38) (17) (12) j Quinoline 22nd CHCl, 30th 11.6 Quinoline 120 PrOH 130 20th 30th 0.5 38.7 275 i 5 (17) (12) (17) (38) 11.6 Quinoline Butane- 30th 20th 50.0 i S. Quinoline 22nd CHCl) 30th 60 1,3-diol 30th 0.5 282 t (17) (38) (17) (12) 5 11.6 Quinoline MeOH 30th 20th 50.2 F. (17) (12) i; I.
t
f. 5 ι
(
( ssssas

Example 3

To a stirred suspension of 7.73 g (20 mmol) (6R, 7R) -3-acetoxymethyl-7- (4'-carboxybutanamido) -ceph-3-em-4-carboxylic acid in 77 ml of dry methylene chloride were 7.3 ml (60 mmol) of N, N-dimethylaniline and 4.2 ml (60 mmol) of acetyl chloride were added, the temperature being kept at 25 ° by external cooling became. After a period of 75 minutes, the pale yellow solution obtained was cooled to -17 °, and 3.6 ml (30 mmol) Ν, Ν-dimethylaniline were added, followed by 6.6 g (31 mmol) of phosphorus pentachloride. The mixture was then stirred for 90 minutes at -17 ° bis -8 ° stirred. 9.0 ml (100 mmol) of butane-1,3-diol were added then added, the first 1 ml dropwise and the remainder over 1 minute. The yellow solution obtained was held at -15 ° to -7 ° for 20 minutes. 80 ml of water were then added and the mi

The mixture was stirred vigorously for 20 minutes, the temperature rising from + 5 ° to + 16 °. The mixture was separated and the aqueous layer was washed with 100 ml of methylene chloride and 100 ml of ethyl acetate. The organic solutions were washed back one after the other with 2 × 100 ml of water. The combined aqueous solutions were stirred and neutralized to pH 3.2 with 6.5 ml of aqueous ammonia (specific gravity 0.880), with a brief pause at pH 1.5 to allow the product to crystallize slowly. The suspension was stirred for 30 minutes at 5 ° and the product was filtered off, washed in slurry with 2 × 20 ml of water, 2 × 10 ml of acetone and finally, replacing with 20 ml of acetone, and air-dried, with 4.23 g ( 6R, 7R) -3-acetoxymethyl ^ -amirioceph-S-em ^ -carboxylic acid; 01! "+ 93, S ⁰ (c, 0.9 in pH 7 buffer); X _max . 264 ηm (E II 297); 76% yield.

Claims (1)

Claim: A process for the preparation of 7-amino-ceph-3-em-4-carboxylic acid de ^r formula I H ₂ N- ) N J-CH ₁ OCOCH ₃ COOH