NO146202B - PROCEDURE FOR CONVERSION OF A 6-ACYLAMIDOPENICILLANIC SULPHOXIDE TO A 7-ACYLAMIDO-3-METYLCEPH-3-EM-4-CARBOXYLIC ACID - Google Patents

Description

The present invention relates to a new method

for the rearrangement of a 6-acylamidopenicillanic acid sulfoxide, of a penicillin produced by fermentation to a 7-acylamido-3-methylceph-3-em-4-carboxylic acid.

Compounds of the latter type can be used for the production of other cephalosporins, e.g. cephalexin and hetacephalexin (see the generally available Norwegian applications no. 4187-72 and 4188-72).

There is an extensive literature available which

concerns the rearrangement of penicillin-1-oxyesters to the corresponding 3-methylceph-3-em-4-carboxylate esters, but everywhere it appears as a necessity that penicillin's 3-carboxyl function is present in the form of a carboxylic acid ester in order for decarboxylation not to take place.

The most closely related prior art in this field

are the following:

1. U.S. patent no. 3,275,626, which deals with rearrangement

of 6|>>--acylamidopenicillanic acid ester. It is further described in the patent that the reaction gives a decarboxylated 3-methyl-3-cephem rearrangement product (column 5, lines 29 - 36 and column 7,

lines 24 - 33), if the penicillin sulphoxide used in the rearrangement is not in the form of a 3-carboxylic acid ester.

2. British Patent No. 1,204,394 deals with rearrangement

of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary sulfonamide solvent system.

3. British Patent No. 1,204,972 deals with rearrangement

of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary carboxamide or tertiary urea solvent system. 4. U.S. patent no. 3,507,861 describes i.a. decarboxylation of the carboxyl function when the free acid is subjected to "sulfoxide rearrangement". 5. The inventors of the same U.S. patent further elaborated these discoveries in a publication entitled "Chemistry of Cephalosporin Antibiotics. XV. Transformation of Penicillin Sulfoxide", "A Synthesis of Cephalosporin Compound", J.Am. Chem. Soc, 91, 1401 (March 12, 1969). It is expressly stated in this publication that "the only product that could be isolated and characterized from the acetic anhydride- and acid-catalyzed rearrangement of penicillin sulfoxide free acids was 3-methyl-7-(2-phenoxy-

acetamido) —3-cephem."

6. In J. Am. Chem. Soc. 85, 1896 (June 20, 1963) Morin, Jackson et al. stated that the rearrangement of penicillin sulfoxide acid results in decarboxylation. 7. In South African patent no. 68/2780, it is clearly stated that "In all cases they (the known penicillins) must be esterified and converted to the corresponding sulfoxide before treatment", i.e. rearrangement to. 3-methyl-3-cephem-4-carboxylate deriv. 8. In the U.S. patent no. 3,197,466 deals with the production of penicillin sulfoxides. 9. Suddal, Morch and Tybring describe the preparation of penicillin sulfoxides in an article entitled "Penicillin Oxides,

•Tetrahedron Letters", 9, page 381 (1962.

10. In South African patent no. 68/4889, a method for the production of penicillin sulfoxide esters is described. 11. South African patent no. 70/1627 describes the rearrangement of penicillin sulfoxide esters to 3-methylceph-3-em-4-carboxylic acid esters using acid-amine complexes with the aid of heat. There is no description of it anywhere that compounds other than penicillin sulfoxide esters can be rearranged without decarboxylation of the carboxyl group. All the examples and patent claims shown are directed at rearrangement of penicillanic acid sulfoxide esters to 3-methylceph-3-em-4-carboxylate esters. 12. In the U.S. patent no. 3,275,626 describes a general method for the production of antibiotic substances, including cephalosporins, which comprises heating a penicillin sulfoxide ester under acidic conditions to a temperature of approx. 100°C to approx. 175°C 13. South African patent no. 70/1627 describes a general process for the preparation of 3-methylceph-3-em-4-carboxylate esters which comprises heating a penicillin sulfoxide ester with a "salt" compound of a nitrogenous base and an acid. Both of these prior art patents state the necessity of performing the rearrangement on penicillin sulfoxide esters to avoid decarboxylation in the resulting ceph product. ;Furthermore, reference should be made to Norwegian application no. 841/70, ;and in relation to this one achieves, according to the invention, that the rearrangement is carried out on the free acid instead of the ester, and one thus avoids converting the free acid into an ester and later having to remove the ester group. The significant technical advance in the process according to the invention is thus a direct rearrangement of 6-acylamidopenicillanic acid-1-oxides to 7-acylamido-3-methylceph-3-em-4-carboxylic acid without it being necessary to first esterify the penicillin's 3-carboxyl function . According to this, the present invention relates to a method for rearranging a 6-acylamidopenicillanic acid sulfoxide of a penicillin produced by fermentation to a 7-acylamido-3-methylceph-3-em-4-carboxylic acid by heating the penicillanic acid sulfoxide in the presence of an acid catalyst, and this method is characterized by the fact that a 6-acylamidopenicillanic acid sulfoxide with the general formula: where R denotes hexyl, thiophene-2-methyl, phenylmethyl, phenyl, phenoxymethyl or phenylmercaptomethyl, which phenyl groups have the formula: where Z denotes H , Cl, CH^ CH30 or N02, is heated in the form of the free acid in a weakly basic solvent selected from dioxane, tetrahydrofuran, ethyl methyl ketone, methyl isobutyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec.- butyl acetate, diethyl carbonate and diethylene glycol dimethyl ether, at a temperature in the interval from 50°C to the reflux temperature of the solvent, for a period of 30 min. to 48 hours, in the presence of 0.05 to 0.5 mol of pyridine-di(phosphoric acid) complex per moles of penicillan acid sulfoxide. ;The catalytic system used in the method according to the invention is that obtained by reacting 1 mol of pyridine and 2 mol of orthophosphoric acid. ;The procedure is carried out in a weakly basic organic solvent to control the acidity, homogeneity and temperature. Usually, the penicillanic acid sulphoxide will be soluble in the organic solvent. The solvent should be essentially inert to the penicillanic acid sulfoxide used in the process and to the 3-methylceph-3-em-4-carboxylic acid produced in the process. The time it takes to achieve optimal yields with the method according to the invention varies according to which solvent and which temperature is used. The rearrangements are suitably carried out at the boiling point of the chosen solvent and, in the case of the solvents that boil in the lower part of the above-mentioned temperature ranges, correspondingly longer reaction times may be necessary, e.g. up to 48 hours, than for the solvents that boil at higher temperatures. E.g. the rearrangement in dioxane usually requires from 7-15 hours to achieve optimal results, while those carried out in methyl isobutyl ketone usually require from 1-8 hours. The yields in the rearrangements are also, but to a lesser extent, dependent on the concentration of catalyst in the solvent and correspondingly longer reaction times are required at lower catalyst kpn concentrations. ;It is particularly preferred to use dioxane as an organic solvent because penicillanic acid sulphoxides can be dissolved in this solvent in high concentration, and there is usually no drop in the yield when the concentration is increased up to the order of 35%. ;The suitable duration for a given reaction can be determined by examining the reaction solution using one or more of the following methods: 1. Thin layer chromatography, e.g. on silica gel, development with 3:1:1 n-butanol-acetic acid-water and visualization of the stain by treatment with a sulfuric acid spray. 2. Determination of the rotation after suitable dilution of the reaction mixture with e.g. chloroform. ; 3. Determination of the ultraviolet spectrum of a sample of the reaction mixture, suitably diluted with ethyl alcohol. This provision cannot be used when ketone solvents are used as reaction media. ; 4. NMR (nuclear magnetic resonance). ;Although satisfactory yields can be obtained by carrying out the reaction under normal reflux, it may be possible to improve the yields by introducing a desiccant (e.g. alumina, calcium oxide, sodium hydroxide or molecular sieves), which is inert to the solvent, in the reflux return line to remove water formed during the reaction. Alter- . naturally, the water formed during the reaction can be removed by using a fractionation column, as water formed is removed by fractional distillation. After completing the reaction, the salt can be removed either before or after concentrating the reaction mixture. As the reaction dissolution medium is immiscible with water, the complex can be removed by simple washing out. If, on the other hand, the reaction medium is miscible with water, for purposes of purification it is appropriate to remove the reaction solvent (this can be done by distillation under reduced pressure), and then to purify the residue in a suitable manner, e.g. by chromatography on silica gel, etc., or precipitation by salt formation, fractional crystallization, etc. It has been shown that the degree of conversion achieved by the method according to the invention can be such that complicated purification methods can be avoided, and the remainder can is worked up into a solution and used directly in other reactions without isolation or purification, or it can be isolated and purified using the above-mentioned methods. The product can be extracted into a solvent and used directly in further reaction steps, or it can, if desired, be purified by recrystallization from a suitable solvent. It has thus surprisingly been shown that, regardless of the state of the art, it is possible and practically feasible to rearrange penicillanic acid sulfoxides to 3-methylceph-3-em-4-carboxylic acids with minimal occurrence of decarboxylation. This discovery produces a number of advantages over the method for rearrangement of penicillin sulfoxide esters, avoiding the necessity to first esterify the penicillanic acid or the penicillanic acid sulfoxide, and after the rearrangement to deesterify the 3-methylceph-3-em-4-carboxylate ester. ;After the rearrangement, the formed 7-acylamido compound can be N-deacylated to form a corresponding 7-amino compound ;and the latter can then be silylated and acylated with a suitable acylating agent.. ;The method according to the invention is explained in more detail in the following examples. ;Example 1 ;Preparation of 7-(phenoxyacetamido)desacetoxycephalosporanic acid ( 2 ) by rearrangement of penicillin V acid sulfoxide ( l) ;The pyridine-di(phosphoric acid) complex (PDPA) is prepared as follows: Pyridine (7.9 g, 0.10 mol) was added portionwise to a stirred and ice-cooled solution of 85% ± g orthophosphoric acid (23.0 g, 0.20 mol) in 100 ml tetrahydrofuran. The white solid precipitate was collected by filtration, washed with THF and ether and dried in vacuo over P2O5 to give a yield of 25.4 g (92%). A mixture of penicillin V sulfoxide (18.3 g, 0.050 mol), PDPA (1.38 g, 0.005 mol) and 300 ml of anhydrous dioxane was heated under reflux (oil bath) for 8 hours. The refluxing dioxane was passed through "Linde 4A" molecular sieves (about 100 g) in a Soxhlet apparatus before being returned to the flask. The solvent was removed under reduced pressure and the residue was treated with a mixture of 200 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was extracted with 60 mL of 1-N aqueous sodium bicarbonate. The bicarbonate extract was cooled and acidified with dilute hydrochloric acid. The semi-solid precipitate was extracted into 125 ml of ethyl acetate. This solution was dried with MgSO 4 and concentrated to dryness to give 14.0 g of a solid yellow foam. By NMR spectroscopy using o-toluene acid as an international standard, the amount of the desired product was estimated to be 6.3 g (36%). Dibenzylamine (7.9 g, 0.040 mol) was added to a cold solution of the crude product in 25 ml of methanol. After adding some seed crystals, the dibenzylamine salt of 2 readily crystallized. After cooling overnight at -15°C, the solid was collected by filtration and washed successively with cold methanol and ether. 7.5 g (28%) of a white airy solid with a melting point of 135-136°C was obtained during decomposition. The infrared spectrum for this salt coincided with that of the dibenzylamine salt of authentic 2 (m.p. 141-142°C during decomposition after recrystallization from methanol). The dibenzylamine salt was shaken for a short time with 75 ml of ethyl acetate and 30 ml of 1-N hydrochloric acid. Dibenzylamine hydrochloride crystallized from this mixture and was collected by filtration and dried to yield 2.5 g or 78%. The ethyl acetate layer was dried with MgSO 4 and concentrated to a volume of approx. 20 ml. A white solid crystallized readily and was collected by filtration after cooling in a yield of 4.1 g (24%), mp 173 - 175°C during decomposition, Y*!?-^01

In 3. X 3450 (NH), 1760 (£ -lactam carbonyl), 1730 (amide carbonyl and 1670 cm<-1> (carbonyl) The infrared spectrum and the NMR spectrum coincided with the corresponding spectra of an authentic sample"-of 2 , melting point 177 - 178.°C during decomposition, prepared-'from phenoxyacetyl chloride and 7-aminodesacetoxycephalosporanic acid?:"' E xample 2 Rearrangement' of penicillin V acid sulfoxide (1) to 7-(phenoxyacetamido)desacetoxycephalosporanic acid (2) under' different conditions .

The essentials of Example 1 were repeated using different conditions, such as 1) different solvents, 2) different reaction times, 3) with or without desiccant, and 4) different reaction temperatures and the results indicated in the table were obtained.

Claims (1)

Process for rearranging a 6-acylamidopenicillanic acid sulfoxide of a penicillin produced by fermentation to a 7-acylamido-3-methylceph-3-em-4-carboxylic acid by heating the penicillanic acid sulfoxide in the presence of an acidic catalyst, characterized in that a 6-acylamidopenicillanic acid sulfoxide with the general formula: where R denotes hexyl, thiophene-2-methyl, phenylmethyl, phenyl, phenoxymethyl or phenylmercaptomethyl, which phenyl groups have the formula: where Z denotes H, Cl, CH^, CH^O or NC^, is heated in the form of the free acid in a weakly basic solvent selected from dioxane, tetrahydrofuran, ethyl methyl ketone, methyl isobutyl ketone, methyl n-propyl ketone, n-propyl acetate , n-butyl acetate, isobutyl acetate, sec.-butyl acetate, diethyl carbonate and diethylene glycol dimethyl ether, at a temperature in the interval from 50°C to the reflux temperature of the solvent, for a period of 30 min. to 48 hours, in the presence of 0.05 to 0.5 mol of pyridine-di(phosphoric acid) complex per moles of penicillanic acid sulfoxide.