IE41837B1 - 7-aminocephalosporanic acid and derivatives thereof - Google Patents

Abstract

Compounds of the formula: in which X is hydrogen, azido or -YR1, Y is oxygen or sulphur and R1 is lower alkyl, acyl or a heterocyclic radical, and Z' is hydrogen or an ester radical, are prepared from corresponding compounds of the formula: in which R is acyl and Z is hydrogen or the residue of a mixed anhydride or of an ester. To do this, the starting material is reacted with an agent which forms imino halide in the presence of an amine under anhydrous conditions, and the reaction product is reacted with an anhydrous alkanol; the resulting 1-deoxy-7-imino ether compound is then subjected to acid hydrolysis. The hydrolysis simultaneously unblocks the 4-carboxyl group when Z is a mixed anhydride or a readily hydrolysable ester. The compounds are intermediates for the preparation of antibiotics of the cephalosporin series.

Description

The present invention is concerned with a process for preparing 7-aminocephalosporanic acid derivatives by the deoxygenation and deacylation of 7-acylamidocephalosporanic acid-l-oxide derivatives.

Thus, according to the present invention, there is provided a process for preparing 7-aminocephalosporanic acid derivatives, wherein a derivative of 7-acylamidocephalosporanic acid-l-oxide of the general formulaίο wherein R is an acyl radical, X is a hydrogen atom or an azido group or a radical of the general formula -YR^, in which 418 3 7 Y is an oxygen or sulphur atom and R^ is an alkyl radical containing up to 6 carbon atoms or a heterocyclic or acyl radical and -COOZ is a free or protected carboxy group, is reacted with an imino halide-forming agent in the presence of a nitrogen-containing organic base in an inert organic solvent under anhydrous conditions, followed by reaction with an anhydrous alcohol containing up to 7 carbon atoms and hydrolysing the product under acidic conditions to give a derivative of 7-aminoeephalosporanic acid of the general formulas- wherein -COOZ' is a free or esterified carboxy group and X has the same meaning as above; or an acid-addition salt thereof.

When it is desired to transform A2-cephem derivatives which have been produced by ring enlargement of penicillins or to introduce substituents at the 3-methyl group of the cephem ring into pharmaceutically-useful Δ3-cephem derivatives, processes are needed for subjecting the δ2-cephem derivatives to oxidation in order to convert them into the corresponding 1-oxide derivatives and for further subjecting them to deoxygenation and deacylation on the 7-aeyl group. An effective method for the preparation of intermediates for antibacterial A3-cephalosporin compounds, which are medicinally useful, is very important from an industrial viewpoint. - 3 41837 A previously known method for converting 7-acylamidoA3-carboxylic acld-l-oxides or esters into 7-aminocephalosporanio acid derivatives or esters required, after the carboxyl group has been protected (the ester compound was used as it is), i) treatment of the compound with an organic acid halide and then with a reducing agent and ii) subjecting the resultant isolated compound to deacylation by which the desired 7-aminocephalosporanic acid derivative or its ester could be obtained (see, for example, J.Am.Chem.Soc.,91, 5674/1969; J.Org.Chem., 35, 2030/1970). However, the above-mentioned step i) is industrially disadvantageous because it is laborious and only gives a low yield.

As a result of various investigations, we have found the new process of the present invention, which uses a new reaction without the use of any specific reducing reagents and is also much less laborious and gives the desired compounds in good yields.

The 7-acylamidocephalosporanic acid-l-oxide derivatives of general formula (X) used as starting materials are described in the following in more detail.

The acyl group at the 7-position may be an acyl radical derived from an unsubstituted or substituted aliphatic or aromatic carboxylic acid, for example, a phenoxyacetyl, phenylacetyl, α-phenoxypropionyl, thienylacetyl, chloroacetyl, bromoacetyl, propionyl, acetyl, formyl, benzoyl, pr niettiylbeirzoyl radical, the industrially preferred examples being phenoxyacetyl, phenylacetyl, formyl, acetyl and chloroacetyl radicals.

In the symbol of Rj, the alkyl radical can be, for example, a methyl, ethyl °r propyl, radical; the acyl radical can be,for example, an acetyl, propionyl, butyryl or benzoyl radical; and the heterocyclic radical can be a l-methyl-lH-l^jS^-tetrazol-S-yl, -methyl-l,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-2-yl, -methyl-l,3,4-oxadiazol-2-yl or l,3,4-oxadiazol-2-yl radical. It is also preferable that Y is an oxygen atom when is an acyl group and that Y is a sulphur atom when Rj is a heterocyclic radical.

A protected carboxy group in -COOZ is one which can be finally converted into a free carboxy group by, for example, hydrolysis or reductive decomposition. Examples of groups which can be converted into a carboxy group by hydrolysis or reductive decomposition include esters formed from alcohols and mixed anhydrides formed with other acids.

Preferred examples of reagents used to form the mixed anhydrides include trimethylchlorosilane, dimethyldichlorosilane, trimethoxychlorosilane, dimethoxydichlorosilane, phosphorus oxychloride, phosphorus trichloride, phosphorus pentaohloride, methoxydichlorophosphine, ethoxydichlorophosphine, 2-chloro-l,3,2-dioxaphospholane, 2-chloro-5-methyl1,3,2-dioxaphospholane, methoxy- and ethoxydichlorophosphate, acetyl chloride, and phosgene-. . Mention may also be made of methoxytrichlorosilane, methyldimethoxy-chlorosilane, methy1-methoxydichlorosilane, propoxydichlorophosphate, butoxydichlorophosphate, propionyl chloride, butyryl chloride, methoxy-carbonic acid chloride, ethoxycarbonic acid chloride, propoxy-carbonic acid chloride, methoxydibromophosphate and mathoxydibromoptiosphine.

Preferred examples of alcohols which can be used for the formation of the esters, i.e. of esterified carboxy groups, include tert.-butanol, 2-chloroethanol, 2-bromoethanol , 2,2,2,-trichloroethanol, 2-methylsulphonylethanol, 2-ethylsulphonylethanol, benzoyl methanol, benzyl alcohol, £-nitrobenzyl alcohol, p-methoxybenzyl alcohol, triphenyl5 methanol, trimethyl-acetoxymethanol, 3-hydroxy-3-methy1-1,3dihydroisobenzofuran-l-one, 5-hydroxy-5-methyltetrahydrofuran-2-one, 1-isobutoxy' butanol and 5-iiydroxy'indaiie Mention may also be made of methanol, ethanol, propanol, butanol, p-bromobenzoylmethanol, 2,6-di-tert.-buty lbenzene-1,410 diol, acetoxy-methanol, benzhydrol, and piiaiol Esters which can be converted into a carboxyl group by reductive decomposition and which include esters formed from the above-mentioned alcohols, include the p-nitrobenzyl esters, benzyl esters, benzhydryl esters, p-methoxybenzyl esters, trichloroethyl esters and haloethyl esters, among which the p-nitrobenzyl esters and trichloroethyl esters are preferred.

Compounds of general formula (I), wherein -COOZ is a protected carboxy group, may be prepared by treating a corres20 ponding compound in which -COOZ is a free carboxy group or salt thereof with an appropriate reagent in accordance with conventional methods. However, when a compound (I), wherein -COOZ is a free carboxy group, or a salt thereof, is used as starting material, the reaction according to the present Invention can be achieved without protection of the carboxy group, because the carboxy group will be changed into a protected form during the reaction with an imino-halide forming agent, such as phosphorus pentahalide.

The compound of general formula (I) is reacted with an imino-halide forming agent in an inert organic solvent in the presence of a nitrogen-containing organic base to give the corresponding imino-halide compound.

Preferred examples of inert organic solvents include methylene chloride, chloroform, ethylene chloride, and propylene chloride as well as carbon tetrachloride, trichloroethane, trichloroethylene, tetrachloroethylene, dioxan, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether Examples of nitrogen-containing organic bases which can be used include aliphatic secondary and tertiary amines, such as triethylamine, trimethylamine, dimethylamine and diethylamine; aromatic and heterocyclic basic compounds, such as dimethylaniline, pyridine, quinoline and N-methylmorpholine and homologues thereof. The most preferred examples include dimethylaniline, diethylaniline, pyridine, picoline, quinoline and lutidine.

As imino-halide forming agents, there may be mentioned, for example, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus oxychloride, phosphorus oxybromlde, and phosgene amongst which phosphorus pentachloride is industrially preferred.

When using phosphorus pentachloride, the reaction is usually completed within one to three hours, even at a temperature of about 0°C. However, reaction with phosphorus trichloride or phosphorus oxychloride at about 0°C. requires several days.

An alcohol containing up to 7 carbon atoms is then added to the above reaction solution to give an iminoether compound.

As the alcohols, there may be used, for example, methanol, ethanol, n-propanol, n- or isobutanol, n- or isoamyl alcohol, ethylene glycol, propylene glycol, ethylene glycol monomethyl ether, and etnylene glycol monoethyl ether it being preferable to use methanol, isobutanol, n-butanol, or propylene glycol from an industrial viewpoint.

The reaction with the alcohol can be carried out at a temperature of from -40 to +40°C. but is usually carried out at -30 to +30°C. Generally, it is carried out at a temperature below 0°C. in the case of a compound (I) in which the carboxy group at the 4-position has been protected in the form of a mixed anhydride and at a temperature above 0°C. for a compound (I) in which the carboxy group has been protected in the form of a stable ester. Furthermore, this reaction proceeds much more quickly when a low molecular weight alcohol is used for the esterification than when ohe with a high molecular weight is used. When methanol is used, the reaction will be completed after about two to three hours at -30° to 10°C.

The two kinds of reactions using an imino-halideforming agent and an alcohol described above should, of course, be carried out under anhydrous conditions.

The reaction mixture is then subjected to hydrolysis under acidic conditions and preferably at a pH of below 3 .

For example, the hydrolysis may be carried out by adding the reaction mixture to ice-water, adjusting the pH to about 1 and stirring for about 30 minutes to an hour. In this procedure, the compound in which the 4-carboxyl group is protected in the form of a mixed anhydride or of an easily hydrolysable ester is simultaneously hydrolysed to give the desired compound (I) in which -COOZ is a free carboxyl group. Easily hydrolysable esters mean esters formed with, for example, tert, butanol, or triphenylmethanol When the 3-position of the compound (I) is substituted by an acyloxy - 8 41837 radical, it is preferable to carry out the hydrolysis at a pH of about 2.

Finally, a base is added to the reaction mixture to isolate the desired compound (II). When the compound (I) contains a 4-carboxy group, the reaction mixture is adjusted to the isoelectric point of the product by means of the base, whereby crystals will usually be precipitated.

If the resulting compound (II) contains an esterified carboxy group in the 4-position, the product can be extracted with an organic solvent at a pH of about 7 and then can be recovered therefrom as a crystalline acid salt.

The bases which can be used for neutralisation include triethylamine, ammonium carbonate, ammonium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and ammonia.

Preferred acid-addition salts of the ester compounds include the salts with hydrochloric acid, sulphuric acid, tartaric acid, citric acid, succinic acid, jo-toluenesulphonic acid, naphthalene-sulphonic acid, methane-sulphonic acid and ethane-sulphonic acid, all of which show a high degree of crystallinity.

The method according to the present invention gives the compounds (II) in high yields, for example of about 95%. They can be used directly for acylation to give Δ 3-cephalosporin.

The following Examples are given for the purpose of illustrating the present invention :EXAMPLE 1. 1.04 g. (3 mM) 7-phenylacetamido-3-methyl-3-cephem-4carboxyllc acid-l-oxide was suspended in 10 ml. anhydrous methylene chloride and to the suspension was added 0.36 g. (3.6 mM) triethylamine at ~10°C., with stirring, a clear solution soon being obtained. To this solution was added 0.65 g. (6 mM) trimethylchloro5 silane and 1.45 g. (12 mM) dimethylaniline. After stirring for 30 minutes, the reaction mixture was cooled to -30°C. 1.46 g. (7 mM).phosphorus pentachloride was added to the mixture, followed by stirring, for an hour at “2 to -10°C. and for a further hour at -10 to 0°C. 2.24 g. (60 mM) anhydrous methanol were stirred in at -30°C. and the mixture left to react for an hour at -30 to -15°C. and for another hour at -15 to -5°C. and then left to stand overnight at -20°C, The reaotion mixture was mixed with 10 ml. ice-water for 30 minutes, then gradually adjusted to ’ pH 3.5 by the addition of ammonium carbonate and left to stand overnight in a refrigerator. The precipitated crystals were collected, washed several times with small amounts of 60% cooled ethanol and then with acetone and dried. 0,61 g 7-amino20 3-methyl-3-cephem-4-carboxylic acid was thus obtained; yield 95% of theory.

IR spectrum: 1800 cm-1 UV spectrum λ : 265 mp(triethylamine, methanol).

ItlciX The product was identical with an authentic sample (elemental analysis and thin-layer chromatography).

EXAMPLE 2 Instead of the 6 mM trimethylchlorosilane used in Example 1, there were used the reagents set out in the following Table 1, which also indicates the amount of reagent used and the yield obtained: TABLE 1 Reagent mM used Yield (%) Dimethyldichlorosilane 3 94 Trimethoxychlorosilane 6 93 Dimethoxydichlorosilane 3 94 MethyImethoxydichlorosilane 3 95 Tetrachlorosilane 3 74 Methoxydichlorophosphine 3 96 Ethoxydichlorophosphine 3 95 2-Chloro-l,3,2-dioxaphospho- lane 6 93 2-Chloro-5-methyl-1,3,2-di- oxaphospholane 6 94 Phosphorus trichloride 3 94 Methoxydichlorophosphoric acid 3 87 Phosphorus oxychloride 3 84 Acetyl chloride 6 76 Phosgene 3 94 EXAMPLE 3 Instead of the 60 mM anhydrous methanol used in Example 1, there were used the anhydrous alcohols set out in the following Table 2, which also indicates the amount of anhydrous alcohol used and the yield obtained: TABLE 2 f Anhydrous alcohol mM used Yield (%) Ethanol 65 91 n-Butanol 75 94 Isobutanol 75 96 2-Chloroethanol 70 70 Ethylene glycol monomethyl ether 70 63 Propylene glycol 60 68 EXAMPLE 4 Instead of the 7-phenylacetamido-3-methyl-3-cephem -4-carboxylic acid-l-oxide used in Example 1, there was used 1.09 g.(3 mM) 7-phenoxy-acetamido-3-methyl-3-cephem4-carboxylic acid-l-oxide. The yield of 7-amino-3-methyl3-cephem-4-carboxylic acid thus obtained was 94% of theory.

EXAMPLE 5 To a mixture of 0.82 g. (2 mM) 7-thienylacetamido-3acetoxymethyl-3-cephem-4-carboxylic acid-l-oxide (cephalothin sulphoxide), 0.30 g. (3 mM) triethylamine and 0.97 g. (8 mM) dimethylaniline in 10 ml. anhydrous methylene chloride were added 0.27 g.(2 mM) methoxydichlorophosphine. The reaction mixture was stirred for 30 minutes at 0°C. and then cooled to -40°C, 1.04 g. (5 mM) phosphorus pentachloride was added to the mixture followed by stirring for one hour at -30 to -15°C. and for another hour at -15 to -5°C.

After cooling to -40°C., 1.60 g. (50 mM) anhydrous methanol were added and the mixture was allowed to react for one hour at -30 to -15°C. and for another hour at -15 to -5°C. and then left to stand overnight at -20°C.

The reaction mixture was poured into ice-water and the pH was adjusted by the addition of ammonium carbonate to about 2.0. After 30 minutes, the mixture was adjusted to pH 3.5 and left overnight in a refrigerator. The crystals which formed were centrifuged off, washed with cooled 60% acetone and then with acetone and dried in vacuo to give 0.47 g. 7-amino-3-acetoxymethyl-3cephem-4-carboxylic acid; yield 86% of theory.

IR spectrum: 1800 cm 3 UV spectrum λ y: 263 mp(water).

EXAMPLE 6 To a mixture of 1.49 g. (3 mM) 7-phenoxyacetamido3-methyl-3-cephem-4-carboxylic acid-l-oxide trichloroethyl ester and 0.95 g. (12 mM) anhydrous pyridine in 10 ml, anhydrous methylene chloride were added 0.19 g.(1.5 mM) dimethyldichlorosilane at 0°C. The mixture was stirred for 30 minutes and then cooled to -40°C., a clear solution soon being obtained. After the addition of 1.46 g. (7 mM) phosphorus pentachloride, the reaction mixture was stirred for one hour at -30° to -15°C., and for another hour at -15 to 0°C. After cooling to -40°C., 1.92 g. (60 mM) anhydrous methanol were added and the reaction mixture was stirred for one hour at -40 to -20°C. and for another hour at -20 to -5°C. and then left to stand overnight at -20°C. 10 ml. ice-water were added to the reaction mixture, followed by stirring for 30 minutes.

The organic layer was extracted with water, the combined aqueous layers were washed with methylene chloride and then 15 ml. ethyl acetate were added to the aqueous layer. The mixture was adjusted to pH 7.5 by the addition of 20% aqueous sodium hydroxide solution. The aqueous layer was extracted several times with ethyl acetate and the organic layers were combined and washed with a saturated aqueous sodium chloride solution and then dried. The solvent was removed under reduced pressure and the residue, after the I addition of toluene, was again distilled Under reduced pressure. The resulting residue was dissolved in ethyl acetate to which 0.51 g. (2.7 mM) £-toluene-sulphonic acid was added, while stirring. Crystals soon appeared.

After standing overnight in a refrigerator, the crystals were collected, washed with ethyl acetate and recrystallised from ethanol and ethyl acetate. 0.98 g. of the £-toluenesulphonic acid salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid trichloroethyl ester was obtained; yield 81% of theory, m.p. 192-193°C. (decomp.).

IR spectrums 1770 cm-1 ( β-lactam) UV spectrum λ ___ : 266 mu (water). max The elemental analysis and thin-layer chromatogram of the product agreed with those of an authentic sample.

EXAMPLE 7 To a mixture of 1.45 g, (3 mM) 7-phenoxyaoetamido3-methyl-3-cephem-4-carboxylic acid-l-oxide-£-methoxybenzyl ester and 0.95 g. (12 mM) anhydrous pyridine in 15 ml. anhydrous methylene chloride were added 0.20 g. (1.5 mM) methyldichlorophosphite (Cf/OPC^). The reaction mixture was stirred for 30 minutes and cooled to -40°C., whereafter 1.46 g. (7 mM) phosphorus pentachloride was added. The mixture was stirred for one hour at -30 to -15°C. and for another hour at -15 to 0°C. After cooling to -40°C,, 5.18 g.(70 mM) anhydrous isobutanol were added dropwise to the mixture, followed by stirring for one hour at -40 to -20°C. and for another hour at -20 to -5°C. and then left to stand overnight at -20°C. The mixture was then mixed with 15 ml. ice-water for 30 minutes, while maintaining the pH below 2.0. The aqueous layers were combined and washed with methylene chloride. 15 ml. ethyl acetate were added to the aqueous layer, the pH of which was adjusted to 7.5 with 20% aqueous sodium carbonate solution. The aqueous layer was extracted several times with ethyl acetate and the organic layers were combined, washed several times with a saturated aqueous sodium chloride solution, dried and evaporated in vacuo. Toluene was added to the residue and the mixture was again distilled under reduced pressure.

The residue was dissolved in ethyl acetate and an ethyl acetate solution containing 0.51 g. (2.7 mM) £-toluenesulphonic acid was added, while stirring. Crystals soon appeared. After leaving overnight in a refrigerator, the crystals were collected, washed with ethyl acetate and recrystallised from ethanol and ethyl acetate to give 0.91 g. of the £-toluene-sulphonic acid salt of 7-amino-3methyl-3-cephem-4-oarboxyllc acid p-methoxy-benzyl ester; yield 73% of theory; m.p. 162-165°C.

IR spectrum: 1770 cm ((3 -lactam) UV spectrum λ : 273 mp (95% ethanol).

EXAMPLE 8 Instead of the 7-phenoxyacetamido-3-methyl-3-cephem4-carboxylic acid-l-oxide jg-methoxybenzyl ester used in Example 7, there was used 7-phenoxyacetamido-3-methyl-3cephem-4-carboxylic acid-l-oxide £-nitrobenzyl ester (m.p. 217-219°C.). There was thus obtained the £-toluenesulphonic acid salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid £-nitrobenzyl ester in a yield of 78% of theory; m.p. 169-172°C.

IR spectrum: 1790 cm 1 (β-lactam) UV spectrum λ : 268 m μ(water). max EXAMPLE 9 Instead of the 7-thienylacetamido-3-acetoxymethyl3- cephem-4-.carboxylic acid-l-oxide used in Example 5, ΐ there was used 7-pheny lacetamido-3-afietoxyme thy 1-3-cephem4- carboxylic acid-l-oxide (m.p. 170°C. (decomp.). There was thus qbtai,ned i7-amino-3-acetoxymethyl-3-cephem-4Carboxylic acid in a yield of 83% of theory.

EXAMPLE 10 Instead of the 7-thienylacetamido-3-acetoxymethyl3- cephem-4-carboxylic acid-l-oxide used in Example 5, there was used 7-phenoxyacetamido-3-acetoxymethyl-3cephem-4-carboxylic acid-l-oxide (m.p. 166°C. (decomp.)), There was thus obtained 7-amino-3-acetoxymethyl-3-cephem -4-carboxylic acid in a yield of 81% of theory.

EXAMPLE 11 Instead of the 7-phenylacetamido-3-methyl-3-cephem4- carboxylic acid-l-oxide used in Example 1, there was used 7-thienylacetamido-3-azidomethyl-3-cephem-4-carboxylic acid-l-oxide (m.p. 172°C., (decomp.)). There was thus obtained 7-amino-3-azidomethyl-3^ceph£m-4-carfaoxylic acid in a yield of 85% of theory.

IR (KBr): 2100 cm 1 (azido group), 1800 cm (β-lactam) UV ^max: 268 mu (triethylamine salt, ethanol).

EXAMPLE 12 Instead of the 7-phenylaeetamido-3-methyl-3-cephem4-carboxylic acid-l-oxide used in Example 1, there was used 7-thienylacetamido-3-(5-methyl-l,3,4-thladiazol-2yl)-thiomethyl-3-cephem-4-carboxylic acid-1-oxide (m.p. 188°C. (decomp,)). There was thus obtained 7-amino-3-(5methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4carboxylic aoid in a yield of 83% of theory; m.p. 201°c. (decomp.).

IR (KBr) : 1800 cm”1 UV : 274 mp (triethylamine salt, ethanol). max EXAMPLE 13.

Instead of the 7-phenylacetamido-3-methyl-3-cephem4-carboxylic acid-l-oxide used in Example 1, there was used 7-thienylacetamido-3-(l,3,4-thiadiazol-2-yl)-thiomethyl4-carboxylic acid-l-oxide (m.p. 154°C. (decomp.)). There was thus obtained 7-amino-3-(l,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid in a yield of 76% of theory; m.p. 184°C. (decomp.).

IR (KBr): 1795 cm-1 UV λ : 273 mu (triethylamine salt, ethanol). max EXAMPLE 14 4.00 g. (7,53 mM) 7-thienylacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid £-nitrobenzyl ester 1oxide (m.p. 178°C. (decomp.)) in 3 ml. anhydrous pyridine were added to 40 ml. anhydrous methylene chloride. The mixture was cooled to -40°C. and 3.6 g. (16 mM) phosphorus pentachloride were added portionwise to the mixture. The reaction mixture was stirred for one hour at -30°C. and for 1.5 hours at -20°C. After monitoring the reaction mixture by thin-layer chromatography, it was cooled to -40°C. 14 ml. anhydrous methanol were added dropwise to the reaction mixture, followed by stirring for 2 hours at -20° to -5°C. The mixture was poured into 50 ml. ice-water and stirred for an hour ι in an ice bath, the pH being adjusted to 2.0 with ammonia. The aqueous layer Was washed with methylene chloride, after which 20 ml. methylene chloride were added to the aqueous layer and the pH adjusted to 7.0-7.5, while stirring. Th.e organic layer was washed with water, dried and then evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml. ethyl acetate and a solution o£ 1.3 g, £-toluene-sulphonic acid in 10 ml. ethyl acetate was stirred in. After stirring for an hour in an ice-water bath, the precipitate formed was collected. Recrystallisation from methanol and ethyl acetate gave 3.4 g. of the £-toluene-sulphonic acid salt of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid £-nitrobenzy! ester; yield 83% of theory; m.p. 144°C.(decamp.).

IR (KBr); 1790 (β-lactam), 1740, 1730 cm1 UV 267 mp (water). ΙΠαΛ EXAMPLE 15 To a suspension of 1.04 g. (3 mM) 7-phenylacetamido3-methyl-3-cephem-4-carboxylic acid 1-oxide in 15 ml. anhydrous methylene chloride were added 0.36 g. (3.6 mM) N-methylmorpholine and 1.21 g. (10 mM) dimethylaniline at 0°C., while stirring. A clear solution was soon obtained. 0.65 g. (6 mM) trimethylchlorosilane was added to the solution, followed by stirring for 30 minutes, 0.83 g. (4 mM) phosphorus pentaehloride was added to the reaction solution and the mixture was stirred for one hour at -20 to 0°C.and for 1.5 hours at 0 to 15°C. After cooling to -30°C., 0.80 g. (25 mM) anhydrous methanol was added dropwise to the reaction mixture, which was stirred for one hour at -30 to -15°C. and for another hour at -15 to 0°C.

The reaction mixture was mixed with 10 ml. ice-water for - 18 41837 minutes at pH 2. The aqueous layer was washed twice with methylene chloride, adjusted to pH 3.5 and then left to stand overnight in a refrigerator. The crystals formed were then collected, washed with cooled 60% aqueous ethanol and then with acetone and dried to give 0.44 g. 7-amino-3-methyl-3-cephem-4-carboXylic acid: yield 68% of theory.

The TLC, IR and UV of the product agreed with those of an authentic sample.

When 4.5 mM phosphorus pentachloride were used in the above experiment, the yield was 87% of theory.

Claims (15)

1. A process for preparing 7-aminocephalosporanic acid derivatives, wherein a 7-acylamidocephalosporanic acid 1-oxide derivative of the general formula :O in which R is an acyl radical; X is a hydrogen atom or an azido group or a radical of the general formula -YR^, in which Y is an oxygen or sulphur atom and is an alkyl radical containing up to 6 carbon atoms or a heterocyclic 10 or acyl radical and -COOZ is a free or protected carboxy group, is reacted with an imino halide-forming agent in the presence of a nitrogen-containing organic base in an inert organic solvent under anhydrous conditions, followed by reaction with an anhydrous alcohol containing up to 15 7 carbon atoms and hydrolysing the product under acidic conditions to give a derivative of 7-amino-cephalosporanic acid of the general formula:- wherein -COOZ 1 is a free or esterified carboxy group and X has the same meaning as above; or an acid-addition salt thereof. 20 41837

2. A process according to claim 1, wherein the acyl radical R is a phenoxyacetyl, phenylacetyl, a-phenoxypropionyl, thienylacetyl, chloroacetyl, bromoacetyl, propionyl, acetyl, formyl, benzoyl or methylbenzoyl radical.

3. Process according to claim 1 or 2, wherein X is a 5-methyl-l,3,4-thiadiazol-2-ylthio or 1,3,4-thiadiazol2-ylthio radical, . .

4. A process according to any of the preceding claims, wherein the imino halide-forming agent is phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus oxychloride, phosphorus oxybromide or phosgene.

5. A process according to any of the preceding claims, wherein the anhydrous alcohol is methanol, ethanol, n-propanol, n-butanol, isobutanol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether or propylene glycol.

6. A process according to any of the preceding claims, wherein the nitrogen-containing organic base is triethylamine, trimethylamine, diethylamine, dimethylamine, pyridine, pieoline, quinoline, N-methylmorpholine, dimethylaniline, diethylaniline, or lutidine.

7. A process according to any of the preceding claims, wherein the inert organic solvent is methylene chloride, ethylene chloride, propylene chloride, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, tetrachloroethylene, dioxan, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. 21 41837

8. A process according to any of the preceding claims, Wherein the protected carboxy group is a group convertible , into a free carboxy group by hydrolysis or reductive decomposition.

9. A process according to any of the preceding claims, wherein the protected carboxy group is a carboxy group esterified by tertrbutanol, 2-chloroethanol, 2- bromoethanol, 2,2,2,-trichloroethanol, 2-methylsulphonyl» ethanol, 2-ethylsulphonylethanol, benzoylmethanol, benzyl alcohol, j>-nitrobenzyl alcohol, £-methoxybenzyl alcohol, triphenylmethartol, trimethylacetoxymethanol, 3- hydroxy-3-methy1-1,3-dihydroisobenzofuran-l-one, 5-hydroxy5-methyl-tetrahydrofuran-2-one, 1-isobutoxybutanol or 5hydroxyindane.

10. A process according to any Of claims 1 to 8 , wherein the protected carboxy group is a group formed by the reaction of a carboxy group with trimethylchlorosilane, trimethoxychlorosilane,. methyldimethoxychlorosilane, dimethyldichlorosilane, dimethoxydichlorosilane, methylmethoxydichlorosilane, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, methoxydichlorophosphine, ethoxydichlorophosphine , methoxydichlorophosphate, ethoxydichlorophosphate, propoxydichlorophosphate, butoxydichlorophosphate, 2-chloro-l,3,2-dioxaphospholane, 2-chloro-5-methyl-l,3,2dioxaphospholane, propionyl chloride, butyryl chloride, methoxycarbonic acid chloride, ethoxycarbonic acid chloride, propoxycarbonic acid chloride, methoxy-dibromophosphate or methoxydibromophosphine.

11. A process according to any of the preceding claims, wherein the reaction with the anhydrous alcohol is carried 22 41837 out at a temperature of from -40 to +40°C.

12. A process according to claim 11, wherein the reaction with the anhydrous alcohol is carried out at a temperature of from -30 to +30°C. 5

13. A process according to any of the preceding claims, wherein the acid hydrolysis is carried out at a pH below 3.

14. A process according to claim 1 for preparing 7-aminocephalosporanic acid derivatives, substantially as herein10 before described and exemplified.

15. 7-Aminocephalosporanic acid derivatives, whenever prepared by the process according to any of claims 1 to 14.