FI58643B - FOER FARING FOR FRAMSTAELLNING AV 3-7-ACYLAMIDO-DESACETOXICEFALOSPORANSYROR - Google Patents

Description

Γ. "Ζ1 · -ΤΊ Γ_, .... PUBLICATION C Ο ϋ Λ Ύ Β ί11) utläggningsskmft 5864 3 C (45) Patent granted 10 03 1931 Patent me d de la t ^ ^ (51) Kv.lk. ^ lnt.CI? C 0? D 501/10 2271/72 ENGLISH —Fl N LAN D (21) PWenttlhakemus - Pmnuraeknlnt (22) Hekemlspilvi — Ansöknlnjsdsg l6.08.72 (23) Alkuptivl - Gllti | h * tsdi {l6. 08.72 (41) Became Stuck - Bllvlt offtntllf 18.02.73

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Patent · och regi (tentyrei <en '' Aratku utlagd och utl.ikrffttn publktrad · χχ · ou (32) (33) (31) Privilege claimed —Begird prlorltet 1T · 08.71 21.12.71 United Kingdom-Storbritannien (GB) 38637 / 71, 59516/71 (71) Gist-Brocades NV, 1, Wateringseweg, Delft, The Netherlands (NL) (72) Jan Verweij, Leiden, Hong Sheng Tan, Bleisvijk, Hermanus Jacobus Kooreman, Delft, The Netherlands ( The present invention relates to a new process for the preparation of Δ 2 -7-acylamido-deacetoxy-cephalosporan syrups. The present invention relates to a new process for the preparation of Δ 3 -7-acylamido-desacetoxy-cephalosporanic acids. for the preparation of which have the general formula: R, - CH - CH CH ~

III III

- N Λ - CH, ίοογ wherein R- ^ represents an acylamido group and Y represents a hydrogen or alkali metal atom, by modification of the corresponding 6-acylamidopenicillanic acid sulfoxides.

The process according to the invention is characterized in that 6-acylamidopenicillanic acid sulfoxide has the general formula:

R 1 - CH - CH Cl 2 IV

1 I Ιχ ° «3

C - N-CH J

S 1

0 COOY

2,58643 wherein R 1 and Y have the same meaning as above, is reacted with a halide of the general formula R 2 - H 1 in which Hal represents a halogen atom and R 2 represents a group having one of the following formulas: R 3 \ R 3 \ V \ R 3 \

Mi- R4 - M, - R4 * "si" R4> M3 - R7 - 5 'V r5 / r5, x r ^ 7 0 R6

V VIA VIB VII VIII

wherein R 1, R 2 ', R 2', R 2 ', R 2', R 5 'and R 8' represent a bromine atom, or R 1 and R 8 together represent an oxygen or sulfur atom, or R 1 ', R 4' and R 2 ' denote methyl or ethyl groups, Ry denotes a methyl or ethyl group which may be substituted by one or more chlorine atoms, or a phenyl group, Mi denotes a boron, aluminum or phosphorus atom, M2 denotes a germanium or tin atom, and M2 denotes phosphorus or tungsten, or with phosgene, thionyl halide, oxalyl bromide or p-toluenesulphonyl chloride, and the resulting protected 6-acylamidido-penicillanic acid sulphoxide or 6-acyl-amido-penicillanic acid sulphoxide of the formula TV is heated in a dry inert solvent at max together with anhydrous acid such as hydrogen bromide, hydrogen chloride, p-toluenesulfonic acid, concentrated sulfuric acid, hydrogen iodide, perchloric acid, periodic acid, nitric acid, chloric acid, iodic acid, selenic acid, bromoacetic acid, trichloroacetic acid, trichloroacetic acid fluoroacetic acid, trichloromethylsulfonic acid, trifluoromethylsulfonic acid, naphthalenesulfonic acid, oxalic acid, picric acid, tris (ethylsulfonyl) methane-trienocyanophenadyanophenylcyanophenylcyanophenocyanophenocyanophenocyanate -bis (trimethylsilyl) acetamide, N, N'-bis (trimethylsilyl) urea, hexamethyldisilazane, Ν, Ο-bis (trimethylsilyl) trifluoroacetamide, N, N'-bis (trimethylsilyl) carbodiimide, N- methyl N- (trimethylsilyl) acetamide or N-methyl-N- (trimethylsilyl) trifluoroacetamide, and the resulting compound is hydrolyzed in situ and the Δ 4 -7-acylamido-deacetoxy-5,58643 cephalosporanic acid thus formed is isolated as such or as an alkali metal salt.

The cephalosporins to be prepared in the above process are compounds containing the "kefam" structure of formula II below, while the penicillins used as starting materials contain the "penamM" structure of formula I.

1 1

S S

6 5 / \ 2 7 6 / \ 2 - CH-CH CH0 - CH-CH ΌΗ-

III III

0 = C - N-CH0 0 = C - N CH0 7 4 3 8 5 \ ^ y 3 2 CH0

I 4 d II

"Xefem" means a ring structure II having a double bond, the position of which is indicated by the symbol "Δ", above which is a number denoting the lower carbon atom to which the double bond is attached.

Recently, much interest has been focused on the preparation of Δ ^ -cephalosporins with antibiotic activity from penicillins. Thus, e.g., U.S. Patent No. 3,275,626, "Penicillin conversion via Sulfoxide," discloses that 7-aminocefam and cephem derivatives can be prepared by heating analogous 6-aminopenicillan sulfoxide derivatives in solution to temperatures of about 80-175 °. C under acidic conditions, which can be promoted, for example, by means of acetic anhydride or toluene-p-sulfonic acid.

This known method, which involves heating under acidic conditions, results in a rearrangement of the heterocyclic structure, resulting in the expansion of the thiazolidine ring of penicillan sulfoxide, and e.g. thiazine ring formation, which is a component of cephalosporin compounds. Many such cephalosporin compounds have useful antibiotic properties and are therefore very important therapeutic agents.

When the ring expansion treatment described in the aforementioned U.S. patent is performed using 6-substituted aminopenicillanic acid sulfoxide, i. a compound of formula I in which the acylamido group R-CO- is attached at the 6-position, R is essentially any organic radical known in penicillan chemistry, oxygen is attached to the sulfur atom, two methyl groups are attached to the 2-carbon atom, and a carboxy group is joined

3-carbon atom or using a salt of this acid, it has been found that the 6-aminopenicillanic acid starting material is decarboxylated during the formation of cephalosporin and consequently no carboxy group is associated with the structure II in the cephalosporin product.

To a 4-carbon atom which is a requirement for the preparation of antibiotically useful cephalosporin compounds. However, when esters of such 6-substituted aminopenicillanic acid sulfoxides, e.g. alkyl, cycloalkyl or phenyl esters, are used as starting materials, ring expansion occurs with a cephalosporin. . . . 3 as a compound according to said U.S. patent satisfactorily and Δ - cephem products have an esterified carboxy group attached to carbon atom 4. Thus, it is apparent from the aforementioned U.S. patent that if cephalosporins having a free carboxy group attached to carbon atom No. 4 are desired, the carboxy group of the starting 6-substituted aminopenicillanic acid sulfoxide must first be esterified with a hydrocarbon radical in a preliminary separate step and the esterification radical in the cephalosporan products must be removed after the ring expansion reaction, e.g. by hydrolysis or catalytic hydrogenation. This process, which requires the initial separate formation of a hydrocarbon ester of 6-aminopenicillanic acid (i.e., an ester in which the COO group is fused to a hydrocarbon, e.g., via a methyl or benzhydryl or substituted hydrocarbon radical), necessitates separation and isolation of at least one intermediate and is due to this disadvantage.

German patent application 2,011,376 also discloses a process for the conversion of penicillanic acid sulfoxide esters to the corresponding deacetoxycephalosporanic acid esters in the presence of certain catalysts. This method has the same disadvantages as the method described above, since the use of esters reduces the yields obtained.

Finnish Patent Publication No. 55,205 discloses for the first time a process by which a similar conversion is obtained starting from penicillin sulfoxides in the free acid form to give directly the corresponding deacetoxycephalosporanic acids and thus avoiding the above-mentioned additional reaction steps for preparing esters before and removing them again after the reaction.

The process according to the Finnish patent publication uses an excess of nitrogenous base and certain silicon-halogen compounds. This process is thus clearly different from the process of the present invention, which uses anhydrous acid in the presence of silicon-containing compounds, all of which contain a silicon-nitrogen bond. It has been found that the use of these reaction components results in considerably better yields than have been possible by the method described in the Finnish patent publication.

The silicon-containing compounds used in the process of this invention are described in German Patent 1950 2 45, although they are used primarily as silylating agents. The German patent states that silylation must be carried out very carefully, i.e. in solvents without Zerewitinoff hydrogen, and even air humidity must be carefully excluded.

In this regard, it is surprising that the corresponding silicon-containing compounds can be used in the process of the present invention for the main purpose of removing the water formed in the ring expansion reaction, and all the more so since these compounds are used in the presence of an acid.

The process for the preparation of cephalosporanic acids according to the invention avoids the decarboxylation of penicillanic acid sulfoxide and the above-mentioned disadvantage can be avoided, since the whole reaction can be carried out in one step and in one vessel, making it more convenient and easier to carry out than the previously known process. compounds that are useful antibiotics.

The process of the invention provides for the formation of anhydride intermediates of 6-substituted aminopenicillanic acid sulfoxides which can be readily hydrolyzed with water alone and extended to ring β-deacetoxycephalosporins (i.e., compounds having structure II, wherein the methyl group is attached to the carboxyl group 3). is attached to the 4-carbon atom and the double bond is between carbon atoms 3 and ^) by acid in the presence of silicone-containing compounds capable of reacting rapidly with water formed during ring expansion to give neutral or basic products after hydrolysis.

Reagents which can be used in the process of the invention to protect the carboxyl group of the starting materials of general formula IV are those of general formula V, VI, VII and VIII and in which the free bonds attached to the atoms represented by the symbols M , is saturated with a halogen atom. When such reagents react with a 6-substituted aminopenicillanic acid sulfoxide, substitution of a hydrogen atom is effected, which atom combines with an activated group of the reagent (e.g., a halogen atom) to form an acid. This acid is then used as the acidic portion in the ring expansion reaction. Examples of compounds having a group of general formula V are compounds which can be considered as acid derivatives such as BBr ^, AlBr ^, and PBr ^.

Examples of compounds which contain a group of general formula VI and which can also be regarded as acid derivatives are compounds such as (CH2) ^ SiBr, (CH2) 2SCl, (CH2) 2SBB, GeBr2, SnBr2.

Silicon-containing reagents other than those mentioned above which are useful for protecting the carboxyl group of the starting material are listed in the list of compounds that must be present to remove water formed during the ring expansion reaction, which are listed below in this specification.

Examples of reagents containing a group of general formula VII are phosphoric acid derivatives such as PBr 2, POBr 2, PSBr 2 and tungsten-containing compounds such as WBr 2.

Compounds containing a group of general formula VIII are acid derivatives such as CH 2 COBr, C 6 H 2 COBr, Cl 2 COCO 2, Cl 2 COCl, CH 2 COCl, C 2 COBr.

Of these preferred protecting reagents, it is preferred to use those that are well known and used in chemistry, such as phosphorus trihalides, phosphorus pentahalides, tri (lower) alkyl halosilanes, di (lower) alkyl dihalosilanes, and carboxylic acid halides. Most preferred reagents are phosphorus-containing compounds such as phosphorus tribromide and phosphorus pentabromide and silicon-containing compounds such as tri (lower) alkyl bromosilanes, e.g. trimethylbromosilane, di (lower) alkyl-dibromosilanes, e.g. dimethyldibromosilane, N, O trialkylsilyl) acetamides, e.g. N, O-bis (trimethylsilyl) acetamide.

Currently, the most preferred molar ratios of carboxylic protecting reagents per mole of 6-substituted aminopenicillanic acid sulfoxide are 1/4 to 2 equivalents of reagent, and preferably 1/3 to 1 equivalent. The term "one equivalent" refers to the number of moles of reagent theoretically required to protect the carboxy group of one mole of benzylpenicillanic acid sulfoxide.

The group R1 in the general formulas III and IV may be any group shown in connection with cephalosporins and penicillins or their analogs. Suitable groups R 1 in general formulas III and IV are benzyloxycarbamoyl, phenylacetamido, phenoxyacetamido, 3-acetylureido, (3,5-dichlorosalicyl) amino, 2-phenoxypropionamido, 2-phenoxybutyramido, 2-phenoxyphenylacetamido, 5-methoxy -3-Phenyl-4-isoxazolecarboxamido, 1,58643 5-methyl-3- (o-chlorophenyl) -4-isoxazolecarboxamido, 5-methyl-3- (2,6-dichlorophenyl) -4-isoxazolecarboxamido, 2,6-methoxy benzamido, 2-ethoxy-1-naphthamido, 2- (o-aminobenzamido) -phenylacetamido-N-methyl, 2- (2-amino-5-nitrobenzamido) -phenylacetamido-N-methyl, N-benzylformamido, N- methyl-2-phenoxyacetamido, N-methyl-2-phenylacetamido, N-ethyl-2-phenylacetamido, N-isobutyl-2-phenoxyacetamido, 2-benzylidene-4,5-dioxo-3-oxazolidinyl, 2- butyl succinido, 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinylphthalimido, α-amino-α- (1-cyclohexa-1,4-dienyl) -acetamido, α-aminophenylacetamido, α-amino- 2-thienylacetamido, 2-thienylacetamido, 3-thienylacetamido, 2-Furylacetamido, 4-chloro-phenylacetamido, 3-bromophenylacetamido, 3-nitrophenylacetamido, 4-nitrophenylacetamido, 3-trifluoromethyl-phenylacetamido, 4-cyanophenylacetamido-2-cyanophenylacetamido, 4-methylthiophenylacetamido, 3-methylthiophenylacetamido, , benzenesulfonylacetamido, p-bromobenzenesulfonamido, and 1-piperidinosulfonamido.

If it is desired to obtain deacetoxycephalosporanic acid derivatives of general formula III having, for example, α-aminophenylacetamido, the free amino group of the corresponding 6-substituted aminopenicillan sulfoxide in the starting material of general formula IV must be protected during ring expansion, e.g., benzyloxycarbonyl group later leaving a free amino group. The free carboxylic acid group in the 6-acyl side chain can be protected, e.g., by esterification, preferably to form an acid anhydride, which consumes more reagent responsible for the formation of the acid anhydride of the carboxyl group attached to the thiazolidine ring.

The silicon-containing compound that must be present in the reaction mixture to remove water formed during the expansion of the ring structure is Ν, Ο-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, Ν, Ν-bis (trimethylsilyl) carbodiimide , N-methyl-N- (trimethylsilyl) acetamide, N, N'-bis (trimethylsilyl) urea and Ni-trimethylsilyl-N-methyltrifluoroacetamide.

These silicon-containing compounds react with water to give neutral compounds which do not affect the course of the reaction or the separation of the Δ 2 -deacetoxycephalosporan product.

A further preferred silicon-containing compound is hexamethyldisilazane. This silicon-containing compound reacts with water to form basic compounds.

The most preferred silicon-containing compounds used in this process are Ν, Ο-bis (trimethylsilyl) acetamide and N, N, -bis (trimethylsilyl) urea, which can react very rapidly with the water formed during ring expansion, thereby forming neutral products of vast, hexamethyldisiloxane and acetamide or urea, and thereby avoiding the degradation of the acid anhydride function by water as the ring expands.

The amount of silicon-containing compound added to the reaction mixture should be such that it completely removes the water formed during the treatment and also, if necessary, pre-silylates each free carboxy group in the original penicillin compound. Thus, starting from the 6-substituted aminopenicillanic acid sulfoxide and using N, O-bis (trimethylsilyl) acetamide as the silicon compound, at least 1 1/2 molar equivalents of silicon compound per 1 mole of water. However, starting from the acid anhydride of 6-substituted aminopenicillan sulfoxide, at least 1 mole of silicon compound is required to remove water. Preferably, at least 2-4 molar equivalents of silicon compound per mole of penicillin sulfoxide are used.

Such acids that can be used in the process of the invention to effect penam ring expansion are those that are not silylated or are not substantially silylated by the silicon-containing compound added to the reaction mixture under the reaction conditions used. Suitable acids include hydrobromic, hydrochloric, toluene-p-sulfone and concentrated sulfuric acid. Other suitable acids may include hydroiodic acid, perchloric acid, periodic acid, nitric acid, chloric acid, iodic acid, selenic acid, bromoacetic acid, trichloroacetic acid and trifluoroacetic acid, naphthalenic acid, trichloromethylsulfonic acid, trifluoromethylsulfonic acid, trifluoromethyl, , tetracyanopropylene, pentyanocyanocyclopentadiene and tetracyanocyclopentylthienene and tricyanocyclopentacyclic acid and dinitroacetonitrile, One preferred strong acid is hydrobromic acid.

The acid can be combined as such in the reaction mixture. The acid is preferably combined with a nitrogen-containing base to form an acid addition salt complex. Suitable bases include aliphatic, cycloaliphatic aromatic or heterocyclic amines, e.g. hexamethylenetetraamine, aniline, diphenylamine, N-methylS aniline, dimethylaniline, pyridine and quinoline, and pyridine and quinoline, "which are substituted by e.g. , aralkyl, aryl or mono- or di (lower) alkylamino groups such as picolines, 2-ethylpyridine, 2-propylpyridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2, 6-dimethylpyridine, collidines and 2-dimethylaminopyridine, quinoline, isoquinoline, 3-methylisoquinoline and also pyrazole, imidazole or N-methylimidazole. The most preferred bases are pyridine, substituted pyridines, quinoline, substituted quinolines, imidazole and substituted indazoles. An excess of base is preferably used relative to the amount of acid.

A complex of an acid and a nitrogenous organic base can be formed in situ in the reaction mixture by initially protecting the 6-substituted aminopenicillanic acid sulfoxide starting material in solution in a dry inert organic solvent by reaction with an acid radical containing a compound such as a halogenated compound, a halogenated compound, with trimethylchlorosilane, dimethylchlorosilane, trimethylbromosilane or triethylbromosilane. In this preliminary step, the hydrogen halide thus formed is preferably bound by a base because the acid anhydride formation occurs more uniformly and the penicillin sulfoxide ring structure is very sensitive to the free strong acid.

In principle, all bases, with the exception of hydroxy-containing bases, are suitable for binding this acid (e.g. the amine component of potassium carbonate or the penicillinic acid sulfoxide-cyclohexylamine salt), but preferably nitrogen-soluble bases with an organic solvent are used.

The hydrogen halide initially formed may be added, or may itself form the acid necessary to effect ring expansion of the penicillin sulfoxide.

The most preferred molar amounts of the substances contained in the reaction mixture per mole of 6-substituted aminopenicillanic acid sulfoxide are 1 / h to 1 mole of acid (preferably about 1/3 to 3 moles) to 1 / h to ii equivalents of carboxylic protecting reagent (preferably 1 / 3-1 equivalents), at least 2 equivalents of silicon compound (preferably 3-7 equivalents), or when using an acid-nitrogen-containing complex 1/10 to 10 moles of acid-base complex (preferably 1/4 to about 4 moles), 1/4 -2 equivalents of carboxyl protecting agent (preferably 1/3 to 1 equivalent), at least 2 equivalents of silicon-containing compound (preferably 3 to 7 equivalents) and preferably an additional amount of base itself, e.g. 1-10 moles, · wherein the additional amount of base is preferably added in direct proportion the amount of acid-base complex used.

The term "one equivalent" refers to the molar amount of carboxylic protecting reagent or silyl compounds theoretically required to react with 1 mole of benzylpenicillanic acid sulfoxide.

The acid anhydride formation and ring expansion reaction is performed in a dry, inert organic solvent. Suitable solvents include acetonitrile, chlorobenzene, toluene, diethylmethylsulfonamide, dimethylformamide. acetate, isoamyl acetate, diethyl oxalate, anisole, benzene, carbon tetrachloride, dimethyl sulfoxide, methyl ethyl ketone, methyl or ethyl isobutyl ketone and haloalkanes such as 1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1 -chloroethane, 1,2,3-trichloropropanemethylene chloride and chloroform. A very preferred solvent is dioxane.

The ring expansion treatment can be performed at a temperature between 50 and 160 ° C, and is preferably performed at a temperature between 60 and 130 ° C, and most preferably in the range of 70-110 ° C. The reaction temperature must be kept below 160 ° C to minimize the formation of decomposition products. In general, the reaction times and reaction times depend on each other to obtain deacetoxycephalosporan derivatives in good yield. Lower temperatures require longer reaction times and higher temperatures require shorter reaction times; e.g. at 80 °, 90 ° and 100 ° C, the reaction times may be about 24 hours, 10 hours and 6 hours, respectively.

• 11,58643

According to a preferred embodiment of the invention, 1 to 4 moles of acid, preferably hydrogen bromide or hydrogen chloride, 1.5 to 15 moles of a nitrogenous base, preferably α-picoline, are used per mole of penicillanic acid sulfoxide (e.g. benzylpenicillin sulfoxide), the amount of base always exceeding the amount of acid, and 2-4 moles of Ν, Ο-bis (trimethylsilyl) acetamide, and the reaction is carried out at a temperature of 80 to 110 ° C in a dry, inert organic solvent, preferably dioxane.

According to another preferred embodiment of the invention, for each mole of penicillanic acid sulfoxide, 1 / 3-1 equivalent of acetyl bromide or phosphorus tribromide, 1.5-15 moles of nitrogenous base, preferably α-picoline, are used, the amount of base always exceeding the amount of acid developed, and 1.5-3 moles of Ν, Ο-bis (trimethylsilyl) acetamide or NjN'-bis (trimethylsilyl) urea.

After completion of the ring expansion reaction, the β-deacetoxycephalosporan product is hydrolyzed in the reaction mixture and the resulting N, N-deacetoxycephalosporanic acid is isolated as such or in the form of a salt by any suitable method such as extraction and / or crystallization. Thus, when the reaction is carried out in an organic solvent which is immiscible with water, the reaction mixture can be extracted after cooling with water at pH 7 using, e.g., dilute aqueous potassium hydroxide solution. From this aqueous solution, after washing with an organic substance such as butyl acetate, Δ 2 -deacetoxycephalosporanic acid (e.g., 7-phenylacetamido derivative) or a salt thereof can be obtained by: (a) adding an aqueous acid solution and recovering the precipitated deacetoxycephalosporan extracting as an organic solvent at a pH below 4.5 and concentrating the extract to crystallize the acid, (c) adding n-butanol, removing water and crystallizing the potassium salt of the acid from a butanol solution, (d) extracting as an organic solvent at a pH below 4.5, then adding an alkali metal salt, e.g. potassium acetate or an alkali metal salt solution, e.g. potassium 2-ethylhexanoate, or an amine, e.g. triethylamine or cyclohexylamine, in an organic solvent and recovering the acid precipitated alkali metal or amine salt, or (e) extracting in an organic solvent below pH 4. , 5 and is 58643 precipitated desasctoxycephalonporanic acid with the addition of non-pe lac.rlst? an anhydrous medium such as diethyl ether or s y k 1 oh e k s a: i.

When the reaction is carried out in a water-miscible orange mixture. . . In a 3 solvent solvent, the A-desaoctoxycefnlosporanic acid derivative can be separated by pouring the reaction mixture into water and adding an orphan solvent. In this case, enough water and an organic solvent are needed to separate the mixture into two layers. The organic layer is re-extracted with water at pI of 7 and the combined aqueous layers are washed with an organic medium such as butyl acetate and then treated as described in (a) to (e) above to separate N, N-desacetoxycephalosporanic acid or a salt thereof. Alternatively, after completion of the reaction, the organic solvent can be evaporated off in vacuo, the amorphous residue dissolved in a water-immiscible solvent and water added. After adjusting the pH to 7, the organic phase is discarded. The aqueous solution is washed with an organic medium and then treated as described in (a) to (e) above. The reaction mixture can be poured into an aqueous acidic solution at a pH of about 2 with stirring and the precipitated deacetoxycephalosporanic acid is collected by filtration.

The yields of Δ 2 -deacetoxycephalosporanic acids obtained by the process of the invention may vary depending on the reagents and reaction conditions used, but the yields exceed. * 15% based on the amount of penicillin sulfoxide used is generally obtained and yields can be as high as 70% and even more than 90%.

The 6-substituted aminopenicillanic acid sulfoxides used as starting materials in the process of the invention can be obtained by treating the corresponding 6-substituted aminopenicillanic acids with an oxidizing agent by known methods. For this purpose, the 6-substituted aminopenicillanic acid derivative is treated in an inert organic solvent or water with a substance which provides an active oxygen, such as sodium periodate, peracid, hydrogen peroxide or iodosobenzene in an amount sufficient to oxidize the thiazolidine sulfur atom to -SO. The resulting sulfoxide can be easily recovered from the reaction mixture by methods known per se. Oxygen anhydrides of 6-substituted aminopenicillanic acid sulfoxides can be obtained from acids or salts by methods known per se and are preferably prepared in situ in a reaction medium used to expand the ring, e.g. a silicon-containing compound used as a dehydrating agent to remove water formed in the penam structure. during. .

13,58643

According to one embodiment of the invention, the starting 6-substituted aminopenicillin sulfoxide is one obtained from penicillin which can be easily prepared by fermentation, such as benzylpenicillin or phenoxymethylpenicillin, but other semisynthetically prepared penicillins are also useful. After ring extension, the corresponding N, N-deacetoxycephalosporan derivative can, if desired, be replaced by another acyl group by a method known per se, which involves deacylation of the 7-amino group and subsequent recylation.

The following examples illustrate the method of the invention. In these examples, where the yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was determined microbiologically, the acid can be obtained by treating the reaction mixture in the same manner as in Example 1.

Example I

To 10.5 g (30 mmol) of benzylpenicillin sulfoxide were added sequentially dioxane (195 mL), N, O-bis (trimethylsilyl) acetamide (25 mL; 102 mmol), α-picoline (6 mL; 61 mmol) and 5 .8 molar solution of α-picoline hydrobromide in dichloromethane (5.2 ml; 30 mmol of α-picoline hydrobromide. The trimethylsilyl derivative of benzylpenicillin sulfodide was formed in situ. After refluxing at 20 ° C for 6 hours (102 ° C), the reaction mixture was heated to 102 ° C). was poured into 1500 ml of ice water.

650 ml of ethyl acetate and 50 ml of butyl acetate were then added and the pH was adjusted to 74 with stirring with 4N potassium hydroxide solution. The mixture was allowed to separate and the organic layer was collected. The aqueous layer was washed with 300 ml of ethyl acetate and 50 ml of ιί 58643 butyl acetate. The obtained organic layer was combined with that previously obtained, and this combination was extracted again with 200 ml of a 0.75 molar aqueous solution of potassium phosphate buffered to pH 7. The extract was added to the main part of the aqueous solution. This combined aqueous mixture contained 9.2 g of Δ 2 -7-phenylacetamido-deacetoxyc

X

the potassium salt of phalosporanic acid, i.e. Δ-Benzyl-deacetoxycephalosporin (yield 83%) determined by a microbiological test using Escherichia coli as the test microorganism.

After adding 500 ml of butyl acetate to the aqueous solution, the mixture was stirred and the pH was adjusted to 2 with 4 N sulfuric acid. The mixture was allowed to stand and the organic extract was separated. The aqueous layer was extracted again with 250 ml of butyl acetate. The combined butyl acetate extracts were filtered as a water repellent filter. The aqueous layer, which still contained some Δ 4 -7-phenylacetamido-des-acetoxycephalosporanic acid, was discarded. To the butyl acetate solution was then added 2.65 g (27 mmol) of anhydrous finely divided potassium acetate with rapid stirring. After stirring for 3 hours at room temperature, the precipitate was filtered off, washed with a small amount of butyl acetate and dried in vacuo at 30 ° C to give 10.2 g of the potassium salt of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid, 85% pure by microbiological test. (yield 23.5 mmol, 78%). λ max (H 2 O): 262 nm. (E ** cm: 175).

The structure was confirmed by IR and PMR spectra.

The analysis of the PMR spectrum was as follows: PMR (as potassium salt in DjO; values in parts per million) <5: 1.91 »(s, 3), 2.99 (d. J * 18 Hz, 1), 3.44 (d, J = 18 Hz , 1), 3.62 (s, 2), 4.97 (d, J = 4.5 Hz, 1), 5.58 (d, J = 4.5 Hz, 1), 7.27 (s , 5).

The sodium salt of 2,2-dimethyl-2-silapentyl-5-sulfonate was used as a reference compound.

Example II

(a) 1.05 z (3 mmol) of benzylpenicillin sulfoxide was added to a mixture of 20 ml of a solution of 3.0 mmol of hydrogen bromide in dioxane and N, Ο-bis (trimethylsilyl) acetamide (2.5 ml; 10 mmol). ). The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.

The reaction mixture was heated to 102 ° C. The reaction was monitored by thin layer chromatography.

After 58 hours, no penicillin sulfoxide remained in the reaction mixture. 5 ml samples were taken and poured into 35 ml of 0.75 molar aqueous potassium phosphate buffer buffered to pH 7. The aqueous solution was washed with 10 ml of ethyl acetate and diluted to 50 ml with water. The amount of the potassium salt of Δ 2 -7-phenylacetamido-deacetoxycephalosporal acid in the aqueous solution was evaluated by a direct microbiological experiment using the strain Escherichia coli as the microorganism in the experiment. After 6 hours, the yield of Δ 2 -7-phenylacetamido-desase-toxicocephalosporanic acid was 47% - (b) The experiment described in (a) above was repeated except that 18 ml of toluene and 2 ml of a 1.5 molar solution of hydrogen bromine in dioxane were used in 20 ml. instead of dioxane. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 46%, which could be determined by a microbiological experiment.

* (c) The experiment described in (a) above was repeated with the difference that an additional 0.9 (9 mmol) of α-picoline was used. The yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was 82 JS, which could be determined by a microbiological experiment.

Example III

To 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added sequentially dioxane (20 mL), N, O-bis (trimethylsilyl) acetamide (3.2 mL; 13 mmol) and p-toluenesulfonic acid (0.57 g). The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ, and after heating the reaction mixture for 6 hours at 101 ° C, no more sulfoxide remained.After work-up of the reaction mixture as described in Example II, Δ 41% as determined by microbiological test.

Example IV

(a) A mixture of 2.1 g (6 mmol) of benzylpenicillin sulfoxide, 20 ml of chloroform, 20 ml (200 mmol) of α-picoline, 8 ml (33 mmol) of Ν, Ο-bis (trimethylsilyl) acetamide and 1 , 6 mL (5.8 mmol) of concentrated sulfuric acid was heated to 83 ° C. The trimethylsilyl derivative of benzyl lipenicillin sulfoxide was formed in situ.

After 24 hours, the yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 12% as determined by microbiological experiment using the method described in Example II.

(b) The experiment described in (a) was repeated except that 6.4 ml (26 mmol) of N, O-bis (trimethylsilyl) acetamide and 1.14 g (6 mmol) of p-toluenesulfonic acid were used in 1.16 ml. 16 58643 concentrated sulfuric acid. The yield of N, N-phenylacetamido-deacetoxycephalosporalic acid after heating at 83 ° C for 24 hours was determined by a 15% microbiological experiment using the method described in Example II.

(c) The experiment described in (a) above was repeated except that 5 ml (20 mmol) of N, O-bis (trimethylsilyl) acetamide and 2 ml of a 5.3 molar solution of α-picoline hydrochloride (6.6 mmol) were used. in dichloroethane instead of 1.6 ml of sulfuric acid. After heating for 24 hours at 85 ° C, the yield of Δ

Example V

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 10 ml of benzyl cyanide, 10 ml (100 mmol) of α-picoline, 3 ml of a 3.3 molar solution of α-picoline hydrochloride (10 mmol) in 1,2-dichloroethane and 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide were heated at 95 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 6 hours, the yield of Δ-7-phenylacetamido-deacetoxycephalosporanic acid was 48% as determined by a microbiological experiment using the method described in Example II.

Example VI

The experiment described in Example V was repeated except that 15 ml of benzyl cyanide and 5 ml (50 mmol) of α-picoline were used. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporal acid after heating at 95 ° C for 6 hours was 48% as determined by a microbiological test using the method of Example II.

Example VII

The experiment described in Example V was repeated except that 17.5 ml of benzyl cyanide, 2.5 ml (25 mmol) of α-picoline and 2 ml of a 3,3 molar solution of α-picoline hydrochloride (6.6 mmol) in 1,2-dichloroethane , was used in this experiment. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid after heating at 95 ° C for 6 hours was 48% as determined by the microbiological method using the method described in Example II.

17,58643

Example VIII

A mixture of 1 g (3 mmol) of benzylpenicillin sulfoxide, 15 ml of benzyl cyanide, 7.2 ml (72 mmol) of pyridine, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.27 ml (1 mmol) of a 3,3-molar solution of α-picoline hydrochloride, heated to 90 ° C. Benzylpenicillin sulfoxide trimethyl

T

the lisilyl derivative was formed in situ. After 6 hours, the yield of Δ-7-phenylacetamido-deacetoxycephalosporanic acid was 38% as determined by the microbiological method described in Example II.

Example IX

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of benzyl cyanide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.2 * 1 g (1.5 mmol) of mmol) of pyridine hydrobromide, heated to 90 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 10 hours, the yield of ΔJ-phenylacetamido-deacetoxycephalosporanic acid was 5 **% as determined by microbiological experiment.

Example X

The experiment described in Example IX was repeated using 0.48 g (3 mmol) of pyridine hydrobromide instead of 0.24 g and adding 0.3 ml (3 mmol) of α-picoline. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating for 10 hours at 90 ° C, the yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was 59% as determined by microbiological experiment.

Example XI

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.48 g (3 mmol) of pyridine hydrobromide and 0.3 ml (3 mmol) of α-picoline, heated to 85 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 22 hours, the reaction mixture was poured into 150 ml of a 0.75 molar aqueous solution of potassium phosphate buffered to pH 7 and washed with 50 ml of chloroform. The pH of the aqueous layer was adjusted to 2 in the presence of 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of ethyl acetate gave 1 g of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid with a purity of 56% as determined by PMR using 2,6-dichloroacetophenone for internal comparison.

18 58643

Example XII

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.5 ml (3 mmol) of 6 of a 1 molar solution of α-picoline hydrobromide in dichloromethane and 0.6 ml (6 mmol) of α-picoline was heated at 102 ° C with stirring. The trimethylsilyl derivative of benzyl lipenicillin sulfoxide was formed in situ. After 6 hours, the reaction mixture was poured into a mixture of 200 ml of a 0.75 molar aqueous solution of potassium phosphate buffered to pH 7 and 50 ml of ethyl acetate. The buffered aqueous layer was washed with 50 ml of ethyl acetate, and after adjusting the pH to 2, the aqueous layer was extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The residue (1.07 g) contained 70% Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid as determined by UV and PMR spectra (yield 2.25 mmol; 75%).

Example XIII

0.64 g (5.3 mmol) of triethylbromosilane was added to a mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane and 0.9 ml (9 mmol) of o-picoline. After stirring for 1/2 hour, the triethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ and its presence could be confirmed by PMR spectrum. 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide were then added, and the mixture containing picoline choline hydrobromide was heated at 102 ° C for 4 hours. After treating the reaction mixture as described in Example II, the yield of β-1-phenylacetamido-deacetoxycephalosporanic acid was 73% as determined by microbiological experiment.

Example XIV

(a) To a mixture of 20 ml of a 0.15 molar solution of hydrogen chloride (3 mmol) in dioxane and 2.5 ml (10.2 mmol) of N, O-bis (trimethylsilyl) α3-amide was added 1.05 g (3 mmol) of benzylpenicillin sulfoxide. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After refluxing for 6 hours (102 ° C), the reaction mixture was treated as described in Example II. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was about 10% as determined by microbiological experiment.

* 19 58643 (b) To a mixture of 2 ml (3 mmol) of a 1.5 molar solution of hydrogen chloride in benzyl cyanide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.9 ml (9 mmol) of α-picoline in 19 ml of benzyl cyanide, 1.05 g (3 mmol) of benzylpenicillin sulfoxide were added. The mixture was heated at 95 ° C for 6 hours and the yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid formed was found to be 48% using the method described in Example II.

Example XV

(a) To 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added dioxane (18 mL), N, O-bis (trimethylsilyl) acetamide (2.5 mL; 10 mmol) and α-picoline (0.9 mL; 9 mmol). After a few minutes, 2 ml of a solution of 1.5 molar hydrogen bromide (3 mmol) in dioxane was added and the resulting mixture was heated at 101 ° C for 6 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. Treatment of the reaction mixture as described in Example II gave Δ 2 -7-phenylacetamido-deacetoxycephalosporal acid in 97% yield as determined by microbiological experiment.

(b) A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide in 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide in 0.3 ml (3 mmol) of α-picoline and 0.25 g of ml (1.5 mmol) of a 6 molar solution of α-picoline hydrobromide in 20 ml of dioxane was heated at reflux for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 2 -7-phenylacetamide-dodecacetoxycephalosporanic acid was 82% as determined by microbiological experiment.

(c) The experiment described in (b) above was repeated except that 0.9 ml (9 mmol) of α-picoline was used instead of 0.3 ml and 420 mg (3 mmol) of bromoacetic acid instead of α-picoline bromide. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was 32% as determined by microbiological experiment.

(d) The experiment described in (c) above was repeated except that 700 mg (3 mmol) of picric acid was used instead of bromoacetic acid. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ4-7-phenylacetamido-deacetoxycephalosporanic acid was 47% as determined by microbiological experiment.

20 58643 (e) The experiment described in (c) was repeated except that 875 mg (3 mmol) of tris (ethylsulfonyl) methane, i.e. (CgHjjSOjp) ^ CH, instead of the bromoacetic acid used. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 28% as determined by microbiological experiment.

Example XVI

(a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide were suspended in 10 ml of dioxane. After the addition of 0.45 ml (4.5 mmol) of α-picoline, the clear solution was cooled to 0 ° C. While stirring vigorously, 0.05 mL (0.5 milole) of phosphorus tribromide was added. The mixture was stirred at 0 ° C for 30 min. Anhydride of benzylpenicillin sulfoxide and phosphorus tribromide formed in situ. 0.9 ml (3.5 mmol) of N, O-bis (trimethylsilyl) acetamide were then added. After heating at reflux for 4.5 hours, the amount of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid formed was 85% as determined by microbiological experiment.

(b) The experiment described in (a) above was repeated except that 0.05 ml (0.5 mmol) of acetyl bromide was used instead of phosphorus tribromide. The intermediate formed in this case was acetyl anhydride of benzylpenicillin sulfoxide. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 87% as determined by microbiological experiment.

(c) The experiment described in (b) was repeated with the difference that acetyl bromide was added while the mixture was at room temperature. The yield was 83% Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid as determined by microbiological experiment.

‘(D) The experiment described in (b) was repeated except that 0.36 ml (45 mmol) of pyridine was used instead of α-picoline. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 94%.

(e) The experiment described in (d) was repeated except that 0.07 ml (1.0 mmol) of acetyl bromide was used instead of 0.05 ml. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 92%.

(f) The experiment described in (d) was repeated except that 0.14 ml (2.0 mmol) of acetyl bromide was used instead of 0.05 ml. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 93 S.

21,58643 (g) The experiment described in (d) was repeated except that 0.05 ml of oxalyl bromide was used instead of acetyl bromide. In this case, the intermediate benzylpenicillin sulfoxide oxalyl anhydride was formed. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 69%.

(h) The experiment described in (e) was repeated except that 10 ml of toluene was used as solvent instead of dioxane. Benzylpenicillin sulfoxide acetyl anhydride was formed in situ. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 76%.

(i) The experiment described in (e) was repeated with the difference that 10 ml of butyl acetate was used instead of dioxane. Δ -7-fe-

the yield of nylacetamido-deacetoxycephalosporanic acid was 78%. Example XVII

A solution of 10.5 g (30 mmol) of benzylpenicillin sulfoxide in 150 ml of dioxane and 7.2 ml (90 mmol) of pyridine was cooled to 6 ° C. After adding a solution of 1.4 ml (18.5 mmol) of acetyl bromide in 50 ml of dioxane, the mixture was stirred at 5 ° C for 30 minutes. Acetyl anhydride of benzylpenicillin sulfoxide was formed in situ. 13 ml (70 mmol) of N, O-bis (trimethylsilyl) acetamide were then added and the reaction mixture was heated under reflux for 4.5 hours. After cooling, the mixture was poured into 1 L of a 0.2 M aqueous solution of potassium phosphate buffered to pH 7. After adjusting the pH to 7 with 600 N potassium hydroxide solution, 600 ml of butyl acetate was added. The mixture was shaken and then the two layers were allowed to separate in a separatory funnel. The aqueous layer was washed with 400 mL of butyl acetate. The combined butyl acetate layers were extracted with 500 mL of 0.75 M aqueous potassium phosphate buffered to pH 7, and the extract was added to the majority of the aqueous solution.

The combined aqueous solutions contained 9.1 g of the potassium salt of Δ 2 -7-phenylacetamodeacetoxycephalosporanic acid (yield 82%) as determined by UV spectroscopy and a microbiological experiment using Escherichia coli strain as the test microorganism.

The potassium salt of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was isolated as described in Example I to give 11.1 g of product with a purity of 67% as determined by microbiological experiment (yield 75%).

Example XVIII

(a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide were suspended in 10 ml of dioxane. After the addition of 0.45 ml (4.5 mmol) »; 22,58643 α-picoline, the clear solution was cooled to 0 ° C. While stirring vigorously, 0.05 ml (0.7 mmol) of acetyl bromide was added and the mixture was stirred at 0 ° C for 30 minutes. Acetyl anhydride of benzylpenicillin sulfoxide was formed in situ. Then, 1.35 g (6.6 mmol) of N, Nf-bis (trimethylsilyl) urea was added, and after heating under reflux for 4.5 hours, the amount of Δ -? - 7-phenylacetamido-deacetoxycephalosporanic acid was determined by microbiological experiment. Yield 54%.

(b) The experiment described in (a) was repeated except that 0.05 ml (0.5 mmol) of phosphorus tribromide was used instead of acetyl bromide. The intermediate formed in this case was benzyl penicillin sulfoxide and phosphorus tribromide anhydride. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 33% as determined by microbiological experiment.

(c) The experiment described in (a) was repeated except that 10 ml of butyl acetate was used instead of dioxane and 0.12 ml (1.5 mmol) of acetyl bromide instead of 0.7 mmol. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 54%.

(d) The experiment described in (a) was repeated except that 0.36 ml (4.5 mmol) of pyridine was used instead of α-picoline and 0.22 ml (2.5 mmol) of trimethylbromosilane instead of acetyl bromide.

The intermediate formed was a trimethylsilyl derivative of benzylpenicillin sulfoxide. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 80%.

(e) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 760 mg (3.7 mmol) of N, N'-bis (trimethylsilyl) urea were suspended in 10 ml of toluene. 0.12 ml (1.5 mmol) of pyridine and 0.12 ml (1.0 mmol) of benzoyl bromide were then added and the mixture was heated at 100 ° C for 5 hours. Benzoyl anhydride of benzylpenicillin sulfoxide was formed as an intermediate. The yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was 57% as determined by microbiological experiment.

(f) The experiment described in (e) was repeated with the difference that several other acid derivatives were used instead of benzoyl bromide. The results are shown in the following table: 23 5864 3

Acid derivative Amido-deacetoxy amount of the acid Δ 2 -7-phenylacetate derivative (mmol) Yield of cephalosporanic acid {%) 1. Trichloroacetyl bromide 1.0 67 2. Trichloroacetyl chloride 1.0 67 3. Propionyl bromide 1.0 75 4. Phosgene 0.5 31 5. Thionyl chloride 0.55 32 6. Thionyl bromide 0.65 67 7 · Toluenesulfonyl chloride 1.0 21 8. Boron tribromide 0.37 8l 9 · Aluminum tribromide 0.34 40 "10. Silicon tetrabromide 0.25 73 11. Germanium tetrabromide 0.25 82 12. Tin tetrabromide 0.25 26 13 · Phosphorus pentabromide 0.2 82 14. Phosphorus oxybromide 0.33 75 15. Phosphorus thio bromide 0.37 74 16. Tungsten pentabromide 0.2 56

It should be noted that trichloroacetyl (1,2), propionyl (3), carbonyl (4), thionyl (5,6) and p-toluenesulfonyl (7) anhydride of benzylpenicillin sulfoxide and benzylpenicillin sulfoxide were formed as intermediates. n anhydride with boron tribromide (8), aluminum tribromide (9), silicon tetrabromide (10), germanium tetrabromide (11), tin tetrabromide (12), phosphorus pentabromide (13), phosphorus oxybromide (14), phosphorothiobromide (15) and tungsten (15) .

Example XIX

525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.4 g (7 mmol) of N, N'-bis (trimethylsilyl) urea were suspended in 10 ml of dioxane. To this was added 0.35 ml (2 mmol) of a 6-molar solution of α-picoline hydrobromide in dichloromethane, and the mixture was heated at 100 ° C for 4 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of Δ4-7-phenylacetamidodesacetoxycephalosporanic acid was found to be 80% using the method described in Example II.

211 58643

Example XX

(a) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 S (5 mmol) of N, N * -bis (trimethylsilyl) urea were suspended in 10 ml of dioxane. 0.25 ml (3 mmol) of pyridine and 0.15 ml (1.6 mmol) of trimethylbromosilane were then added and the mixture was heated at 100 ° C for 4.5 hours. The 5-methylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid formed was 85% as determined by microbiological experiment.

(b) The experiment described in (a) was repeated with the difference that 0.16 ml (1.6 mmol) of α-picoline was used instead of pyridine. The yield was 85%.

(c) The experiment described in (a) was repeated except that 0.83 ml (3.3 mmol) of N, O'-bis (trimethylsilyl) acetamide was used instead of N, N'-bis (trimethylsilyl) urea. The yield of Δ 2 -7-phenylacetamide-dodecacetoxycephalosporanic acid was 69% as determined by microbiological experiment.

Example XXI

525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 g (5 mmol) of N, N'-bis (trimethylsilyl) urea were suspended in 10 ml of butyl acetate. To this was added 0.23 ml (2.3 mmol) of α-picoline and 0.2 ml (2.2 mmol) of trimethylbromosilane. The trimethyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating to 100 ° C for 4.5 hours, the yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was 78% as determined by microbiological experiment.

Example XXII

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 3.1 ml (15 mmol) of hexamethyldisilazane, 6 ml of a 0.5 molar solution of hydrogen bromide in dioxane and 14 ml of dioxane was heated at 100 ° C for 4.5 hours. . The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was found to be 48% by the method described in Example 2.

Example XXIII

(a) A mixture of 1.05 g (3 mmol) of benzylpenicillin-3-sulfoxide, 18 ml of dioxane, 0.9 ml (9 mmol) of α-picoline, 2.6 g of 25 5 8 6 4 3 (10 mmol) N .0-bis (trimethylsilyl) trifluoroacetamide and 2 ml of a 1.5 molar solution of hydrogen bromide in dioxane were heated under reflux for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid formed was found to be 73 by microbiological experiment.

(b) The experiment described in (a) was repeated except that N, N'-bis (trimethylsilylx) carbodiimide (1.8 g; 10 mmol) was used instead of N, O'-bis (trimethylsilyl) trifluoroacetamide. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was found to be 14% by microbiological experiment.

Example XXIV

1.05 g (3 mmol) of benzylpenicillin sulfoxide was suspended in 15 ml of dioxane. To this were added 2.5 nl (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.2 ml (9 mmol) of 2-methylquinoline and 6 ml of a 0.5 molar solution of hydrogen bromide in dioxane and the mixture was heated at 100 °. C 4.5 hours. The trimethylsilyl derivative of benzylpenic silyl sulfoxide was formed in situ. The yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid formed was found to be the same as using the microbiological test of Example 2 and the strain Escherichia coli as a test microorganism 49 56.

The experiment was repeated using several bases other than 2-methylquinoline. The results are shown in the following table.

Base Amount of base Yield of Δ 2 -7-phenylaceto- (mmol) amido-deacetoxycephalosporanic acid (%) 1. diphenylamine 3 54 2. aniline 9 58 3. N-methylaniline 9 53 4. hexamethylenetetraamine 2.25 73 5. 3-methylpyridine 9 75 6. 4-methylpyridine 9 82 7. 2,3-dimethylpyridine 9 80 8 2,6-dimethylpyridine 9 52 26 5 8 6 4 3

Base Amount of base Δ ^ -7-phenylacet- (mmol) amido-deacetoxy cephalosporanic acid yield (%) 9. 2-ethylpyridine 9 68 10. 2-propylpyridine 9 85 11. 4-benzylpyridine 9 75 12. 4-phenylpyridine 9 8l 13 · 2-dimethylaminopyridine 9 84 14. 1,3,5-collidine 9 84 15. quinoline 9 84 16. isoquinoline 9 89 17. 3-methylisoquinoline 9 72 18. pyrazole 9 54 19. imidazole 3 69 20 N-methylimidazole 3 87

Example XXV

(a) A mixture of 525 mg (1.5 mmol) of benzylpenicillin sulfoxide, 10 ml of toluene, 0.12 ml (1.5 mmol) of pyridine, 1.45 ml (9 mmol) of N-methyl-N-trimethylsilyl -acetamide and 0.35 ml of a β-molar solution of α-picoline hydrobroride in dichloromethane were heated at 100 ° C for 5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of the formed Δ 2 -7-phenylacetamide-deacetoxycephaloscranic acid was found to be by microbiological experiment 58 3.

(b) The above experiment was repeated except that 1.7 ml (9.2 mmol) of N-methyl-N-trimethylsilyl-trifluoroacetamide was used instead of N-methyl-N-trimethylsilylacetamide. The yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid was 86 S.

Example XXVI

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.6 ml (6 mmol) of α-picoline and 0.5 ml of ml of a 6 molar solution of α-nicoline hydrobromide in methylene chloride in 20 ml of dioxane was heated at reflux for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.

The amount of Δ4-7-phenylacetamido-deacetoxycephalosporanic acid was determined by the microbiological experiment described in Example II. The yield was 32%.

The experiment was repeated in solvents other than dioxane. The results are shown in the following table.

Solvent Yield of Δ 4 -7-phenylacetamido-deacetoxycephalosporanic acid (%) 1,2,3-trichloropropane 40 n-toluene 41 N, N-dimethylacetamide 44 diethylmethylsulfonamide 49 chlorobenzene 52 isoamylacetate 60-butylacetate 60 butylacetate 64 diethylacetate 64 diethyl tetraethylene glycol dimethyl ether 81 triethylene glycol dimethyl ether 64

Example XXVII

1.3 g (3 mmol) of 2-ethoxynaphthylpenicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.3 ml (3 mmol) of α-picoline and 0.25 ml (1.5 mmol) of mmol) of a 6-molar solution of α-picoline hydrobromide in methylene chloride was dissolved in 20 ml of dioxane. The trimethylsilyl derivative of 2-ethoxynaphthylpenicillin 3 sulfoxide was formed in situ. The mixture was heated to reflux for 4.5 hours and then poured into a cold mixture of 200 ml of 0.75 molar aqueous potassium phosphate buffered to pH 7 and 50 ml of ethyl acetate. After adjusting the pH to 7 with 4N potassium hydroxide solution, the mixture was transferred to a separatory funnel, shaken and allowed to stand. The aqueous layer was washed with 50 ml of ethyl acetate, and after adjusting the pH to 2 with 4 N sulfuric acid solution, extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The dried residue (490 mg) contained 30% Δ -7- (2-ethoxynaphthalam-28 5 8 6 4 3 do) -deacetoxycephalosporanic acid as determined by PMR using 2,6-dichloroacetophenone as a control. Yield 31 JS.

Example XXVIII

The experiment described in Example XXVII was repeated using 1.1 g (3 mmol) of phthalimidopenicillin sulfoxide, except that 0.25 ml of α-picoline hydrobromide solution and 0.3 ml of α-picoline were replaced by 0.5 ml (3 mmol) of 6 -molar solution of α-picoline hydrobromide in methylene chloride. The trimethylsilyl derivative of phthalimidopenicillin sulfoxide was formed in situ. The reaction mixture was treated in the same manner as described in Example XXVII to give 380 mg of Δ 2 -7-phthalimido-deacetoxycephalosporanic acid in 85% purity · Yield 72%.

Example XXIX

The experiment described in Example XXVII was repeated using 1.3 g (3 mmol) of benzenesulfonamidomethylpenicillin sulfoxide. The trimethylsilyl derivative of benzenesulfonamidomethylpenicillin sulfoxide was formed in situ. 1.3 g of Δ4-7-benzenesulfonamidomethyl-deacetoxycephalosporanic acid with a purity of 63 JS were obtained. Yield 66%.

Example XXX

(a) To 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide was added dioxane (20 mL) N, O-bis (trimethylsilyl) acetamide (2.5 mL; 10 mmol) α-picoline (0.6 mL; 6 mmol) and a 6 molar solution of α-picoline hydrobromide in methylene chloride (0.5 mL; 3 mmol). The trimethylsilyl derivative of phenoxymethylpenicillin sulfoxide was formed in situ. The mixture was heated to reflux for 4.5 hours and then treated as described in Example II. The yield of Δ 2 -7-phenoxyacetamido-deacetoxycephalosporanic acid was 71% as determined by a direct microbiological experiment using Escherichia coli strain as the test microorganism.

(b) The experiment described in (a) was repeated except that the reaction mixture was treated as described in Example XXVII to give 860 mg of Δ 2 -7-phenoxyacetamido-deacetoxycephalosporanic acid with a purity of 35% as determined by its PMR spectrum using Comparison 2. 6-dichloroacetophenone. The yield was 70%.

Example XXXI

To a suspension of 1.35 g (3 mmol) of the cyclohexylammonium salt of benzylpenicillin sulfoxide in 15 mL of dioxane was added 2.8 mL (11 mmol) of N, O-bis (trimethylsilyl) acetamide and 29,58643 of 6 mL of 0.5 molar a solution of hydrogen bromide in dioxane. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.

The mixture was heated to reflux for 4.5 hours and the yield of Δ 2 -7-phenylacetamido-deacetoxycephalosporanic acid was found to be 55% by microbiological experiment.

Example XXXII

Preparation of a mixture of phenoxymethylpenicillin sulfoxide and acetic anhydride.

(a) A solution of 0.28 ml (3 mmol) of acetyl bromide in 5 ml of 1,2-dichloroethane was added to a solution of 1.1 g (3 mmol) of phenoxyacetylpenicillin sulfoxide and 0.72 ml (9 mmol) of py -ridine in 20 ml of 1,2-dichloroethane. After stirring for 1 hour at 0 ° C, the mixture was filtered and evaporated to dryness. The residual foam (1.08 g; 2.6 mmol) was formed by a mixture of phenoxymethylpenicillin and acetic anhydride.

IR spectrum analysis: (in CHCl 3): 1820, 1800 and 1753 cm PMR spectrum analysis (in CDCl 3), δ: 1.35 (s, 3); 1.74 (S, 3); 2.32 (s, 3); 4.55 (s, 2); 4.67 (s, 1); 5.17 (d, 1, J = 4.5 Hz): 6.12 (q, 1, J s 11 Hz and J = 4.5 Hz); 6.98 (s, 5).

(b) 2.2 g (5 mmol) of phenoxymethylpenicillin sulfoxide and acetic anhydride were dissolved in 30 ml of dioxane. After adding 3 ml (11.7 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.1 ml (15 mmol) of pyridine and 0.6 ml of dichloroethane containing 3.6 mmol of α-picoline hydrobromide, the mixture was heated to reflux. 4.5 hours. The reaction mixture was cooled to room temperature and poured into a stirred mixture of 400 ml of a 0.75 molar aqueous solution of potassium phosphate buffered to pH 7 and 100 ml of ethyl acetate. After adjusting the pH to 7 with 4N potassium hydroxide, the mixture was introduced into a separatory funnel, shaken and allowed to stand. The aqueous layer was separated, washed with 100 ml of ethyl acetate, and after adjusting the pH to 2 with 4N sulfuric acid solution, extracted twice with 200 ml of ethyl acetate. After the reaction mixture was dried over anhydrous magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The dried residue (1.28 g) contained 86% of Δ 2 -7-phenoxyacetamidodesacetoxycephalosporanic acid as determined by its PMR spectrum using 2,6-dichloroacetophenone for comparison. Yield 63 S.

3 ° 5864 3 This example shows that the anhydride formed as an intermediate can be separated from the reaction mixture, and in the case where the anhydride is formed in situ, it can be used to expand the ring.

Example XXXIII

A mixture of 1.05 g (3 mmol) of benzylpenicillin, 0.9 ml (9 mmol) of α-picoline and a dioxane solution of 3.0 mmol of hydrogen bromide was refluxed over> 4.5 hours with various amounts of N, O-bis - (trirethylsilyl) acetamide as described in more detail below. (The total amount was 2, ¾ ml at all times.) The yield of Δ 2 -7-phenylacetamido-desaceto-xicephalosporanic acid as determined by microbiological experiment is shown in the table below.

Amount used (mmol) Δ 4 -7-phenylacetamido-N, O-bis (trimethylsilyl) -deacetoxycephalosacetamide yield% of ranoic acid) 4.5 0 6 56 7.5 82 9 85 10 85 12.5 70 15 46 20 21 40 0

The table shows that the maximum yield under the above conditions was 35% and this was obtained with 9-10 mmol of N, O (trimethylsilyl) acetamide.

Claims (1)

A process for the preparation of N, N-acylamido-deacetoxycephalosporanic acids having the general formula: R, -CH - CH CH-III III - NC - CH3 O (jT COOY wherein R1 represents an acylamido group and Y represents a hydrogen or alkali metal atom, by modification corresponding 6-acylamidopenicillanic acid sulfoxides, characterized in that 6-acylpenicillanic acid sulfoxide having the general formula: / S \ / 3 R1 - CH - CH C [\ h3 IV C - N-CH2COOY wherein Rj and Y have the same meaning as above, is reacted with a halide having the general formula: R 2 - Hai wherein Hai represents a halogen atom and R 9 represents a group having one of the following formulas: R 3 \ R 3 \ R 3 * \ R 3 \> 1 "r 4-m 2 “R4> M3- R7 - g 'R11 R5X R5 * yo r6 V VIA VIB VII VIII in which formulas R1, R1', R1, R4 ', R1, R1' and R8 represent a bromine atom, or R Rg together denote an oxygen or sulfur atom, or r3'j R1 ('and Rg' denote a methyl or ethyl group, Ry denotes a methyl or ethyl group which may be substituted by one or more chlorine atoms or a phenyl group represents a boron, aluminum or phosphorus atom, M2 represents a germanium or tin atom, and represents a phosphorus or tungsten atom, or 32 58643 phosgene, thionyl balogen , oxalyl bromide or p-toluenesulfonyl chloride, and the resulting protected 6-acylamido-penicillanic acid sulfoxide or 6-acylamido-penicillanic acid sulfoxide of formula IV is heated in a dry inert organic solvent to not more than 160 ° C together with anhydrous acid. is hydrogen bromide, hydrogen chloride, p-toluenesulfonic acid, concentrated sulfuric acid, hydrogen iodide, perchloric acid, periodic acid, nitric acid, chlorine, acid, iodic acid, selenous acid, bromoacetic acid, tri-chloroacetic acid, trifluoroacetic acid, trikloorimetyylisulfonihappo, trifluoro-rimetyylisulfonihappo, naphthalenesulfonic acid, oxalic acid, lT-acid, tris (ethylsulfonyl) methane, pentocyanopropene, tetracyanopropene ni, pentyanocyclopentadiene, tetracyanocyclopentadiene, tricyanocyclopentadiene or dinitroacetonitrile, and 2-7 equivalents of a silicon-containing compound which is N, O-bis- (trimethylsilyl) acetamide, N, N'-bis (trimethylsilyl) di-amylamethyl , O-bis (trimethylsilyl) trifluoroacetamide, N, N * -bis (trimethylsilyl) carbodiimide, N-methyl-N- (trimethylsilyl) acetamide or N-methyl-N- (trimethylsilyl) trifluoroacetamide, and the obtained compound hydrolyzed in situ and the Δ 4 -7-acylamido-deacetoxy-cephalosporanic acid thus formed is isolated as such or as an alkali metal salt. For the preparation of Δ ^ -7-acylamido-deacetoxic-phalosporic compounds with the following formulas: Rn - CH - CH CH0 III III C - NC - CH3 oxc iooY color of the acylamido group and of the y-bond of the alkali metal 6-acylamido-penicillansyrasulfoxide is selected from the group consisting of 6-acylamido-penicillansyrasulfoxide with the following formula: / CH3 R-, - CH - CH C v! I jS », c - N - CH 0 ^ I u COOY 33 58643 colour R · ^ och Y har samma betydelser som ovan, omsättes med en halo-genid med den allmänna formuleln R2 - Hai colony Hai betecnar en halogenatom och R2 betecknar en the group with the above form is as follows: R3 \ R3 \ R4-M2- V'-Si- RM> M3- R7 - 5 - RjT R5X r5 '^ R5 "/ 0 R6X V VIA VIB VII VIII i vilka formler Rg, Rg ', Rjj, R ^', Rg, Rg f och Rg betecnar en bromatom, eller Rg och Rg betecknar tillsamman en syre- eller sva-velatom, eller Rg1, R ^ 'och Rg' betecknar en methyl- eller ethyl ethyl, Ry is a methyl or ethyl group which may be substituted by a chlorine atom or a phenyl group, a phenyl or a boron, aluminum or phosphorus atom, M2 is a germanium or tertatom and Mg is a phosphorus or tungsten atom, or with phosgene, thionyl halide, oxalyl bromide or p-toluenesulfonyl chloride, with the addition of 6-acylamido-penicillansyrasulfoxides or 6-acylamido-penicillansyrasulfoxides with formula IV and pertiary and tertiary inert organic solvents to a temperature of 160 ° C to a mixture with bromine, chlorine, chlorine, p-toluenesulfonyl, concentrates of iodine, iodine, perchlorate, chlorine, perryodium, , bromättiksyra, triklorfittiksyra, tri-fluorättiksyra, triklormetylsulfonsyra, trifluormetysulfonsyra, naftalensulfonsyra, oxalsyra, pikrinsyra, tris (etylsulfonyl) Imetan, pentacyanopropen, tetracyanopropen, pentacyanoeyklopentadien, tetracyanocyklopentadien, tricyanocyklopentadien eller dinitroaceto-Nitrile, OC 2-7 equivalents of kiselhaltig of a compound to N, O-bis (trimethylsilyl) acetamide, N, N'-bis (trimethylsilyl) urea, hexamethyldisilazane, N, O-bis (trimethylsilyl) trifluoroacetamide, N, Nf-bis (trimethylsilyl) carbodiimide, N- methyl N- (trimethylsilyl) acetamide or N-methyl-N- (trimethylsilyl) trifluoroacetamide, and in particular with in-situ hydrolysis in situ and with the addition of Δ4 -7-acylamido-deacetoxy-cephalosporan eras som sädan eller i form av ett alkalimetallalt.