IL30392A - Process for the preparation of 7-aminocephalosporanic acid and its derivatives - Google Patents

Description

PROCESS FOR THE PREPARATION OF INOCEPHALOSPORANIC ACID AND ITS DERIVATIVES This invention relates to the tion of in to a process for producing acid a d acid fication may be obtained by the of Cephalosporin is described and claimed in fication No 957 569 it may be obtained by the catalytic hydrogenation of Cephalosporin followed by acid hydrolysis of the bydrogenated It is known to e the group of and its analogues which differ in the nature of the substituent the to produce losporins other than the original which cephalosporins may also have antibiotic activity This technique makes it possible to substitute various alternative side chains in the for the side chain of Cephalosporin This procedure i for in Specifications 955695 976225 988527 and Several methods are known for the deacylation of A particularly useful technique comprises converting the o group in a cephalosporin into an imino halide converting the latter into an and then hydrolysing the imino ether t o obtain a must be taken to protect the acid group in the cephalosporin during deacylation and it is known to the group by esterification prior to formation of the imino halide and to remove the ester blocking group after deacylation for hydrolysis or This cess is for in and to published Specifications 6401421 and In the free amino and carboxylic acid groups of Cephalosporin C or a derivative thereof of the in which E is an esterified hydroxyl group or in which R and the group of the group replaced by a lactone oxygen atom are suitably protected prior to This protection is preferably effected by converting Cephalosporin C into the ester of Cephalosporin T compound with protected amino and acid groups is then treated with an agent forming an imino halide group at the Typical imino agents such acid halides as phorus or phosphorus The imino halide is converted into an imino ether by treatment with an in particular with an such as methanol or The formation of the halide the imino ether is preferably carried out in the presence of a tertiary such as triethylamine or dimethylaniline In the next the imino ether is hydrolysed water in the presence of an acidic or basic catalyst to form the corresponding of the Examples of suitable catalysts are mineral such as phuric phosphoric or hydrochloric or organic such as trifluoracetic acid or To obtain the corresponding compound free the blocking group must then be removed by hydrogenolysis or acid Specification describes an imino ether deacylation process similar to that but starting specifically from dibenzhydryl After the treatment of the dibenzhydryl ester of trifluoracetic the latter compound is then converted to by reaction with a tertiary amine in a polar is obtained by sation from the have now developed an improved process for cephalosporins can give as good or better yields of the desired products than the processes described in and and which avoids the necessity of carrying out a separate step to remove the protecting According to the present we provide a process for the preparation of a compound of the formula COC wherein R is hydrogen or an esterified hydroxy1 which comprises treating a ester of the wherein R is as specified is an acyl group having any functional groups and is a si yl with an agent to form a preferably at a temperature below treating the halide with an agent to form a preferably at a temperature below and hydrolysing or alcoholysing the product obtained to split the ether and to liberate the compound of formula The compounds of formula prepared by the process according to the invention may he used for the preparation of a compound of formula a process which comprises introducing an group on to the group of the compound of formula in R is an group the group present in the starting material used for the of the compound of formula The R group is preferably introduced by the compound of formula if after protection of the acid with the appropriate acid In a further aspect of the we provide a ceutical comprising a compound of formula or an obvious chemical equivalent when prepared by the above specified together an inert Suitable starting materials which may be used to form the of formula above are Cephalosporin C and its and other losporanic or derivatives such as which ha3 the and salt of a or derivative a sodium The feature of the ing is that it must be capable of being converted into an The ester may be by the use a variety of such as compounds having the formula in which X is a halogen an amino or an and are carbon such as radicals or X is a halogen one or more of and in be a halogen atom or one of them may be Bifunctional silylating such as and trifunctional ating such as can also be are icularly and can also be other suitable silylating agents are ncetamides or The halide can be prepared from the silyl ester by methods by reaction an acid as phosphorus pentachloride or phosphorus oxychloride however it is preferable that a temperature below should be Suitable solvents for use in this stage of the process for and nitrome During the conversion of the halide to the or during the cleavage of the imino the group is also split off and the free acid is The imino ether way also he split as it is during the of the halide with an The of the imino halide may he carried out with hut is preferably carried out on alkanol having three or more carbon and vantageously at a temperature below To the acid liberated during the a tertiary amine a dimethyla lut or is preferably added to the reaction The of tertiary amine used may be such that only a portion of the acid formed is bound by the acid binding the amount of tertiary amine used is such that the pH of the reaction mixture would than 1 if only and no further ising were added the amount of ary amine calculated for and a small excess of halogenosilane is preferably less than four and advantageously less than three In order that the invention may be more fully understood the following Examples are given by way of illustration g of the sodium salt of cephalothin in 35 of to ml of dimethylaniline had been were reacted with ml of diiaethyldichlorosilanc to produce the ester After cooling this solution to about g of were in consequence of which the rose to For hours the temperature was kept at after which the mixture was then cooled to ml of was then added to over about 15 of The was then maintained at After about the reaction mixture was poured into a mixture of of water and ml of methanol after which the of the mixture was adjusted to with the aid of ammonium After about 20 hours the was filtered at Purification of the precipitate was effected by dissolution in water at pH and treatment with active After to the aqueous solution was added times its volume of after ihich the pH was adjusted to with the aid of hydrochloric The crystals formed then filtered at about after 2 hours storage to yield g of acid yield of II g of anhydrous cephalosporin were suspended in 42 of methylene chloride and of triethylamine 5 of tri and ml of dimethylaniline added thereto to the corresponding After a time of 1 the was cooled to about after which S of phosphorxs pentachloride were added with thorough The temperature then rose to about After hours reaction at this the mixture was cooled to about and ml of dimethylaniline and JO ml of rapidl added with in consequence of which the ture again The solution was then kept at for the reaction mixture with thorough into a mixture of of water and of after which the of the mixture was adjusted immediately to with the aid of ammonium After about 20 hours storage at the precipitate was filtered and washed methylene chloride and Purification of the cr stals was effected by dissolution in water at pH treatment with active After to the aqueous solution was added times its volume of after which the pH was adjusted to with the aid of 4 hydrochloric After 2 hours the crystals were filtered off at about to yield g acid yield about g of C was suspended in ml of methylene and ml of a weight solution of triethylamine in methylene chloride and of dimethylaniline added The ally clear solution was then reacted with ml of silane to produce C having both carboxylic After a reaction of the ture was cooled to and g of continued the temperature was kept at for hours and then the mixture was to A mixture of ml of meth laniline and 5 of was then rapidly added to the The of the mixture was sequently kept at for 2 hours and the mixture then poured into a mixture of JO ml of water and ml of The pH of the solution was then adjusted to with the aid of ammonium After 20 hours storage at the precipitate was washed with methylene and and then The yield of crystals was g Example IV g of the salt of acid was in 18 of chloride after the addition of ml of dimethylaniline was reacted with 1 ml of to produce the corresponding After 1 the mixture was cooled to and g of For hours the temperaturp of the was kept at and then lowered to To the cooled a solution of of dimethylaniline and 12 ml of ol was and subsequently the temperature is kept at for The reaction mixture was then poured into a mixture of of water and of and adjusted immediately to with aid of After about 20 hours storage at the precipitate was washed with methylene end and The yield of crystals was g of acid insufficientOCRQuality

Claims (1)

1. WHAT CLAIM A process for the preparation of a compound of the formula COOH wherein R is hydrogen or an esterified which comprises treating a ester of the formula wherein R is as specified is an acyl group having any functional groups present and is a with an agenu to form a halide at a temperature below treating the o halide with an agent to form a o ether at a temperature hydrolysing or alcoholysing the product obtained split the imino ether and to liberate the compound of formula A process according to claim in which the agent is an acid A process according to claim in which the acid halide is phosphorus pentachloride or phosphorus A process according to any of claims 1 to in which formation of the imino halide is effected in the presence of a tertiary A process according to any of claims 1 to in which formation of the halide is effected below A process according to any of claims 1 to in which the imino agent is an A process according to claim in which the alcohol is an A process according to claim which the alkanol is methanol or A process according to claim the alkanol contains at least three carbon A process according to any of claims 1 to n which formation of the imino ether is effected in the presence of a tertiary A process according to any of claims 1 to in which formation of the ether is effected below A process according to claim 4 or in which the tertiary amine is or A process according to any of claims 1 to in the ester of formula is prepared by the corresponding free or a salt with a silylating agent of the formula wherein X is a halogen and which may be the same or are hydrocarbon radicals or halogen one of or may be a hydrogen A process according to claim in which the hydrocarbon radicals are or aryl process according to claim in which the silylating agent is trimethylchlorosilane A process according to claim in which the silylating agent is a dialkyld halosilane or an A process according to claim in which the silylating is 18c A process according to any of claims 1 to in which the ester of formula is prepared by reacting the corresponding free or a salt with a silylating agent of the fo o group or which may be the same o are hydrocarbon process according to claim in which the hydrocarbon radicals are alkyl or A process according to any of claims 1 to in which the ester of formula is prepared by reacting the corresponding free or a salt with a an a silylacetamide or a A process for the preparation of cephalosporanic acid or a derivative thereof of formula as specified in claim substantially as herein described in any of the A process for the preparation of a compound of the formula as specified in claim 1 which prises treating a ester of the formula as specified in claim 1 an agent to form a halide treating the halide with an agent to form a and hydrolysing or alcoholysing the product obtained to split the ether and to liberate the compound of Λ of as specified in or an obvious chemical when prepared by the process as claimed in of claims 1 to A process for the preparation of a compound of formula or an obvious chemical equivalent which comprises introducing an group on to the group of a compound as claimed in claim if after protection of the acid wherein is an acyl group other than the group present the s arting material used for the preparation of the said compound claimed in claim A process according to claim which comprises acylating a compound as claimed in claim 23 with an acid A compound of the formula as fied in claim or an obvious chemical equivalent when prepared by the in 2 or A phar aceutical composition comprising a as in claim 26 together with an 17th July 1968 AGENT FOR APPLICANTS WHAT CLAIM A process the preparation of a compound of the formula COOH wherein R is hydrogen an esterified which comprises treating a ester of the formula wherein R is as specified R is an acyl group having any functional groups present and is a with an to a halide at a temperature below treating the halide with an agent to form a ether at a temperature below and hydrolysing or alcoholysing the product obtained to split the ether and to liberate the compound of formula A process according to claim in which the agent is an acid A process according to claim in which the acid halide is phosphorus or phosphorus Λ process according to any of claims 1 to in wi ch formation of the imino halide is effected in the of a tertiary A process according to any of claims 1 to in which formation of the iraino halide is effected below A process Recording to any of claims 1 to which the imino agent is an A process according to claim in which the alcohol is an A process according to claim which the alkanol is methanol or A process according to claim in which the alkanol contains at least three carbon A process according to any of claims 1 to in which formation of the imino ether is effected in the presence of a tertiary A process according to any of 1 to in which formation of the imino ether is effected below Λ to claim or in which the tertiary amine is triethylamine A process according to any of 1 to in the ester of formula is prepared by reacting the corresponding free or a salt with a silylating agent of the formula wherein X is a halogen and which may be the same or are hydrocarbon radicals or halogen or one of a hydrogen A process according to claim in which the hydrocarbon radicals are or A process to claim in which the silylating agent A process ac ording to claim in which the silylating agent i a dialkyldihalosilane or an A process according to claim in which the silylating ngent i process accjording to any of claims 1 to in the ester of formula is prepared by reacting the free or a salt with a silylating of the formula wherein is an group or a and R and may be the same or are hydrocarbon process according to claim in which the hydrocarbon radicals are alkyl or A process according to any of claims 1 to in which the ester of is prepared by reacting the corresponding free or a salt with a an a silylaceta ide or a A process for the preparation of cephalosporanic acid or a derivative thereof of formula as specified in claim substantially as herein described in any of the A process for the preparation of a compound of the formula as specified in claim 1 which prises treating a ester of the formula as specified in claim 1 with an agent to form a imino treating the halide with an agent to form a and hydrolysing or the product obtained to split the imino ether and to liberate the of Λ of formula as specified in claim or an obvious chemical equivalent prepared by the as claimed in any claims 1 to A process for the preparation of a compound of formula or an obvious chemical equivalent which compr introducing an R group on to the group of a compound as claimed in claim if desired after protection of the acid wherein R is an group other than the group present in the starting material used for the preparation of the said compound as claimed in claim A process according to claim which comprises acylating a compound as claimed in with an acid A compound of the formula as fied in claim or an obvious chemical equivalent 1 when prepared process in claim or A pharmaceutical composition comprising a compound claimed in 26 together with an 17th 1968 AGENT POR APPLICANTS insufficientOCRQuality