IL32408A - Process for preparing 7-aminocephalosporanic acid - Google Patents

Description

IMPROVED PROCESS FOR PREPARING ACID The present invention provides an improved process preparing acid from sporin C and salts Cephalosporin which obtained by fermentation as described in British Patent has a low order of biological it is necessar to chemically convert cephalosporin C to more active This chemical conversion involves the cleavage the amido group in the of cephalosporin nucleus to obtain Processes for the production of by the chemical cleavage of the group of cephalosporin C or a salt thereof have previously been Patent 17054 describes process whereby cephalosporin cephalosporanic or a salt is treated with a reagent which induces deamination of the group and consequent cyclization of the resultant ium ion to the stabilized derivative of This cyclic intermediate is then hydrolytically cleaved to yield The reaction is conducted in a solvent which is preferably formic Useful reagents for converting sporin C to the cyclic intermediate include nitrosating carbocyclic and compound s that afford Upon completion of the reaction of sporin C with this reagent the solvent is by tion and the is recovered by the addition of water to the residue from the followed by precipitation of the from aqueous solution by the addition of a base to a pH of about Israel 18883 Unitod Patent describes an improve ment on this process in which the solvent comprises formic a haloloweralkane containing both hydrogen gen or a loweralkyl and the intermediate cyclic compound is treated with The methanol treatment may be effected by evaporation of the solvent followed ment of the residue with or the tion mixture may be added to a large volume of methanol out evaporation of the In either case the is then precipitated from solution by the addition of a The solvent system employed in the cleavage may be reused after recovery from the reaction This recovery of the solvent is simplified if the solvent evaporation method of product recovery is If the recovered by the addition of the reaction mixture to the formic acid is converted to methyl formate and cannot be it is necessary to completely remove the methanol from the if one was to use since methanol reacts with nitrosyl which the preferred nitrosating agent for use the it is desirable to recover the by the vent evaporation method heretofore the use of this method has resulted in lower yields of which more than offsets the lower processing cost resulting from the fied solvent We have now found that in the production of by treating cephalosporin C or a salt thereof with the ing a carbocyclic arenediazonium salt or a compound that affords positive halogen at a temperature of not more than in a followed by removal of the solvent from the reaction mixture to leave a and recovering the from the yields of are cyclizing reagent to the use of our improved process increased yields of are yet the solvent can be economically recovered reuse More this invention provides a process for the production of acid which prises treating cephalosporin C or a salt thereof with a re agent comprising a nitrosating a carbocyclic azonium or a compound that affords pos itive halogen at a temperature of not more than in a adding to the reaction a substance that destroys excess reagent and comprises a compound having one of the following formulas YSOg Hg HNHg X X S X I I X R wherein M is or an alkali Y is R taken alone R or a group having the formula R R C C R or two together with the atoms to which they are form a ring containing five or six carbon R is or aryl or is alkyl or aryl or aralkyl evaporating the solvent from the reaction mixture to leave a and recovering from the In a further more specific embodiment of the tion there is provided a process for the production cephalosporanic acid which comprises treating the sodium salt of cephalosporin C with nitrosyl chloride in a mixed solvent of formic acid and acetonltrile at a temperature within the range of about to adding ammonium sulfamate to the reaction mixture to destroy excess nitrosyl evaporat ing the dissolving the residue and adding ammonium hydroxide to a of about to precipitate the aminocephalosporanic Our process is Improvement on the prior solvent evaporation method of recovering In accordance with our improvement a substance that destroys unreacted cyclizing reagent is added to the reaction mixture to the tion of the As a result of the use of such an tive high yields of are The initial reaction step may be conducted as reaction may be conducted in formic acid it is preferred to use formic acid with a diluent as described in the latter This diluent is preferably acetonitrlle or a mixture of nitromethane and Other diluents Israel Patent 18883 are described in 3 J 933 The reagent employed in the cleavage reaction is preferably nitrosyl Other suitable reagents include nitrosating carbocyclic arenediazonium salts and stances affording positive halogen as described 17054 3 For we shall refer throughout this specification to nitrosyl chloride with the understanding that other reagents may be The molar ratio of nitrosyl ride to starting cephalosporin compound must be at least 1 1 and is preferably within the range of 1 to 2 The reaction is quite rapid at temperatures above about and is substantially complete upon completion mixing at these it will be necessary to allow the reaction to continue for only a short time such for 5 to 15 minutes after addition of nitrosyl ride is Lower temperatures may be used but longer reaction times are The reaction should be conducted at temperatures below preferably below and still more preferably at about such as between and At the completion of the reaction there is added a substance that reacts with and destroys the excess nitrosyl The excess of nitrosyl chloride can readily be culated in any given An amount of additive ly equivalent to the excess nitrosyl chloride may be We have found yields of to be optimal when about 9 Some yield improvement is obtained when more or less than this optimum amount of additive is The practical range of additive is about based on excess nitrosyl chloride The substances that will destroy the excess reagent and may be used as the additive in our improved are compounds represented by the following Sulfamates Sulfamides Sulfonylhydrazldes Semicarbazides and thiosemicarbazides Carbazides and X II thiocarbazides S II Thioureas Carbamates and X II thiocarbamates Carbazates and X thiocarbazates Hydrazines Hydrazides and X II thlohydrazides R Unsaturated hydrocarbons wherein R and have the same meaning as Specific examples of suitable additives include monium potassium tetramethylammonlum methane ethyl benzyl ethyl ethyl phenyl methyl ethyl ethyl meth ethylenedlamlne tetraacetlc acid and It will be noted that the additives we have found to be effective contain one of the following groups in the 0 0 II II II II 0 6 suggests that it is the presence of such a group that is responsible for the beneficial results we have It is to be understood that comppunds containing other groups that destroy the excess cyclizlng reagent might also be Our invention lies in the discovery that improved yields result from the addition of a material that destroys unreacted and not in the discovery of which materials will troy this reagent After the additive has been added to the the solvent is removed by preferably at reduced The solvent so removed may be recovered and reused in the The evaporation of the solvent leaves a viscous residue from which may be Recovery of from the viscous residue may be Israel accomplished in any of a number of In Patent 17054 the residue is dissolved in water and the is then precipitated by the addition of an alkylene the residue may be treated with an alkylene oxide out first being dissolved in water or an The alkylene oxide is preferably in solution in an inert solvent such as a diluent of the type used in the cleavage A solid product is obtained from the residue in this The ular manner in which the is recovered from the residue is not to our process In a particularly preferred embodiment of cess the sodium salt of cephalosporin C is treated with syl chloride in a mixed solvent of formic acid and trlle at a temperature between and At the tion of the reaction the excess nltrosyl chloride s destroyed by the addition of ammonium the solvent is removed by and the residue is dissolved in is then precipitated from the aqueous solution by the addition of ammonium hydroxide to a pH of about 3 Our improved process will be further illustrated by the following In all the examples the purity of the product was determined by ultraviolet spectroscopy and the yield figure corrected to reflect the yield of 100 percent The cephalosporin C referred to in the examples is actually the sodium salt Example I A solution of 28 of cephalosporin C a mixture of of formic acid and 100 of acetonitrlle was cooled to and of nltrosyl chloride in of acetonitrlle was added over 4 mixture was red at for an additional 11 minutes and then of ammonium was added gradually with cooling to keep concentrated under The resulting viscous residue was dissolved in 200 of ice water and the pH was adjusted to with 20 of 28 percent ammonium After ing aqueous solution to stand at for one hour the was collected by The product was washed with 50 of ice water followed by 100 of acetone and dried in a vacuum over at was obtained in 7 percent Example II Cephalosporin C was allowed to react with nltrosyl chloride as in Example Prior to evaporation of the solvents 8 of ammonium sulfamate was The cous residue from the evaporation was slurried with 300 of acetontlrile containing 80 of propylene The slurry was allowed to stand for 15 minutes and the insoluble product was collected by filtration and washed with 100 of acetonitrile The yield of dried was 53 Examples III XXXII A series of runs was made using 28 of sporin C and of nitrosyl chloride in Examples XXI in a mixed solvent formic acid and In Examples III VII no additive was added prior to evaporation of the solvent while in Examples VIII XXXII an additive was The residue from the evaporation was taken up in water or an alcohol and the was by the addition of a base or an alkylene The results are presented in Table In Examples XIII XVII an amount of water ranging from 52 to 180 was added after of the ammonium As can be Examples III the yields an additive is used the yields from 40 percent to 57 Examples XXXVI In these examples cephalosporin C was treated with nitrosyl as in the preceding examples employing formic acid and a diluent as In all but Example 28 of cephalosporin C and of nitrosyl chloride the last example double these amounts were The was recovered from the evaporation residue by the addition of propylene oxide in acetonltrile as in Example Results are summarized in Table Re sid ue Example Additive m 70 1 0 None 150 IV 70 1 None I V 70 210 None 150 VI 100 210 None 150 VII 100 210 None 150 VIII 100 210 5 150 IX 100 210 5 I XII 100 210 150 XIII 100 210 5 XVI 100 210 XVII 100 210 100 XVIII 100 210 1 Table 1 Example XIX 100 210 XX 100 210 S03 0 30 s XXI 80 210 200 0 XXII 100 200 S XXIII 100 200 4 200 XXV 150 200 s XXVI 150 200 XXVII 100 200 2 200 XXVIII 100 200 10 200 XXIX 100 200 200 Table 1 HCO CH Residue Example 0 II 100 200 10 200 XXXII 100 200 10 200 Table 2 Example Residue XXXIII 100 5 30 prop CH C wash with 6 XXXIV 100 XXXV 100 XXXVI 200 We have also found that additional beneficial results are obtained in addition to an additive of the type scribed there is also added an acid that is stronger than formic This acid may be either organic or Examples of such acids include sulfuric phosphoric trichloroacetic oxalic sulfonic and toluenesulfonic Methanesulfonic acid particularly The amount of acid to be used is within the range of about lents per mole of nitrosyl chloride employed in the The acid is added with the additive prior to the evaporation The use of an acid will be further trated by the following Example XXXVII Example I was repeated except that instead of the ammonium sulfamate there e added of azide and 10 of methanesulfonic After concentration of the reaction mixture the residue was dissolved in 200 of ice The pH was adjusted to by the addition of 25 of ammonium The yield of In Example XXVI when thiosemlcarbazide was used alone the yield was Other examples in which an acid was used with the additive are listed in Table In virtually every case the yield using the combination was substantially higher than when the additive was used In it appears that the greatest benefit to be derived from the use of an acid is with those additives which do not result in large yield creases when used those which do not produce yields in excess of about 40 percent when used CH Residue Example XXXVIII 100 4 200 0 it XXXIX 100 4 200 CH 100 10 200 10 100 0 II XLI 100 200 0 XLV 100 200 10 Table 3 CH Residue Example S 100 200 200 10 200 200 I insufficientOCRQuality

Claims (7)

32408/2

1. A process for the production of 7-aminocephalo-sporanic acid (7-ACA) which comprises reacting cephalosporin C or a salt thereof with a reagent comprising a nitrosating agent, a carbocylic arenediazonium salt, or a compound that affords positive halogen at a temperature of not more than 0 in a solvent 60 C ./ evaporating the solvent from the reaction mixture to leave a residue, followed by a hydrolytic cleavage to yield said 7-ACA and recovering said 7-ACA from the residue the improvement consisting of adding to the reaction mixture prior to the evaporation step a substance that destroys excess of the said reagent and is selected from a compound having one of the following formulas MS03 H2 YS02NH2 YS02NHNH2 X R2N-C-NHNH2 X R2NNH-C-NHNH2 S R2n-C-NH2 X H2 -C-0R ' X H2NNH-C-0R' 32408/2 R ''-C-kflNH2 Z2C=CHZ wherein M is hydrogen, NR^, or an alkali metal: X is oxygen or sulfur; T is R or R2; Z, taken alone, is R or a group having the formula or two Z's together with the atoms to which they are attached form a. ring containing five or six carbon atoms: R is hydrogen, Cj-C^alkyl, or c6-c12 aryl or aralkyl ; and R is C^-C^ alkyl or C^-C^ ary or aralkyl.

2. The process ot claim 1 , wherein the reagent is nitrosyl chloride.

3. The process of claim 1 or 2, wherein the substance employed to destroy excess reagent is ammonium su Ifamate .

4. The process of any If claims 1 to 3, wherein the solvent is a mixture of formic acid and acetonitrile or 4 ί 32408/2 a mixture of nitromethane and 2-nitropro ane .

5. A process for the production of 7-aminocephalo sporanic acid which comprises reacting the sodium salt of cephalosporin C with nitrosyl chloride in a solvent which is a mixture of formic acid and acetonitrile at a temperature within the range of -10° to +5°C., adding ammonium sulfamate to the reaction mixture to destroy excess nitrosyl chloride, evaporating the solvent, dissolving the residue in water, and adding ammonium hydroxide to a pH of 3.5 to precipitate the 7-aminocephalosporanic acid.

6. A process for the production of 7-aminocephalosporanic acid, substantially as herein described with particular reference to Examples II and VIII-XXXII.

7. 7-aminocephalosporanic acid when obtained by the process of any of claims 1