IL35901A - Process for producing 6-aminopenicillanic acid - Google Patents

Description

PROCESS FOR ACID The present invention relates to a process for producing acid of the formula from a acid of the general formula R wherein signifies a hydrogen atom or a substituted or unsubstituted or aryloxy by a chemical acid referred to as per se does not show any significant biological activities such as but is an important compound as the starting material for producing penicillins An object of this invention is to provide a novel chemical process without using enzymatic process for producing containing no harmful proteins from acids Quite few reports been published concerning chemical processes for producing from acids Among the 69 19145 and Patent disclose a process which is characterized by protecting the carboxyl group by converting into an This process is considered relatively but is not satisfactory from an industrial It is known that there is a process for paring a imino chloride by reacting a acid amide with phosphorus pentachloride Chemische 1231 in preparing a acid ester Japanese Patent Publication acid 112959 and a acid ester ja 607 there has already been utilized a process which is characterized by reacting an imino chloride with an alcohol to form an imino and then splitting the imino ether grouping by As a result of a of researches on the protection of the carboxyl group at of the present inventors have found out a method for protecting the carboxyl group by conversion into a mixed acid Based on this the present invention has been That the present invention relates to a process for producing which is characterized by reacting a compound of the general formula or a salt thereof with a halogenated compound of the general R2 signifies a residue of the protecting group and X signifies a halogen in the presence of an converting the reaction product into a corresponding imino halide by reacting with an imino reacting said imino halide with a hydroxyl compound of the general signifies a substituted or unsubstituted or cycloalkyl and then hydrolyzing the reaction According to this while any acylamidopenicillanic acid may be used as the starting suitable from the practical viewpoint are salts of penicillins obtained by the biological Examples of such penicillins include those in which the acyl group is derived for aliphatic carboxylic acids such as and aralkyl carboxylic acids such as and phenylacetic and aryloxyacetic These penicillins are ordinarily used as a tertiary amine alkali metal alkaline earth metal The compounds of the formula used in this invention for introducing the protecting group include the following Compounds of the general formula wherein each of and which may be the same or signifies or unsubstituted or aralkyloxy group or a halogen and and may jointly form a signifies phosphorus and X signifies a halogen compounds of the general wherein each of and which may be the same or signifies a or unsubstituted or aralkyloxy group or a halogen and and may jointly form a or or and may jointly caption form or and M signifies a provided that when is a silicon atom all of and are halogen or at least one of and forms a pounds of the general wherein signifies a halogen atom or a substituted or unsubstituted or aralkyloxy each of and signifies a halogen and and may jointly form a ring or or M signifies a phosphorus and X signifies a halogen Examples the compounds of the formula include Examples of the compounds the formula include halocarbonc acid esters suh as silicon compounds such as Examples of the compounds of the formula include phosphorus compounds such as Among the compounds of the formula used in this had been known as a halogenating agent hut not as a tecting group until the present inventors have made it clear for the first time that these compounds have cellent properties as a protecting group It is interesting that which had been as have been found useful also as a protecting When a compound of the formula contains two or more halogen atoms in its it is not clear whether all of the halogen atoms are included in the formation of a mixed acid anhydride or For in the case of phosphorus when to mol of this compound was used for one mol of the compound of formula an extremely high yield may be From this fact it may be assumed that the reaction proceeds according to the following scheme In carrying out the present a compound of the formula or a salt thereof is dissolved or suspended in an inert solvent such for e methylene ethylene chloroethylene ethyl or the and an agent is added As the agent may be trialkylamines pyridine and its quinoline and its Among these and are especially to the mixture at room temperature or at a temperature below is added a compound of the formula in excess of the amount calculated from the number of halogen to form a mixed acid It may sometimes be necessary to heat the mixture at a temperature above room depending upon the reactants To the resulting solution of mixed acid anhydride is added at room perature or at a temperature below an imino forming reagent in excess of the equivalent As the imino may be for phosphorus oxychloride phosphorus pentachloride phosphorus tribromide Among these compounds phosphorus pentachloride and p ogene are particularly The optimum conditions of this reaction are variable according to the kind of solvents and agents For when methylene and phosphorus pentachloride are the reaction is complete in 2 to 3 hours at a temperature of to The resulting imino halide is reacted with a compound at a temperature below As the compound of formula there are used benzyl Among these especially preferred are isoamyl The compound of the formula is used in an amount of 3 to 20 mols per mol of the compound of formula preferably together with a small amount of a tertiary amine such for or the The formation of imino ether is complete in to 3 hours at a reaction temperature of to by adding dropwise an alcohol into the reaction mixture or by adding dropwise a solution of imino chloride into an alcohol and the imino ether is formed almost quantitativel Upon addition of ice water with stirring to the thus obtained solution of imino there occur simultaneously both hydrolysis of the imino ether and gradual removal of the group to regenerate a carboxylic Then the reaction mixture is neutralized with a basic substance such for trieth lamine aqueous ammonium an alkali metal hydrogencarbonate an alkali metal an alkali metal or the to a pH of about the isoelectric point of the deposit The crystals are collected by and washed with aqueous aqueous aqueous or the to obtain crude crystals of Under the plate crystals of purity may be obtained in a yield of about 90 which may be used without further purification as the starting material for synthetic As mentioned above in the present invention provides a process for producing penicillanic acid by chemical means from penicillanic acids which comprises blocking the carboxyl group of the latter with a novel protecting group heretofore never been and conducting a series of reactions through an imino then and finally straight to acid in the present process acid containing none of proteins may be obtained in high yields by simplified procedures from inexpensive starting materials These advantages make the process extremely valuable for the The invention is further illustrated below in detail with reference to Example 1 Grams of a dry fine powder of technical grade was added to 30 ml of methylene chloride containing ml of and the mixture was cooled to To the stirred mixture was added wise a liquid mixture of g of phosphorus trichloride and 5 ml of methylene After the the mixture was further stirred for 20 to minutes while being cooled in In the almost all of the salt of which is the ing disappeared and different crystals of potassium chloride were To this while being cooled at a temperature below and stirred was added at a time g of which had been finely ground just before the the powder adhered on the inlet wall having been washed down with a small amount of methylene Since the reaction was accompanied by moderate evolution of care was taken so that the temperature might not rise above After ing stirred at to for about 2 the mixture was cooled again to a temperature below To the vigorously stirred mixture was added dropwise a mixed solution of 1 ml of and ml of Since heat was evolved at the beginning of the the dropping rate of said solution was controlled so as to keep the temperature below After completion of the the mixture was stirred at to for about 2 and then the cooling bath was removed while stirring was continued until the temperature of the reaction mixture rose to to Then the mixture was poured into 30 ml of ice water0 The reactor was washed with 10 ml of 60 and the washings were added to said reaction mixture in ice The combined mixture was vigorously stirred while being cooled in whereupon the pH of the ture began to After about 10 to 20 ammonium carbonate was added thereto in small portions to raise the pH At a pH of about crystals began to deposit The pH was finally adjusted to and the solution was kept overnight in an ice cabinet The crystals were washed several times with cold 60 then with and There was obtained g of plate crystals ing at 190 The thin layer and infrared absorption spectrum of the product showed agreement with those of the standard The purity was found to be by the hydroxylamine method and alkali was used in place of to obtain the same Example 2 The procedure of Example 1 was repeated under the same reaction except that mol of each halogenated phosphorus compound shown in the following table was used per mol of the potassium instead of phosphorus was obtained in yields of 74 to 89 as shown in the table was used in place of to obtain comparable results Example The procedure of Example 1 was repeated under the same reaction except that of each halogenated phosphorus compound shown in the following table was used per mol of the potassium in place of phosphorus was obtained in yields of 76 to 90 as shown in the Example 4 A cold ethylene chloride solution containing 2 g of phosgene was added to a mixture comprising g of technical grade 5 ml of anhydrous and ml of ethylene which had been cooled in After being stirred for about one hour in an ice the reaction mixture was cooled to and g of a fine powder of phosphorus pentachloride was After being stirred at to for 2 the mixture was again cooled to and thereto was rapidly added dropwise a cold solution of ml of triethylaaine in 30 ml of isopropanol while maintaining the temperature below The mixture was stirred at to for 2 to 3 and then the cooling bath was When the temperature reached the mixture was poured into 30 ml of ice water with After 20 pH of the mixture was gradually adjusted to with ammonium and then the mixture was kept overnight in an ice The crystals deposited were collected in an ordinary and dried to obtain g of the product Example In place of phosphorus trichloride in Example mol of phosphorus pentachloride per mol of the was The reaction was ducted at a temperature below and immediately after the disappearance by dissolution of a greater part of the crystals of the mixture was cooled to a temperature below After addition of equivalent mol of phosphorus the cedure of Example 1 was except that the hydrolysis was carried out at a pH of lower than 1 for about minutes The yield was 67 Example 6 In place of phosphorus trichloride in Example mol of phosphorus oxychloride per 2 mol of was The reaction was ducted with stirring at a temperature of to and immediately after the disappearance by dissolution of a greater part of the ture was cooled to After addition of phosphorus the procedure of Example 1 was except that the hydrolysis was carried out at a pH of lower than 1 for about 30 The yield was Example 7 The procedure of Example was repeated under the same conditions except that compounds of shown in the following table used in place of phosphorus oxychloride in Example The yields were 2 to 83 as shown in the Example 8 The procedure of Example 1 was except that was used in place of phosphorus trichloride in Example 1 and the hydrolysis was carried out at a pH of lower than 1 for about The yield was 72 Comparable results were obtained when was used instead of phosphorus Example 9 In place of the compounds of phosphorus in Example to of a silicon dichloride compound per mol of the was and the reaction and other treatments were carried out in a manner similar to that in Example was obtained in yields of 72 to 86 as shown in the ing Example The procedure of Example 1 was repeated under the same except that mol of silicon monochloride compound shown in the following table was used per mol of the in place of phosphorus trichloride in Example was obtained in yields of 74 to 86 as shown in the table Example The procedure of Example 1 was exce that mol of silicon tetrachloride per mol of the was used in place of phosphorus trichloride and the hydrolysis was carried out at a pH of less than 1 for about The yield was 47 insufficientOCRQuality

Claims (1)

1. Claimsί 1. A process for producing 6-aminopenicillanic acid, which comprises (A) reacting an acylamino acid of the formula wherein R* is hydrogen or residual group of organic carboxylic acid having 1 to 17 carbon atoms, or a salt thereof with a halogenated compound in the presence of on acid-binding reagent to protect the carboxyl group of the said acylamino acid by forming a mixed acid anhydride grouping, said halogenated compound being of the formula, 2 R'\ wherein X is halogen and R is selected from the group consisting of / H- R" (wherein each of R' and R", which may be the same or different, is halogen; halogen substituted or unsubstituted alkyl, alkoxy, or alkylthio, each having 1 to 7 carbon atoms; aryl, aralkyl, aryloxy, or aralkoxy, each having 1 to 4 alkyl carbon atoms and wherein the alkyl moieties of R* and R" may be joined to form aid n with ¾ and K- is phosphorus; R* R"^——— H- (wherein each of E*, Rw and Rn', which may be the same or different, is halogen; halogen substituted or unsubstituted alkyl, alkoxy, or alkylthio, each having 1 to 7 carbon atoms aryl, aralkyl, aryloxy, or aralkoxy, each having 1 to 4 alkyl carbon atoms; and R' and R" may jointly form a ring, and M is phosphorus), - (wherein each of R', R" and R'" , which may be the same or different, is halogen; halogen or alkoxy substituted or unsubstituted alkyl, alkoxy, or alkylthio, each having 1 to 7 carbon atoms; aryl, aralkyl, aryloxy, or aralkoxy, each having 1 to 4 alkyl carbon atoms; and Rp and R" may jointly form a ring, or R" and R1*' may form =0 or =S, and Mjs silicon, or carbon provided that when M is silicon all of R', R" and R'" are halogens or at least one of E*, R" and R,, forms M~ (wherein 1 is halogen; halogen or alkoxy substituted or unsubstituted alkyl, alkoxy, or alkylthio, each having 1 to 7 carbon atoms; aryl, aralkyl, aryloxy, or aralkoxy, each having 1 to 4 alkyl carbon atoms, each of R", R"' and Rww is halogen, and R" and R* * may jointly form a ring, or =0 or =S; and M is phosphorus), (B) converting the resulting acylamino acid having its carboxyl group protected into a corresponding imino halide by reaction with an imino halide-forming reagent under anhydrous - 2Q - « «» , J*. conditions at room temperature or a lower temperature as low as below 0°C, (C) reacting at a temperature not higher than -10°C the said imino halide with an alcohol of the formula, R3-0H wherein alkyl of 1 to 12 carbon atoms, aralkyl having 1 to 7 alkyl carbon atoms, cyclohexyl, hydroxy- alkyl of 2 to 12 carbon atoms, alkoxyalkyl of 3 to 13 carbon atoms, monocyclic aryloxyalkyl having 2 to 7 alkyl carbon atoms, monocyclic aralkoxyalkyl having to 7 alkyl carbon atoms, or hydroxyalkoxyalkyl of 4 to 7 carbon atoms, to form a corresponding imino ether, and (D) reacting the imino ether under acid conditions with water, a hydroxyl-containing compound, or a hydroxyl- containing solvent to form 6-aminopenicillanic acid of the formula, 2. A process according to Claim 1, wherein the a ylamino acid is selected from the group consisting of biosynthetic penicillins. 3. A process according to Claim 2, wherein the biosynthetic penicillins are penicillin G- and penicillin V. 4„ A process according to Claim 1, wherein the imino halide-forming reagent is selected from the group consisting of PCI5, PB 5, PBr^, POCI3, and C0C12. 5. A process according to Claim 4, wherein the imino halide-forming reagent is PC1^0 6c A process according to Claim 1, wherein the halogenated compound for protecting the carboxyl group of acylamino acid is selected from the group consisting of C0C12, CH^OSiCl^, n-C^gOSiCl^ , (CH3O) 2SiCl , (C2H50)2SiCl2, (CH30CH2CH20)2SiCl2, (C1CH2CH20) 2SiCl2, (n-C4HgO)2SiCl2, CH3 (CH50)SiCl2, CH3 (C2H50 )SiCl2 , CH3(ClCH2CH20)SiCl2, (CH^Oj^SiCl, CH3 (CH3O) 2SiCl, 7. A process according to Claim 1, wherein the halogenated compound for protecting the carboxyl group of acylamino acid is selected from the group consisting [halogen of (R'0).2SiCl2 (wherein R' is^substituted or unsubstituted lower alkyl), ROPCI2 (wherein R' is the same as in the preceding formula), PCI3, POCl^, PGI5, and C0C12. 8. A process according to Claim 7, wherein the halogenated compound for protecting the carboxyl group of acylamino acid is a compound of the formula, R'0PC12 v halogen (wherein R' is a substituted or unsubstituted lower alkyl group) or PCI3. 9„ A process according to Claim 8, wherein the halogenated compound for protecting the carboxyl group 10. A process according to any one of Claims 1 to 5, wherein the acid-binding agent is selected from the group consisting of Ν,Ν-dimethylaniline , 2, 6-lutidine , pyridine, quinoline, and triethylamine . ri A process according to Claim wherein the acylamino acid having its carboxyl group protected is reacted with the imino halide-forming reagent at a temperature of about to A process according to Claim wherein the imino halide is reacted with an alcohol at a temperature of about to °C. A process according to Claim wherein the alcohol is selected from the group consisting of methanol, n-propanol, and n-butanol. A process according to Claim wherein the acylamino acid having its carboxyl group protected is reacted with the imino halide-forming reagent at a temperature of about to -40°C, and the resulting imino halide is reacted with an alcohol selected from the group consisting of methanol and n-butanol at a temperature of about to -50°C. j acid according to claim 1f A process for producing -aminopenicillanicV which comprises (A) reacting penicillin G-potassium or penillin V-potassium with phosphorous trichloride in a solvent selected from, the group consisting of methylene chloride, chloroform and ethylene chloride, in the presence of Ν,ϋΓ-dimethylaniline to protect the carboxyl group of the said penicillin, (B) reacting the resulting acylamino acid having its carboxyl group protected with phosphorous pentachloride at to -40°C to form the imino halide thereof, (C) reacting the imino halide with methanol or n-butanol, containing a small amount of N,N-dimethyl-aniline, at to °C to form the imino ether and then (D) hydrolyzing the imino ether under acidic condition with water to obtain 6-arainopenicillanic acid . Attirratfy for Applicants