DE2062925A1 - 6-aminopenicillanic acid prepn - Google Patents

Abstract

6-APA is prepd by reacting an N-R1CO substd penicillanic acid (where R1 = H or 1-17C carboxylic residue) with a cpd. R2X (where X = halogen, R2 is R'R"M, where R' and R" = opt substd. alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, aralkyloxy or halogen, or R' and R" together form a ring, and M = B, Al or P; or R'R"R'"M', where R'" is as R' or together with R' or R" forms = O or =S, and M' = C, Si, S or Ge, with the proviso that when M = Si, R'=R"=R'" = halogen or at least one forms a =C-O-Si= link, or R'R"R'"R''"P, where r' is as above and R", R'" and R"" are halogen, or R= and R'" together form a ring or =O or =S; or R'SO2-, where R' is as above but not halogen), in presence of acid binder, converting the mixed anhydride formed to the corresp. iminohalide; reacting this with an alcohol R3OH (where R3 is opt substd alkyl, aryl, aralkyl, or cycloalkyl) to form an imino ether; and acid hydrolysing this.

Description

"Process for the preparation of 6-aminopenicillanic acid The present invention relates to a chemical process for the preparation of 6-aminopenicillanic acid of the formula (II) from 6-acylamidopenicillanic acid of the general formula (I) wherein R 'is a hydrogen atom or an optionally substituted alkyl, aryl, alkenyl, aralkyl or aryloxy group. 6-aminopenicillanic acid (II), hereinafter referred to as 6-APS, as such has no significant biological activity, such as antibiotic activity, but is an important compound as a starting material for the production of semi-synthetic penicillins.

It is an object of this invention, a novel chemical Method without using an enzymatic process to produce the 6-APS (II) to make available, this being no. harmful proteins from the 6-acylamidopenicillan acids (I).

So far there has been only a few about chemical methods of manufacture the 6-APS (II) from 6-acylamidopenicillanic acids (I) published. In Chem. Abstr. 69, 19145 (1988) and U.S. Patent 3,499,909 is one method described, in which the carboxyl group is converted into an alkylsilyl ester protects. This method, which is to be regarded as relatively advantageous, is out of the question unsatisfactory from an industrial point of view.

A process for the production of is-monosubstituted is known Iminochloride by reacting an N-substituted acid amide with phosphorus pentachloride [Chemical reports, 28, 2367 (1895); ibid, 93, 1231 (1960)]. noenso one has for the preparation of 7-aminocephalosporanic acid ester g hem. Abstr. 65, 10596, (1966), Japanese Patent 13 862/667, 7-aminocephalosporanoic acid [Chem. Abstr. 71 61403, (1969), ibid 71, 112959 (1969)] and 6-hminopenicillanic acid ester [J. Med. Chemistry, 13, 607 (1970)] uses a method in which an N-monosubstituted Brings imino chloride with an alcohol to form an imino ether and then cleaves the imino ether group by means of hydrolysis.

Investigations regarding the protection of those in 3-position Carboxyl group of penicillins resulted in a process that carboxyl group carried out Protect conversion to a mixed acid anhydride. Based on this knowledge the present invention.

The present invention therefore relates to a method for Manufacturing of 6-APS, including a compound of the general formula (I) or a salt thereof with a halogenated compound of the general formula R²-X (III) (wherein R² is Radical protecting group and @ is a halogen atom) in the presence of an acid binder converts the reaction product into a corresponding iminohalide with an iminohalide-forming Reagent reacts the imino halide with a hydroxyl compound of the general Formula R³-OH (IV) (wherein R³ is an optionally substituted alkyl, aryl, aralkyl or Cycloalyklgruppe) and the reaction product is then hydrolyzed.

While according to the invention each 6-acylamidopenicillanic acid (I) as Starting material can be used are special from a practical point of view Penicillin salts obtained by means of biological processes are suitable. For examples Such penicillins include those in which the acyl group from for example aliphatic carboxylic acids such as acetic, propionic, # ² - pentenylcarboxylic and n- @ optylcarboxylic acids, Aralkylcarboxylic acids such as p-hydroxyphenylacetic and phenylacetic acids and aryloxyacetic acids originates. These Penicillins are usually used as a tertiary amine salt, Alkali metal salt, alkaline earth metal salt, etc. are used.

Compounds of the formula R²-K (III) which are used to introduce the protecting group in accordance with this invention include: Compounds of the general formula wherein each of R 'and R "can be the same or different and is an optionally substituted III, aryl, aralkyl, alkyloxy, alkylthio, aryloxy or aralkyloxy group or a halogen atom and R' and R", provided they are are verbunuen, can form a ring, M is a boron, aluminum or phosphorus atom and X is a halogen atom, - compounds of the general formula wherein each of the radicals R ', R "and R"' can be the same or different, is an optionally substituted alkyl, aryl, arakyl, alykyloxy, alkylthio, aryloxy or aralkyloxy group or a halogen atom and R 'and " when connected, can form a ring or R 'or R "and R" together can be = O or = S and M is a carbon, silicon, sulfur or germanium atom, provided that when M is a silicon atom, all radicals R ', R "and R"' are halogen atoms or at least one of the radicals R "and R"'forms a # CC-Ci # bond - compounds of the general formula wherein Rl is a halogen atom or an optionally substituted alkyl, alkoxy, alkylthio, aryl, aralkyl, arloxy or aralkyloxy group or phenyl or phenoxy group, each of the radicals R ", R"'and A "" being a halogen atom and the radicals R "and R"'together form a ring or can be = O or = S, M is a phosphorus atom and X is a halogen atom and - compounds of the general formula wherein R 'is an optionally substituted alkyl, alkyloxy, aryl, aralkyl, aryloxy or aralxyloxy group or a phenyl or phenoxy group, M is a sulfur atom, O is an oxygen atom and @ is a halogen atom. Typical examples of these compounds follow.

Examples of the compounds of formula (III-1) include BCl3, AlCl3, PCl3, PBr3, C4H9BCl2, (C4H9) 2BCl, (C2H5) 2AlCl, (C4H9) 2AlCl, C6H5PCl2, C6H5PBr2, C4H9PCl2, CH3OPCl2, C2H5OPCl2, C3H7OPCl2, C4H9OPCl2, C6H5OPCl2, ClCH2CH2OPCl2, C6H5CH2OPCl2, ClCH2CH (Cl) CH2OPCl2, CH3CH (Cl) CH2OPCl2, CH3OCH2CH2OPCl2 and C2H2SPCl2.

Examples of the Verbinaunoen of the formula (III-2) include halocarboxylic acid esters such as COCl2, CSCl2, C2H5OCOCl, CB3, J? 0c90l, C * E QClt q6HiCH20CGC1, etc., xcylaalobeti- de like CHCOGl? NCC X COC1 «C2E5COGl, Cu3 / CCçvl, CH5Cr.2- COCl, etc .; Silicon compounds like SiCl4, CH3OSiCl3, C2H5OSiCl3, C4H9OSiCl3, CH3OCH2OH2OSiCl3, ClCH2CH2OSiCl3, (CH3O) 2SiCl2, (C2H5O) 2SiCl2, (CH3OCH2OH2O) 2SiCl2) (C3OCH2OH2O) 2SiCl2, (C3OCH2OH2O) 2SiCl2) (C6H5CH2O) 2SiCl2, (ClCH2OH2O) 2SiCl2, [CH3CH (Cl) CH2O] 2-SiCl2, (CH3O) 3SiCl, (C2H5O) 3SiCl, (C4H9O) 3SiCl, Cl (CH2CH2O) 3SiCl, [CH3CH (Cl) CH2O] 3SiCl, etc .; Germanium compounds such as (C2H5) 2GeCl2, (C4H9) 2GeCl2, etc.

and sulfur compounds such as SOCl2, C2H5OSOCl, C6H5OSOCl, etc.

Examples of the compounds of the formula (III-3) include phosphorus compounds such as PCl5, POCl3, C6H5POCl2, CH3OPOCl2, C2H5OPOCl2, C2H5OPOCl2, C3H7OPOCl2, C4H9OPOCl2, ClCH2CH2OPOCl2, CH3OCH2CH2OPOCl2, C6H5OPOCl2, C2H5SPOCl2, etc.

Examples of the compounds of the formula (III-4) include sulfur compounds like C2H5OSO2Cl, C4H9OSO2Cl, C6H5SO2Cl, C6H5OSO2Cl, C6H5CH2OSOCl, etc.

The compounds of formula (III) used in this invention, PCl3, POCl3, PCl5, CCCl2, etc. are known as @slogenating agents, but not as a protective group, until now for the first time within the scope of the present invention established was found that these compounds have excellent properties as a protecting group for Have carbon sturgeon. It is of interest that it has now been established that the boron halides, AlCl3, SiCl4, etc .; those previously known as Friedel Kraft catalysts were known, are united as a protective group.

When a compound of formula (III) has two or more halogen atoms contains in its molecule, it is not clear co all the halogen atoms in the Formation of a mixed acid anhydride are contained or not. hen for example im all from phosphorus trichloride 0.6 to 0.9 moles of this compound per mole of compound of the formula (I) was used, an extremely high yield can be achieved.

From this fact it can be concluded that the reaction proceeds according to the following reaction scheme.

When carrying out the present process, a compound of the formula (1) or one of the same is dissolved in an inert solvent such as methylene chloride, chloroform, ethylene chloride, trichlorethylene, tetrahydrofuran, dioxane, diglyme, ethyl acetate, nitromethane or the like and an acid binder for this admitted. Trialkylamines, N-alkylmorpholines, N-alkylpiperidines, pyridine and its homologues, quinoline and its homologues, N, N-dialkylarylamines, etc. can be used as acid binders. Among these compounds, N, N-dialkylanilines and 2,6-lutidine are particularly preferred. Then the mixture is added at room heat or at a temperature below 0 ° C. of a compound of the formula (III) in excess of the amount calculated from the number of halogen atoms to form a mixed acid anhydride. It may sometimes be necessary to heat the mixture to a temperature above room heat, depending on the reaction partners used. An iminohalide-forming agent is added to the resulting solution of the mixed acid anhydride at room temperature or at a temperature below 0 ° C. in excess of equivalent moles. As an iminohalide-forming agent, for example phosphorus oxychloride (POCl3), phosphorus pentachloride (PCl5), phosphorus tribromide (PBr3), phosgene (COCl2), oxalyl chloride (COCl.COCl), protocatechyl phosphorus trichloride etc. are mentioned.

Among these compounds are phosphorus pentachloride and phosgene particularly preferred. The optimal reaction conditions are according to Art the reactants, solvents and acid binders are different. For example, if Methylene chloride, N, N-dimethylaniline and phosphorus pentachloride can be used the reaction ended in 2 to 3 hours at a temperature of -50 ° C to -20 ° C.

The imino halide obtained is linked to a hydroxy bond (IV) reacted at a temperature below 0 ° C. As compounds of the formula (IV) can Methanol, ethanol, propanol, butanol, amyl alcohol, 2-ethylhexyl alcohol, @enzyl alcohol, 2-phenethyl alcohol, cyclohexanol, etc. can be used. Be among these alcohols particularly methanol, n-propanol, n-butanol, isoamyl alcohol, etc. preferably The compound formula (IV) is used in an amount of 3 to 20 moles per mole of compound of formula (I), preferably together with a small amount of a tertiary amine such as, for example N, N-dimethylaniline, triethylamine or the like are used. The formation of the imino ether is in 0.5 to 3 hours at a reaction temperature of -60 ° C to 0 ° C under dropwise Adding an alcohol (TV) to the reaction mixture or by adding it dropwise the iminochloride solution ends in the alcohol (IV) and the iminoether is mostly formed quantitatively.

After stirring the imino ether solution thus obtained, ice water admitted, both the hyarolysis of the iminoether and follows at the same time the gradual removal of the carboxyl protecting group with renewed formation of a Carboxylic acid. Then the reaction mixture with a basic substance such as Triethylamine, aqueous ammonia, ammonium carbonate, an alkali metal hydrogen carbonate, an alkali metal carbonate, a Alkali metal hydroxide or the like to a pH value of approximately 4.0, i.e. the isoelectric point of 6-APS (II) neutralized, whereby crystals are precipitated. The crystals are means Filtration collected with water, aqueous methanol, aqueous ethanol, aqueous Acetone or the like to obtain 6-APS crystals. Under optimalon Conditions are crystal flakes with a purity of 96.5 to 90% with a.

Approximately 90% yield obtained without further purification than Starting material for synthetic penicillins can be used.

In summary, the present invention includes a method for the production of 6-aminopenicillanic acid, including (A) 6-acylaminopenicillanic acid or a salt thereof with a halogenated compound such as a trinalogenide of boron, aluminum or phosphorus, tetranalide of carbon, sulfur, silicon or germanium, phosphorus pentahalide, phosgene or thiophosgene, in the presence of one Acid binder to protect the carboxyl group of 6-Acylami @ openicillanic acid under Formation of a mixed acid anhydride converts, (@) the resulting mixed acid anhydride converted into the corresponding iminohalide by ending it with an iminohalide-pil @ Reagent, such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trisromide, phosgene, Oxalyl chloride or protocatechyl phosphorus trichloride, to form the corresponding Iminohalide converts, (C) converts the iminohalogen @@ obtained into the corresponding imino ether, for which one reacts as with an alcohol and finally (D) the imino ether is hydrolyzed and the protective group of the carboxyl group to form 6-aminopenicilic acid removed.

The foregoing method of the present invention provides a chemical route to the production of 6-aminopenicillanic acid (II) from 6-acylamidopneicillanic acids (I) available, in which the carboxyl group of the compound (I) with a novel Protection group, which has not yet been used for this purpose, is blocked and a series of reactions via an imino halide, an imino ether and finally to 6-aminopenicillanic acid (II). In addition, according to the present Process 6-aminopenicillanic acid (II) without proteins with high yield simplified processes can be obtained from inexpensive starting materials. These Advantages make the process particularly valuable for industry.

The invention is further illustrated by the examples.

Example 1 7.8 g technical grade benzylpenicillin potassium (95% purity) in the form of a dry fine powder were added to 30 ml of alcohol-free methylene chloride, the 5.0 ml of N, N-dimethylaniline contained, admitted and the Gemisen cooled to 0 ° C. To the mixture was added dropwise a liquid mixture with stirring of 2.2 g of phosphorus trichloride and 5 ml of methylene chloride were added. After the addition the mixture was stirred for an additional 20 to 30 minutes while being cooled in ice. In the meantime, most of the raw material used has disappeared i-ncillin potassium salt and various crystals of potassium chloride are deposited. To this mixture were while it was cooled to a temperature below -60 ° C and was stirred vigorously, 4.5 g of potassium pentachloride were added all at once, which was before the The addition was finely granulated, with the powder adhering to the inner wall being eggs a small amount of methylene chloride was washed down.

Since the reaction was accompanied by a moderate generation of heat, was made sure that the temperature did not rise above -30 ° C. After going about 2 hours Had stirred at -50 ° C to -30 ° C, the mixture was again brought to a temperature Chilled below -60 ° C. The vigorously stirred mixture was mixed dropwise Solution of 1 ml of N.N.-dimethylaniline and 30 ml of n-butanol were added. Because from Starting the addition from heat forms, the dropping rate of the solution became set so that: the temperature was kept below -40 ° C. After the In addition, the mixture was stirred at -50 ° to -40 ° C for about 2 hours and then was removed the cooling bath while the Stirring was continued until the temperature of the mixture had risen to -15 ° to -10 ° C. then the mixture was poured into 30 ml of ice water. the reaction vessel was filled with 10 ml ice-cold 60% ethanol and the washing liquors to the reaction mixture added in ice water. The combined mixture was stirred vigorously while it was chilled in ice, whereupon the pH of the imish began to drop. To about 10 to 20 minutes, ammonium carbonate became gradually in small proportions Increase in pH added. Started at a pH of around 3 To deposit crystals.

The pH was finally adjusted to 4.0 and the solution over Maintained in a refrigerator overnight. The crystals were collected several times using cold 60% methanol, then washed with acetone and dried. 3.8 was obtained g (88% yield) of crystal flakes with a melting point of 190 to 191 ° C (Decay). The thin layer chromatogram and the infrared absorption spectrum of the Product showed that it corresponded to the standard sample. The purity was 97.3%, determined by the hydroxylamine method and by alkali titration.

One used phenoxymethylpenicilin potassium (98% purity) instead of benzylpenicilin-potassium, the same results were obtained.

Example 2 The procedure of Example 1 was followed under the same reaction conditions repeatedly, except because @ 0.7 @is 0.9 mol of the respective halogenated phosphorus compound, as indicated in the table below, per mole of penicillin potassium ansvelle of phosphorus trichloride was used. 6-APS (II) was obtained in yields of 74 to 89 @ as indicated in the table.

Connection Molverb. Yield% CH3OPCl2 0.3 85 C2H5OPCl2 0.8 85 n-C3H7OPCl2 0.8 85 n-C4H9OPCl2 0.8 89 ClCH2CH2OPCl 0.9 81 ClCH2CH (Cl) CH2OPCl2 0.7 74 ClCH2CH2CH2OPCl2 0.8 75 CH3CH (Cl) CH2OPCl2 0.8 74 CH3OCH2CH2OPCl2 0.8 86 C2H3OCH2CH2OPCl2 0.8 86 C6H5PCl2 0.7 84 Ma @ Phono @ y @@ t used. @@ @@ is @@ lis- @ ul @@@ @@@@ s @@@ from benzylpenicillin - @@ l @@@, @@ @@ den @@@ - @ is @@@@ @rg @@@ ises ern @@ ten.

Example 3 The procedure of Example 1 was followed under the same reaction conditions repeatedly except that 1.3 to 1.5 moles of the respective halogenated phosphorus compound, as indicated in the table below, per mole of penicillin potassium instead of Phosphorus trichloride were used. 6-APS (II) was obtained in yields of 76 to 90%, as indicated in the table.

Connection Molverh. $ Yield% (CH.30) 2PCl 1.3 7 CII, O i L PC1 1.3 o CR20 2 Example 4 30 ml of methylene chloride containing 5.6 ml of NK-dimethylaniline was added to 7.8 g of dry fine powder of technical grade benzylpenicillin-potassium, and the mixture was cooled to 0 ° C. To this, a methylene chloride solution containing 4.5 g of ClCH2CH2OBCl2 was added with stirring, and the mixture was continuously stirred while being cooled with ice until it became almost translucent. The mixture was then cooled to -60 ° C. and 4.3 O of fine phosphorus pentachloride powder was added to it. Then, in a similar manner to Example 1, the modification was carried out. 1.2 g of product was obtained (28% yield).

Example 5 3.0 g of @ Cl3 was added to a mixture of 8.0 g of benzylpenicillin potassium technical grade and 5.6 ml of N.N-dimethylaniline, which had been cooled to -40 ° C., were added. After stirring for several hours at a temperature below 0 ° C, was the mixture is treated in a similar manner to Example 1, yielding 0.9 g (21% Yield) product obtained.

Example 6 3.1 g of fine powder of AlCL3 was made into a mixture of 8.0 g of technical grade benzylpenicillin potassium and 6 ml of N.N-dimethylaniline, that had been chilled in ice was added. The mixture was about an hour wrinkled and treated in a similar manner in Example 1 except that during 2 g of itric acid were added to the hydrolysis to control the pH. It approximately 1 g of product was obtained. The thin-layer chromatogram and infrared spectrum clearly showed the presence of a β-lactam, but the purification was due difficult due to the presence of a small amount of aluminum hydroxide.

Example 7 A cold ethylene chloride solution containing 2 g of phosge @ @@ t @ nt, became a mixture of 8.0 g benzylpenicillin - @@ lium technical grade, 5 ml of anhydrous 2.6-@utidine and 30 ml of ethylene chloride, the Germisch in @ls had cooled, admitted. After stirring in an ice bath for one hour, the The reaction mixture was cooled to - @ 0 ° C. and 4.5 g of fine phosphorus pentachloride powder were added. After stirring for a further 2 hours at -50 ° to -30 ° C, the mixture was again up -60 ° C cooled it was quickly dropwise a cold solution of 0.5 ml of triethylaniline in 30 ml of isopropanol was added while the temperature was kept below -40 ° C. The mixture was stirred at -50 ° C for 2 to 3 hours and then the cooling bath was used removed. After the temperature reached -10 ° C, the mixture was stirred with stirring poured into 30 ml of ice water.

After 20 minutes the pH of the mixture gradually became 4.0 adjusted with ammonium carbonate and then the mixture was left overnight in a Kept refrigerator. The deposited crystals were collected in the usual way, washed and dried to give 3.3 g of the product (77% yield).

Example 8 The procedure of Example 1 was followed under the same conditions repeated except that 1.5 to 1.5 moles of everyone in the the following table indicated halogenated carbonyl compound per mole of penicillin potassium was used instead of phosphorus trichloride. Because the amount of deposited crystal was only slight, the aqueous solution was concentrated under reduced pressure and the obtained crystals were washed in an ordinary manner and formed of the product dried in yields of 4 to 13%. The results obtained are to be taken from the following table.

Connection Molverh. Yield% C6H3OCOCl 1.3 8 C2H5OCOCl 1.4 13 CH3COCl 1.5 4 Example 9 The procedure of Example 1 was followed under the same conditions repeated, except that @ 1 mole (C2H2) 2GeCl2 per mole of penicillin potassium instead of phosphorus trichloride of Example 1 was used. 6-APS was found in one yield received by 23%.

Example 10 Instead of the phosphorus trichloride from Example 1 were 0.7 Moles of phosphoroentachloride used per mole of penicillin potassium. The response was carried out at a temperature below -10 ° C and taken immediately after the disappearance The mixture became a solution of a greater part of the crystals of penicillin potassium cooled to a temperature below -60 ° C. With the addition of equivalent moles of phosphorus pentachloride the procedure of Example 1 was continued, except that the hydrolysis at a pH below 1 was carried out for 30 minutes. The yield was 67 % Example 11 instead of phosphorus trichloride from Example 1 were 1.8 ol phosphorus oxychloride per 2 ols of penicillin potassium used. The reaction was carried out with stirring at a Temperature carried out from 0 ° to 20 ° C and immediately after the disappearance of the larger Part of the penicillin potassium by dissolving the mixture was cooled to -60 ° C. To Addition of phosphorus pentachloride proceeded as indicated in example 1, except that the hydrolysis at a pH below 1 for about 30 minutes was carried out. The yield was 63.

Example 12 The procedure of Example 11 was followed by the same Conditions repeated except those in the table specified Phosphorus (V) compounds used in place of the phosphorus trichloride of Example 11 became. The yields were 42 to 83%, as can be seen from the table.

Connection Molverh. Yield% CH3CH (Cl) CH2OPOCl2 0.8 47 ClCH2CH2OPOCl2 0.8 46 ClCH2CH (Cl) CH2OPOCl2 1.0 42 C2H5OPOCl2 1.0 71 C6H5OPOCl2 1.0 73 C2H5OCH2CH2OPOCl2 1.0 64 n-C4H9OPOCl2 1.2 67 C6H5POCl2 «1.2 83 Example 13 Instead of phosphorus trichloride Example 1 used 1.3 moles of C4H9OSO2Cl per mole of penicillin potassium. the Reaction was carried out at a temperature of -20 ° to 0 ° C and immediately after the disappearance of the greater part of the penicillin potassium by dissolving it Mixture cooled to -60 ° C. The procedure of Example 11 was then followed. The yield was 24%.

Example 14 The procedure of Example 13 was followed by the same Conditions carried out, except that n-C4-9O @ SOCl instead of n-C4H9OSO2Cl as used in Example 13.

The yield was 27%.

Example 15 The procedure of Example 1 was repeated except that n-C4H9OSiCl3 was used instead of the phosphorus trichloride of Example 1 and hydrolysis was carried out at a pH below 1 for about 30 minutes. The yield was 72%.

Similar results were obtained when ClCH2O @ 2O-SiCl3 was used instead of phosphorus trichloride was used.

Example 16 Instead of the phosphorus (III) compounds of the example 2 were 0.7 to 0.9 moles of a silicon dichloride compound per mole of penicillin potassium used and the reaction and further treatments were carried out in a manner similar to how indicated in Example 1 carried out. @an obtained 6-ARS in yields of 72 86 % as shown in the following table.

Connection Molverh. Yield% (ChO) 2 C ;, 81 CtI7 öX. 0 -9 (CTCf4.Ca20) 2iCT2 Q; -, 7 (nG4 £ t% 0) 2iGT2 G, d C12 Ci, c, 20) 2bis Example 17 The procedure of Example 1 was repeated under the same conditions except that 1.5 moles of each silicon monochloride compound as shown in the table below was used in place of the phosphorus trichloride of Example 1 per mole of penicillin potassium. 6-APS was obtained in yields of 74 to 86% as indicated in the table.

Compound yield% .i ) 9 111./ ) '-L) 9 Table (continued) Compound Yield% CH3 13 - CH0 9 Example 18 The procedure of Example 1 was repeated except that 0.7 moles of silicon tetrachloride per mole of penicillin potassium was used in place of phosphorus trichloride, and hydrolysis was carried out at a pH below 1 for about 30 minutes. The yield was 47%.

Claims (15)

P a t e n t a n s p r ü c h e: 1. A process for the preparation of 6-aminopenicillanic acid, characterized in that (A) an acylamino acid of the formula wherein R¹ is hydrogen or aic residual ¼ cap of the organic carboxylic acid having 1 to 17 carbon atoms or a salt thereof with a halogenated compound in the presence of an acid binder to protect the carboxyl group of the acylamino acid to form a mixed acid anhydride group, the halogenated compound having the formula R²-X wherein X is a halogen atom and R² is the group (wherein R¹ and II, which can be the same or different, halogen, an optionally substituted alkyl, alkoxy or aikylthio, each with r as 7 carbon atoms, aryl, aralkyl, aryloxy or aralkoxy, each with 1 to 4 carbon atoms, phenyl or phenoxy group and M is boron, aluminum or phosphorus), (wherein each of the radicals RI, RII and RIII, which can be the same or different, halogen, an optionally substituted alkyl, alkoxy or alkylthio, each with 1 to 7 carbon atoms, aryl, aralkyl, aryloxy or aralkoxy , each with 1 to 4 alkyl carbon atoms, phenyl or phenoxy group and RI and RII together can form a ring and M is boron, aluminum or phosphorus), (in which each of the radicals RI, RII and RIII, which can be the same or different, halogen, an optionally substituted alkyl, alkoxy or alkylthio, each with 1 to 7 carbon atoms, aryl, aralkyl, aryloxy or aralkoxy , each having 1 to 4 alkyl carbon atoms, is phenyl or phenoxy and RI and RII can together form a ring or RII and RIII can be = 0 or = S and M is a carbon, silicon, sulfur or germanium atom, provided that if M is silicon, all of the radicals RI, RII and RIII are halogens or at least one of the radicals Ri, R and RIII forms # CO-Si), (wherein RI is halogen, an optionally substituted alkyl, alkoxy, or alkylthio group having 1 to 7 carbon atoms, aryl, aralkyl, aryloxy or aralkoxy, each having 1 to 4 alkyl carbon atoms, phenyl or phenoxy group, any of the RII, RII I and RII II is halogen and RII and RII I can together form a ring or = O or = S and M is phosphorus) and (wherein RI is halogen, an optionally substituted alkyl or loy, each with 1 to 7 carbon atoms, aryl, aralkyl, aralkoxy or aryloxy, each with 1 to 4 alkyl carbon atoms, phenyl or rhenoxy group and 1 1 sulfur and 0 is oxygen), (B) the acylamino acid obtained, the carboxyl group of which is protected, is converted into a corresponding iminohalide by reaction with an iminohalide-forming reagent under anhydrous conditions at room temperature or at a temperature lower than 0 ° C, (C) the iminohalide at a temperature not higher than -10 ° C with an alcohol of the formula R³-OH in which R³ is alkyl with 1 to 12 carbon atoms, aralkyl with 1 to 7 alkyl carbon atoms, cyclonexyl, hydroxyalkyl with 2 to 12 carbon atoms, alkoxyalkyl with 3 to 13 carbon atoms, monocyclic aryloxyalkyl having 2 to 7 alkyl carbon atoms, monocyclic aralkoxyalkyl having 3 to 7 alkyl carbon atoms, or hydroxyalkoxyalkyl having 4 to 7 carbons is material atoms, converts to form a corresponding imino ether and (D) the imino ether under acidic conditions with Nasse, a hydroxyl-containing compound or a hydroxyl-containing solvent to form 6-aminopenicillanic acid of the formula implements. 2. The method according to claim 1, characterized in that one is one Acyl amino acid used, which is selected from biosynthetic penicillins. 3. The method according to claim 2, characterized in that the used biosynthetic penicillins are penicillin G and penicillin V. 4. The method according to claim 1, characterized in that a is used as iminohalide-forming Reagent PCl3, PBr3, PBr3, POC15 and COCl2 used. 5. The method according to claim 4, characterized in that the iminohalide-forming Reagent is PCl5. 6. The method according to claim 1, characterized in that the halogenated compound used to protect the carboxyl group of the acylamino acid COCl2, CH3OSiCl3, n-C4H9OSiCl3, (CH3O) 2SiCl2, (C2H5O) 2SiCl2, (CH3OCH2CH2O) 2-SiCl2, (ClCH2CH2O) 2SiCl2 (n-C4H9O) 2SiCl2, CH3 (CH3O) SiCl2, CH3 (C2H5O) SiCl2, CH3 (Cl CH2CH2O) SiCl2, (CH3O) 3SiCl, CH3 (CH3O) 2SiCl, CH3O (CH3) 2SiCl, C6H5PCl2, C6H5PCl2, C6H5PCl2, C6H5PCl2, C6H5PCl2 , CH3OPCl2, C2H5OPCl2, CH3OCH2CH2OPCl2, ClCH2CH2OPCl2, PCl3, POCl3, PCl5, C6H5POCl2, O6H5OPOCl2 and C2H5OPOCl2. 7. The method according to claim 1, characterized in that the to Halogenated compound used to protect the carboxyl group of acylamino acid (R'O) 2SiCl (where R 'is an optionally substituted lower alkyl group), R'OPCl2 (where.R 'has the same meaning as in the preceding formula), PCl3, Is POCl3, PCl5 and COCl2. 8. The method according to claim 7, characterized in that the for Halogenated compound used to protect the carboxyl group of acylamino acid a compound of the formula R'OPCl2 (where R 'is an optionally substituted lower alkyl group is) or PCl3. 9. The method according to claim 8, characterized in that the for The halogenated compound used to protect the carboxyl group is PCl3. 10. The method according to any one of claims 1 to 5, characterized in that that the acid binding agent used is N.N.-dimethylaniline, 2,6-lutidine, pyridine, quinoline and triethylamine used. 11. The method according to claim 1, characterized in that the acylamino acid, whose carboxyl group is protected with de iminohalide-forming @ own, atI a temperature of about -10 ° to -40 ° C is reacted. 12. The method according to claim 1, characterized in that the iminohalide reacted with an alcohol at a temperature of about -10 ° to about -50 ° C will. 130 The method according to claim 12, characterized in that as Alcohol methanol, n-propanol, and n-butanol are used. 14. The method according to claim 1, characterized in that that the acylamino acid, the carboxyl group of which is protected, with the iminohalide-forming one Reagent is reacted at a temperature of about -10 ° to -40 ° C and the obtained Iminohalide with an alcohol, namely methanol and / or n-ßutanol at a Temperature of about 100 to -50 ° C is implemented. 15. Process for the preparation of 6-aminopenicillanic acid, characterized in that that one (A) penicillin G-potassium or penicillin-V-potassium with phosphorus trichloride in a solvent, namely methylene chloride, chloroform and / or ethylene chloride, in the presence of N.N-dimethylaniline to protect the carboxyl group of penicillin reacts, (B) the acylamino acid obtained, the carboxyl group of which is protected, with Phosphorus pentachloride reacts at -10 ° to -40 ° C to form the imino halide, (G) the imino halide with methanol or n-butanol containing a small amount of N.N. Contains dimethylaniline at -10 ° to -50 ° C with formation of the imino ether and then (D) the imino ether under acidic conditions with water to form hydrolyzed by 6-aminopenicillanic acid.