CS226151B2 - Method of prepararing 6-amino penicillanic acid - Google Patents

Description

The invention relates to a process for the preparation of 6-aminopenicillanic acid of the formula II _{/ S} ch ₃

HgN-CH-HC (II) - CH, //

C-j-CH-COOH by chemical process from 6-ecylaminopenicillanic acid of general formula I

R @ ¹ -CO-NH-CH-HC3

CH, (I)

CH-COOH wherein R ¹ -CO- is an organic carboxylic acid organic group containing 1 to 17 carbon atoms.

The 6-aminopenicillanic acid of formula II (hereinafter referred to as 6-APA) does not in itself possess significant biological activity, such as an antibiotic effect, but is an important starting material for the production of semi-inert penicillins.

SUMMARY OF THE INVENTION The present invention provides a novel chemical, non-enzymatic process for the preparation of 6-APA of formula II which provides said acid-free, harmful protein derived from 6-ecyleminopenicillanic acids of formula I.

So far, very few reports have been published on chemical plants for the production of 6-APA of formula XI from 6-ecyleminopenicillanic acids of formula I. Among them is Chem. Abetr. 69 19145 (1968) and U.S. Pat. No. 3,499,909 discloses a process characterized in that the carboxyl group is protected by conversion to an alkylsilyl ester. This method is considered to be relatively advantageous but not satisfactory from an industrial point of view.

It is known that there is a process for preparing N-monosubstituted imidichlorides by reacting N-substituted acid amides with phosphorus pentachloride. Chemieehe Berlchte 28, 2367 (1895); ibid. 21 · 1231 (1960)). In the preparation of the 7-aminocephalosporanic acid ester, Chem. Abstr. 65, 10596 (1966), Japanese Patent 13862/66), 7-aminocephalosporanic acid Chem. Abstr. 71 61403 (1969); ibid. 71, 112959. (1969)) and 6-aminopenicilenic acid ester. Copper. Chemters 13, 607 (1970)) has already used a process characterized in that the N-mono-substituted imide chloride is converted by reaction with an alcohol to an iminoether, and the iminoether group is then hydrolytically cleaved.

The present inventor has now found, based on extensive research, a method of protecting the 3-position penicillin molecule of a carboxylic acid group by converting it to a mixed acid enhydride. This method is an object of the present invention.

The principle of the preparation of the 6-aminopenicilenic acid of the above formula II from 6-acyleminopenilicenoic acid of the above formula I by the method of the invention is that the carboxyl group at the 3-position of the 6-acyleminopenicilenic acid of formula I is protected by reaction a chlorinated compound of the general formula III- ² (Cl) wherein R ² represents a group of the formula Cl-Cl-, CH 2 OP-, Cl 2 P-, ^ 2 ^ 5θ ^ ~

Cl

Cl

CL,

Cl n C ₄ H ₆ O ₂ -, n C ₄ H _g O-P-, CH 2 O-CH 2 CHgO-P-, Ο ^ ΟΟΙ ^ ΟΗ ^ -ΡC1

Cl

Cl

Cl CHgO '

CH-O ^ p 2 .P-,

CH,

CH.

Si-, (nC ₄ H ₉ O) ₂ Si-, (CH ₃ OCH ₂ CH ₂ O) ₂ Si-, (C ₁ O ₅ -Si, CH, ¹ Cl Cl Cl CH, o ^BH 3f)

CBjO

CH, O-S1, CH-S1-, y.

CH.

in an anhydrous inert medium in the presence of an acid-binding agent, the corresponding mixed anhydride is acidified, the resulting 6-acylaminopenicillanic acid e protected by the carboxyl group in the 3e position is converted to the corresponding iminohalide by reaction with the iminohalide reagent in anhydrous medium at -40 to 0 ° C, the iminohalide obtained ee is converted to the corresponding iminoether by reaction with a hydroxy compound of formula IV wherein R R is C el-C el alkyl, C až-Ceny phenylalkyl or cyclohexyl, at a temperature in the range of -50 to -10 ° C and the resulting iminoether is reacted in an acidic medium with water, a hydroxy compound or 8 solvent containing a residence of acyl and cleavage of the iminoether group, concomitant regeneration of the carboxyl group and formation of the 6-aminopenicillan k acids of formula II.

When a compound of formula III contains two or more chlorine atoms in the molecule, it is unclear whether all chlorine atoms are involved in the formation of the mixed anhydride. If, for example, in the case of phosphorus trichloride, 0.6 to 0.9 mol of this compound is used per mole of the compound of the formula I, an extremely high yield can be achieved. On this basis, it can be assumed that the reaction p. Runs according to the following scheme.

-CH, / S \ X ' ⁱⁿ “ ³

^-CONH-CH-HC C

OC - K - CH -. OOOK

PCl ₃ , C ₆ H ₅ N (CH ₃ ) ₂

Z ^S \ ^ ^CH 3

R = -CONH-CH-HCC?

CH 2 Cl 2

I 3 I oc - N - CH - COO (P),

PCl _c

X ^ch 3

RC = N-CH-HC-cf mH, Cl ³ 1

Cl OC — N • CH — COO (P) n-BuOH, RgO with _x ^ ch ₃ H ₂ N-CH-HC ^{X c} \ ^1,1 ^ ^CH 3 (II)

OC- N ·

CH-ΌΟΟΗ

The process of the invention is carried out by dissolving or suspending a compound of formula I or a salt thereof in an inert solvent such as ethylene chloride, chloroform, ethylene chloride, trichlorethylene, tetrahydrofuran, dioxane, diglyme, ethyl acetate, nitromethane and the like; an acid binding agent is added to the mixture. As such agents, for example, trialkylamines, N-alkylmorpholines, N-alkylpiperidines, pyridine and its homologues, quinoline and its homologues, Ν, dial-dialkylarylamines and the like can be used. Of these, Ν, Ν-dialkylanilines and ϋ, ϋ-lutidine are particularly preferred. In order to prepare the mixed anhydride, the compound of formula III is then added to the mixture at room temperature or below 0 ° C in excess of the amount calculated from the number of halogen atoms,

Depending on the nature of the reactants, it is sometimes necessary to heat the reaction mixture to a temperature above room temperature. To the resulting reduced anhydride solution is added at room temperature or below 0 ° C an agent suitable for the formation of the imide halide in excess of the molar equivalent. Suitable reagents for the preparation of imidhalogen may be, for example, phosphorus oxychloride (POCLj), phosphorus pentachloride (PCl 4), phosphorus tribromide (PBr ·), phosgene (COClg), oxalyl chloride (COCl.COC1), trichlorophosphoric acid o-phenylene ester σ ° \ ^ zPCl 3) and the like. Of these compounds, phosphorus pentachloride and phosgene are particularly suitable. The optimum conditions for this reaction vary depending on the nature of the reactants, the solvents used and the acid-binding agents. For example, when methylene chloride, Ν, Ν-dimethylaniline and phosphorus pentachloride are used, the reaction is completed in 2 to 3 hours at a temperature of -50 to -20 ° C.

The resulting imide chloride is reacted with a hydroxyl compound of formula IV at a temperature below 0 ° C. Methanol, ethanol, propanol, butanol, amyl alcohol, 2-ethylhexyl alcohol, benzyl alcohol, cyclohexanol and the like can be used as compounds of formula IV. Of these alcohols, methanol, n-propanol, n-hutanol, isoamyl alcohol and the like are particularly suitable. The compound of the formula IV is used in an amount of 3 to 20 moles per mole of the compound of the formula I, preferably together with a small amount of a tertiary amine such as Η, Μ-dimethylaniline, triethylamine and the like. The iminoeter is prepared by dropwise addition of an alcohol of formula IV to the reaction mixture or by dropwise addition of an imide chloride solution to an alcohol of formula IV at a temperature of -60 to 0 ° C; the reaction is complete within 0.5 to 3 hours and the iminoether yield is almost quantitative.

The addition of ice water to the thus obtained Iminoeter solution while stirring causes simultaneous hydrolysis of the Iminoeter e and the gradual deprotection of the carboxyl group to give the free carboxylic acid. The reaction mixture is then neutralized with a base such as triethylamine, aqueous ammonia, ammonium carbonate, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydroxide and the like to a pH of about 4.0, i.e. to the isoelectric point of acid 6. -APA of formula II.

The precipitated crystalline material is filtered off, washed with water, aqueous methanol, aqueous ethanol, aqueous acetone or the like xo-solvents to give crude crystalline 6-APA. Under optimal conditions, 6-APA platelet crystals with 96.5-98% yield are obtained. in a yield of about 90%, which can be used as a starting material for the preparation of synthetic penicillins without further purification.

•

As described in detail above, the present invention relates to a process for the preparation of 6-aminopenicillanic acid of formula II from 6-acylaminopenicillanic acids of formula I by chemical means, and the method is characterized in that the carboxyl group of said acids is blocked with a new protecting group The process according to the invention yields protein-free 6-aminopenicillanic acid in high yields, in a simple procedure and from low-cost starting materials. These advantages make the process particularly suitable for industry.

The following examples illustrate the process according to the invention.

MOlady execution? . p: 1 c al of an alcohol-free alcohol containing 5.6 ml of Μ, Μ-dimethylanilimide, 7.8 g of dry, finely comminuted, technical potassium salt of benzylpenicillin (10%), the mixture was cooled to 0 ° Then, 2.2 g of phosphorus trichloride in 5 ml of methylene chloride were added dropwise. After the solution was added, the mixture was stirred for an additional 20 to 30 minutes under ice-cooling; during this time, almost all of the starting penicillin potassium salt went into solution and a different appearance of potassium chloride crystals was formed.

To this mixture, cooled to below -60 ° C, 4.5 g of phosphorus trichloride, finely divided just prior to the addition, was added all at once with vigorous stirring, and the substance adhering to the walls was washed away with a small amount of methylene chloride.

Since the reaction was accompanied by a slight development of heat, it was necessary to ensure that the temperature did not rise above -30 ° C. The mixture was stirred for about 2 hours at -50 to -30 ° C, then cooled again to below -60 ° C and a solution of 1 ml of Ν, Ν-dimethylaniline in 30 ml of n-butanol was added dropwise with vigorous stirring. At the beginning of the dripping, heat was released, so it was necessary to control its velocity so that the temperature was kept below -40 ° C.

After completion of the dropwise addition, the mixture was stirred for about 2 hours at -50 to -40 ° C, then the cooling bath was removed and stirring was continued until the temperature of the reaction mixture rose to -15 to -10 ° C.

Then the mixture was poured into 30 ml of ice water, the reaction vessel was washed with 10 ml of ice-cold 60% methanol, and the wash solution was added to the reaction mixture in ice water. The combined solutions were vigorously stirred with ice-cooling while the pH of the mixture dropped. After about 0 to 20 minutes, ammonium carbonate was introduced in small portions so that the pH of the mixture gradually increased. Crystals started to precipitate at a pH of about 3; The pH was then adjusted to 4.0 and the solution was stored in a refrigerator overnight. The precipitated crystalline material was filtered off, washed several times with cold 60% methanol, then acetone, and dried.

3.8 g (88% yield) of platelet crystals having a melting point of 190 DEG -191 DEG C. (with decomposition) were attracted. The thin layer chromatogram and the infrared absorption spectrum of the substance were in accordance with the standard. Found content 97.3% (hydroxylamine method and titration of alkali).

Using the phenoxymethylpanicillin potassium salt (98% content) instead of the benzylpenicillin potassium salt gave the same results.

Example 2

The procedure described in Example 1 was repeated under the same conditions except that from 0.7 to 0.9 mol of the halogenated phosphorus compound listed in the following table was used per milled phosphorus trichloride per mole of penicillin potassium salt. The 6-APA acid of formula II was obtained in yields of 85-89% as also shown in the table.

Compound Molar ratio Yield,% ch ₃ option ₂ 0.8 85 c ₂ h ₅ Option ₂ 0.8 86 α-C ₃ H ₇ OPCl ₂ 0.8 85 nC ₄ H ₉ OPCl ₂ 0.8 89 ch ₃ and ₂ ch ₂ option ₂ 0.8 86 C ₂ H ₅ OCH ₂ CH ₂ OPCl ₂ 0.8 86

Similar results were obtained using phenoxymethylpenicillin potassium instead of benzylpenicillin potassium.

Example 3

The procedure described in Example 1 was repeated under the same conditions except that 1.3-1.5 mol of the halogenated phosphorus compound shown in the following table was used per mole of potassium penicillin salt. The 6-APA acid of formula II was obtained in 90% yields as also shown in the table.

Compound

Molar ratio

Yield,%

CH „O

I ²

CHgO

1.5

Example 4

Instead of the trivalent phosphorus compounds listed in Example 2, 0.7 to 0.9 moles of dichlorosilicate per mole of penicillin potassium was used, and the reactions and the procedure were carried out in the same manner as in Example 1. 6-APA was obtained in yields of 84 to 86 % as shown in the following table.

Compound

Molar ratio

Yield,%

(nC ₄ H ₉ O) ₂ SiCl ₂ 0.8 (ch ₃ and ₂ ch ₂ o) ₂ Si 0.9

Example 5

The procedure described in Example 1 was repeated under the same conditions, except that instead of phosphorus trichloride in Example 1, 1.5 mol of the monochlorosilicate shown in the following table was used per mole of the penicillin potassium salt. 6-APA was obtained in yields of 84-86% as also shown in the table.

Compound

Yield,%

Table continuation.

Compound Yield,% CH, - ch ₃ ——SICI CH ₃ C) 86

Example 6

The procedure described in Example 1 was repeated except that instead of phosphorus trichloride, 0.7 mol of silicon tetrachloride was used per mole of penicillin potassium salt and that the hydrolysis was carried out for about 30 minutes at a pH lower than 1. The yield was 47%.

226.51

Claims (9)

(II) SUBJECT OF THE INVENTION A process for the preparation of 6-aminopenilcilic acid of the formula II. CH, h ₂ n-ch-hc CH, f, C-NCH-COOH from 6-acylaminopenicillanic acid of the general formula I (I) wherein R ¹ -CO- represents an acyl group organic carboxylic acids having 1 to 17 carbon atoms, characterized in that they are: a) the carboxyl group in the 3-position of the 6-acylaminopenilcilic acid of the formula I is protected by reacting the acid or a salt thereof with a chlorinated compound of the formula III -Cl (III) wherein R represents a group of the formula Cl-Ρ-, CH ^O-P-, Cl ^P-, Cl AND WHOSE 0 = P-, li Cl ₂ c ₂ h ₅ op-, Cl n-C 1 H 6 O-P-, n C ₄ H ₈ O-P-, CH ₃ O-CH 2 HgO-P-, C 4 OCH ₄ HgO-P-, CH 3 C Cl Cl Cl Cl CHgOSP-, CH- ( CH. _o ^ Si-, <nC ₄ H ₉ O) ₂ Si-, (CH ₃ OCH ₂ CH ₂ O) ₂ Si-, ¹ H-OKS ¹ -, CH, ¹ -Cl Cl CH ₃ - ^ Si-, or Cl ci CH. CH ₃ o CH ₃ - n Si-, CH ₃ <TV anhydrous inert atmosphere in the presence of an acid scavenger to afford smčsnáho anhydride, (b) the resulting 6-acylaminopenicillanic acid and the carboxyl protecting group at the 3-position are converted to the corresponding iminohalide by reaction with an iminohalide-providing reagent in an anhydrous environment at a temperature between -40 ° C and 0 ° C; o) converting the obtained iminohalide into the corresponding iminoether by reaction with a hydroxy compound of formula IV Η ^3- OH (IV) wherein H ³ is a C 1 -C 8 alkyl, C 1 -C 8 phenylalkyl or cyclohexyl group, at a temperature in the range of ~ 50 to -10 ° C; d) reacting the resulting iminoether in an acidic medium with water, a hydroxy compound or a hydroxy-containing solvent to cleave the iminoether group, concurrently regenerating the carboxyl group and forming the 6-aminopanililenic acid of formula II. 2. A process according to claim 1, wherein the salt of 6-ecylaminopenicillanic acid of the formula I is potassium salt of penicillin G or potassium salt of penicillin V. 3. The process of claim 1 wherein the chlorinated compound of formula III is phosphorus trichloride. 4. The process of claim 1 wherein the anhydrous inert medium is an anhydrous solvent selected from the group consisting of methylene chloride, chloroform and ethylene dichloride. 5. The process of claim 1 wherein the iminohalide providing agent is phosphorus pentachloride, phosphorus tribromide, phosphorus tribromide, phosphorus oxychloride, and phosgene. 6. A process according to claim 1, wherein the hydroxy compound of formula IV is methanol or n-butanol. 7. A process according to claim 1, wherein the carboxylic acid group is protected by reacting a [beta] -benzylpenicillanic acid salt or a phenoxymethylpenicillanic acid salt with a phosphorous or silicon compound chloride or oxychloride selected from the group consisting of &lt; 1 &gt; OBCl.,., Ίλ, Η ^ ΟΡΟΙ ^. Η.-Ο ^ ίγΟΚΙ- ,, η-Ο ^ Η ^ ΟϊΌ ^, CH ₃ O-CH ₂ CH ₂ OPGl _{? s} C _? H _t -OCH 3, C 18 ,, OPO 1, CH 2 O 4. _rc - _} OH ₂ O ^ ^CH 3 - SiCl 2, ^{K t;} 4 ^ta 9 ⁰ > 2 ^: ' ⁵ - ^C 12' ^CH 3 ^{0 /} (ΟΜ ,, ΟΟΚ.ΟΗ ,, Ο ,, δϋΌΙρ, CCH. _? O) ₃ SiCl, CH. CH, O-1-3Cl Target in anhydrous inert CHý) medium in the presence of an acid-binding agent, b) the protected benzylpenicllanic acid or phenoxymethylpenicillanic acid is treated with an imino-halide-providing agent; c) reacting the product obtained with an alcohol of the formula Wherein S ³ is alkyl and 1 to 6 carbon atoms, phenylalkyl and 1 to 6 carbon atoms; 8 ethoxy carbon in the alkyl salt or cyclohevyl, to form the ininoether a d) the resulting iminoeter is hydrolyzed in an acidic medium with the cleavage of the Lateroater group together with the regeneration of the cyrbosyl group, 9, The method according to claim 1, characterized in that sts L, '' lt ll n - λ. ,,,>. , methylpenicilane protects by reaction with a chlorinated phosphorus or silicon compound selected from the group consisting of CH ₃ OPCl ₂ , C 2 OPCl 2, nC 2 OPC 2, nC ₊ H ₂ OPCl ₂ , CH ₃ O-CH ₂ CH ₂ OPC ₂ , CjH ₅ and ₂ ch ₂ option ₂ , ch ₂ oCH ₂ O ' PCI ^CH3 ^ * ~: SiCl _2, (nC ₄ H _g O) ₂ SiCl _2, (CH ₃ OCH ₂ CH ₂ O) ₂ SiCl _2, CH, ^CH 3 ' ^CH 3' (CH ₃ O) ₃ SiCl ₃ , CH ₃ O ₂ SiCl and CH ₃ O ₃ SiCl 2, to give the corresponding readily hydrolyzable CH ₃ O ₂ CH ₃ O 2 mixed anhydrides. (b) the protected 6-benzylpenicillanic or phenoxymethylpenicllanic acid is treated with an iminohalide-providing agent in an anhydrous environment in the presence of an acid-binding agent; c) reacting the obtained product with an organic hydroxy compound of the formula R ³ -OH in ng, R ³ denotes alkyl of 1 to uhlíku carbon atoms, phenylalkyl of 1 to 8 carbon atoms in the alkyl moiety or cyclohexyl, to form an imlnoether; and d) the resulting product is hydrolyzed in an acidic medium to remove the iminoether group while regenerating the carboxyl group.