DE2344274A1 - PROCEDURE FOR THE TEMPORARY PROTECTION OF CARBOXYL GROUPS IN PENICILLINES, PENICILLIN SULFOXIDES OR CEPHALOSPORINES AND THEIR DERIVATIVES - Google Patents

Description

BIOCHEMIE Ges.Ri.b «H.

Men Case 97O-9622

Patentonwöff »

Dipl-fng. P. Wirfh

Dr. V. Scfitntscf-Kcwcrzilc

DtpL-fng. G. Dcn.Ter.Wg

Dr. P. Viticulture, Dr. D. Gadei

dftoBkfortfM., Gf. Ash devolves sir. 39

¥ inquire about the passing of time Sctot.z vott Carboxylgrtippan _f in PenicilllneR, PenicilÜBSuIfoxiden or Cephalosporine ^ gad their perivafcen

B ± e invention concerns an experience for the preliminary protection of carboxyl groups in penicillins _ff penicilliosalfoKiden or CeplialosporiKea vmüigen derivatives, by esterification BBd subsequent cleavage of the ester grouping * and is characterized by “that” the carboxyl groups are converted into pentachloroplienyl esters Ester then splits if necessary «

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The process according to the invention is therefore directed both to the temporary protection of carboxyl groups in the carboxylic acids mentioned by conversion into pentachlorophenyl esters and to the separate process for the preparation of the corresponding free acids by cleavage of the respective pentachlorophenyl esters.

The inventive method can be very general apply to the esterification of the compounds mentioned at the outset. Example catfish are compounds of the Forisel I,

CH

R-HM-T

O = C-µ 1

Cl

Cl

Cl

of formula II.

O = C IT

CH

Cl

ti

II

or the Forsiel III.

III

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produced, in each of which the substituent R

a) either a radical R-CH-CO- in which R- stands for phenyl, cyclohexyl, phenyl or cyclohexyl substituted by alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen, hydroxy or amino, for cyclohexadienyl, thien-2-yl, thien-3-yl, 2, 6-Dimethoxypheny1 So-chlorophenyl-S-methyl-isoxazol-4-yl 4-yl, or 3- {2,6-dichlorophenyl} -5-methyl-isoxazol ~,

b) or a radical R ₁ -CO-, in which R .. has the meaning given above,

c) or represents a radical R-O-CH-CO-,

in which R. has the meaning given above and R is hydrogen
or phenyl,

R for hydrogen, alkyl with 1-6 carbon atoms

d) or represents a radical R-S-CH-CO- in which

R. and R_ have the meaning given above,

e) or a radical R ₃ -CO-, in which R stands for straight-chain or branched alkyl with 1-12 carbon atoms, straight-chain or branched alkyl with a total of 1-12 carbon atoms interrupted by oxygen or sulfur, or cyano.

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f) or a radical R -CII-CO-, in which R

^R 4

has the meaning given above and R ^ for a sulfonic acid residue, for azido, carboxyl, hydroxy, amino or by trityl, tritylsulfenyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, o-nitrophenylsulfenyl or tert. Butyloxycarbonyl protected amino,

g) or is formyl,

h) or for trityl, tritylsulfenyl, benzyloxycarbcnyl, p-nitrobenzyloxycarbonyl), 2,2,2-trichloroethyloxycarbonyl, o-nitrophenylsulfenyl or tert. Butyloxycarbonyl.

The invention preferably relates to the preparation of such compounds of formulas I, II or III and those of them derived free carboxylic acids, in which the substituent R in each case has the meaning R ', the remainder R 'for phenylacetyi, thien-2-yl-acetyl, thien-3-yl-acetyl, 2,6-dimethoxybenzoyl, S-o-chlorophenyl-S-methyl-isoxazol-4-yl-carbonyl, 3- (2,6-dichlorophenyl) -5-ynethyl-isoxazol-4-ylcarbonyl, Phenoxyacetyl, oc-phenoxybutyryl, n-butoxyacetyl, Cyanoacetyl, hexanoyl, a-aminophenylacetyl, a-carboxyphenylacetyl, a ~ sulfonic acid-phenylacetyl, ct-amino-p-hydroxyphenylacetyl, a-Amino-cyclohxadienylacetyl, tert. Butoxycarbonyl, Benzyloxycarbonyl ^ -nitrobenzyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl or trityl.

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In particular, the invention relates to the preparation of compounds of the formulas 1,11 or III and the free carboxylic acids derived from them, in which the substituent R in each case has the meaning R ¹¹ , where R ' ^{1 is} 2,6-dimethoxybenzoyl, 3-0 "chlorophenyl -5-methyl-isoxazol-4-yl-carbonyl, 3- (2,6-dichlorophenyl) -5-methyl-isoxazol-4-yl-carbonyl, phenoxyacetyl or et-aminophenylacetyl.

The elimination of the pentachlorophenyl radicals from the compounds mentioned at the outset and in particular those mentioned above Compounds of the formulas I, II or III then lead to the corresponding compounds, and in particular the compounds of the formulas I, II or III, in which the pentachlorophenyl radical has in each case been replaced by hydrogen, namely on the respective free carboxylic acids.

The free acids of the carboxyl groups can be used for esterification containing compounds or activated acid derivatives. As activated acid derivatives are for example mixed anhydrides are used. However, it is preferred to start from the free acids. The esterification can for example be carried out by means of Pentachlorphenylsulfxt. However, it is preferably done using pentachlorophenol. For esterification by means of Pentachlorphenylsulfxt you can either proceed directly from this, or you can use the pentachlorophenyl phosphite produce in an upstream reaction stage by reacting thionyl chloride with Pentachlorophenol. In both cases you work

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in the presence of a suitable organic solvent such as dimethylformamide, benzene, pyridine or mixtures thereof. The use of an acid binder, for example triethylamine, is also recommended. The esterification by means of pentachlorophenol is also expediently carried out in an organic solvent, for example methylene chloride, dimethylformamide, chloroform, acetonitrile or tetrahydrofuran. It is preferable to work in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. The esterification is advantageously carried out at low temperatures, preferably at temperatures between -15 and +25 ^0C, in particular at a temperature between -5 and +5 ⁰ C. After the reaction, the pentachlorophenyl ester obtained from the usual organic solvents may be recrystallized, for example from Acetonitrile, ethyl acetate or ethyl acetate / petroleum ether. They are compounds that crystallize well and can therefore be easily isolated and purified.

The saponification of the pentachlorophenyl esters prepared according to the invention, of penicillins, penicillin sulfoxides or cephalosporins and their derivatives, with cleavage the pentachlorophenyl protective groups can be made under a wide variety of conditions. It takes place already in fairly mild conditions, so that other sensitive areas of a molecule, such as the ß-lactam ring the penicillins or cephalosporins or their amino group side chains are not attacked, The saponification can, for example, by means of dilute

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Sodium hydroxide solution or by means of organic bases, v? Ie triethylamine, carried out in the presence of a little water, in which case additional catalytic amounts of imidazole are expediently used. However, saponification is best carried out using imidazole in the presence of a little water. . Preferably each, is carried out in an inert organic solvent such as dioxane, acetone, Methylisobuty! _F ketone or butyl acetate Essigester, whereby there is conveniently carried out at low temperatures, for example at room temperature.

The pentachlorophenyl esters prepared according to the invention offer a number of advantages. They make well crystallizing Compounds and can therefore be easily cleaned. In addition, their production does not cause any difficulties. Furthermore, they can be specifically converted into the corresponding free carboxylic acids and pentachlorophenol columns. The cleavage conditions are so gentle that sensitive molecules such as pentachlorophenyl ester of penicillins oder.Cephalosporinen, are cleaved without attacking the ß-lactam ring. On the other hand, they are Pentachlorophenyl ester compared to the most diverse reactions, especially those taking place in the acidic range Reactions, extremely resilient. So can these esters heated or recrystallized with various organic solvents without a reaction occurring. In the production of basic penicillins or cephalosporins protecting groups used can be split off under acidic conditions or hydrogenolytically without the ester group is affected. The 6-aminopenicillanic acid optionally obtained here

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pentachlorpheny! ester or w. T-Air.inodeoxyacetylcephalosporanic acid pentachloropheny! Ester can be acylated by a wide variety of methods, for example using acid chlorides, Acid anhydrides, in the presence of condensing agents such as dicyclohexylcarbodiimide or carbonyldiimidazole, without the ester group being affected. From the N-trityl aminopenicillanic acid pencachlorophenyl ester For example, the trityl radical can be split off without affecting the pentachlorophenyl group. Furthermore, one can penicillin sulfoxide pentachlorophenyl ester with good success of a ring expansion to the corresponding Cephalosporins ^ subject without losing the ester group is affected. Finally, penicillins can easily be oxidized to penicillin sulfoxides will.

The invention is explained in more detail by means of the examples. They show both the production of the inventive Pentachlorophenyl esters and their saponification to the respective free acids, as well as a number of conversion reactions the pentachlorophenyl ester without affecting this pentachlorophenyl protective group.

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Example 1: PJ ^ en ^ x ^ e thj / JU> e ^

35 g of phenoxymethyl penicillin are dissolved in 800 ml of methylene chloride. The solution is cooled to 0 ° C. and 23.7 g of dicyclohexylcarbodiimide are added while stirring. After 35 minutes, 29.25 g of pentachlorophenol are added. , and the equipment is stirred for a further 3 hours while cooling. The precipitated dicyclohexylurea is filtered off with suction, the methylene chloride solution is concentrated, filtered again and precipitated with petroleum ether. The colorless, crystalline mass obtained is recrystallized in acetonitrile or ethyl acetate / petroleum ether, and colorless prisms of the title compound are obtained at 150-151 ° C melts.

Example 2: " Phenoxymethylpenicillin -peiijbachlorphenylester

5.86 g of pentachlorophenol and 7.0 g of phenoxymethylpenicillin are dissolved in 50 ml of dimethylformamide in the presence of 5.6 ml of triethylamine, and the mixture is cooled to −10 ° C. On the dropwise addition of 1.4 ml of thionyl chloride, a precipitate of triethylamine hydrochloride immediately falls the end. After 10 minutes, the cold bath is removed and the batch is left to stand for one hour at room temperature. To the Working up, the batch is poured into 200 ml of ice water and the material which has separated out is extracted with 200 ml of methylene chloride. After washing the extract with 100 ml of 1% sodium bicarbonate solution and the same volume of phosphate buffer pH 6.2 is dried with sodium sulfate and evaporated in vacuo. When moving the residue with Hexane crystallizes. After filtering off with suction, washing with hexane and drying, a pure product is obtained Recrystallization from acetonitrile at 149-152 ° C melts.

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Example

23.7 g of dicyclohexylcarbodiimide and 29.2 g of pentachlorophenol are added to an ice-cooled suspension of 36.6 g of phenoxymethylpenicillin sulfoxide in 700 ml of acetonitrile and the mixture is ^{stirred at 0 °} C. for 20 hours. The precipitate obtained is filtered off with suction and washed with acetonitrile. The solution is concentrated, the fine, colorless needles obtained are filtered off with suction and washed with a little acetonitrile, whereupon the title compound is obtained, which melts at 130-132 ° C. after recrystallization from acetonitrile.

Example 4: Benz yIpenleillin-p ent a ch1o rpheny! Ester

An aqueous solution of 7.4 g of K-Benzy! Penicillin is with 70 ml of methylene chloride under acidification with dilute

Phosphoric acid extracted. The methylene chloride solution is washed with water, dried and cooled nit ice. 4.1 g of dicyclohexylcarbodiimide and 5.3 g of pentachlorophenol are added with stirring, and stirring is continued for 3 hours with cooling. The precipitated urea is filtered off, whereupon the methylene chloride solution is concentrated and petroleum ether is added. The resulting crystalline, colorless needles of the title compound melt at 160-163 ° C. After recrystallization from acetonitrile they have a melting point of 162 to 165 ⁰ C.

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Example 5 ; ItJI-LiJ ^ lriiiSii ¹ ? ^^
pheny lester

A solution of 14.5 g of freshly prepared N-trityl-aminopenicillanic acid in 145 ml of methylene chloride is ^{cooled to 0} ° C. and mixed with 6.55 g of dicyclohexylcarbodiimide. After stirring for 15 minutes, 8.45 g of pentachlorophenol are added and stirring is continued for 4 hours with cooling. The precipitated urea is filtered off and the solution is evaporated to dryness in vacuo. Aethei: is added to the residue, with first solution and then rapid crystallization starting. It is allowed to cool completely, the residue is filtered off, washed with a little ether and dried. The title compound obtained in this way melts at 192-194 ° C.

Example 6 : Phen oxymet ^ xyjy ^ ej ^^ j. IjLin sulfoxide pentachlorophenyl esters r

The conversion of pentachlorophenol and thionyl chloride in benzene-pyridine leads to crude di- (pentachlorophenyl) sulfite, which melts at 136-138 ° C.

b) Phenoxymethylpenicillin sulfoxide pentachlorophenyl ester

1.83 g {0.005 mol) of phenoxymethylpenicillin-sulfoxide, 20 ml dimethylformamide and 1.4 ml (0.01 mol) of triethylamine with shaking in solution, and placed with 2.89 g _(r 0 005 mol) of di- (pentachlorophenyl ) -sulfite added in 2 portions. A solution will soon emerge. After standing for one hour at room

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temperature is poured onto about 100 ml of ice water, and the deposited oil is taken up in ethyl acetate. The organic Phase is made with 2 N hydrochloric acid, sodium hydrogen carbonate solution and water, dried with sodium sulfate and evaporated. The resulting residue of 3.35 g practically consists of the pure Tite! compound.

Example 7: Phenoxymethylpenicillin sulfoxide pentachlorophenyl ester

3.66 g of phenoxymethylpenicillin sulfoxide (0.01 mole) will be used suspended in 2O ml of acetone and by adding 1.4 ml Triethylamine dissolved. After good cooling with ice water, 1 ml of ethyl chlorocarbonate is added, which rapidly dissolves Triethylamine hydrochloride separates.

After 15 minutes, a solution of 2.7 g of pentachlorophenol and 1.4 ml of triethylamine in 20 ml of dimethylformamide is added to the solution containing phenoxymethylpenicillin-sulfoxide-ethyl carbonic anhydride obtained according to process step aJ. After standing in ice water for 30 minutes, the precipitate is filtered off with suction, washed with a little acetone and the acetone is evaporated off on a rotary evaporator. The residue is mixed with water and filtered off. The thus obtained crude phenoxymethylpenicillin sulfoxide pentachlorphenyleeter iet less pure than that obtained by the procedure of Example 6. Fig.

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Example 8 : Pentachlorophenyl-T-phenoxyacetamido-S-diethyl-3? -Cephem-4-carboxylate

A solution of 3.48 g of T-phenoxyacetamido-S-methyl-S-cephera-4-carboxylic acid and 2.66 g of pentachlorophenol in 50 ml of methylene chloride is mixed with 2.06 g of dicyclohexylcarbodiimide while cooling with ice added and stirred at 0 ° C for 3 hours. Then the precipitated urea is sucked off, the methylene chloride solution evaporated to dryness in vacuo and the solid residue was heated with a little ethyl acetate. After suctioning off, washing with ethyl acetate and drying, 5.2 g (87%} of the title compound are obtained in the form of needles with a melting point of 175-178 ° C,

Example 9 : Phenoxymethylpenicilin

5.98 g of phenoxymethylpenicillin pentachlorophenyl ester (prepared according to Example 1} are dissolved in 6O ml of dioxane, whereupon a few drops of water are added and finally 1.36 g of imidazole are added. From the colorless, clear Solution slowly crystallizes out pure pentachlorophenol. After standing for two hours at room temperature it is suctioned off, the solution is concentrated and dilute sodium bicarbonate solution is added. It is then filtered off, the filtrate acidified and extracted with butyl acetate. The butyl acetate solution is mixed with potassium ethylhexoate dissolved in methanol, whereby the potassium salt of the title compound precipitates. The precipitate is filtered off with suction, washed with ethanol and dried, and pure potassium phenoxymethylpenicillin is obtained in this way.

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Example 10 ; 7- (N-2, 2, 2-Trichloräthyloxycarbonyl) -Da-phenylglycylamido) -B ipethyl-S-cephem ^ -carboxylic acid

A suspension of pentachlorophenyl-7- (N-2,2,2-trichloroethyloxycarbonyl ) -D-oc-phenyl-glycylamido) -3-methyl-3-cephem-4-carboxylate (prepared according to Example 22) in 150 ml of acetone is stirred within two hours treated dropwise with 10 ml of 2N sodium hydroxide solution, during which solution occurs. After concentrating in vacuo, 100 ml of ethyl acetate are added and 50 ml of water are added, whereupon the mixture is acidified to pH 2 with dilute hydrochloric acid while stirring. The ethyl acetate solution is dried, treated with activated charcoal and extracted with sodium hydrogen carbonate solution. Another extraction the aqueous solution under acidification with ethyl acetate and evaporation gives an amorphous substance, which with ether is washed. The acid obtained, which is pure by thin-layer chromatography, is, according to CMR measurements, the λ2-cephem.

To convert it into the ^ 3-cephem, 2.6 g of acid are suspended in 15 ml of glacial acetic acid, and 0.87 ml of 35% hydrogen peroxide are added while stirring. After 24 hours at room temperature, it is carefully diluted with water, filtered off with suction, washed with water and dried. The obtained here; pure product by thin layer chromatography shows by NMR measurements dasSulfoxid of 43-cephem. It melts at 179-180 ⁰ C, which is discolored already at 160 ⁰ C.

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To reduce the sulfoxide obtained above is a Suspension of the sulfoxide with excess hexachlorodisilane in methylene chloride refluxing with exclusion of moisture heated until solution occurs. Then it is washed with dilute hydrochloric acid and water »the methylene chloride solution is dried, evaporated and the residue washed with ether. The product obtained in this way shows in the KMR spectrum the Signals for the / 13 acid, namely the title compound.

Example 11: Benzylpenicillin

A solution of 3 g of benzylpenicillin-pentachlorophenyl ester (prepared according to Example 4) in 50 ml of dioxane is slowly added at 0 ⁰ C by addition of a trace of imidazole at pH meter with stirring with 0.1 N sodium hydroxide solution. The addition takes place in such a way that the pH value of the solution remains below 8. If there is no further consumption of sodium hydroxide solution, 100 ml of butyl acetate are added, whereupon the mixture is acidified to pH 2 with hydrochloric acid while stirring. The butyl acetate phase is washed with water, dried and mixed with N-ethylpiperidine. In the process, N-ethylpiperidine-benzylpenicillin crystallizes out in pure form, which can be converted in a known manner into the free penicillin or a salt, for example potassium benzylpenicillin.

Example 12 ; T-Phenoxyacetamldo-S-methyl-S-cephem ^ - carboxylic acid

A solution of 6 g of pentachlorophenyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (prepared according to Example 8) in 100 ml of water-saturated ethyl acetate is added with 0.7 g

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Imidazole added. After standing for one hour at room temperature the acid formed is treated with sodium hydrogen carbonate solution extracted, whereupon the aqueous phase is extracted again with ethyl acetate after acidification. The ethyl acetate solution is evaporated / the amorphous residue in ethyl acetate dissolved and inoculated. The $ 3 acid, namely the title compound, crystallizes out in almost pure form, as by NMR measurement, thin-layer chromatography and polarimetry results. M.p. 175-178 ° C.

Example 13 : 7- (D-2-Tritylsulfenylamino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid

A solution of 2 g of pentachlorophenyl 7- (D ~ 2-tritylsulfenylamino-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylate (prepared according to Example 23) in 10 ml peroxide-free Dioxane is mixed with a few drops of water and 0.31 g of imidazole offset. The imidazole salt of pentachlorophenol slowly crystallizes out on standing at room temperature. To This is sucked off for hours and the dioxane solution is evaporated. For cleaning or separating off small amounts / 12-acid, the residue is digested with benzene, from filtered off undissolved components and chromatographed on a silica gel column. Mixtures are grounded out for elution Benzene / ethyl acetate used. This gives the £ 3 acid, namely the title compound, as an amorphous, thin-layer chromatography pure substance.

Example 14 ; 7-phenoxyacetamido-3-methyl-2-cephem-4-carboxylic acid

A solution of 3 g of pentachlorophenyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (prepared according to Example 8) in 50 ml of dioxane is mixed with 5 ml of water and 1.5 g of triethylamine

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offset. After standing for 24 hours at room temperature, im Gently evaporated under vacuum and the residue shaken with water and ethyl acetate. The aqueous phase is separated off and extracted with ethyl acetate while acidifying with dilute hydrochloric acid. When concentrating the ethyl acetate solution a residue is obtained which, after recrystallization from ethyl acetate, melts at 180-182 ° C. NMR measurement and the optical rotation show that it is the pure Ä2 acid, namely the title compound.

Example 15 : Pentachlorophenyl-T-phenoxyacetamido-S-methyl-3-cephem-4-carboxylate

10 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester are added to 220 ml of boiling xylene and 300 mg of p-toluenesulfonic acid hydrate entered and heated under reflux for 60 minutes. After refluxing for 60 minutes, use a rotary evaporator evaporated to dryness, whereupon the residue is dissolved in chloroform with 5% sodium hydrogen carbonate solution and extracted with water, dried, decolorized with 3% activated charcoal and again up to the rotary evaporator Evaporate dry. The residue is chromatographed on silica gel plates and is in the chromatogram with a authentic sample in the R value identical.

Example 16; Pentachlorophenyl V-amino-S-methyl ^ -cephem-4-carboxylate

In 10 ml of alcohol-free chloroform, 0.85 g of phosphorus

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Pentachloride and 1.25 ml of quinoline are added, and the solution is cooled to ^{0 ° C. while passing nitrogen through.} 1.2 g of pentachlorophen3'l-3-niethyl-7-phenoxyacetanndo-3-cephem-4-carboxylate (prepared according to Example 8 or 15) are then added, whereupon the batch is stirred at ^{0 ° C. for 3 hours while constantly flushing with nitrogen} «Stirs and then cools ^{to -10 0 C.} Then, v / ground within 30 minutes 4.5 mL of n-Fropanol added dropwise, followed by bringing the temperature to 0 ⁰ C and v / urther 60 minutes

stirs. Then add 12 ml with vigorous mixing Add water, stir for 15 minutes, add 50 ml of petroleum ether and stir for a further 5 minutes. The unusual one The crude HCl salt of the title compound is filtered off, washed well with cold diethyl ether and placed in a vacuum desiccator dried.

Example 1 7: Pent achlorphe nyl ~ 3-methy1-7-phenoxyacetami de- 3 -cephem- 4-carboxyl at

To a cooled to 0-5 ⁰ C Mongrel of 4.0 ml · methylene chloride, 0.1 g phenoxyacetyl chloride and 0.08 g of sodium bicarbonate, 0.2 g of pentachlorophenyl-7-amino - 3-methyl -3-cephem-4 -carboxylate (as KCl salt) (prepared according to Example 16) given, and the batch is 1, 5 'hours'

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stirred at room temperature. Then it is filtered, the residue is washed with a little methylene chloride, the filtrate is concentrated in vacuo and the residue is washed with ether offset. After standing for a short time in the refrigerator, the precipitate is filtered off, in as little chloroform as possible taken up and slowly precipitated again with excess ether. After 15 to 20 minutes it is filtered off, mixed with a little cold ether and dried in a vacuum desiccator, and so the title compound is obtained,

Example 18: 6-aminopenicillanic acid pentachlorophenyl ester

5 g of N-trityl aminopenicillanic acid pentachlorophenyl ester (prepared according to Example 5) are in methylene chloride dissolved and treated with 1 equivalent of ethanolic hydrochloric acid. After standing for several hours at room temperature evaporated to dryness and the residue triturated with ether. After suctioning off the precipitate, washing with Ether and drying gives the hydrochloride of the title compound as a colorless connection.

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Example 19 : 6-minopenicillanic acid pentachlorophenyl ester

2.4 g of phenoxymethylpenicillin pentachlorophenyl ester (prepared according to Example 1 or 2) v / earth dissolved in 24 ml of dichloroithane, whereupon the solution is cooled to -25 ° C while stirring and under a nitrogen atmosphere and is treated with 1.6% N, Ni> imethylaniline and 0 , 92 g of phosphorus pentachloride added. The ¹ batch is kept at ~ 25 ° C. for 1.5 hours, then 16 ml of methanol are added dropwise, and finally more

Stirred at -25 ° C for 2.5 hours. Then v / ground 400 mg Finely powdered sodium carbonate is added in small portions, and the mixture is stirred for a further two hours at -25 ° C. The batch V7 is left to stand overnight at -2O ° C, under Stirring brought to room temperature and finely powdered sodium carbonate added until after Addition of water to the reaction medium results in a pH of about 4. 35 ml of water are then added and the mixture is stirred 30 minutes at room temperature, taking the pH adjusted to 6 to 6.5 by adding sodium bicarbonate. After the phases have separated, the aqueous portion is extracted with 40 ml of ethyl acetate. The organic Phases are combined, dried over sodium sulfate and concentrated to about 5 ml in vacuo. The concentrate will taken up in 70 ml of ethyl acetate and, while stirring, dropwise with an etv / a 1 ν hydrochloric acid in ethyl acetate added until a weakly acidic reaction occurs when spotting on a moistened pH paper is. The batch is placed in the refrigerator for 30 minutes and the HCl salt which has separated out filtered off, each with 3O ml of ethyl acetate and <a Washed diethyl ether and dried in vacuo.

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Example 20 : Phenoxymethylpenicill an-pentachlor " phenyl ester

A suspension of 5 g of 6-aminopenicillanic acid peritachlorophenyl ester hydrochloride (prepared according to Example 18) and 2.4 g of potassium bicarbonate in 50 ml of methylene chloride is mixed with a solution of 1/6 g of phenoxyacetyl chloride in 10 ml of methylene chloride while stirring vigorously at room temperature. After stirring for 4 hours, the mixture is filtered off, the methylene chloride solution is concentrated and petroleum ether is added. The precipitate obtained is filtered off and recrystallized from acetonitrile, and so leads to the title compound, melting at 148-15O ^D C.

Example 21; Dicloxacillin pentachloropheny ester

A suspension of 5 g of 6-aminopenicillanic acid pentachlorophenyl ester hydrochloride (prepared in accordance with Example 20) in 50 ml of methylene chloride is shaken with a dilute, aqueous sodium bicarbonate solution until it is completely dissolved. After the aqueous phase has been separated off, the methylene chloride solution is dried and ^{cooled to 0} ° C., 2.7 g of 3- (2,6-dichlorophenyl) -S-methyl-isoxazole ^ -carboxylic acid and 2.1 g of dicyclohexylcarbodiimide are added, with stirring, and one stirs for another 4 hours. The urea which has precipitated out is filtered off and the solution is evaporated to dryness in vacuo. The material which crystallizes out when the oily residue is triturated with ether is filtered off with suction, washed with a little ether and recrystallized from acetonitrile / ether. The title compound obtained in this way melts at 136-14O.degree

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Example 22 ; Pentachlorophenyl-7- N- (2,2,2-trichloroethyloxycarbonyl) -D-oc -phenylglycyl amido -3-methyl-3-cephem-4-carboxyIafc

A suspension of 26.2 g of pentachlorophenyl ^ -amino-S-methyl-3-cepheiti-4-carboxylate hydrochloride (prepared according to example "16) in 250 ml of methylene chloride is under 7.3 ml of triethylamine are slowly added to stirring and ice-cooling, during which solution occurs. Then 17.1 g of N- (2,2,2-trichloroethyloxycarbonyl) -D-a-pheny! Glycine and 10.8 g of dicyclohexylcarbodiimide are added, and the mixture is stirred for three hours at room temperature. The precipitated urea is filtered off with suction, washing thoroughly with methylene chloride. The methylene chloride solution is washed with water, dilute hydrochloric acid and sodium hydrogen carbonate solution, dried and concentrated. Crystallization then occurs. After filtering off with suction, washing with ether and drying, 30.5 g of colorless are obtained Substance. It is recrystallized from ethyl acetate and then melts at 180-182 ° C.

Example 23 ; Pentachlorophenyl-7- (D-2-tritylsulfenylamino-

2-phenylacetamido) -3-methyl-3-cephem-4-carboxylate

A solution of 11.2 g of D-α-aminophenylacetic acid methyl ester hydrochloride in 220 ml of methylene chloride, the equivalent amount of triethylamine is added while cooling with ice. then 21.1 g of tritylsulfenyl chloride are added with stirring, and the batch is stirred for 6 hours at room temperature.

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The reaction mixture is then initially diluted with Acetic acid and then extracted with sodium bicarbonate solution »dried over sodium sulfate and finally evaporated. The solid residue is mixed with ethyl acetate, filtered off with suction, washed with ethyl acetate and dried, being used for TritylsuXfenylaminophenylessigsäuremethylester arrives.

33.4 g of tritylsulfenylaminophenylacetic acid methyl ester will be dissolved in 750 ml of pyridine and stirred for 20 hours with 75 ml of 10 N potassium hydroxide solution. It is then evaporated to dryness in vacuo and the oily residue distributed between 750 ml of ether and 750 ml of water. The water phase is initially used twice 375 si each! Aether is extracted, whereupon it is cooled with ice and stirring slowly with glacial acetic acid until a pH of 5 is reached. The D-cc-tritylsulfenylaminopheny / acetic acid crystallizes in the process which is filtered off, washed with water and dried. M.p. 151-153 ° C.

A suspension of 10 g of pentachlorophenyl - ^ - amino-S-methyl-3-cephem-4-carboxylate hydrochloride (produced according to example 16). in 100 ml of methylene chloride is under Stirring iait 2g triethylamine added, whereby solution occurs » Then 8.5 g of D-ct-tritylsulfenylaminophenylacetic acid and 4.1 g of cyclohexylcarbodlimide are added and the mixture is stirred 5 hours at room temperature. The urea that precipitated in the process

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is filtered off with suction, the methylene chloride solution is washed with water, dilute hydrochloric acid and sodium hydrogen carbonate solution and evaporated. A foam resin is obtained which crystallizes on trituration with ether. Mp. 130-135 ⁰ C.

Example 24 ; Phenoxymethylpenicillin sulfoxide pentachlorophenyl ester

29.5 g of phenoxymethylpenicillin pentachlorophenyl ester (prepared according to Example 3) are dissolved in 60 ml of methylene chloride dissolved, treated with 30 ml of acetic acid and cooled in an ice bath. The solution is now 5 ml of 35% strength within 30 minutes Hydrogen peroxide added with stirring. The mixture is stirred for a further 2 hours at room temperature and then the batch is left over Standing at night. For isolation, the solution is concentrated in a rotary evaporator, a little water is added and the mixture is stirred. The resulting crystals are filtered off with suction, washed with water and dried thoroughly. M.p. 173-177 ° C.

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Example 25; Pentachlorophenyl-T-phenoxyacetaiaiao-S-ntethyl " 3-cephem-4-carhoxylate

12 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester and 35 mg of toluenesulfonic acid hydrate are introduced into 24 ml of boiling, anhydrous butyl acetafc and refluxed for 70 minutes. After cooling, it is extracted with sodium hydrogen carbonate solution and with water, dried and the solution is decolorized with activated charcoal. Then it is evaporated to dryness on a rotary evaporator and the residue is taken up in 50 ail ethyl acetate. After seeding, the ester slowly crystallizes in needles, mp. From 172 to 176 ⁰ C.

example 26: Pentachlorophenyl ^ -phenoxyacetainido-S-methyl-3-cephem-4-carboxylate

12 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester and 35Ο mg of p-toluenesulfonic acid amide are dissolved in 25Ο ml of boiling butyl acetate and refluxed for 70 minutes. After cooling, the solution is extracted with 5% sodium hydrogen carbonate solution and with water , dried, decolorized with 2% activated charcoal and evaporated to dryness in vacuo. After adding ethyl acetate, white pentachlorophenyl ^ -phenoxyacetamido-S-ynethyl-3-cephem-4-carboxylate crystallizes out. It melts at 168-172 ° C,

Example 27 ; Pentachlorophenyl ^ -phenoxyacetamido-S-rmethyl-3-cephem-4- * car boxy lat

In 300 ml of boiling, anhydrous butyl acetate, 15 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester and

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400 mg of p-toluenesulfonic acid hydrazide entered, whereupon Boils under reflux for 2 hours. The solution is after cooling with 5% sodium hydrogen carbonate solution and with Water extracted, dried, and decolorized with 2% activated charcoal. It is concentrated to dryness on a rotary evaporator and the residue crystallized with ethyl acetate. M.p. 173-175 ° C.

Example ^{28 :} Pentachlorophenyl-T-phenoxyacetamido-S-methyl-3-cephem-4-carboxylate

IO g Phenoxymethylpenlcillin sulfoxide-pentachlorophenyl ester (prepared according to Example 3 or 6} are entered into a boiling, anhydrous mixture of 1OO ml benzene and 1OO ml of xylene, treated with 300 mg p-toluenesulfonic acid hydrate and boiled for 90 minutes under reflux. Then evaporated to dryness in vacuo, removed in chloroform, extracted with 5% sodium hydrogen carbonate solution and with water , dried, decolorized with 3% activated charcoal and again evaporated on a rotary evaporator. The residue is chromatographed on silica gel plates and is an authentic sample of pentachlorophenyl -7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate identical.

Example 29 ; Pentachlorophenyl-T-phenoxyacetamido ^ -methyl-3-cephem-4-carboxylate

5 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester and 12Ο mg of 7-amino-1,3-naphthalene disulfonic acid are introduced into 100 ml of boiling butyl acetate. After two hours Boiling under reflux, the reaction mixture is cooled with 5% sodium hydrogen carbonate solution and with water

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extracted, dried, decolorized with 2% activated charcoal, am Rotary evaporator concentrated to dryness and crystallized with ethyl acetate. M.p. 172-173 ° C.

Example 30 : Pentachlorophenyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

6 g phenoxymethylpenicillin sulfoxide pentachlorophenyl ester are mixed with 150 mg sulfamic acid in a boiling mixture entered of 75 ml of xylene and 75 ml of benzene and refluxed for 100 minutes. The approach will then be carried out on Rotary evaporator concentrated to dryness, taken up in chloroform, with 5% sodium hydrogen carbonate solution and with Extracted water, dried, decolorized with 3% activated charcoal, again concentrated to dryness and chromatographed. Of the The residue is in the thin layer chromatogram on silica gel plates in the R value with pentachlorophenyl ^ -phenoxyacetamido-S-methyl-3-cephem-4-carboxylate identical.

Example 31 : Pentachlorophenyl ^ -phenoxyacetamido-S-methyl-3-cephem-4-carboxylate

In 500 ml of boiling, anhydrous butyl acetate, 24 g Phenoxymethylpenicillin sulfoxide pentachlorophenyl ester and 500 mg sulfamic acid entered. After 110 minutes of cooking the reaction is terminated under reflux. After cooling down is extracted with 5% sodium hydrogen carbonate solution and with water, dried, decolorized with 2% activated charcoal, evaporated to dryness on a rotary evaporator and crystallized with ethyl acetate. The crystallized product

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has an mp. 170-174 ⁰ C and is identical with an authentic sample of 7-pentachlorophenyl-3-methyl phenoxyacetarnido in the IR spectrum * 3-'cep? Yeni-4-carbaxylat.

Example 3 2 : Pentachloropheny 1-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate

800 ml of anhydrous butyl acetate are heated to the boil and then 30 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester dissolved therein, whereupon 8OO mg of pyridine-3-sulfonic acid added and refluxed for 90 minutes. After 90 minutes the reaction mixture is cooled with 5% sodium hydrogen carbonate solution and extracted with water, dried and decolorized with 2% activated charcoal. After concentrating to dryness, the residue is dissolved in ethyl acetate added, from which pentachlorophenyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate crystallized in the form of long, white needles. M.p. 172-174 ° C.

Example 3 3: Penta: chlorophenyl -7-phenoxyacetamldo ^ 3-methyl- ^ -cepKem-4; -oarboxyiat

10 g of phenoxymethylpenicillin-sulfoxy-pentachrorphenyi ^ ester and 250 mg of 2-aminobenzolaric acid are introduced into 200 ml of butyl acetate and kept at the boil under reflux. After 100 minutes, the reaction mixture is extracted with 3% sodium hydrogen carbonate solution and with water, dried, decolorized with 2% activated charcoal and concentrated to dryness on a rotary evaporator. The residue is crystallized with ethyl acetate. Mp. 168-172 ⁰ C.

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Example 3 4 ; Pentachlorophenyl-7-phenoxyacetamido-3-iaeth γ 1-3 ~ -cephera- 4 -car boxy lat

2O g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester are added to 400 ml of boiling butyl acetate and 500 mg of 4-aminobenzolaric acid dissolved and refluxed for 100 minutes. After the reaction, the solution is cooled with 5% strength Sodium hydrogen carbonate solution and extracted with water, dried, decolorized with 2% activated charcoal, concentrated to dryness on a rotary evaporator and crystallized with ethyl acetate. M.p. 170-173 ° C.

Example 35 ; Pentachlorophenyl 7-phenoxyacetamido-3-n-ethyl-3-cephem-4-carboxylate

In 8O ml of a boiling mixture of benzene and xylene im The ratio of 1: 1 is 3 g of phenoxymethylpenicillin sulfoxide pentachlorophenyl ester registered and with 100 mg of pyridine-3 ^ -sulfonic acid offset. After refluxing for 70 minutes, the reaction mixture is turned up on a rotary evaporator concentrated to dryness, dissolved in chloroform, extracted with 5% sodium hydrogen carbonate solution and with water, dried, decolorized with 3% activated charcoal, whereupon on a rotary evaporator the chloroform is distilled off again. The residue is taken up in ethyl acetate, from which white pentachlorophenyl-7-phenoxyacetaraido-3-methyl-3-cephem-4-carboxylate Crystallized from mp 17O-173? ß.

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Example 36 :

carboxylic acid

2.1 g of 7-phenoxyacetamido-3-methyl-2-cephem-4-carboxylic acid are suspended in 3O ml of dichloroethane, with 0.7 ml of 2,6-lutidine and 0.55 ml of acetylbroinide are added. The approach will Stirred for one hour at room temperature and, after adding 2 ml of 2,6-lutidine, left to stand in the refrigerator overnight. For isolation, the solution is concentrated in a rotary evaporator and then, with stirring and cooling, in a mixture of 50 ml of 3N HCl and 50 ml of ethyl acetate registered. After stirring for 15 minutes, the phases have been separated off and the aqueous portion is extracted again with 50 ml Ethyl acetate, the organic phases are combined and washed twice with water at pH 3.0. The solution will be Treated with 2% activated charcoal, dehydrated and evaporated to dryness, creating a foam resin.

To separate the A 2 / ά 3 isomers, the residue is dissolved in ml of acetone, mixed with 5 ml of a 1 molar imidazole solution in acetone, rubbed with a glass rod and, after the onset of crystallization, placed in the refrigerator for one hour to complete. The precipitated imidazole salt of AE2 acid is filtered off, washed with ether and dried, mp. 158 ⁰ C. The mother liquor is concentrated and carefully added to a mixture of 50 ml of 2 N HCl and 5O ml of ethyl acetate under stirring and cooling. After phase separation and washing of the organic extract with water, it is dehydrated with sodium sulfate and evaporated to dryness. After recrystallization of the residue, pure 7-phenoxyacetalnido-3-Hιethyl-3-cephem-4-carboxylic acid with a melting point of 174-177 * c is obtained.

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Claims (1)

970-9622 Patent claims: 1. Method for the temporary protection of carboxyl groups in penicillins, penicillin sulfoxides or cephalosporins and their derivatives, by esterification and subsequent cleavage of the ester group, characterized in that the carboxyl groups are converted into pentachlorophenyl esters and the esters thus obtained are then optionally cleaved. 2. Method for the temporary protection of carboxyl groups in penicillins, penicillin sulfoxides or cephalosporins and their derivatives, characterized by esterification, that one converts the carboxyl groups in pentachlorophenyl ester. 3. Process for the production of penicillins, penicillin sulfoxides or cephalosporins and their derivatives with free carboxyl groups, from those protected by esterification Compounds, characterized in that one consists of compounds esterified on the carboxyl groups with pentachlorophenyl splits off the ester group. 4. The method according to claim 1 or 2, characterized in that the free acids are esterified goes out. : ν 409812/1209 970-9622 5. The method according to claim 1 or 2, characterized in that that one to the esterification of activated. Acid derivatives. 6. The method according to claim 5, characterized in that mixed anhydrides are used as activated acid derivatives. 7. The method according to claim 1, 2, 4, 5 or 6, characterized in that a Pentachloi— phenyl sulfite is used. 8. The method according to claim 1, 2, 4, 5 or 6, characterized characterized in that pentachlorophenol is used for the esterification. 9. The method according to claim 8, characterized in that the esterification is carried out in the presence of a condensation agent. 10. The method according to claim 9, characterized in that the condensing agent is dicyclohexylcarbodiimide or carbonyldiimidazole is used. 11. The method according to claim 1 or 3, characterized in that the ester cleavage by means of imidazole in Presence of small amounts of water. 409812/1209 970-9622 12. The method according to claim 1 or 3, characterized in that that the ester cleavage by means of dilute alkali or by means of organic bases in the presence of less Amounts of water. 13. The method according to claim 12, characterized in that that the ester cleavage is carried out in the presence of catalytic amounts of imidazole. 14. The method according to any one of the preceding claims, characterized in that one in an inert organic Solvent works. 409812/1209 - aar- 3 » 970-9622 Germany 15. Penicillins, penicillin sulfoxides or cephalosporins esterified by pentachlorophenyl radicals on the carboxyl groups and their derivatives. Compounds of formula I, CH. of formula II / R-HK
O = C J. CH ^ci x ^cl O = C ~ O ~ <f \ _C1 or of the formula III, III 409812/1209 - We- 970-9622 Germany in which jevicils the substituent R a) either a radical R-CH-CO- in which R _{1 is} phenyl, cyclohexyl, phenyl or cyclohexyl substituted by alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen, hydroxy or amino, for cyclohexadienyl, Thien-2 ~ yl, thien-3 ~ yl, 2,6-dimethoxyphenyl, 3 ~ o-chlorophenyl-5 ~ methylisoxazol-4 ~ yl or 3- (2,6-dichlorophenyl} -5-methylisoxazol-4-- yl stands, b) or a radical R-CO- in which R. the has the meaning mentioned above, c) or represents a radical R-O-CH-CO-, in which R. has the meaning given above and R for hydrogen, alkyl with 1-6 carbon atoms or phenyl, d) or for a .Rest R-S-CH-CO- in which R ₂ R, and R _? have the above meaning e) or a radical R-CO-, in which R stands for straight-chain or branched alkyl with 1-12 carbon atoms, straight-chain or branched alkyl interrupted by oxygen or sulfur with a total of 1-12 carbon atoms or cyano, 4098 12/1209 »70-9622 Germany f) or a radical R -CH-CO- in which R has the meaning given above and R. for a sulfonic acid residue, for azido, carboxyl, hydroxy, amino or by trityl, tritylsulfenyl, benzyloxycarbonyl ^ p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, o-nitrophenylsulfenyl or tert. Butyloxycarbonyl protected amino stands, g) or is formyl, h) or for Trityl, Tritylsulfenyl, Benzyloxycarbcnyl, p-Nitrobenzyloxycarbonyl), 2,2,2-Trichloräthyloxycarbonyl _r o-Nitrophenylsulfenyl or tert. Butyloxycarbonyl stands, 17. Compounds of the formulas I, II or III mentioned in claim 16, in which the substituent R in each case has the meaning R ¹ , where the radical R ^{1 is} phenylacetyl, thien ~ 2 ~ yl-acetyl, thien-3-yl-acetyl , 2,6-D.imethoxybenzoyl, 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl, 3- (2,6-dichlorophenyl) -5-methyl-isoxazoi-4-yl-carbonyl, phenoxyacetyl , ct-phenoxybutyryl, n-butoxyacetyl, cyanoacetyl, hexanoyl, ct-aminophenylacetyl, α-carboxyphenylacetyl, a-sulfonic acid-phenylacetyl, a-aitiino-p-hydroxyphenylacetyl, cx-airiino-cyclohxadienylacetyl, tert. Eutoxycarbonyl, benzyloxycarbonyl ^ -nitrobenzyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl or trityl. 409812/1209 97O-9C22 Germany 18, compounds of the formulas I, II or III mentioned in claim 16, in which the substituent R in each case has the meaning R ^1! where R ^{11 has} 2,6-dimethoxybenzoyl, 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl, 3- (2,6-diehlophenyl) -5-methyl-isoxazol-4-yl-carbonyl , Phenoxyacetyl or α-aminophenylacetyl means. 3700 / SP / GD Biochemie Ges.m.b.H. 409812/1209