CS208473B2 - Method of making the 1 alpha-oxide of the penicilane acid - Google Patents

Description

(54) A method for producing 1alpha-penicillanic acid

The present invention relates to a process for the preparation of .alpha.-penicillanic acid oxide useful as an intermediate for the preparation of the novel penicillinic acid 1,1-dioxide and esters thereof.

The intermediate produced by the process of the invention can be used for the preparation of the novel penicillanic acid 1,1-dioxide and its esters, readily hydrolyzable in vivo, which are useful as oitibacterial agents and, in addition, increase the effectiveness of some beta-lactam antibiotics against numerous prolonging bacteria. - beta-lactctimase, as described in our related patent specification 208,472.

Well-known and widely used antibacterial agents include beta-lactam antibiotics. These compounds are characterized by the presence of a core containing a 2-azetidinone (beta-1-cam) ring, not fused to a thiazolidine or 1,3-thiazine ring. If the core contains a thiazolidine ring, such compounds are referred to as penicillins, whereas in the presence of a dihydrothiazine ring they are cephalosporins. Typical examples of penicillins commonly used in clinical practice include bennylpinnine (penncilin G), phenoxymethylpentine (peincillin V, ampineH and carbennicin).

Typical examples of conventional cephalosporins include cephalothin, cephalexin and cephaloline.

Although beta-1k antibiotics are widely used and useful as valuable chemotherapeutic agents, however, the main disadvantage is that certain substances in this group are not effective against certain microorganisms. Resistance of a particular microorganism to a given beta-1-beta-antibiotic antibiotic is believed to be due to the fact that the microorganism produces an enzyme that cleaves the beta-glucose ring cleavage of percillins and cephalospherins to produce products with no antibacterial activity. However, some agents have the ability to inhibit beta-lactamase and, when used in combination with the appropriate penicillin or cephalosporin, can enhance or enhance the antibacterial activity of either β-lactamase or cephalosporin against certain microorganisms. It is believed that an increase in aatibacterial efficacy occurs when the β-lactate and the efficacy of the combination of the substance by inhibiting beta-lactase and beta-acacia antibiotic are significantly higher than the sum of the β-lactate efficacy of the individual components.

Our co-pending U.S. Patent No. 208,472 discloses certain novel penicillin series compounds useful as tetibacterial agents as well as potent bett-lacttmts inhibitors. These new compounds are

Penicillinic acid dioxide and its esters readily hydrolyzable in vivo.

The above-mentioned Czechoslovak patent specification describes a process for the production of new derivatives

Penicillinic acid dioxide of the formula I

.. O-O (I) in which

R represents a hydrogen atom or an ester residue readily hydrolyzable in vivo, and pharmaceutically acceptable salts of those compounds in which R represents a hydrogen atom.

Z ^H 3 CH ₃ COOR

The above-mentioned ester residues readily hydrolyzable in vivo are non-ester ester residues which are rapidly cleaved in the blood or tissue of an animal to regenerate the corresponding free acid, i.e., a compound of formula I wherein R is hydrogen. Typical examples of these ester radicals include a C 3 -C 8 -cyclooyloxy-ethyl group, a C 4 -C 9 -cyclooyloxyethyl group, a C 5 -C 10 -cyclooyl- (1-isocyloxy) ethyl group. carbon atoms tlkoxyktrbonyloxyietlцylovou group having 3-6 carbon atoms, 1- (benzyloxy tlkoxyktrbOIe ^г) ethylovol - group with 4 and $ 7 carbon atoms, 1-iethy1-1- (tlkoxykerbOln ^of loэχУ ethyl having from 5 to - 8 carbon atoms, a 1-phthaldyl group, a 4-crotonoltctonyl group, or a tert -butylacton-4-yl group.

According to our above-mentioned Czechoslovak patent specification, the process for the production of the above-mentioned compounds is characterized in that the compound of formula II,

(II)

O 0 in which Ξ ^f

X is -S-, -S- or -S-, and R 1 has the same meaning as R or is a carboxyl-protecting group, oxidized with an oxidizing agent to form an oxooxide of formula I '

'COOR (Γ) in which r' is as defined above, optionally from which the carboxyl function protecting group R @ 1 is cleaved and the product of formula I in which R is hydrogen is optionally converted by treatment with a base into its pharmaceutically acceptable salt ·

The starting materials of formula (II) above are novel compounds.

The novel compounds of the above formulas I and II are named as penicillanic acid derivatives, which can be represented by formula III (III).

In the above formulas, the dotted line denotes bicyclic core substituents that are below the plane of the core. Typically, the configuration of such a substituent is referred to as the alpha configuration. On the other hand, crosslinking refers to substituents that are above the plane of the bicyclic nucleus, this configuration being referred to as the beta configuration.

The terms 4-crotonolactonyl and gamma-butyrolacton-4-yl refer to residues of the following formulas IV and V.

(IV)

If R in the compound of formula (I) is an ester moiety readily hydrolyzable in vivo, it is, of course, an alcohol-derived group of formula R-OH, so that the -COOR moiety in the compound of formula (I) is an ester moiety. The residue R is such that the -COOR moiety readily cleaves in vivo to release the carboxyl group. Thus, R represents a group of the type such that when a compound of formula I in which R is an ester residue readily hydrolyzable in vivo is exposed to the blood or tissue of a mammal, a readily corresponding compound of formula I in which R is hydrogen is formed. Such R groups are generally known in penicillin chemistry. Furthermore, the radical R is intended to confer pharmaceutically acceptable properties on the compound of formula (I) and to permit the release of pharmaceutically acceptable fragments upon cleavage in (vii).

Typical R groups are 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl and radicals of formulas VI and VII,

(VI) (VII) where

R ³ and R independently znaineeají DIST ^Y is hydrogen, methyl or ethyl and R is an alkyl group having 1 to 6 carbon atoms.

Preferred radicals for R are, however, the groups listed above for Formula I.

The present invention relates to a process for the preparation of .alpha.

COOH (IIa) characterized in that the compound of formula X,

O

(X) in which

R 'represents a hydrogen atom or a benzyl group, subjected to hydrogenolysis.

Hydrogenolysis of the invention will debromination starting lalpha-oxide, 6,6-dlbrompeniciltmové acid and optionally for simultaneous cleavage of the benzyl group in the event that the starting qateriál used bennylester above acid (compound vzorce.X ^wh e ^R1 is a benzyl group).

The throrogenolysis according to the invention is carried out by treating a solution of .alpha.-alpha acid

6.6. The mixture is stirred or shaken under an atmosphere of hydrogen, or a mixture of hydrogen with an inert gaseous diluent, such as nitrogen or argon, in the presence of hydrogen. Aqueous solvents for this hydrogenolysis are lower alkanol moles such as methanol, ethers such as tetrachloride, dihydrate, and dioxane, lower esters such as ethyl acetate, and the like. Acetic acid, water and mixtures of these solvents are generally used, such that the dibromo derivative is usually dissolved in the solvent. The catalyst is usually used in an amount of from about 10% by weight, based on the dibromo derivative, up to the same weight as the dibromolate used, although higher levels may be used. the compound of formula IIIa simply isolates after from filtering the catalyst by evaporating the solvent in vacuo.

Default lalpha-oxide of 6 _l 6-dibгompenacilaasvé is prepared by oxidation of

6.6-dibromopenacilane using 1 equivalent of 3-benzo-benzoic acid in tetrahydrofuran at 0 to 25 ° C, usually for 1 hour. The procedure is that described by Harrison. et al., J Chem. Soc. (London), Perlin I, 1976. I. 772. Kisldna 6,6-dibromo-propyl and ava is prepared according to the procedure of Clann, J. Chem. Soc. (London), I969. 2 I23 (O.

The compound of formula IIa, produced according to the invention can be conveniently este ^^ k ^ ^CI bilge obsahuuící converted into an ester such as an ester of ^the above ^b yte tofinovaný from ^the TE ^to easily ^rI hydrsl ^yz svatr1ný in vivo. In ^{EXAMPLE IP} e ^{d that R} is 3-fial ^d dy ^of oats Sapin, 4-krsisno ¹ if ⁱ o and ^y nominal group gamвe ^b bjyrola ^the Toa-4-y1svou or a radical of the formula VI or VII wherein R ³ , r 'and r 1 are as defined above, the compound of formula (IIa) may be reacted with 3-phthallyl 1 -sulfonyl, 4-crotonoyl halide, gamma-buil-lacton-4-yl-halide. or with a compound of formula VIII or IX,

V (viii)

q-C-O-C-R

R ³

II

QCOCOR ²

R ⁴ (Ш where

Q 'represents a halogen atom and

· R ^3, R ⁴ and ^{R 5} mei ^£ Stora defined.

By halogen or halide is meant chlorine, bromine and iodine atoms and derivatives. The reaction is conveniently carried out by dissolving the salt of the compound of formula (IIa) in a suitable polar organic solvent, such as in Ν, Ν-dimethylforraamide, and adding about 1 moleldvalent of the aforementioned halide. After the reaction is complete, the product is isolated in the usual manner. In this case, a simple dilution of the reaction mixture with an excess of water, extraction of the product with a water-immiscible organic solvent and subsequent evaporation of the solvent is often sufficient.

Alkali metal salts, such as sodium and potassium salts, and salts with tertiary amines such as thietylethylamine, N-ethylpipeeidine, Ν, Ν-dimethlialiline and N-meetylmorpholine are generally used as starting salts in this reaction. . The reaction is carried out at a temperature of about 0 to 100 ° C, usually at about 25 ° C. The reaction time required to complete the reaction varies depending on a number of factors, such as the concentration of the reactants and the reactivity of the individual reaction components. Thus, as far as talogene derivatives are concerned, iodides react faster than chlorides. In the case of killing of the chlorine derivatives, it is sometimes advantageous to add up to 1 mol of alkali metal iodide to the reaction mixture, thereby urging the reaction. Given all these factors, the reaction time usually ranges from 1 to 24 hours.

Similarly, the carboxyl group of this compound may be protected by introducing a suitable carboxyl function protecting group prior to further use of the compound of formula IIa produced by the process of the invention.

The compound of formula IIa is acidic in nature and can form salts with basic agents. These salts can be prepared by methods known per se, which are also within the scope of the invention, for example by mixing acidic and basic components, usually in a 1: 1 molar ratio, in an aqueous, non-aqueous or partially aqueous medium. The resulting salts are then isolated by filtration, solvent precipitation, or, in the case of aqueous solutions, by II -ophilization. Bases useful in the preparation of salts may be organic or inorganic, and examples of suitable bases include ammonium, organic amines, hydroxides, carbonates, carbonates, alkali metal hydrides and alkoxides, and alkali metal hydroxides, carbonates, hydrides, and alkoxides. alkaline earth metals.

Representative of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, and oktylamil, sekundární- amines such dimethylemin, moorolin, Oio ^e oyrrolidil and controls a tertiary amine such triehyLlmii, Ne piperidine, N-methhide, and 1,5-diazabicyclo [4.3.0] 10-1-el, hydroxides such as sodium, potassium, ammonium and bulbous hydroxides, alkoxides such as sodium and potassium ethoxide, .

hydrides, such as calcium hydride and sodium hydride, nitrates, such as potassium and sodium carbonate, potassium ethers, such as sodium carbonate and potassium hydrogel, and alkali metal salts of long-chain fatty acids, such as latrile-2-ethyl ethyltexeloate.

Preferred salts of the compound of formula (IIa) are the sodium, potassium and erythlyl ammonium salts.

The invention is illustrated by the following non-limiting examples.

Infrared spectra were measured in compressed tablets bromide draselrým or chloroform and ^b ssrpční strips, UVA dreams in ^d '. in a floating ^Th ec ^h (cm). The sp-spectra was measured at 6060 MHz in chloroform (CDCl 3) or perdeuterovirus dimethylsulfoxide (DMSO-dd), and the position of the signal is expressed in ppm against tetramethylsilane or sodium acid stendard.

Example 1

1Alpha-penicillanic acid oxide

1.4 g of 5% Pd on calcium carbonate are prehydrogenated in 50 mL of water and a solution of 1.39 g of 6,6-bromobenzene p-benzyl ester in 50 ml of tetrahydrofuran is added. The reaction mixture was shaken under an atmosphere of hydrogen at about 0.32 M @ 2 for 1 hour, at 25 ° C, filtered, and the filtrate concentrated in vacuo to remove the major portion of tetratydrobran. The aqueous residue is extracted with ether and 0.5 g of the material is obtained by concentrating the ether extract, which is predominantly .alpha.-benzyl ester of penicillanic acid.

This isolated portion was mixed with another portion (2.0 g) of 6,6-dibromopentanoic acid benzyl ester, 1-phthalate, dissolved in 50 ml of tetralydrofuran, added to a suspension of 4.0 g of 5% palladium on calcium carbonate. in 50 ml of water, and the mixture was triturated overnight ^P ev atmoolTéře hydrogen at a pressure of about ^0, 3 ² MPa at rt te ^{pl of 2} 5 ° C. ^p o ^^ r ^ is t ^fil Tr ^and extracted with ether, the extract was concentrated in vacuo and the residue purified ctaromatoorrafí on silica gel eluting with chloroform. 0.50 g of product is obtained.

This reagent was hydrogenated again at 0.32 M @ 2 and at 25 DEG C. in a 1: 1 mixture of water and methanol in the presence of 0.50 g of 5% palladium on calcium carbonate for 2 hours, then added. another portion of 0.50 g of 5% palladium on calcium carbonate and hydrogenation at 0.32 M @ 2 at 25 DEG C. was continued overnight. The reaction mixture is filtered, the filtrate is extracted with ether, the ethereal extract is discarded, the pH of the remaining aqueous phase is adjusted to 1.5 and further extraction with ethyl ether ether is carried out. The solution in this solvent was dried over anhydrous sodium sulfate, and 0.14 g of penicillanic acid was isolated by concentration in vacuo.

The Msr spectrum in CDClyDSSO-dg contains signals at 1.4 (singlet, 3H), 1.64 (singlet, 3H), 3.60 µplet, 2H), 4.3 (singlet, 1H) and 4, 54 (muutiplet, 1 H) ppm ·

In infračervnném with ^p ektru ^{(bromo- l dd} rtpe ^Oy) ^ sy are at ¹⁷⁹⁵ and ^{1745 cm} '.

Example 2

1Alpha-penicillanic acid oxide

1.0 g of 5% palladium on calcium carbonate is added to 30 ml of water, the suspension is prehydrogenated, and a solution of 1.0 g of 6,6-carboxylic acid, 6,6-carboxylic acid, is added. . The reaction mixture was shaken for 1 hour in hydrogen thiosphere under a pressure of approximately 0.32 M @ 2 and at 25 DEG C., then filtered and the filtrate was concentrated in vacuo to give methanol. The remaining aqueous portion was diluted with a moderate volume of water, the pH of the solution was adjusted to 7, the solution was washed with ether, the aqueous portion acidified to pH 2 by addition of dilute hydrochloric acid, and the acidic portion was extracted with acetic acid. The solution in this solvent is dried over anhydrous sodium sulphate and concentrated under vacuum to isolate laphthalic anhydride, the characteristics of which correspond to those of Example 1.

The following describes the preparation of the starting materials used in the preceding examples:

6,6-Diboompenicillinic acid

The title compound was prepared by oxidation of 6,6-dibromopenicillanic acid with 1 equivalent of acid-NY-C 3 ^H lorperbenzoové in tetaah ^, THF at ⁰ to 25 ° C for 1 hour, to poožití procedure poppsai Harrison · SPPO. J. Chem. Soc. (London), Perkin I, 197 < 6. 1 772.

Preparation

6,6-Dibromopenicillanic acid benzyl ester

To a solution of 54 g (0.165 mol) of 6,6-dibromopenicenic acid in 350 ml of Ν, Ν-dimethihetiacetamide is added 22.9 m (0.165 mol) of triethylamine. The solution was stirred for 40 minutes, 19.6 ml of benzyl bromide (0.165 mol) was added and the reaction mixture was stirred at room temperature for 48 hours. The precipitated trifluoride hydrobromide is filtered off, 1500 ml of ice water are added to the filtrate, the pH is adjusted to 2, the mixture is extracted with ether, the combined extracts are washed successively with a saturated solution of sodium bicarbonate and sodium chloride, then with ether It is dried over anhydrous magnesium sulphate and the solvent is removed in vacuo. To give an off-white solid which, after re-Ysta-CONTRARY TO of iso-propylamino-l-co-lu gives 7 ⁰ 0 ^{g (95%)} slouteni ^ uvefoné in ntov ^ melting ^at 75 and ⁷⁶ ° C.

^{V i e} iiřlč ereiném spectrum ^(dd raselný romi ^b) are ^{p p} říoomny Asa ¹⁷⁹⁵ 1 74 ⁰ cm "'.

In the NM-Spectrum in CDCC, signals at 1.53 (singlet, 3H), 1.58 (singlet,

3), 4.50 (singlet, 1H), 5.13 (singlet, 2H), 5.72 (singlet, 1H) and 7.37 (singlet, 5H) ppm.

and α 1 α-α-η 6 -dimido-2-chloroic acid renin ester

To a stirred solution of 13.4 g (0.03 mol) of 6,6-renizjesteru diboompenicianoové in ²⁰⁰ ml ^ cOLormettonu with ^p ^ s pulse of about 0 · ° C with a solution of ^{6.12 g} ^ ^(0, 03 mo ^o) of 3-chloroperbenzoic acid in 100 ml of phthloromethane. The reaction mixture was stirred at the same temperature for 1.5 hours, then filtered, washed successively with 5% aqueous sodium hydrogencarbonate solution and water, and then dried over anhydrous sodium sulfate. After distilling off the solvent from the filtrate in vacuo, 12.5 g of the title compound is obtained as an oil. Trituration with ether solidified the oil and solids were collected to give 10.5 g of 6,6-diboomrenitinic acid benzo-β-ester as a solid.

^In inflata ^e evniném spectrum (cOLoroform) are ^straight ioomny sy ^ ^p s 1 .a ⁸ 00 ¹ 7150 cm ''.

The NM-product spectrum (CDCC) contains signals at 1.3 (singlet, 3H), 1.5 (singlet, 3H), 4.5 (singlet, 1H), 5.18 (singlet, 2H), 5.2 (singlet, 1H) and 7.3 (singlet, 5H) ppm.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of 1alpha-penacillanic acid of the formula IIIa, COOH characterized in that the compound of formula X, (X) in any one of: R is hydrogen or nibo binoyl, subjected to hydrogenolysis. ’ 2. A process according to claim 1, wherein the hydroginolysis is carried out in the presence of a catalytic bridge of palladium on calcium carbonate. 3. Method according to point 1. Nibo 2, i.e., by carrying out hydroginolysis in a group selected from the group consisting of lower alkanols, low-molecular-weight esters, water and mixtures of these ro-surfactants. 4. A process according to any one of claims 1 to 3, characterized in that the hydrogenolysis is carried out at a pressure ranging from atmospheric pressure to 0.35%. Sevarografia. n. plant 7, Most