CS228945B2 - Preparation of halogenmethyl esters of 6-substituted or 6,6-disubstituted 1,1-dioxides of penicillanic acid - Google Patents

Description

The present invention relates to a process for the preparation of 6-substituted and 6,6-disubstituted penicillanic acid 1,1-dioxide halides which are useful as intermediates for the preparation of penicillanic acid 1,1-dioxide 6-acyliaminopeinicilanoyloxymethyl esters.

U.S. Patent 4,234,579 discloses penicillanic acid 1,1-dioxide and esters thereof that are readily hydrolyzable in vivo, their use as antibacterial agents, and for enhancing the efficacy of (3-lactam antibiotics against many producing bacteria (Miaktaimase. Penicillanic Acid, its sulfoxides and certain esters thereof, but which do not include halomethyl esters or sulfonyloxymethyl esters, are mentioned as useful intermediates which, after oxidation, form penicillanic acid 1,1-dioxide.

U.S. Patent No. 4,244,951 discloses novel antibacterial agents wherein penicillinic acid 1,1-dioxide is bound to a known penicillin antibiotic via a methylenedioxy group of formula X

where.

R ^b is an acyl group of natural or semi-synthetic penicillin. The compound of formula X is prepared, for example, by reacting a penicillin carboxylate salt, such as a sodium, potassium or tertiary ammonium salt with a halomethyl ester (or a related ester) of penicillanic acid 1,1-dioxide. The halomethyl esters used as intermediates are prepared by esterification of penicillanic acid 1,1-dioxide.

Dutch Patent Application No. 8,000,775, and corresponding published British Patent Application No. 2,044,255 disclose compounds of Formula X that can be prepared from intermediates of Formula I. The compounds of Formula X and I are prepared in the same manner as disclosed in U.S. Patent No. 4 These applications also disclose chloromethyl-6,6-dibrompenicilanoic acid and compounds of formula

where

R3 is hydrogen or methyl,

X ¹ is a leaving group such as a halogen atom and

R 6 is a halogen atom.

6-.alpha.-chloro (1α, 6-.alpha.-bromo) penicillanic acid 1,1-dioxide halide methyl esters are prepared by esterification of the corresponding 6-.alpha.-halopenicillanic acid 1,1-dioxide and are also claimed in this patent.

European Patent Application No. 13,617 describes a process for the preparation of inhibitors of (3-lactamase of formula XII) and a process for their preparation from intermediates of formula XI

where

R ^e is (inter alia) a hydrogen atom or a halogen atom, n is 0, 1 or 2,

Y ^a is an isocyanate when R ^e is a hydrogen atom and Y ^a is an arylselenyl when R ^e is a chlorine atom,

R ^x is a hydrogen atom or a carboxyl protecting group, including certain tertiary ammonium salts and certain reactive ester-forming moieties such as benzyl, certain substituted bemzyl, certain tertiary alkyl, 2,2,2-trichloirethyl, trimethylsilyl or trialkyltin esters, by reaction of the compound of formula XI with triaryl tin hydride, dialkyl tin hydride or trialkyl tin hydride, optionally followed by one or more of the following steps:

i) converting the sulfide (n = 0), sulfoxide (n-1j or sulfone (n = 2) and various of these groups; ii) removing the carboxyl protecting group, if any; iii) converting the free acid into a pharmaceutically acceptable salt thereof.

U.S. Patent No. 3,996,235 claims 6-isocyano (C = N-substituted substituted penicillins, corresponding sulfoxides and their corresponding carboxylic acid salts and esters), as well as a process for their preparation from the corresponding 6- / 3-formylaminopenicilamates by reaction with phosgene in the presence of acceptors The products are isolated as mixtures of 6-.alpha.-isocynamo and 6- / 3-isocyanopenicillanates.

Barton et al., Journal of the Chemical Society (London J, Perkin I, 2657 (1980)) discloses the use of tri-n-butyltin hydride in the hydrogenolysis of aminoglycoside-derived isonitriles and isothiocyanates to form the corresponding hydrocarbons.

6-halo-penicillanic acids are disclosed in Cignarell ¹ et al., Journal of Organic Chemistry, 27, 2668 (1962) and in U.S. Patent No. 3,206,469. Hydrogenolysis of 6-halo-penicillanic acid on pemicillanic acid. 1,072 108.

Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) discloses (a) oxidation of 6,6-dibromopenilic acid by m-chloroperbenzoic acid to form a mixture corresponding to α- and (3-sulfoxides, b) oxidation of methyl ester 6,6-dibrompenicillanic acid with m-chloroperbenzoic acid to give 6,6-dibrompenicillanic acid methyl ester 1,1-dioxide; and d] oxidizing 6-bromo-p-encianoic acid methyl ester with m-chloroperbenzoic acid to form a mixture of the corresponding α-β-sulfoxides.

Clayton, Journal of the Chemical Society (London) (C), 2123, (1969), discloses (a) 6,6-dibromo and 6,6-diiodo-penicillanic acid, (b) oxidation of 6,6-dibromo-penicillanic acid with sodium periodate to forming a mixture of the corresponding sulfoxides, cj hydrogenolysis of 6,6-dibrompenicillanic acid methyl ester to form 6-α-bromopenicillanic acid methyl ester; Of 6-diiodopenicillanic acid and 6-iodopenicillanic acid methyl ester to give pure 6-iodopenicillanic acid methyl ester.

Belgian Patent No. 882,028 describes a process for the preparation of penicillanic acid 1,1-dioxide and its readily in vivo hydrolysable esters by oxidation of 6-halo-penicillanates or 6,6-di-halo-penicillanates to give the corresponding 1,1-dioxide and then dehalogenation to the desired 1,1-dioxide -dioxide penicillanate.

Description of the invention to MS. No. 228,919 describes a process for the preparation of penicillanic acid 1,1-dioxide halomethyl esters of the general formula I

O O

ch ₃ 'co ^ ch ^ x (I) where

X is chlorine, bromine or iodine. The compounds of formula I are useful as intermediates for preparing valuable antibiotics of formula X above. These compounds are particularly useful in the treatment of infections caused by β-lactarnasia producing bacteria. Particularly valuable compounds of formula X are those wherein R ^b is 2-amino-2-phenylacetyl, 2-amino-2- (4-hydroxyphenyl) acetyl, 2-amino-2- (4-hydroxyphenyl) acetyl, 2-kairboxy-2- phemylacetyl and pharmaceutically acceptable salts thereof.

The process of this patent, which has considerable advantages over the prior art processes for the preparation of compounds of formula I, consists in reducing the compound of formula VI

X is as defined for a compound of formula I, n is 0, 1 or 2,

Y and Z are both chlorine or bromine, or Y is hydrogen and Z is chlorine or bromine, hydrogen in the presence of a noble metal catalyst to form a compound of formula V

wherein n and X are as defined above, then when n is 0 or 1, the compound of formula V is oxidized with an oxidizing agent selected from the group consisting of potassium permanganate or m-chlorobenzoic acid to form a compound of formula I.

The reduction is carried out with hydrogen in the presence of a noble metal catalyst, and these catalysts are preferably nickel, palladium, platinum and rhodium, preferably in the presence of an inert solvent at a pressure of atmospheric to 9.8 MPa at a temperature of 0 to 60 °. C.

The preferred temperature range for the oxidation step is from -30 ° C to 60 ° C.

The invention also relates to a process for the preparation of 1,1-dioxo-intermediates of formula VIC

where

X, Y and Z are as defined for compound VI, characterized in that a sulfide or sulfoxide of the formula VID is oxidized wherein (O) n

XQlS ^c ^ Cw ₂ x (vn

wherein m is 0 or 1, and

X, Y and Z are as defined above with an oxidizing agent selected from the group consisting of potassium permanganate and m-chloroperbenzoic acid in the presence of a reaction of the inert solvent at a temperature of from -30 to 60 ° C.

Particularly preferred meanings of p and Y and Z are both bromine and

Y is hydrogen and

Z is bromo.

It is known from the literature that the above sulfoxides are present in both the β-configurations and mixtures thereof. All forms of the above sulfoxides are included within the scope of the invention.

The invention relates to a process for preparing penicillanic acid derivatives of the formula

In penicillanic acid derivatives, the dashed line (| | | j means that the substituent is attached below the plane on the bicyclic nucleus. Such a substituent has a--configuration. Conversely, a broad unbroken line indicates that the substituent is bonded above the plane to the bicyclic nucleus. Uninterrupted bond (............... j means that the substituent is attached to the bicyclic nucleus in either the α- or β-configuration.

As used in the description, the capital letters A, B or C placed after the Roman numerals denote chemical structures related to the meanings for η 0, 1 or 2. Thus, in the above Sultans of the formula VIC n - = 2, the corresponding sulfides, where n = 0 are designated VIA and the corresponding sulfoxides, where n = 1, are designated (VIB).

In the process of the invention wherein the starting compound is a compound of formula VID, wherein m is zero, using potassium permanganate, the reaction is conveniently carried out by reacting a compound of formula VID with 0.5 to 10 molar equivalents and preferably 1 to 4 molar equivalents. molar equivalents of permanganate in a suitable inert reaction system. If the compound of formula VID is a sulfoxide where m is 1, then about one-half of the total amount of potassium permanganate is used.

A suitable reaction-inert solvent system is one that does not react with either the starting materials or the product, and water is commonly used. Optionally, a water-miscible cosolvent is also used but does not react with permanganate, such as tetrahydrofuran or acetone. The reaction is carried out at a temperature in the range of -30 ° C to 60 ° C, and preferably the reaction is carried out at a temperature of from -10 ° C to 10 ° C. At 0 ° C, the reaction is normally completed in a short time, for example within two hours. While the reaction may be carried out under neutral, basic or acidic conditions, it is preferred to carry out the reaction at a pH in the range of 4 to 9. However, it is important to select conditions that prevent decomposition of the (3-lactam ring system of the final product). buffer the pH of the reaction medium to the area around the neutral reaction The product is recovered in a conventional manner Any excess of permanganate is normally decomposed using sodium bisulfite and once the product has been dissolved out of the solution is isolated by filtration. Alternatively, if the product does not precipitate from the solution at the end of the reaction, it is isolated by conventional extraction into a solvent.

If the compound of formula VID, wherein m is 0, is oxidized with m-chloroirbirbenzoic acid, then the reaction is conveniently carried out by reacting the starting compound with 1 to 6 molar equivalents, preferably 2.2 molar equivalents of the oxidizing agent in an inert organic solvent. As mentioned above, only half the amount of peroxycarboxylic acid is required when the corresponding sulfoxides of formula VID are used. Preferred organic solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is conveniently carried out at a temperature of from -30 to 60 ° C, preferably from 15 to 30 ° C. A reaction time of 2 to about 16 hours is commonly used at 25 ° C. The product is conveniently isolated by evaporation of the solvent in vacuo. The reaction product can be purified by conventional methods as described in the examples above.

The products of formula VIC are useful as intermediates for preparing esters of formula I as described above.

The following examples and preparations are given for further clarification only. Infrared spectra (IRJ) were measured in pure form or in potassium bromide tablets and diagnostic bands are given in cm ^-1 . Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz in deuterated chloroform (CDCl 3), water (D 10) solutions. and deuterated acetone (CD3COCD3J and peak positions are given in ppm down from tetramethylsilane. The following abbreviations are used for peak appearance: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet and dd-double doublet,

Example 1

Chloromethyl 6,6-dibrompenicilate

6.6 Dibromopenicilanic acid (8.0 g, 22 mmol) was stirred with 75 mL of methylene chloride and 35 mL of water was added. The pH was adjusted to 8 by addition of tetrabutylammonium hydroxide. The organic phase was separated and the aqueous phase was extracted with 30 ml of methylene chloride. The combined organic phases were evaporated to dryness in vacuo to give the tetrabutylammonium salt of 6,6-dibromopenicillanic acid 14.2 g as a light brown oil. To this oil was added 40 mL of chloroiodomethane and the resulting mixture was stirred at room temperature under nitrogen for three hours. The reaction mixture is concentrated in vacuo, the residue is allowed to stand overnight at room temperature and purified by chromatography on 300 g of silica gel, eluting with 95: 5 (v / v) toluene / ethyl acetate. The fractions containing the less polar material were combined and evaporated to give 5.4 g (59%) of the desired product, mp 105-106 ° C.

1 H-NMR (CDCl 3) ppm (delta):

1.6 (s, 3H);

1.75 (s, 3H).

4.62 (s, 1 H),

5.8 (dd, 2H).

5.82 (s, 1 H).

When the above procedure is repeated except that instead of chloro iodomethane equimolecular amounts bromochloromethane, diiodomethane, di (methylsulfonyloxy jmethanu dl (isobutylsulfonyloxy) methane, di (n-hexysulfonyloxy Jmethanu di (benzenesulphonyl Jmethanu or a compound of the formula (R ² C 6 H 4 SO ² O ¹² CH ² wherein R ² is

4-Cl, 2-B: r, 4-1, 3-NO2, 4-CH3, 3- (CH3) 2CH, 4-CH3O, 3-C2H5O or 4-n-C3H7O, obtained by:

bromomethyl-6,6-dibromopenicenilate, iodomethyl-6,6-dibromopenicenilate, methylsulphonyloxymethyl-6,6-dibromopenicilate, isobutylsulphonyloxymethyl-6,6-dibromopenicillanate, n-hexylsulphonyloxymethyl-6,6-dibromopentenesilane, and

R ² -C 6 H 4 -sulfonyloxymethyl-6,6-dibromo pemicilane, wherein

R ² is as defined above for the di (substituted fenylsulfonyloxyjmethanové reagent.

To 25 ml of acetone was added 4.15 g (10.2 mmol) of chloromethyl 6,6-dibromo-penicillanic acid and 7.5 g (50 mmol) of sodium iodide. The mixture was stirred at room temperature overnight and the acetone was evaporated to give a dark residue. The residue was dissolved in 150 mL of ethyl acetate, washed with water (3 X 25 mL), saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate and evaporated in vacuo to give an oil which was purified by chromatography on 100 g silica gel eluting 1: 1 (v / v ethyl acetate / hexane). A 30 m fraction was collected. The product was eluted in fractions 4-6 which were combined and evaporated to give 5.95 g of a colorless oil which crystallized on standing. to 68 ° C.

1 H-NMR (CDCl 3) ppm (delta):

1.55 (s, 3HJ,

1.65 (s, 3H);

4.54 (s, 1 H),

5.8 (s, 1 H),

5.98 (s, 2 H).

Example 2

Chloromethyl-6,6-dibromopenicenilate 1,1-dioxide

A solution of 7.1 g (17.4 mmol) of chloromethyl 6,6-dibromopenicillanate in 75 mL of ethyl acetate was cooled to 0 ° C and 7.3 g (36 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred under nitrogen at 0 ° C overnight, diluted to 150 mL with ethyl acetate and 50 mL water was added at 0 ° C. Sufficient sodium bisulfite is added to quench the excess peracid, the mixture is adjusted to pH 2 to pH 7.5 by the addition of sodium bicarbonate, the organic phase is separated, washed with 50 ml of saturated sodium bicarbonate, 50 ml of water and 25 ml of sodium chloride solution. The washed extracts are dried over magnesium sulphate, concentrated to dryness in vacuo and the residue purified by chromatography on 300 g of silica gel eluting with 9: 1 (v / v) toluene / hexane to give 5.0 g (65%) of the desired dioxide as a crystalline solid. mp 95-96 ° C.

@ ¹ H-NMR (CDCl3) ppm .delta.

1.5 (s, 3H).

1.7 (s. 3H),

4.58 (s, 1 H),

5.04 (s, 1 H),

5.8 (dd, 2 H).

For CgHioNOsSBrzCl:

Example 1A calculated:

H, 2.29; N, 3.18.

Iodomethyl-6,6-dibrompenicilate

IX found:

% C, 24.63;% H, 2.49;% N, 3.31.

A second more polar component (0.8 GJ isolated from column chromatography was identified as a mixture of 9: 1 «- / J sulfoxides chlormet.hyl-6,6-dibrompenicilainátu. Identification by ^X H NMR.

Example 2A

Iodomethyl-6,6-dibromopenicenilate 1,1-dioxide

Method 1

To 40 ml of acetone is added 0.25 g (0.5 mmol) of iodomethyl 6,6-dibromopenicilate and the mixture is stirred until complete dissolution, 10 ml of water are added and then the mixture is brought to pH 4 by addition of concentrated phosphoric acid. 0. 158 mg (1 mmol) of potassium permanganate powder are then added and the mixture is stirred at room temperature for 1.25 hours. Ethyl acetate (100 mL) and water (50 mL) were added and the mixture was adjusted to pH 2.0 by addition of 6 N hydrochloric acid. Addition of sodium bisulfite decomposes excess oxidizing agent (pH 2.9). The organic phase is separated, the aqueous phase is extracted with 50 ml of ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution (3 X 25 ml). After drying over anhydrous sodium sulfate and evaporating the solvent, 0.29 g of a colorless oil is obtained. The oil was purified by chromatography on 25 g silica gel eluting with 1: 1 ethyl acetate: hexane. 15 ml fractions were collected. Fractions 4 and 5 were combined and evaporated in vacuo to give 0.27 g (100%) of a colorless oil which crystallized on standing. Mp 71-73 ° C.

¹ H-NMR (CDCl 3) ppm (delta):

1.5 (s, 3H).

1.62 (s, 3H);

4.49 (s, 1 H),

5.02 (s, 1 H),

5.98 (dd, 2H).

By using an equivalent amount of sodium permanganate or calcium permanganate instead of potassium permanganate in the above process, the same product is obtained in the same manner.

Attempts preparation of iodomethyl penicillanate 1,1-dioxide-6,6-dibromopenicillanate of chloromethyl ester prepared in Example 2 by reaction with sodium iodide in acetone by the procedure of Example 1A gave iodomethyl 1,1-dioxide-6-b, rompenicilanátu ^X H NMR ( CDCl 3 ppm (delta):

1.55 (s, 3H);

1.70 (s, 3H);

4.43 (s, 1H),

5.2 (d, 1 H),

5.75 (d, 1H), 6.0 (dd, 2H).

Example 3

Iodomethyl-N-bromobenicenilate 1,1-dloxide

A solution of 0.12 g (0.33 mmol) of chloromethyl-6 (3-bromo-penicillanate) and 0.25 g (1.66 mmol) of sodium iodide in 5 ml of acetone was stirred at room temperature for 30 hours. the suspension was evaporated under reduced pressure and taken up in 50 ml of ethyl acetate, washed carefully with 2 X 10 ml of water, 10 ml of saturated sodium chloride solution and dried over anhydrous sodium sulphate, and the resulting solution was evaporated to give the title compound as a solid. Yield 0.14 g.

1 H-NMR (CDCl 3) ppm (delta):

1.45 (s, 3H);

1.65 (s, 3H);

4.5 (s, 1 H),

4.83 (d, 1 H),

5.42 (d, IH);

6.0 (dd, 2 H).

Example 4

6α-Bromo-penicillanic acid 1,1-dioxide

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-ol-triphenylicillanic acid was added 4 N sodium hydroxide solution until a stable pH of 7.2 was reached. This requires 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 for 10 minutes and then filtered. The phases are separated and the organic phase is discarded. The aqueous phase is then quickly poured into the oxidation mixture while stirring, which is prepared as follows.

In a 3 liter flask, 63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid are mixed. The mixture was stirred at 20 ° C for 15 minutes and then cooled to 0 ° C.

The 6S-bromopenicillanic acid solution is then added to the bath-cooled oxidation mixture at -15 ° C. The internal temperature rises to 15 ° C and then drops to 5 ° C in 20 minutes. After this time, 30.0 g of sodium bisulfite was added with stirring, and the reaction mixture was stirred at 10 ° C for 10 minutes. After a further 15 minutes the mixture was filtered, the filtrate was lowered to pH 1.2 by addition of 170 ml of 6 N hydrochloric acid. The aqueous phase was extracted with chloroform and then with ethyl acetate. Both the chloroform and ethyl acetate extracts were dried over magnesium sulfate and then evaporated in vacuo. The heparin solution provided 10.0 g (16% yield) of the title compound The ethyl acetate solution gave 57 g of an oil which was poured into hexane to give a white solid.

228943, 41.5 g (66% yield) of the title compound, mp 134 ° C (dec.).

For CsHioBirNOsS:

calculated:

% C, 30.78;% H, 3.23;

4.49 O / O N, 10.27% S; found:

31.05% C, 3.24% H, 25.54% Br,

4.66% N, 10.21 0 / o S.

Oxidation of the 6α-chloropenicillanic acid and the .alpha.-β-diphemicillanic acid with potassium permanganate according to the above procedure affords the .beta.-chloro-penicillanic acid 1,1-dioxide and 6a-.alpha.-pentaemicillanic acid 1,1-dioxide.

Example 5

6/1-Chloro-penicillanic acid 1,1-dioxide

An oxidation solution is prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of 6 ' -dichlorpenicillanic acid sodium salt in 5 ml of water. Add dropwise at 0-5 ° C until the violet color of potassium permanganate is maintained. This requires approximately one-half of the oxidation solution. The violet color of potassium permanganate was removed by addition of sodium bisulfite and the reaction mixture was filtered. Ethyl acetate was added to the filtrate and the pH was adjusted to 1.8. The phases were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate phases were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound.

The NMR spectrum (in CD3COCD3) shows bands at:

5.82 (d, IH);

5.24 (d, 1 H),

4.53 (s, 1 H),

1.62 (s, 3H);

1.50 (s, 3H) ppm.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 by addition of dilute sodium hydroxide solution, the tetrahydrofuran was evaporated in vacuo and the remaining aqueous solution was lyophilized. This gives the sodium salt of the title compound.

Example 6

6R-bromopenicillanic acid 1,1-dioxide

To a solution of 255 mg of 6/3-bromo-penicillanic acid sodium in 5 ml of water at 0 to 5 ° C is added a solution prepared from 140 g of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water at 0 to 5 ° C. During the addition, the pH is maintained between 6.0 and

6.4. The reaction mixture was stirred at pH 6.3 for 15 minutes and then the violet solution was overlaid with ethyl acetate. The pH was adjusted to 1.7 and 330 mg of sodium bisulfite was added. After 5 minutes, the phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. This gave 216 mg of the title compound as white crystals.

The NMR spectrum (D2O) shows bands at:

5.78 (d, 1 H,

J = 4Hz)

5.25 (d, 1 H, I = 4 Hz),

4.20 (s, 1 H),

1.65 (s, 3H);

1.46 (s, 3H) ppm.

Claims (1)

SUBJECT A process for the preparation of 6-substituted or 6,6-disubstituted halomethyl esters Pemicillanic acid 1,1-dioxide of formula VIC wherein X is a chlorine, bromine or iodine atom and both Y and Z are chlorine or bromine atoms; Y is hydrogen and Z is chlorine or bromine, OF THE INVENTION characterized in that a sulfide or sulfoxide of the formula VID is oxidized wherein m is 0 or 1 and X, Y and Z are as defined above, an oxidizing agent selected from the group consisting of potassium permanganate or m-ehilorperbenzoic acid, in the presence of an inert solvent reaction at a temperature of from -30 to 60 ° C. AND Severografia, n. P „závod 7, Most price 2,40 Kcs