CA1142174A - Method for producing penicillanic acid derivatives - Google Patents
Method for producing penicillanic acid derivativesInfo
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- CA1142174A CA1142174A CA000362093A CA362093A CA1142174A CA 1142174 A CA1142174 A CA 1142174A CA 000362093 A CA000362093 A CA 000362093A CA 362093 A CA362093 A CA 362093A CA 1142174 A CA1142174 A CA 1142174A
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- esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Cephalosporin Compounds (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
An improved process is provided herein for producing a compound of the formula I
I
in which R1 stands for hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group, the compounds of formula I, depending upon the meanings of R1 and R2, being of value at .beta.-lactamase inhibitors and/or antibiotics, and/or as intermediates in the production of antibiotics and/or .beta.-lactamase inhibitors. According to the improved process, certain penicillanic acid derivatives or their sulfoxides are oxidized to the corresponding sulphones with hydrogen peroxide in the presence of a tungsten or molybdenum catalyst. This new process eliminates secondary degradative oxidative side reactions and simplifies the isolation and purification of the product, thus providing high yields and thereby being particularly suited for large scale produc-tion.
An improved process is provided herein for producing a compound of the formula I
I
in which R1 stands for hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group, the compounds of formula I, depending upon the meanings of R1 and R2, being of value at .beta.-lactamase inhibitors and/or antibiotics, and/or as intermediates in the production of antibiotics and/or .beta.-lactamase inhibitors. According to the improved process, certain penicillanic acid derivatives or their sulfoxides are oxidized to the corresponding sulphones with hydrogen peroxide in the presence of a tungsten or molybdenum catalyst. This new process eliminates secondary degradative oxidative side reactions and simplifies the isolation and purification of the product, thus providing high yields and thereby being particularly suited for large scale produc-tion.
Description
1~421q4 The present invention relates to a new and improved process for producing a compound of the formula I
H
R
O= -N
in which Rl stands for hydrogen, alkyl, alkoxy, halogen, or trifluoro-methyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group.
According to the prior art, some of the compounds of formula I
have been prepared by oxidation of a compound of formula II or formula III:
R
in which Rl and R2 have the above meanings, or a salt thereof as defined above.
According to German patent application, laid-open-number
H
R
O= -N
in which Rl stands for hydrogen, alkyl, alkoxy, halogen, or trifluoro-methyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group.
According to the prior art, some of the compounds of formula I
have been prepared by oxidation of a compound of formula II or formula III:
R
in which Rl and R2 have the above meanings, or a salt thereof as defined above.
According to German patent application, laid-open-number
2,824,535 and European patent application No. 2927, publ. July 11, 1979, this oxidation can be carried through, using a number of oxidizing agents known in the technique for oxidizing sulphides or sulphoxides to sulphones.
According to that prior art, the oxidation is advantageously performed using metal permanganates, e.g., ~I;ali metal permanganates and alkaline earth metal permanganates, or by using organic peroxycarboxylic acids, e.g., 3-chloroperbenzoic acid nnd peracetic acid. These processes, how-ever, tend to give problems, in p~rticular when applied on a large scale, in the form of lower yields and/or technical difficulties, e.g., filtra-tion problems.
The oxidation of simple organic sulphides into the corresponding sulphones has also been described by using hydrogen peroxide in the presence of a suitable catalyst (J. Org. Chem., Vol. 28 (1963), p. 1140-42). However, when applied to penam-derivatives, this process has pre-viously only led to sulphoxides. Thus, ~nited States Patent No. 3,993,646 describes a process for converting compounds of formula II to compounds of formula III by subjecting the first-mentioned to an oxidation process using peracids, salts of peracids, or hydrogen peroxide as oxidizing agent, in the presence of a compound containing a metal of group Vb or VIb of the Periodic Table.
It has now surprisingly been shown that it is possible to oxidize certain penicillanic acid derivatives or their sulfoxides to the corresponding sulphones without destroying the lactam ring by using the mild oxidizing agent, hydrogen peroxide, provided a tungsten or molybdenum catalyst is present. This process eliminates secondary degradative oxidative side reactions and simplifies the isolation and purification of the product, thus providing high yields and thereby being particularly suited for large scale production.
Thus, according to a broad aspect of the present invention, a process is provided for producing a compound of the Formula I
Rl H O O
~, ' S
O=C N ~ R
in which Rl stand for hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl~
and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 ls a carboxy group or R2 contains a basic or acidic group, which process comprises sub~ecting a compound of the formula II or III
R H ll ~ ,~ 1 " r--O=C N ~" 0=C _ N - _ II ~ 2 III R2 in which Rl and R2 have the above meanings, or a salt thereof as defined above, to an oxidation process using hydrogen peroxide as oxidizing agent in the presence of a tungsten or molybdenum catalyst.
By a variant thereof, the oxidation process is carried out in a suitable solvent at a temperature between the boiling point of the solvent used and a temperature at or below room temperature.
By a variation thereof, the temperature is from 20C. to 30C.
By another variant, the catalyst is used in the form of a salt.
By another variant, Rl represents hydrogen and R2 is a carboxy group.
By another variant, Rl represents bromine and R2 is a carboxy 2Q group.
By another variant, Rl represents hydrogen and R2 is -COOCH2Cl.
By another variant, Rl represents bromine and R2 is -COOCH2Cl.
By another variant, a salt of a compound of Formula I is formed.
Depending upon the meanings of Rl and R2, the compounds of For-mula I are of value as ~ -lactamase inhibitors and/or antibiotics, and/or as intermediates in the production of antibiotics and/or ~ -lactamase inhibitors.
Rl may preferably represent a member selected from the group con-sisting of hydrogen, chlorine and bromine.
114Z~.74 When R2 stands for an esterified carboxy group, it may both represent an ester group which is easily hydrolyzable either spontaneously or under the influence of esterases, or an ester group which can be cleaved by hydrogenolysis. ~en R2 represents an ~-haloalkyl ester group, the compound of formula I i9 a useful intermediate. The easily hydroly~able esters are well known types of esters, e.g., acyloxyalkyl esters, e.g., alkanoyloxyalkyl esters, e.g., acetoxymethyl and pivaloyloxy-methyl esters and the corresponding l-acetoxyethyl and l-pivaloyloxyethyl esters, alkoxycarbonyloxyalkyl esters, e.g., methoxycarbonyloxymethyl and l-ethoxycarbonyloxyethyl esters, lactonyl esters, e.g., phthalidyl esters, or lower alkoxymethyl and acylaminomethyl esters. Examples of other useful esters are the lower alkyl esters, the benzyl esters, the haloalkyl esters, e.g., the chloromethyl esters, and the cyanomethyl esters.
The salts of Formula I may be formed by any basic or acidic group present in R2 reacting with suitable acids or bases, respectively. If the compounds of Formula I are to be used as ~ -lactamase inhibitors or anti-biotics, the salt-forming acid or base should be pharmaceutically accep-table and non-toxic, whereas if the compound of Formula I is an inter-mediate, then any acid or base which is stuiable with a view to the use of the intermediate may be applied in the salt formation.
The salts of the compounds of Formula I are thus, in addition to their inner salts (zwitterions) salts, formed with non-toxid pharmaceuti-cally acceptable acids, e.g., hydrochloric acid, phosphoric acid, nitric acidS p-toluenesulphonic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc., but any pharmaceutically acceptable, non-toxic inorganic or organic acids can be used as well.
Also included in the invention are the process for the prepara-tion of salts with pharmaceutically acceptable, non-toxic, inorganic or orgsnic bases, e.g., alkali met~l q~lts and :lhaline earth metal salts, .
~i42174 for example, sodium, potassium, magneslum or calcium salts, as well as salts with ammonia or suitable non-toxic amines, e.g., lower alkyl amines, for example triethylamine, hydrnxy-lower alkylamine5, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, cycloalkylamines, for example dicyclohexylamine, or benæylamines, for example N,N'-dibenzyl-ethylenediamine, and diben~ylamine, without these examples limiting the invention. Thus, for instance, other antibiotics with acid or basic character can be used as components of such salts of the compounds of Formula I.
According to an aspect of the present invention, the oxidation is generally performed by dissolving the starting material of Formula II or III or a salt thereof in water, or, if insoluble in water, in a suitable organic solvent. The catalyst is dissolved in water or a suitable organic solvent, the two solutions are mixed, and hydrogen peroxide is added to the mixture either in one portion or gradually, with efficient stirring, pre-ferably keeping the reaction temperature at or below room temperature.
Even if the starting material of Formula II or III has limited solubility in water, it is possible, with good stirring, to carry the present process through in aqueous medium with a satisfactory result. In case of extreme insolubility of the starting material, water-miscible sol-vents, e.g., an alkanol or dioxane, may be added. Water-immiscible sol-vents may be applied as well, provided a phase transfer catalyst, e.g., a quaternary ammonium salt, e.g., tetrabutylammonium bromide, is added.
Examples of suitable organic reaction media include, but are not limited to the following: alkanols, e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, dialkyl ethers, lower alkyl esters of lower fatty acids, unsubstituted or substituted aliphatic and aromatic hydrocarbons, tetrahydrofuran, dimethylformamid~, and hexamethylphosphoric acid triamide.
Examples of preferred organic reaction medla are ethanol, isppropanol, methylene chloride and tetrahydrofuran.
. The need for an efficient cooling may be particularly approp-riate during the conversion of the sulphide into the sulphoxide because the reaction rate is high, and the reaction is exothermic, whereas the conversion from sulphoxide to sulphone needs heating or a longer reaction time at ambient temperatures.
The process of aspects of the present invetnion is of specific interest also in the preparation of certain esters of Formula I, in parti-cular the important intermediates of Formula Ia:
Rl H ~S~
~ ~ Ia O=C - N "
COOIH-X
in which Rl has the above meanings, R3 is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical, preferably hydrogen, methyl, phenyl or benzyl, and X stands for a halogen atom, preferably chlorine. The com-pounds of Formula Ia are important intermediates in the production ofdi-esters of the Formula IV:
R ~ ~ ~ ~ ` IV
O=C 'lc-o-lcH-O-c-R4 in which Rl and R2 have the above meanings, and ~4C0- represents the acyl radical of a penicillin, or an amidinopenicillanoyl radical.
The compounds of Fol~ula Ia can be prep~red according to the 1~42174 fo]lowing reaction scheme:
OOM 3 ~COO~HX Ia V VI ~II R3 ) = oxidation according to the process of an aspect of the present inven-tion in which reaction scheme Rl, R3 and X have the above meanings, M
stands for a cation, e.g., Na , K , an ammonium ion, a trialkylammonium ion or a tetraalkylammonium ion, e.g., a tetrabutylammonium ion, and Y
stands for a bromine or iodine atom or for an alliylsulphonyloxy, halo-sulphonyloxy, ~C-halo-alkoxysulphonyloxy, or arylsulphonyloxy radical.
The esterification process V VII is performed in a suitable solvent, e.g., dimethyl formamide, acetone or hexamethylphosphoric acid triamide, for sufficient time and at an adequate temperature with a view to accomplishing the desired conversion, usually at a temperature from 0C. to 60C.
The compounds of Formula Ia may also be produced by first sub-jecting a compound of Formula V to the oxidation process of an aspect ofthe present invention and thereafter esterifying the sulphone obtained to give the desired compound of Formula Ia. However, it is preferred when preparing the compounds of Formula Ia, to first p~rform the esterifisation process and thereafter the oxidation process of ~n aspect of this inven-tion. Both processes for preparing the compounds of Formula Ia are ~ithin the scope of aspects of this invention.
Some of the compounds of Formula VII are new and are as such within the scope of other aspects of the present invention. A particular - example of a valuable intermediate is the hitherto u~ nown compound of ~ 7 -~42174 Formula VTI in which Rl and R stand for hydrogen, and X is chlorine.
The catalyst used in the oxidation process of an aspect of this invention is appropriately in the form of a salt. If the reaction medium is aqueous, an alkali metal salt may be the preferred form, whereas in an organic reaction medium, it may be appropriate to use the catalyst in the form of a salt with an organic cation, e.g., in the form of a quaternary ammonium salt, e.g., a tetrabutylammonium salt.
The invention in its various aspects will be further illustrated by the following, non-limiting examples.
Example 1 Chloromethyl 1.l-dioxopenicillanate -A Tetrabutylammonium penicillanate .
To a cooled (~5C) solution of tetrabutylammonium hydrogensulphate (35.7 g, 0.105 mole) in water (80 ml), dichloromethane (100 ml) was added, followed by 30~
sodium hydroxide to bring the pH to about 3. Potassium penicillanate (24 g, 0.1 mole) was added, and pH adjusted to 7 with 30~ sodium hydroxide. The organic layer was separated, and the aqueous phase was extracted thrice with 25 ml portions of dichloromethane. The combined extracts were dried, and the solvent removed in vacuo to give the title compound as a yellow-brown oil (45 g).
B. Chlorometh~l penicillanate Tetrabutylammonium penicillanate (45 g) was dissolved in chloroiodomethane (100 ml) and left for 20 hours at ambient temperature. Excess of chloroiodomethane was removed at reduced pressure, first at 10 mm Hg, finally at 0.1 mm Hg. The semi-crystalline residue was treated with ethyl acetate (200 ml~, and separated tetrabutyl-ammonium iodide was filtered off and washed with ethyl i acetate. The filtrate was evaporated in vacuo, and the brown residue was chromatographed on silica gel (hexane-ethyl acetate (4:1)) to give the title compound as a faintly yellow oil. The IR spectrum (chloroform) showed ., _ g _ ll~Z174 a strong band at 1765-1785 cm The NMR spectrum (CDC13) showed peaks at 3 = 1. 55 (s), 1.87 (s), 3.10 (dd, J=16,J=2), 3.~2 (dd, J=16~ J=4)~
4-50 (s), 5.30 (dd, J=2~ J-4), 5.65 d, J=6.5), 5.88 (d, J=6. 5).
C. Chloromethvl~ -dioxopenicillanabe To a stirred solution of chloromethyl penicillanate (12.5 g, 0.05 mole) -i~ 960/o ethanol (50 ml), sodium tungstate (100 mg! dissolved in water (0.5 ml) was added. Hydrogen peroxide (30%, 11 ml) was added in one portion. No immediate heat was evolved; but after a few minuteC an exothermic reaction set in. The temperature was kept below 30C by cooling in ice-wate~, and the mixture was left at ambient tempèrature for 20 hours.
The crystalline mass was cooled to 0 C, and the crystals were filtered off, washed and dried, and recrystallized from ethyl acetate-hexane to give the title compound with a melting point of 95-96 C. The IR spectrum (chloro-form) showed strong bands at 1805, 1780, 1330 and 1120 cm Example 2 Dioxopenicillanic acid To a cooled (10C), stirred solution of potassium penicillanate (12 g, 0.05 mole) and sodium tungstate (100 mg) in water (50 ml), 30% hydrogen peroxide (11 ml) was added portionwise. During addition of the first five ml, heat was evolved and the temperature was kept below 30 C by cooling in ice-water. The mixture was left at room temperature for 20 hours, and excess of hydrogen peroxide was destroyed with ~odium bisulphite. The mixture was saturated with sodium chloride, and pH was adjusted to 1.5 with concentrated hydrochloric acid under ethyl acetate (50 ml). The layers were separated, and the aqueous phase was extracted twice with 25 ml portions of ethyl acetate. The combined extracts were dried, and the solvent stripped in vacuo. The crystalline ; residue was washed with hexane to yield the title compound as colourless crystals with a melting point of 154 C
(decomp.).
Example ~
Chloromethyl l,l-dioxopenicillanate To a stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) in ether (25 ml), 30~ hydrogen peroxide ~14~174 (2.5 ml) and sodium tungstate (40 mg) in water (0.25 ml) were added. The mixture was stirred for 2 days at ambient temperature, whereafter the ether was removed in vacuo, and the separated crystals were filtered off, washed with water followed by cold propanol-2 to give the title compound as colourless crystals with a melting point of Example 4 Chloromethvl l~l-dioxopenicillanate To s stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) and tetrabutylammonium bromide (0.5 g) in dichloromethane (25 ml), 30% hydrogen peroxide (2.5 ml) and sodium tungstate (40 mg) in water (0.25 ml) were added. The temperature was kept below 30 C by cooling in water. After stirring for 2 days at ambient tempera-ture, dichloromethane was removed in vacuo, and the residue was extracted with ether. The ether phase was evaporated in vacuo, and the residue was chromatographed on silica gel (hexane-ethyl acetate (3:2)) to give the title compound as colourless crystals with a melting point of 96-97 C.
11421~
Example ~
Chloromethyl l,l-dioxopenicillanate To a stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) in propanol-2 (25 ml)~ 30~ hydrogen peroxide (2.5 ml) and sodium tungState (40 mg) in water (0.25 ml) were added. The temperature was kept below 30 C and then left at ambient temperature for 24 hours.
After cooling to 0 C, the crystals ~ere filtered off and washed with cold propanol-2 to give the title compound as colourless crystals with a melting point of 96-97C.
l-Chloroethvl 1.1-dioxopenicillanate A. Chloroethyl penicillanate By following the procedure of Example lB, but re-p]acing chLoroiodomethane with l,l-chloroiodoethane, the title compound was obtained as an oily substance which was used in the next step without further puri-fication.
B l-Chloroethyl l.1-dioxo~enicillanate By following the procedure of Example lC, but re-placing chloromethyl penicillanate with the chloroethyl penicillanate prepared according to step A o~ this Example, the title compound was obtained as a crystalline mixture of the two diastereoisomers.
11421q4 Example 7 6a-Bromo-l,l-dioxoPenicillanic acid To a solution of 6~-bromopenicillanic acid (4.3 g~
0.015 M) in ethanol (15 ml), 0,5 M aqueous sodium tung-state (1.5 ml) was added, followed by 30% hydrogen peroxide (4 ml). After about 5 minutes, the temperature rose gradually to 50 C, and the mixture was kept at this temperature for two hours. After cooling in ice, excess of hydrogen peroxide was destroyed with sodium bisulphite, and the mixture was taken to dryness in vacuo. The residue was extracted with ether (50 ml), and the extract evaporated in vacuo. The residue was crystallized from ether-diiso-propyl ether to give the title compound as colourless crystals, melting point: 124-126C.
The NMR-spectrum (CD30D) showed peaks at ~ = 1,48 (s)~
1.59 (s), 4.48 (s), 5.10 (d, J=2Hz, 5 35 (d, J=2Hz).
Example_8 1,l-DioxoPenicillanovloxYmethyl phenoxvmethYlpenicillanate To a solution of chloromethyl penicillanate l,l-dioxide (1.41 g, 5 mmol) in dimethylformamide (25 ml) was added potassium phenoxymethylpenicillanate (1.94 g, 5 mmol), and the mixture was stirred at room temperature for 18 hours.
After dilution with ethyl acetate (100 ml), the mixture was washed with water (4 x 25 ml), dried, and evaporated 114~174 in vacuo. The residual oil was purified by dry column chromatography on silica gel (ethyl acetate-petroleum ether, 8:2), to yield the desired compound as a slightly yellowish foam.
- Example 9 l,l-Dioxopenicillano~lox~methYl 6_(D-~-amino-~-~henyl-acetamido)penicillanate, hydrochloride By following the procedure of Example 8, but replacing potassium phenoxymethylpenicillanate with potassium 6_(D-a~aminophenylacetamido)penicillanate, the title compound was obtained as a colourless foam.
The NMR-spectrum (D20) showed signals at ~ = 1.38 (s, 6H; 2-CH3), 1.46 (s, 3H; 2-CH3), 1.58 (s, 3H; 2-C_3),
According to that prior art, the oxidation is advantageously performed using metal permanganates, e.g., ~I;ali metal permanganates and alkaline earth metal permanganates, or by using organic peroxycarboxylic acids, e.g., 3-chloroperbenzoic acid nnd peracetic acid. These processes, how-ever, tend to give problems, in p~rticular when applied on a large scale, in the form of lower yields and/or technical difficulties, e.g., filtra-tion problems.
The oxidation of simple organic sulphides into the corresponding sulphones has also been described by using hydrogen peroxide in the presence of a suitable catalyst (J. Org. Chem., Vol. 28 (1963), p. 1140-42). However, when applied to penam-derivatives, this process has pre-viously only led to sulphoxides. Thus, ~nited States Patent No. 3,993,646 describes a process for converting compounds of formula II to compounds of formula III by subjecting the first-mentioned to an oxidation process using peracids, salts of peracids, or hydrogen peroxide as oxidizing agent, in the presence of a compound containing a metal of group Vb or VIb of the Periodic Table.
It has now surprisingly been shown that it is possible to oxidize certain penicillanic acid derivatives or their sulfoxides to the corresponding sulphones without destroying the lactam ring by using the mild oxidizing agent, hydrogen peroxide, provided a tungsten or molybdenum catalyst is present. This process eliminates secondary degradative oxidative side reactions and simplifies the isolation and purification of the product, thus providing high yields and thereby being particularly suited for large scale production.
Thus, according to a broad aspect of the present invention, a process is provided for producing a compound of the Formula I
Rl H O O
~, ' S
O=C N ~ R
in which Rl stand for hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl~
and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 ls a carboxy group or R2 contains a basic or acidic group, which process comprises sub~ecting a compound of the formula II or III
R H ll ~ ,~ 1 " r--O=C N ~" 0=C _ N - _ II ~ 2 III R2 in which Rl and R2 have the above meanings, or a salt thereof as defined above, to an oxidation process using hydrogen peroxide as oxidizing agent in the presence of a tungsten or molybdenum catalyst.
By a variant thereof, the oxidation process is carried out in a suitable solvent at a temperature between the boiling point of the solvent used and a temperature at or below room temperature.
By a variation thereof, the temperature is from 20C. to 30C.
By another variant, the catalyst is used in the form of a salt.
By another variant, Rl represents hydrogen and R2 is a carboxy group.
By another variant, Rl represents bromine and R2 is a carboxy 2Q group.
By another variant, Rl represents hydrogen and R2 is -COOCH2Cl.
By another variant, Rl represents bromine and R2 is -COOCH2Cl.
By another variant, a salt of a compound of Formula I is formed.
Depending upon the meanings of Rl and R2, the compounds of For-mula I are of value as ~ -lactamase inhibitors and/or antibiotics, and/or as intermediates in the production of antibiotics and/or ~ -lactamase inhibitors.
Rl may preferably represent a member selected from the group con-sisting of hydrogen, chlorine and bromine.
114Z~.74 When R2 stands for an esterified carboxy group, it may both represent an ester group which is easily hydrolyzable either spontaneously or under the influence of esterases, or an ester group which can be cleaved by hydrogenolysis. ~en R2 represents an ~-haloalkyl ester group, the compound of formula I i9 a useful intermediate. The easily hydroly~able esters are well known types of esters, e.g., acyloxyalkyl esters, e.g., alkanoyloxyalkyl esters, e.g., acetoxymethyl and pivaloyloxy-methyl esters and the corresponding l-acetoxyethyl and l-pivaloyloxyethyl esters, alkoxycarbonyloxyalkyl esters, e.g., methoxycarbonyloxymethyl and l-ethoxycarbonyloxyethyl esters, lactonyl esters, e.g., phthalidyl esters, or lower alkoxymethyl and acylaminomethyl esters. Examples of other useful esters are the lower alkyl esters, the benzyl esters, the haloalkyl esters, e.g., the chloromethyl esters, and the cyanomethyl esters.
The salts of Formula I may be formed by any basic or acidic group present in R2 reacting with suitable acids or bases, respectively. If the compounds of Formula I are to be used as ~ -lactamase inhibitors or anti-biotics, the salt-forming acid or base should be pharmaceutically accep-table and non-toxic, whereas if the compound of Formula I is an inter-mediate, then any acid or base which is stuiable with a view to the use of the intermediate may be applied in the salt formation.
The salts of the compounds of Formula I are thus, in addition to their inner salts (zwitterions) salts, formed with non-toxid pharmaceuti-cally acceptable acids, e.g., hydrochloric acid, phosphoric acid, nitric acidS p-toluenesulphonic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc., but any pharmaceutically acceptable, non-toxic inorganic or organic acids can be used as well.
Also included in the invention are the process for the prepara-tion of salts with pharmaceutically acceptable, non-toxic, inorganic or orgsnic bases, e.g., alkali met~l q~lts and :lhaline earth metal salts, .
~i42174 for example, sodium, potassium, magneslum or calcium salts, as well as salts with ammonia or suitable non-toxic amines, e.g., lower alkyl amines, for example triethylamine, hydrnxy-lower alkylamine5, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, cycloalkylamines, for example dicyclohexylamine, or benæylamines, for example N,N'-dibenzyl-ethylenediamine, and diben~ylamine, without these examples limiting the invention. Thus, for instance, other antibiotics with acid or basic character can be used as components of such salts of the compounds of Formula I.
According to an aspect of the present invention, the oxidation is generally performed by dissolving the starting material of Formula II or III or a salt thereof in water, or, if insoluble in water, in a suitable organic solvent. The catalyst is dissolved in water or a suitable organic solvent, the two solutions are mixed, and hydrogen peroxide is added to the mixture either in one portion or gradually, with efficient stirring, pre-ferably keeping the reaction temperature at or below room temperature.
Even if the starting material of Formula II or III has limited solubility in water, it is possible, with good stirring, to carry the present process through in aqueous medium with a satisfactory result. In case of extreme insolubility of the starting material, water-miscible sol-vents, e.g., an alkanol or dioxane, may be added. Water-immiscible sol-vents may be applied as well, provided a phase transfer catalyst, e.g., a quaternary ammonium salt, e.g., tetrabutylammonium bromide, is added.
Examples of suitable organic reaction media include, but are not limited to the following: alkanols, e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, dialkyl ethers, lower alkyl esters of lower fatty acids, unsubstituted or substituted aliphatic and aromatic hydrocarbons, tetrahydrofuran, dimethylformamid~, and hexamethylphosphoric acid triamide.
Examples of preferred organic reaction medla are ethanol, isppropanol, methylene chloride and tetrahydrofuran.
. The need for an efficient cooling may be particularly approp-riate during the conversion of the sulphide into the sulphoxide because the reaction rate is high, and the reaction is exothermic, whereas the conversion from sulphoxide to sulphone needs heating or a longer reaction time at ambient temperatures.
The process of aspects of the present invetnion is of specific interest also in the preparation of certain esters of Formula I, in parti-cular the important intermediates of Formula Ia:
Rl H ~S~
~ ~ Ia O=C - N "
COOIH-X
in which Rl has the above meanings, R3 is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical, preferably hydrogen, methyl, phenyl or benzyl, and X stands for a halogen atom, preferably chlorine. The com-pounds of Formula Ia are important intermediates in the production ofdi-esters of the Formula IV:
R ~ ~ ~ ~ ` IV
O=C 'lc-o-lcH-O-c-R4 in which Rl and R2 have the above meanings, and ~4C0- represents the acyl radical of a penicillin, or an amidinopenicillanoyl radical.
The compounds of Fol~ula Ia can be prep~red according to the 1~42174 fo]lowing reaction scheme:
OOM 3 ~COO~HX Ia V VI ~II R3 ) = oxidation according to the process of an aspect of the present inven-tion in which reaction scheme Rl, R3 and X have the above meanings, M
stands for a cation, e.g., Na , K , an ammonium ion, a trialkylammonium ion or a tetraalkylammonium ion, e.g., a tetrabutylammonium ion, and Y
stands for a bromine or iodine atom or for an alliylsulphonyloxy, halo-sulphonyloxy, ~C-halo-alkoxysulphonyloxy, or arylsulphonyloxy radical.
The esterification process V VII is performed in a suitable solvent, e.g., dimethyl formamide, acetone or hexamethylphosphoric acid triamide, for sufficient time and at an adequate temperature with a view to accomplishing the desired conversion, usually at a temperature from 0C. to 60C.
The compounds of Formula Ia may also be produced by first sub-jecting a compound of Formula V to the oxidation process of an aspect ofthe present invention and thereafter esterifying the sulphone obtained to give the desired compound of Formula Ia. However, it is preferred when preparing the compounds of Formula Ia, to first p~rform the esterifisation process and thereafter the oxidation process of ~n aspect of this inven-tion. Both processes for preparing the compounds of Formula Ia are ~ithin the scope of aspects of this invention.
Some of the compounds of Formula VII are new and are as such within the scope of other aspects of the present invention. A particular - example of a valuable intermediate is the hitherto u~ nown compound of ~ 7 -~42174 Formula VTI in which Rl and R stand for hydrogen, and X is chlorine.
The catalyst used in the oxidation process of an aspect of this invention is appropriately in the form of a salt. If the reaction medium is aqueous, an alkali metal salt may be the preferred form, whereas in an organic reaction medium, it may be appropriate to use the catalyst in the form of a salt with an organic cation, e.g., in the form of a quaternary ammonium salt, e.g., a tetrabutylammonium salt.
The invention in its various aspects will be further illustrated by the following, non-limiting examples.
Example 1 Chloromethyl 1.l-dioxopenicillanate -A Tetrabutylammonium penicillanate .
To a cooled (~5C) solution of tetrabutylammonium hydrogensulphate (35.7 g, 0.105 mole) in water (80 ml), dichloromethane (100 ml) was added, followed by 30~
sodium hydroxide to bring the pH to about 3. Potassium penicillanate (24 g, 0.1 mole) was added, and pH adjusted to 7 with 30~ sodium hydroxide. The organic layer was separated, and the aqueous phase was extracted thrice with 25 ml portions of dichloromethane. The combined extracts were dried, and the solvent removed in vacuo to give the title compound as a yellow-brown oil (45 g).
B. Chlorometh~l penicillanate Tetrabutylammonium penicillanate (45 g) was dissolved in chloroiodomethane (100 ml) and left for 20 hours at ambient temperature. Excess of chloroiodomethane was removed at reduced pressure, first at 10 mm Hg, finally at 0.1 mm Hg. The semi-crystalline residue was treated with ethyl acetate (200 ml~, and separated tetrabutyl-ammonium iodide was filtered off and washed with ethyl i acetate. The filtrate was evaporated in vacuo, and the brown residue was chromatographed on silica gel (hexane-ethyl acetate (4:1)) to give the title compound as a faintly yellow oil. The IR spectrum (chloroform) showed ., _ g _ ll~Z174 a strong band at 1765-1785 cm The NMR spectrum (CDC13) showed peaks at 3 = 1. 55 (s), 1.87 (s), 3.10 (dd, J=16,J=2), 3.~2 (dd, J=16~ J=4)~
4-50 (s), 5.30 (dd, J=2~ J-4), 5.65 d, J=6.5), 5.88 (d, J=6. 5).
C. Chloromethvl~ -dioxopenicillanabe To a stirred solution of chloromethyl penicillanate (12.5 g, 0.05 mole) -i~ 960/o ethanol (50 ml), sodium tungstate (100 mg! dissolved in water (0.5 ml) was added. Hydrogen peroxide (30%, 11 ml) was added in one portion. No immediate heat was evolved; but after a few minuteC an exothermic reaction set in. The temperature was kept below 30C by cooling in ice-wate~, and the mixture was left at ambient tempèrature for 20 hours.
The crystalline mass was cooled to 0 C, and the crystals were filtered off, washed and dried, and recrystallized from ethyl acetate-hexane to give the title compound with a melting point of 95-96 C. The IR spectrum (chloro-form) showed strong bands at 1805, 1780, 1330 and 1120 cm Example 2 Dioxopenicillanic acid To a cooled (10C), stirred solution of potassium penicillanate (12 g, 0.05 mole) and sodium tungstate (100 mg) in water (50 ml), 30% hydrogen peroxide (11 ml) was added portionwise. During addition of the first five ml, heat was evolved and the temperature was kept below 30 C by cooling in ice-water. The mixture was left at room temperature for 20 hours, and excess of hydrogen peroxide was destroyed with ~odium bisulphite. The mixture was saturated with sodium chloride, and pH was adjusted to 1.5 with concentrated hydrochloric acid under ethyl acetate (50 ml). The layers were separated, and the aqueous phase was extracted twice with 25 ml portions of ethyl acetate. The combined extracts were dried, and the solvent stripped in vacuo. The crystalline ; residue was washed with hexane to yield the title compound as colourless crystals with a melting point of 154 C
(decomp.).
Example ~
Chloromethyl l,l-dioxopenicillanate To a stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) in ether (25 ml), 30~ hydrogen peroxide ~14~174 (2.5 ml) and sodium tungstate (40 mg) in water (0.25 ml) were added. The mixture was stirred for 2 days at ambient temperature, whereafter the ether was removed in vacuo, and the separated crystals were filtered off, washed with water followed by cold propanol-2 to give the title compound as colourless crystals with a melting point of Example 4 Chloromethvl l~l-dioxopenicillanate To s stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) and tetrabutylammonium bromide (0.5 g) in dichloromethane (25 ml), 30% hydrogen peroxide (2.5 ml) and sodium tungstate (40 mg) in water (0.25 ml) were added. The temperature was kept below 30 C by cooling in water. After stirring for 2 days at ambient tempera-ture, dichloromethane was removed in vacuo, and the residue was extracted with ether. The ether phase was evaporated in vacuo, and the residue was chromatographed on silica gel (hexane-ethyl acetate (3:2)) to give the title compound as colourless crystals with a melting point of 96-97 C.
11421~
Example ~
Chloromethyl l,l-dioxopenicillanate To a stirred solution of chloromethyl penicillanate (2.5 g, 0.01 mole) in propanol-2 (25 ml)~ 30~ hydrogen peroxide (2.5 ml) and sodium tungState (40 mg) in water (0.25 ml) were added. The temperature was kept below 30 C and then left at ambient temperature for 24 hours.
After cooling to 0 C, the crystals ~ere filtered off and washed with cold propanol-2 to give the title compound as colourless crystals with a melting point of 96-97C.
l-Chloroethvl 1.1-dioxopenicillanate A. Chloroethyl penicillanate By following the procedure of Example lB, but re-p]acing chLoroiodomethane with l,l-chloroiodoethane, the title compound was obtained as an oily substance which was used in the next step without further puri-fication.
B l-Chloroethyl l.1-dioxo~enicillanate By following the procedure of Example lC, but re-placing chloromethyl penicillanate with the chloroethyl penicillanate prepared according to step A o~ this Example, the title compound was obtained as a crystalline mixture of the two diastereoisomers.
11421q4 Example 7 6a-Bromo-l,l-dioxoPenicillanic acid To a solution of 6~-bromopenicillanic acid (4.3 g~
0.015 M) in ethanol (15 ml), 0,5 M aqueous sodium tung-state (1.5 ml) was added, followed by 30% hydrogen peroxide (4 ml). After about 5 minutes, the temperature rose gradually to 50 C, and the mixture was kept at this temperature for two hours. After cooling in ice, excess of hydrogen peroxide was destroyed with sodium bisulphite, and the mixture was taken to dryness in vacuo. The residue was extracted with ether (50 ml), and the extract evaporated in vacuo. The residue was crystallized from ether-diiso-propyl ether to give the title compound as colourless crystals, melting point: 124-126C.
The NMR-spectrum (CD30D) showed peaks at ~ = 1,48 (s)~
1.59 (s), 4.48 (s), 5.10 (d, J=2Hz, 5 35 (d, J=2Hz).
Example_8 1,l-DioxoPenicillanovloxYmethyl phenoxvmethYlpenicillanate To a solution of chloromethyl penicillanate l,l-dioxide (1.41 g, 5 mmol) in dimethylformamide (25 ml) was added potassium phenoxymethylpenicillanate (1.94 g, 5 mmol), and the mixture was stirred at room temperature for 18 hours.
After dilution with ethyl acetate (100 ml), the mixture was washed with water (4 x 25 ml), dried, and evaporated 114~174 in vacuo. The residual oil was purified by dry column chromatography on silica gel (ethyl acetate-petroleum ether, 8:2), to yield the desired compound as a slightly yellowish foam.
- Example 9 l,l-Dioxopenicillano~lox~methYl 6_(D-~-amino-~-~henyl-acetamido)penicillanate, hydrochloride By following the procedure of Example 8, but replacing potassium phenoxymethylpenicillanate with potassium 6_(D-a~aminophenylacetamido)penicillanate, the title compound was obtained as a colourless foam.
The NMR-spectrum (D20) showed signals at ~ = 1.38 (s, 6H; 2-CH3), 1.46 (s, 3H; 2-CH3), 1.58 (s, 3H; 2-C_3),
3.56 M, 2H; 6a-H and 6~-H), 4.60 (s, lH; 3-H), 4.63 (s, lH;
3-H), 5.03 (m, lH; 5-H), 5.27 (s, lH; CH-NH2), 5.53 (s, 2H;
5-H and 6-H), 5,97 (bs, lH; OCH20), and 7.53 (s, 5H; arom.
CH) ppm.
Tetramethylsilane was used as external reference.
Example lO
l,l-DioxoPenicillanic acid A stirred solution of penicillanic acid morpholine salt (288 g, 1 mole) in water (1 1) was acidified to pH
3.4 with hydrochloric acid, whereafter sodium tungstate 1~4Z174 (12.5 g) was added. Hydrogen peroxide (30~, 330 ml, 3.3 moles) was added portionwise over about 4 hours, the tem-perature being kept below 25 C. Aft2r standing over night, at 5 C, excess of hydrogen peroxide was destroyed with sodium bisulphite. Sodium chloride (300 g) was added, and pH was adjusted to 1,1 with hydrochloric acid, whereafter the mixture was extracted thrice with 1 1 portions of -- ethyl acetate. After drying~ the organic phase was concen-trated to about 1 1 in vacuo, whereafter heptane (3 1) was added. After standing over night at 5 C, the crystals were collected and washed with heptane to yield the title compound as faintly yellow crystals with melting point:
148-150C.
Example 11 Potassium l~l-dioxopenicillanate A solution of l,l-dioxopenicillanic acid (23.3 g~
0.1 mole) in ethanol (99~o, 100 ml) was warmed to about 45 C on the steam bath. A solution of potassium acetate (10 g) in warm ethanol (99%~ 60 ml) was added, and crys-tallization was induced by scratching. After standing for about 10 minutes, the crystals were filtered off and washed with ethanol and ether to give the title compound as colourless crystals.
114;~174 Example 12 6a_Chloropenicillanic acid l,l-dioxide By substituting 6a-chloropenicillanic acid for the 6_bromopenicillanic acid in the procedure of Example 7, 6a_chloropenicillanic acid l,l-dioxide was obtained as crystals from diisopropyl ether, melting point: 134-137 C.
The NMR-spektrum (CDC13) showed signals at ~ = 1.50 (s, 3~; 2-CH3), 1.64 (s, 3H; 2-CH3), 4.46 (s, lH; 3-H),
3-H), 5.03 (m, lH; 5-H), 5.27 (s, lH; CH-NH2), 5.53 (s, 2H;
5-H and 6-H), 5,97 (bs, lH; OCH20), and 7.53 (s, 5H; arom.
CH) ppm.
Tetramethylsilane was used as external reference.
Example lO
l,l-DioxoPenicillanic acid A stirred solution of penicillanic acid morpholine salt (288 g, 1 mole) in water (1 1) was acidified to pH
3.4 with hydrochloric acid, whereafter sodium tungstate 1~4Z174 (12.5 g) was added. Hydrogen peroxide (30~, 330 ml, 3.3 moles) was added portionwise over about 4 hours, the tem-perature being kept below 25 C. Aft2r standing over night, at 5 C, excess of hydrogen peroxide was destroyed with sodium bisulphite. Sodium chloride (300 g) was added, and pH was adjusted to 1,1 with hydrochloric acid, whereafter the mixture was extracted thrice with 1 1 portions of -- ethyl acetate. After drying~ the organic phase was concen-trated to about 1 1 in vacuo, whereafter heptane (3 1) was added. After standing over night at 5 C, the crystals were collected and washed with heptane to yield the title compound as faintly yellow crystals with melting point:
148-150C.
Example 11 Potassium l~l-dioxopenicillanate A solution of l,l-dioxopenicillanic acid (23.3 g~
0.1 mole) in ethanol (99~o, 100 ml) was warmed to about 45 C on the steam bath. A solution of potassium acetate (10 g) in warm ethanol (99%~ 60 ml) was added, and crys-tallization was induced by scratching. After standing for about 10 minutes, the crystals were filtered off and washed with ethanol and ether to give the title compound as colourless crystals.
114;~174 Example 12 6a_Chloropenicillanic acid l,l-dioxide By substituting 6a-chloropenicillanic acid for the 6_bromopenicillanic acid in the procedure of Example 7, 6a_chloropenicillanic acid l,l-dioxide was obtained as crystals from diisopropyl ether, melting point: 134-137 C.
The NMR-spektrum (CDC13) showed signals at ~ = 1.50 (s, 3~; 2-CH3), 1.64 (s, 3H; 2-CH3), 4.46 (s, lH; 3-H),
4.7O (d9 J=1.5Hz, lH; 6-H), and 5.18 (d, J=1.5Hz, lH;
5-H) ppm. Tetramethylsilane was used as internal reference.
A crystalline potassium salt of the above compound was obtained by addition of an equimolar amount of o.8 M
potassium 2-ethylhexanoate in acetone to a stirred solution of 6a-chloropenicillanic acid l,l-dioxide in acetone.
Example 1~
PivaloYlox~methyl 1 l-dioxopenicillanate A. Pivaloyloxymethvl penicillanate To a stirred suspension of potassium penicillanate (12 g, O.O5 mole) in DMF (5O ml), chloromethyl pivalate (7.5 ml) was added. After stirring for 24 hours, ether (lOO ml) was added, and the mixture was washed twice with water (lOO + 5O ml). The organic layer was dried and taken to dryness in vacuo, giving the title compound as a faintly yellow oil.
The IR-spectrum (CHC13) showed a strong broad band centered at 1765 cm B. PivalovloxYmethvl l,l-dioxopenicillanate To a stirred solution of A (3.14 g, 0.01 mole) in ethanol (96~, 25 ml) hydrogen peroxide (30~0, 2,2 ml) was added~ followed by 0.5 M aqueous sodium tungstate (1 ml).
The temperature rose to about 35 C in the course of 10 minutes. After stirring for 20 hours, water (50 ml) was added, and ethanol was removed in vacuo. The separated oil was extracted with ethyl acetate which was dried and evaporated to dryness. The residue crystallized from ether to give the title compound as colourless crystals with melting point: 103-104C
The NMR-spectrum (CDC13) showed peaks at ~ = 1.27 (s~
1.47 (s), 1.62 (5), 3.52 (m), 4.47(s), 4.70(m), 5.73 (d, J=6Hz, 5.98 (d, J=6 Hz).
Example 14 Acetox~methyl 6-methoxy-1,1-dioxopenicillanate A. ~cetoxymethyl 6-methoxv-penicillanate To a stirred suspension of acetoxymethyl 6-aminopeni-20 cillanate 4-toluenesulphonic acid salt (4.61 g, 0.01 mole) in a cold (0-3 C) mixture of dichloromethane (~00 ml) and water (400 ml), sodium nitrite (3.45 g, 0.05 mole) and 4-toluenesulphonic acid (1.90 g, 0.01 mole) were added.
The la~ter was added in three equal portions at intervals of 5 minutes. After stirring at 0-3C for a further 20 minutes, the organic layer was separated, dried, and con-`` 1~4Z174 centrated to about 40 ml in vacuo. Methanol (2 ml) and horon trifluoride etherate (0.2 ml) were added under stirring, whereby an immediate evolution of nitrogen occurred. After stirring for 5 minutes, aqueous potassium hydrogencarbonate (0.2 M, 10 ml) was added. The organic layer was separated, washed with saturated aqueous sodium chloride (2 x 5 ml), dried, and evaporated in vacuo.
The residual oil was purified by chromatography on silica gel (ethyl acetate-hexane (3:7)) to afford the pure lQ title compound as a faintly yellow oil.
The NMR spectrum (CDC13) showed signals at ~ = 1.46 (s), 1.55 (s), 2.11 (s) 9 3.51 (s), 4.50 (s), 4.57 (d, J=1.5 Hz), 5.29 (d, J=1.5 Hz), and 5.78 (s).
B. Acetoxymethyl 6a-methoxv-1,1-dioxopenicillanate To a stirred solution of A (0.72 g, 0.0024 mole) in tetrahydrofuran (6 ml)~ hydrogen peroxide (30~o, 0.52 ml) was added, followed by aqueous sodium tungstate (0.5 M, 0.24 ml). The temperature rose to 36C in the course of 5 minutes. After stirring for 20 hours, water (20 ml) was added, and tetrahydrofuran was removed in vacuo. The residue was worked up through ethyl acetate to give a yellowish oil, which was purified by chromatograpy on silica gel (ether) to yield an oil, which crystallized from ether to give the title compound ~s colourless `` 1142~74 crystals with melting point 88-90C.
The NMR-spectr~m showed signals at S = 1.41 (s), 1.56 (s), 2.14 (s), 3.57 (s), 4,41 (s), 4.62 (d, J=1.5 Hz), 5,02 (d~ J=1.5 Hz)~ and 5.72-5.91(ABq~ J=5,8 Hz).
A crystalline potassium salt of the above compound was obtained by addition of an equimolar amount of o.8 M
potassium 2-ethylhexanoate in acetone to a stirred solution of 6a-chloropenicillanic acid l,l-dioxide in acetone.
Example 1~
PivaloYlox~methyl 1 l-dioxopenicillanate A. Pivaloyloxymethvl penicillanate To a stirred suspension of potassium penicillanate (12 g, O.O5 mole) in DMF (5O ml), chloromethyl pivalate (7.5 ml) was added. After stirring for 24 hours, ether (lOO ml) was added, and the mixture was washed twice with water (lOO + 5O ml). The organic layer was dried and taken to dryness in vacuo, giving the title compound as a faintly yellow oil.
The IR-spectrum (CHC13) showed a strong broad band centered at 1765 cm B. PivalovloxYmethvl l,l-dioxopenicillanate To a stirred solution of A (3.14 g, 0.01 mole) in ethanol (96~, 25 ml) hydrogen peroxide (30~0, 2,2 ml) was added~ followed by 0.5 M aqueous sodium tungstate (1 ml).
The temperature rose to about 35 C in the course of 10 minutes. After stirring for 20 hours, water (50 ml) was added, and ethanol was removed in vacuo. The separated oil was extracted with ethyl acetate which was dried and evaporated to dryness. The residue crystallized from ether to give the title compound as colourless crystals with melting point: 103-104C
The NMR-spectrum (CDC13) showed peaks at ~ = 1.27 (s~
1.47 (s), 1.62 (5), 3.52 (m), 4.47(s), 4.70(m), 5.73 (d, J=6Hz, 5.98 (d, J=6 Hz).
Example 14 Acetox~methyl 6-methoxy-1,1-dioxopenicillanate A. ~cetoxymethyl 6-methoxv-penicillanate To a stirred suspension of acetoxymethyl 6-aminopeni-20 cillanate 4-toluenesulphonic acid salt (4.61 g, 0.01 mole) in a cold (0-3 C) mixture of dichloromethane (~00 ml) and water (400 ml), sodium nitrite (3.45 g, 0.05 mole) and 4-toluenesulphonic acid (1.90 g, 0.01 mole) were added.
The la~ter was added in three equal portions at intervals of 5 minutes. After stirring at 0-3C for a further 20 minutes, the organic layer was separated, dried, and con-`` 1~4Z174 centrated to about 40 ml in vacuo. Methanol (2 ml) and horon trifluoride etherate (0.2 ml) were added under stirring, whereby an immediate evolution of nitrogen occurred. After stirring for 5 minutes, aqueous potassium hydrogencarbonate (0.2 M, 10 ml) was added. The organic layer was separated, washed with saturated aqueous sodium chloride (2 x 5 ml), dried, and evaporated in vacuo.
The residual oil was purified by chromatography on silica gel (ethyl acetate-hexane (3:7)) to afford the pure lQ title compound as a faintly yellow oil.
The NMR spectrum (CDC13) showed signals at ~ = 1.46 (s), 1.55 (s), 2.11 (s) 9 3.51 (s), 4.50 (s), 4.57 (d, J=1.5 Hz), 5.29 (d, J=1.5 Hz), and 5.78 (s).
B. Acetoxymethyl 6a-methoxv-1,1-dioxopenicillanate To a stirred solution of A (0.72 g, 0.0024 mole) in tetrahydrofuran (6 ml)~ hydrogen peroxide (30~o, 0.52 ml) was added, followed by aqueous sodium tungstate (0.5 M, 0.24 ml). The temperature rose to 36C in the course of 5 minutes. After stirring for 20 hours, water (20 ml) was added, and tetrahydrofuran was removed in vacuo. The residue was worked up through ethyl acetate to give a yellowish oil, which was purified by chromatograpy on silica gel (ether) to yield an oil, which crystallized from ether to give the title compound ~s colourless `` 1142~74 crystals with melting point 88-90C.
The NMR-spectr~m showed signals at S = 1.41 (s), 1.56 (s), 2.14 (s), 3.57 (s), 4,41 (s), 4.62 (d, J=1.5 Hz), 5,02 (d~ J=1.5 Hz)~ and 5.72-5.91(ABq~ J=5,8 Hz).
Claims (22)
1. Process for producing a compound of the formula I
I
in which R1 stands for hydrogen, alkyl, alkoxy, halogen, or trifluoro-methyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group, which process comprises subjecting a compound of the formula II or III
II III
in which R1 and R2 have the above meanings, or a salt thereof as defined above, to an oxidation process using hydrogen peroxide as oxidizing agent in the presence of a tungsten or molybdenum catalyst.
I
in which R1 stands for hydrogen, alkyl, alkoxy, halogen, or trifluoro-methyl, and R2 stands for a carboxy group or for a protected carboxy group, in particular an esterified carboxy group; or a salt thereof in case R2 is a carboxy group or R2 contains a basic or acidic group, which process comprises subjecting a compound of the formula II or III
II III
in which R1 and R2 have the above meanings, or a salt thereof as defined above, to an oxidation process using hydrogen peroxide as oxidizing agent in the presence of a tungsten or molybdenum catalyst.
2. The process according to claim 1 which comprises carrying out the oxidation process in a suitable solvent at a temperature between the boiling point of the solvent used and a temperature at or below room temperature.
3. The process of claim 2 wherein said solvent is water.
4. The process of claim 2 wherein said solvent is an organic solvent selected from the group consisting of alkanols, selected from methanol, ethanol, propanol, isopropanol and tert-butanol, dioxane, dialkyl ethers, lower alkyl esters of lower fatty acids, unsubstituted or substituted aliphatic and aromatic hydrocarbons, tetrahydrofuran, dimethyl-formamide, and hexamethylphosphoric acid triamide.
5. The process of claim 2 wherein said solvent is ethanol, iso-propanol, methylene chloride or tetrahydrofuran.
6. The process of claim 2 wherein the temperature is 20°C. - 30°C.
7. The process according to claim 1 in which said catalyst is used in the form of a salt.
8. The process of claim 7 wherein the reaction medium is aqueous, and wherein said salt is an alkali metal salt.
9. The process of claim 7 wherein the reaction medium is an organic solvent, and wherein said salt is a salt with an organic cation, or in the form of a quaternary ammonium salt.
10. The process of claim 9 wherein said salt is a tetrabutylammon-ium salt.
11. The process of claim 1 including the step of forming said compound into a salt by reaction with a non-toxic pharmaceutically accep-table acid.
12. The process of claim 11 wherein said acid is selected from the group consisting of hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulphonic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid.
13. The process of claim 1 including the step of forming said compound into a salt by reaction with a pharmaceutically acceptable, non-toxic, inorganic or organic base,
14. The process of claim 13 wherein said base is an alkali metal salt, an alkaline earth metal salt, a salt with ammonia or suitable non-toxic amines, selected from lower alkyl amines, hydroxy-lower alkyl amines, cycloalkylamines, or benzylamines.
15. The process of claim 14 wherein said base is triethylamine, 2-hydroxethylamine, bis-(2-hydroxyethyl)-amine, tris-(2-hydroxyethyl)-amine, dicyclohexylamine, N,N'-dibenzyl-ethylenediamine, or dibenzylamine.
16. The process of claim 1 wherein R2 is an esterified carboxy group selected from alkanoyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, lactonyl esters, lower alkoxymethyl and acylaminomethyl esters, lower alkyl esters, benzyl esters, haloalkyl esters and cyanomethyl esters.
17. The process of claim 16 wherein R2 is selected from acetoxy-methyl and pivaloyloxymethyl esters and the corresponding l-acetoxyethyl and l-pivaloyloxyethyl esters, methoxycarbonyloxymethyl and l,-ethoxy-carbonyloxyethyl esters, phthalidyl esters, and methyl esters.
18. The process of claim l wherein R1 is hydrogen, chlorine and bromine.
19. The process of claim 1 in which R1 represents hydrogen and R2 is a carboxy group.
20. The process of claim 1 in which R1 represents bromine and R2 is a carboxy group.
21. The process of claim 1 in which R1 represents hydrogen and R2 is -COOCH2Cl.
22. The process of claim 1 in which R1 represents bromine and R2 is -COOCH2Cl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7935284 | 1979-10-11 | ||
| GB7935284 | 1979-10-11 | ||
| GB7942062 | 1979-12-05 | ||
| GB7942062 | 1979-12-05 |
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| Publication Number | Publication Date |
|---|---|
| CA1142174A true CA1142174A (en) | 1983-03-01 |
Family
ID=26273161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000362093A Expired CA1142174A (en) | 1979-10-11 | 1980-10-09 | Method for producing penicillanic acid derivatives |
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| Country | Link |
|---|---|
| CA (1) | CA1142174A (en) |
| CH (1) | CH646174A5 (en) |
| DE (1) | DE3037896A1 (en) |
| DK (1) | DK154085C (en) |
| FR (1) | FR2467210A1 (en) |
| GB (1) | GB2059960B (en) |
| IE (1) | IE50650B1 (en) |
| IT (1) | IT1132938B (en) |
| LU (1) | LU82842A1 (en) |
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| SE (1) | SE449613B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977120A (en) * | 2012-12-14 | 2013-03-20 | 江西富祥药业股份有限公司 | Method for preparing and crystallizing sulbactam pivoxyl |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4331599A (en) * | 1981-02-02 | 1982-05-25 | Pfizer Inc. | Sparingly water-soluble salts of penicillanic acid 1,1-dioxide |
| IN159362B (en) * | 1981-03-23 | 1987-05-09 | Pfizer | |
| US4381263A (en) * | 1981-03-23 | 1983-04-26 | Pfizer Inc. | Process for the preparation of penicillanic acid esters |
| US4502988A (en) * | 1983-08-08 | 1985-03-05 | Eli Lilly And Company | Oxidation process |
| GB2206579B (en) * | 1987-07-10 | 1991-05-29 | Erba Farmitalia | 6a and 6b-(substituted methyl)-penicillanic acid derivatives |
-
1980
- 1980-09-22 IE IE1963/80A patent/IE50650B1/en unknown
- 1980-09-23 GB GB8030709A patent/GB2059960B/en not_active Expired
- 1980-10-07 DE DE19803037896 patent/DE3037896A1/en not_active Withdrawn
- 1980-10-08 DK DK424080A patent/DK154085C/en active
- 1980-10-09 CA CA000362093A patent/CA1142174A/en not_active Expired
- 1980-10-09 IT IT25223/80A patent/IT1132938B/en active
- 1980-10-10 NL NL8005626A patent/NL8005626A/en not_active Application Discontinuation
- 1980-10-10 FR FR8021730A patent/FR2467210A1/en active Granted
- 1980-10-10 LU LU82842A patent/LU82842A1/en unknown
- 1980-10-10 CH CH760280A patent/CH646174A5/en not_active IP Right Cessation
- 1980-10-10 SE SE8007141A patent/SE449613B/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977120A (en) * | 2012-12-14 | 2013-03-20 | 江西富祥药业股份有限公司 | Method for preparing and crystallizing sulbactam pivoxyl |
Also Published As
| Publication number | Publication date |
|---|---|
| IE50650B1 (en) | 1986-06-11 |
| IT8025223A0 (en) | 1980-10-09 |
| LU82842A1 (en) | 1981-06-04 |
| GB2059960B (en) | 1983-10-19 |
| IT1132938B (en) | 1986-07-09 |
| DK154085B (en) | 1988-10-10 |
| SE8007141L (en) | 1981-04-12 |
| DE3037896A1 (en) | 1981-04-23 |
| CH646174A5 (en) | 1984-11-15 |
| GB2059960A (en) | 1981-04-29 |
| DK154085C (en) | 1989-02-27 |
| IE801963L (en) | 1981-04-11 |
| FR2467210A1 (en) | 1981-04-17 |
| SE449613B (en) | 1987-05-11 |
| FR2467210B1 (en) | 1983-08-19 |
| DK424080A (en) | 1981-04-12 |
| NL8005626A (en) | 1981-04-14 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |