CA1164402A - Electrolytic reduction of cephalosporin p-nitrobenzyl esters - Google Patents
Electrolytic reduction of cephalosporin p-nitrobenzyl estersInfo
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- CA1164402A CA1164402A CA000373328A CA373328A CA1164402A CA 1164402 A CA1164402 A CA 1164402A CA 000373328 A CA000373328 A CA 000373328A CA 373328 A CA373328 A CA 373328A CA 1164402 A CA1164402 A CA 1164402A
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/25—Reduction
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- Electrochemistry (AREA)
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- Cephalosporin Compounds (AREA)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An electrolytic process for removing the p-nitrobenzyl (pNB) ester protecting group from a cephalosporin 4-carboxylic acid pNB ester is described herein. The pNB ester is electrolytically reduced in an acidic liquid medium containing 0 - 50% water, an acid having a pKa (determined in water) of 0 or below, the amount of said acid being at least 4 moles per mole of compound to be reduced, and an organic solvent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, at a temperature from about 0°C to about 75°C, and at a potential ranging from about the potential of the initial onset of current flow at which a first reduction takes place to about the potential of the initial onset of current flow at which a second reduction takes place. The working electrode may be made of carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, and preferably is of mercury, silver or lead.
An electrolytic process for removing the p-nitrobenzyl (pNB) ester protecting group from a cephalosporin 4-carboxylic acid pNB ester is described herein. The pNB ester is electrolytically reduced in an acidic liquid medium containing 0 - 50% water, an acid having a pKa (determined in water) of 0 or below, the amount of said acid being at least 4 moles per mole of compound to be reduced, and an organic solvent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, at a temperature from about 0°C to about 75°C, and at a potential ranging from about the potential of the initial onset of current flow at which a first reduction takes place to about the potential of the initial onset of current flow at which a second reduction takes place. The working electrode may be made of carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, and preferably is of mercury, silver or lead.
Description
~-4509 -1-ELECTROL~TIC REDUCTION OF
CEPHALOSPORIN p-NITROBENZYL ESTERS
This invention provides a superior method for the removal of the ~-nitrobenzyl (hereinafter abbreviated to "pNB") ester group from cephalosporin carboxylic acids. The process is economically important, because cephalosporin antibiotics are often processed ln the form of pNB esters, since the esters are convenient and economical to handle in chemical processing. The ester group must eventually be removed, however, because the cephalosporins are used as pharmaceuticals in the acid or salt form.
The pNs ester group has been used in the manufacture of cephalosporins for some time. See U.S.
15 Patent 3,632,850, of Garbrecht. The pNB group has been removed chemically, su-h as with zinc and a strong acid r or catalytically, as taught by Garbrecht, Other deesterification methods have since been devised, such as the methods of Hatfield, using zinc and an a-hydroxy-20 carboxylic acid, U.S. Patent 4,091,214, or zinc and an orsancthiol, Belgian Patent 856,288, and the metho~ of Jackson, U.S. Patent 3,799,924, using a dithionite sâlt .
All of the chemical and catalytic methods of ~5 deesterification, however, have the disadvantage that they may affect functional groups of the molecule other than the pNs ester.
According to the p~esent lnvention there is provided a process for remo~Ting the p~B ester protecting 3Q group from a cepna'osporin 4-carbo~ylic acid pNB ester thereby liberatins the free sephalosporin 4-carbo~ylic acid;
characterized in that the pNB ester is electrolytically reduced in an acidic liquid medium comprising from about 0 to about 50% water, an acid having a PKa determined in water of 0 or below, the amount of said acid being at least four moles per mole of the compound to be reduGed, and an organic sol~ent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, said working electrode sub~
stantially comprising carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, at a temperature from about 0C. to about 75C., at a potential in a range from about the potential of the initial onset of current flow of the first reduction to a~out the potential of the initial onset of current lS flow of the second reduction.
Preferred compounds prepared by the process of the invention are those having the formula:
(P)m (P)m RHN-~---t/ \ RHN_I___t/ \
---N I-R1 Or l N l=CH2 wherein X is hydrogen;
m is 0 or 1;
R2 is hydrogen or methoxy;
R is hydrogen or -CGR3;
R3 is hydrogen, Cl-C3 alkyl, halomethyl, benzyloxy, 2,2,2-trichloroethoxy, t-butoxy, ~ J~
X-4509 -3~
R4, R4-(o)n-CH2-, R4-CH(R5)-, R -CH2-, or ~N/ ~R7 wherein R7 is hydrogen or Cl-C3 alkyl and R8 is hydrogen or an amino-protecting group;
R4 is cyclohexadienyl or phenyl, or cyclohexadienyl or phenyl substituted with one or two halo, hydroxy, protected hydroxy, aminomethyl, protected amino-methyl, Cl-C4 alkyl or Cl-C4 alkoxy groups;
n is 0 or 1;
R5 is hydroxy, protected hydroxy, amino, protected amino, carboxy or protected carboxy;
R is 2-thienyl, 2-furyl, 5-tetrazolyl or l-tetrazolyl;
Rl is chloro, Cl-C3 alkyl or -CH2R ;
R9 is Cl-C4 alkanoyloxy, benzoyloxy, ~luoro, chloro, carbamoyloxy, Cl-C4 alkylcarbamoyloxy, O-N/ ~
/1 = , ~-=1' -NH--~ ,N-CH3 H
pyridinio, pyridinio substit~.ed with Cl-C4 alkyl, Cl-C~ alkanoyl, carbamoyl, Cl-C4 alkyl-carbamoyl, chloro, fluoro, hydroxy or trifluoro-methyl, or the corresponding pyridinio chlorides or bromides, or -S-R10;
R10 is -CH2CO2(Cl-C4 alkyl), carbamoyl, phenyl, phenyl substituted with one or two chloro, fluoro, Cl-C4 alkyl, hydroxy, Cl-C4 alkylsulfonamido or tri-fluoromethyl groups;
triazol-3-yl unsubstituted or substituted with one or two groups independently selected from Cl-C3 alkyl, -CO2(C1-C4 alkyl), -CONH2 and -CH2NHOCO(benæyl or Cl-C4 alkyl);
OH
~ /
tetrazol-l-yl or tetrazol-5-yl substituted with one or two groups independently selected from C1-C4 alkyl and -CH2CO2(Cl-C4 alkyl or hydrogen);
4-cyano-5-aminopyrimidin-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl;
provided that n is 0 when R4 is cyclohexadienyl.
In the above general ~ormula, various gen-eralized terms are used to describe the various groups.
The generalized terms have their usual meanings in organic chemistry. For e~ample, the term halomethyl includes bromomethyl, chloromethyl, fluoromethyl and iodomethyl.
The group R3 is a 2-amino-4-thiazolyl(alkoxy-imino~methyl group. ~he alkoxyimino group of this group may be in either the syn or anti form.
The terms Cl-C3 alkyl, Cl-C4 alkyl and Cl-C4 alkoxy include groups such as methyl, ethyl, propyl, butyl, s-butyl, t-butyl, methoxy, isopropoxy and i-butoxy.
The term protected amino refers to an amino group substituted with one of the commonly employed amino-protecting groups such as t-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 1-carbomethoxy-2-propenyl.
Other accepted amino-protecting groups such as are described by J. w. Barton in Protective Groups in Organic Chemistry, J.E.W. McOmie, Editor, Plenum Press, ~ew York, 1973, chapter 2 will be recognized by organic chemists as suitable for the purpose.
The term protected carboxy refers to an acid group protected with any group which is conventionally used to block or protect the carboxylic acid function-ality of a cephalosporin while reactions involving other functional sites are car~ied out. Such carboxylic acid protecting groups are noted for their ease of cleavage and for their ability to protect the acid from unwanted reactions. Such groups are thoroughly described by E. Haslam in Protective Gro~æs in Organic Chemistry, Chapter 5. Any such group may be used, of course. The preferred groups, however, are Cl-C4 alkyl, C4-C6 t-alkyl, C5-C8 t-alkenyl, benzyl, methoxybenzyl~ di-phenylmethyl, phthalimidomethyl, succinimidomethyl or trichloroethyl.
Similarly, the term protected hydroxy refers to groups for~ed with a hydroxy group such as formyloxy, p~
CEPHALOSPORIN p-NITROBENZYL ESTERS
This invention provides a superior method for the removal of the ~-nitrobenzyl (hereinafter abbreviated to "pNB") ester group from cephalosporin carboxylic acids. The process is economically important, because cephalosporin antibiotics are often processed ln the form of pNB esters, since the esters are convenient and economical to handle in chemical processing. The ester group must eventually be removed, however, because the cephalosporins are used as pharmaceuticals in the acid or salt form.
The pNs ester group has been used in the manufacture of cephalosporins for some time. See U.S.
15 Patent 3,632,850, of Garbrecht. The pNB group has been removed chemically, su-h as with zinc and a strong acid r or catalytically, as taught by Garbrecht, Other deesterification methods have since been devised, such as the methods of Hatfield, using zinc and an a-hydroxy-20 carboxylic acid, U.S. Patent 4,091,214, or zinc and an orsancthiol, Belgian Patent 856,288, and the metho~ of Jackson, U.S. Patent 3,799,924, using a dithionite sâlt .
All of the chemical and catalytic methods of ~5 deesterification, however, have the disadvantage that they may affect functional groups of the molecule other than the pNs ester.
According to the p~esent lnvention there is provided a process for remo~Ting the p~B ester protecting 3Q group from a cepna'osporin 4-carbo~ylic acid pNB ester thereby liberatins the free sephalosporin 4-carbo~ylic acid;
characterized in that the pNB ester is electrolytically reduced in an acidic liquid medium comprising from about 0 to about 50% water, an acid having a PKa determined in water of 0 or below, the amount of said acid being at least four moles per mole of the compound to be reduGed, and an organic sol~ent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, said working electrode sub~
stantially comprising carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, at a temperature from about 0C. to about 75C., at a potential in a range from about the potential of the initial onset of current flow of the first reduction to a~out the potential of the initial onset of current lS flow of the second reduction.
Preferred compounds prepared by the process of the invention are those having the formula:
(P)m (P)m RHN-~---t/ \ RHN_I___t/ \
---N I-R1 Or l N l=CH2 wherein X is hydrogen;
m is 0 or 1;
R2 is hydrogen or methoxy;
R is hydrogen or -CGR3;
R3 is hydrogen, Cl-C3 alkyl, halomethyl, benzyloxy, 2,2,2-trichloroethoxy, t-butoxy, ~ J~
X-4509 -3~
R4, R4-(o)n-CH2-, R4-CH(R5)-, R -CH2-, or ~N/ ~R7 wherein R7 is hydrogen or Cl-C3 alkyl and R8 is hydrogen or an amino-protecting group;
R4 is cyclohexadienyl or phenyl, or cyclohexadienyl or phenyl substituted with one or two halo, hydroxy, protected hydroxy, aminomethyl, protected amino-methyl, Cl-C4 alkyl or Cl-C4 alkoxy groups;
n is 0 or 1;
R5 is hydroxy, protected hydroxy, amino, protected amino, carboxy or protected carboxy;
R is 2-thienyl, 2-furyl, 5-tetrazolyl or l-tetrazolyl;
Rl is chloro, Cl-C3 alkyl or -CH2R ;
R9 is Cl-C4 alkanoyloxy, benzoyloxy, ~luoro, chloro, carbamoyloxy, Cl-C4 alkylcarbamoyloxy, O-N/ ~
/1 = , ~-=1' -NH--~ ,N-CH3 H
pyridinio, pyridinio substit~.ed with Cl-C4 alkyl, Cl-C~ alkanoyl, carbamoyl, Cl-C4 alkyl-carbamoyl, chloro, fluoro, hydroxy or trifluoro-methyl, or the corresponding pyridinio chlorides or bromides, or -S-R10;
R10 is -CH2CO2(Cl-C4 alkyl), carbamoyl, phenyl, phenyl substituted with one or two chloro, fluoro, Cl-C4 alkyl, hydroxy, Cl-C4 alkylsulfonamido or tri-fluoromethyl groups;
triazol-3-yl unsubstituted or substituted with one or two groups independently selected from Cl-C3 alkyl, -CO2(C1-C4 alkyl), -CONH2 and -CH2NHOCO(benæyl or Cl-C4 alkyl);
OH
~ /
tetrazol-l-yl or tetrazol-5-yl substituted with one or two groups independently selected from C1-C4 alkyl and -CH2CO2(Cl-C4 alkyl or hydrogen);
4-cyano-5-aminopyrimidin-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl;
provided that n is 0 when R4 is cyclohexadienyl.
In the above general ~ormula, various gen-eralized terms are used to describe the various groups.
The generalized terms have their usual meanings in organic chemistry. For e~ample, the term halomethyl includes bromomethyl, chloromethyl, fluoromethyl and iodomethyl.
The group R3 is a 2-amino-4-thiazolyl(alkoxy-imino~methyl group. ~he alkoxyimino group of this group may be in either the syn or anti form.
The terms Cl-C3 alkyl, Cl-C4 alkyl and Cl-C4 alkoxy include groups such as methyl, ethyl, propyl, butyl, s-butyl, t-butyl, methoxy, isopropoxy and i-butoxy.
The term protected amino refers to an amino group substituted with one of the commonly employed amino-protecting groups such as t-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 1-carbomethoxy-2-propenyl.
Other accepted amino-protecting groups such as are described by J. w. Barton in Protective Groups in Organic Chemistry, J.E.W. McOmie, Editor, Plenum Press, ~ew York, 1973, chapter 2 will be recognized by organic chemists as suitable for the purpose.
The term protected carboxy refers to an acid group protected with any group which is conventionally used to block or protect the carboxylic acid function-ality of a cephalosporin while reactions involving other functional sites are car~ied out. Such carboxylic acid protecting groups are noted for their ease of cleavage and for their ability to protect the acid from unwanted reactions. Such groups are thoroughly described by E. Haslam in Protective Gro~æs in Organic Chemistry, Chapter 5. Any such group may be used, of course. The preferred groups, however, are Cl-C4 alkyl, C4-C6 t-alkyl, C5-C8 t-alkenyl, benzyl, methoxybenzyl~ di-phenylmethyl, phthalimidomethyl, succinimidomethyl or trichloroethyl.
Similarly, the term protected hydroxy refers to groups for~ed with a hydroxy group such as formyloxy, p~
2-chloroacetoxy, benzyloxy, diphenylmethoxy, triphenyl-methoxy, phenoxycarbonyloxy, t-butoxy and methoxy-methoxy. Other accepted hydroxy-protecting groups, such as those described by C. B. Reese in chapter 3 of Protective Groups in Organic Chemistry will be under-stood to be included in the term protected hydroxy.
Since the process of this invention is carried out in an acid medium, any acid-labile groups which may be on the starting compound will be attacked.
Such groups include, for example, the widely used trimethylsilyl protecting group. Acid-labile groups should be avoided in the practice of this invention, unless it is desired to remove them from the starting compound.
The term Cl-C4 alkanoyloxy includes groups such as formyloxy, acetoxy, propionyloxy and butyryloxy.
The term Cl-C4 alkylcarbamoyloxy includes N-methyl-carbamoyloxy, N-propylcarbamoyloxy, N-i-butylcarbamoyl-oxy and the like groups.
The pyridinio and substituted pyridinio groups, and the pyridinio chlorides and bromides, are groups comprising a pyridine ring joined through its nitrogen, and having three double bonds, so that the nitrogen atom is in the quaternary form.
2S The term Cl-C~ alkylsulfonamido refers to groups such as methylsulfonamido, ethylsulfonamido, isopropylsulfonamido and t-butylsulfonamido.
Fo-mation of esters of cephalosporin acids is a routine expedient in the art, for instance, as taught by U.S. Patent 3,632,850. The pNB esters are usually formed at a relatively early stage in the synthesis of .~
the cephalosporin, and the compound is carried throush synthetic steps in the pNB ester form. The ester may be formed, for example, by simple contact of a cephalo-sporin acid with p-nitrobenzyl bromide in any con-venient solvent at ambient temperature. It may also beadvantageous to form the pNB ester of a penicillin, especially a penicillin l-oxide, and transform the penicillin into a cephalosporin by one of the well-known ring e~pansion techniques. The cephalosporin ester so made may then be subjected to additlonal steps to form the desired compound, and finally deesterified by the process of this invention to obtain the anti-biotically active cephalosporin acid.
.~ particularly preferred group of compounds includes those wherein ~1 is chloro, and those wherein R is -CH2S~ .
The most preferred products of the present process are 7-(D-2-amiho-2-phenylacetamido)-3-meth
Since the process of this invention is carried out in an acid medium, any acid-labile groups which may be on the starting compound will be attacked.
Such groups include, for example, the widely used trimethylsilyl protecting group. Acid-labile groups should be avoided in the practice of this invention, unless it is desired to remove them from the starting compound.
The term Cl-C4 alkanoyloxy includes groups such as formyloxy, acetoxy, propionyloxy and butyryloxy.
The term Cl-C4 alkylcarbamoyloxy includes N-methyl-carbamoyloxy, N-propylcarbamoyloxy, N-i-butylcarbamoyl-oxy and the like groups.
The pyridinio and substituted pyridinio groups, and the pyridinio chlorides and bromides, are groups comprising a pyridine ring joined through its nitrogen, and having three double bonds, so that the nitrogen atom is in the quaternary form.
2S The term Cl-C~ alkylsulfonamido refers to groups such as methylsulfonamido, ethylsulfonamido, isopropylsulfonamido and t-butylsulfonamido.
Fo-mation of esters of cephalosporin acids is a routine expedient in the art, for instance, as taught by U.S. Patent 3,632,850. The pNB esters are usually formed at a relatively early stage in the synthesis of .~
the cephalosporin, and the compound is carried throush synthetic steps in the pNB ester form. The ester may be formed, for example, by simple contact of a cephalo-sporin acid with p-nitrobenzyl bromide in any con-venient solvent at ambient temperature. It may also beadvantageous to form the pNB ester of a penicillin, especially a penicillin l-oxide, and transform the penicillin into a cephalosporin by one of the well-known ring e~pansion techniques. The cephalosporin ester so made may then be subjected to additlonal steps to form the desired compound, and finally deesterified by the process of this invention to obtain the anti-biotically active cephalosporin acid.
.~ particularly preferred group of compounds includes those wherein ~1 is chloro, and those wherein R is -CH2S~ .
The most preferred products of the present process are 7-(D-2-amiho-2-phenylacetamido)-3-meth
3-cephem-4-carboxylic acid, 7-(D-2-amino-2-phenyl-acetamido)-3-chloro-3-cephem-4-carboxylic acid, 7-(tetrazol-l-ylacetamido)-3-(S-methyl-1,3,4-thiadiazol-2-yLthiomethyl)-3-cephem-4-carboxylic acid, and 7-(2-phenyl-2-hydroxyacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
The electrolytic cells used for the process of this invention are the conventional types now known in the electrochemical art. This invention does not provide and does not need any new cells or other equip-ment. Some discussion o~ electroiytic cells will, however, be given.
An electrolytic cell of the type used for electrolytic reductions has a working electrode, some-times called the cathode, at which the reduction takes place. The working electrode is maintained at a potential which is negative with respect to the auxiliary electrode, or anode, at which only electrolyte re-actions should take place. A reference electrode is usually also used. The reference electrode, at which no reactions should take place, supplies a reference point from which the potential of the working electrode is measured. A typical and frequently-used reference electrode is the saturated calomel electrode; others are -the mercury/mercuric chloride electrode and the silver/silver chloride electrode. The reference electrode is electrically connected to the working fluid through a conductive bridge or a porous junction.
Cells are very often divided into compart-ments, so that each of the electrodes is immersed in fluid which is physically separated from the fluids of the other compartments, but is electrically connected to them. Such division of the cell is optional in the context of the present invention, unless the cornpound to be reduced bears a group which can be electrically oxidiæed, such as the compounds in which R is 4 hydroxy-phenylacetyl. In general, groups having oxygen sub-stitution on an aromatic ring are likely to be readily oxidized. The oxidizability of the starting compound may be readily determined by running a voltammogram on the auxiliary electrode in a positive direction with respect to the reference electrode.
Figure l in the accompanying drawing is included to illustrate a typical voltammogram which results when a system adapted to the practice of this invention is subjected to an increasing negative potential. The bottom axis, labeled E, measures the potential applied to the working electrode of the cell, compared to the reference electrode, and the potential is increasingly negative as one progresses to the right along the E axis.
The vertical axis, labeled i, indicates current flow through the cell, from the secondary electrode to the working electrode, and increases as one proceeds up the i axis.
A typical voltammogram curve is shown in Figure 1. The curve is drawn in the usual manner, by slowly subjecting the system to increasingly negative potential, measuring the current at each potential, and plotting current against potential. The voltammogram shown represents a compound which has two groups subject to electrolytic reduction.
The first reduction occurs at the point of the E-i curve between ~ and B. Point A marks the inltial onset of current flow of the first reduction, and point ~ ~arks the initial onset of current flow of the second reduction.
Point C indicates the onset of background discharge, which is the point where the solvent-electrolyte system begins to break down in an uncon-trolled electrolysis, discharging hydrogen.
~.~. f;~
~-4509 -10-The presence of inflection points, such as are shown in the figure, indicates that one or more oxidizable groups are present and that a divided cell is necessary, so that the auxiliary electrode is physically separated from the working fluid which contains the compound.
The arrangement of electrolytic cells, the construction of electrodes, and the materials which may be effectively used as dividers are all part of the common knowledge of the electrochemical art, and may easily be learned by reference to text books and journal articles. Particularly useful text books which may be mentioned include Organic Electrochemistry, ~.
M. Baizer, Editor, Marcel Dekker, Inc., New ~ork (1973), and Technique of Electroorganic Synthesis, N. L. Weinberg, Editor, John Wiley and Sons, New York (1974).
Working electrodes for use in the process of this invention are made of carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium. The preferred working electrodes are mercury, sil~er and lead. The electrodes should be rather highly purified, as is normally the case in electrochemistry. The form of the electrode is not important; it may be solid sheet, gauze or cloth, a basket of shot, or a fluidized bed of particles, with equally good results. The electrode may also be made of an inert substrate plated with the electrode metal, or it may be made in the form of a sheet of the electrode composition, wrapped with gauze of the same composition to increase the electrode area.
The auxiliary electrode does not participate in the reductive process, and so it may be made of any suitable substance which is not attacked by the oxi-dative side of the electrolytic process. Auxiliary electrodes are most often made of the noble metals, especially platinum, or of carbon. Platinum oxide, or platinum coated with platinum oxide, is the preferred anode composition. Lead oxide, silver oxide and such metallic oxides are also usable auxiliary electrode compositions.
It is most effective to arrange the cell so that the distance between the auxiliary electrode and the working electrode is everywhere the same, and i5 as small as possible. The relationship is desirable in all electrolytic processes, to maximize current flow and minimize temperature rise caused by the resistance of the fluid to the flow of current.
The process of this invention is carried out in an acidic working fluid, which is made acid by the addition of an acid having a PKa of 0 or less, deter-mined in water, preferably sulfuric acid or hydro-chloric acid. Other strong acids such as phosphoric acid, nitric acid, p-toluenesulfonic acid and the like may also be used.
~he acid is necessary to give up protons to the reaction at the working electrode, and also to keep the working fluid acid, because the products are unstable in basic conditions. Since the reduction is a ~-electron process, the working fluid must contain at least four ~oles of acid per mole of compound to be reduced~ Greater amounts of acid, even up to ten or twenty moles per mole of compound, may be used if desired.
If an undivided cell is used, the fluid in contact with both the working electrode and the auxiliary electrode will be the same. If the cell is divided, however, the working fluid will undoubtedly be different from the fluid in the auxiliary electrode compartment.
The working fluid used in this invention is a mixture containing up to about 50% water, preferably from about 10~ to about 50% water. The organic portions of the working fluid may be either wa~er-miscible or water-immiscible. It is preferred to use a water-miscible solvent, so that the working fluid is a homo-geneous solution.
Suitable water-miscible organic solvents include the amides, especially dimethylformamide and dimethylacetamide, acetone, the water-miscible alkanols, such as methanol, ethanol and propanol, and tetra-hydrofuran.
If a water-immiscible solvent is used in the working fluid, the choice of solvents is extremely broad, because any solvent may be used which is not reduced at the working electrode. Especially desirable solvents include the halogenated solvents, such as dichloromethane, 1,1,2-trichloroethane, chloroform, chlorobenzene, l,l,l-trichloroethane and the like.
Other immiscible sol~Jents which may advantageously be used include the ketones including methyl ethyl ketone, methyl butyl ketone and methyl isobutyl ketone, to mention only those which are economically available in commerce, the aromatic solvents such as benzene, toluene and the xylenes, the alkanes such as pentane, hexane and the octanes, the alcohols such as phenol, the butyl alcohols and the like, and ethers such as diethyl ether, diisopropyl ether and hexahydropyran.
When a water-immiscible solvent is used, the working fluid necessarily consists of two distinct phases. The acid remains in the aqueous phase, of course, and it is necessary to provide an electrolyte for the solvent phase of the working fluid, Such electrolytes are commonly used in the electrochemical art, and are preferably chosen from the class of tertiary amine salts~ Useful electrolytes for this purpose include, for example, tetraethylammonium perchlorate, tetrabutylammonium perchlorate, benzotri-butylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride, methyltributylammonium iodide, tribenzylethylammonium p-toluenesulfonate, and the like electrolytes.
The same organic electrolytes are used when the working fluid is non-aqueous, if the acid ls im-miscible with the solvent.
If the process of this invention is to be carried out in a divided cell, the divider may be made of any of the materials commonly used in electrochemistry for the purpose. Especially useful dividers are made from the ion exchange membranes, especially those which can pass cations. Dividers may also advantageously be made of finely porous substances such as ceramic mem-branes and sintered glass membranes. Such porous di~iders may be made permeable to ions, but not to the fluids themselves, by sealing the membranes with a conductive gel, of which a typical e~ample is agar gel saturated with an ionic substance such as, for example, potassium sulfate.
When the auxiliary electrode occupies a cell compartment by itself, it is immersed in a conductive fluid. If the divider is a porous membrane, it is advisable to provide an auxiliary electrode fluid which is compatible with the working fluid, such as an aqueous solution of the mineral acid used in the working fluid. If the cell divider is porous only to ions, then the au~iliary electrode fluid may be any convenient conductive fluid, such as dilute aqueous solutions of ionizable salts and acids.
The temperature of the process is from about 0C. to about 75C., preferably from about 0C. to about 30C.
The potential of the working electrode, or the potential between the working electrode and the auxiliary electrode, may be controlled in various ways.
The most effective and precise way to control the potential is to use a reference electrode, with its junction to the working fluid placed as physically close as possible to the working electrode. The desired potential for the process is determined from examination of a voltammogram of the system, and the potential between the working electrode and the auxiliary electrode is adjusted to give the desired constant potential between the reference electrode and the z working electrode. This method o~ control is much more effective than control by the overall voltage between the working electrode and the auxiliary electrode, because that voltage depends on the condition of the dividing membrane, if any, the concentration of the acid in the working fluid, and the concentration of the compound to be reduced in the working fluid.
Similarly it is relatively inefficient to control the system by means of the current flow between the auxiliary electrode and the working electrode, because the current flow is directly dependent on the concentration of the compound to be reduced, as well as upon the physical condition of the electrodes and of the divider. However, when an individual reduction has been thoroughly studied and the relationship between current, time and concentration is known, controlled-current electrolysis can be used for production of repeated batches.
Thus, the best way to control the system is by the potential between a reference electrode and the working electrode, and the con-trol most advantageously is provided by an automatic instrument which constantly senses that potential and adjusts the voltage between the workin~ electrode and auxiliary electrode accord-ingly. Such instruments are now readily available; onemaker of them is Princeton Applied Research, Inc., Princeton, M.J., U.S.A.
As has been briefly discussed above, the potential for operating the process of this invention with any given combination of electrodes, working fluid and compound is determined according to the routine method of the electrochemical art, by running a volt-ammogram of the system. It has been found, in per-forming voltammograms of many compounds of the formula described above, that the first current plateau cor-responds to the reduction of the nitro group of the p-nitrobenzyl group of these compounds. Accordingly, it is selectively possible to reduce that nitro group without affecting other portions of the compound. Once the nitro group has been reduced, the benzyl ester group spontaneously hydroly~es from the compound, producing the antibiotic cephalosporin acid.
It is not possible, of course, to name a precise potential range for the operation of the process of this invention, since the potential for every system will necessarily be different. It has been observed, however, that the potential of the working electrode for reductions accordin~ to this process is from about -0.3 volt to about -l volt, relative to a saturated calomel reference electrode, in the majority of systems which have been used.
The reduction of this invention appears to be a 4-electron process, and so the reduction of a gram-mole of compound requires 385,948 coulombs. The length of time necessary to pass this amount of current necessarily depends upon the overall resistance of the cell and the e~fective area of the electrodes.
Electrolytic cells usually require good agitation, and the process of this invention is typical in this respect. It has been found advisable to
The electrolytic cells used for the process of this invention are the conventional types now known in the electrochemical art. This invention does not provide and does not need any new cells or other equip-ment. Some discussion o~ electroiytic cells will, however, be given.
An electrolytic cell of the type used for electrolytic reductions has a working electrode, some-times called the cathode, at which the reduction takes place. The working electrode is maintained at a potential which is negative with respect to the auxiliary electrode, or anode, at which only electrolyte re-actions should take place. A reference electrode is usually also used. The reference electrode, at which no reactions should take place, supplies a reference point from which the potential of the working electrode is measured. A typical and frequently-used reference electrode is the saturated calomel electrode; others are -the mercury/mercuric chloride electrode and the silver/silver chloride electrode. The reference electrode is electrically connected to the working fluid through a conductive bridge or a porous junction.
Cells are very often divided into compart-ments, so that each of the electrodes is immersed in fluid which is physically separated from the fluids of the other compartments, but is electrically connected to them. Such division of the cell is optional in the context of the present invention, unless the cornpound to be reduced bears a group which can be electrically oxidiæed, such as the compounds in which R is 4 hydroxy-phenylacetyl. In general, groups having oxygen sub-stitution on an aromatic ring are likely to be readily oxidized. The oxidizability of the starting compound may be readily determined by running a voltammogram on the auxiliary electrode in a positive direction with respect to the reference electrode.
Figure l in the accompanying drawing is included to illustrate a typical voltammogram which results when a system adapted to the practice of this invention is subjected to an increasing negative potential. The bottom axis, labeled E, measures the potential applied to the working electrode of the cell, compared to the reference electrode, and the potential is increasingly negative as one progresses to the right along the E axis.
The vertical axis, labeled i, indicates current flow through the cell, from the secondary electrode to the working electrode, and increases as one proceeds up the i axis.
A typical voltammogram curve is shown in Figure 1. The curve is drawn in the usual manner, by slowly subjecting the system to increasingly negative potential, measuring the current at each potential, and plotting current against potential. The voltammogram shown represents a compound which has two groups subject to electrolytic reduction.
The first reduction occurs at the point of the E-i curve between ~ and B. Point A marks the inltial onset of current flow of the first reduction, and point ~ ~arks the initial onset of current flow of the second reduction.
Point C indicates the onset of background discharge, which is the point where the solvent-electrolyte system begins to break down in an uncon-trolled electrolysis, discharging hydrogen.
~.~. f;~
~-4509 -10-The presence of inflection points, such as are shown in the figure, indicates that one or more oxidizable groups are present and that a divided cell is necessary, so that the auxiliary electrode is physically separated from the working fluid which contains the compound.
The arrangement of electrolytic cells, the construction of electrodes, and the materials which may be effectively used as dividers are all part of the common knowledge of the electrochemical art, and may easily be learned by reference to text books and journal articles. Particularly useful text books which may be mentioned include Organic Electrochemistry, ~.
M. Baizer, Editor, Marcel Dekker, Inc., New ~ork (1973), and Technique of Electroorganic Synthesis, N. L. Weinberg, Editor, John Wiley and Sons, New York (1974).
Working electrodes for use in the process of this invention are made of carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium. The preferred working electrodes are mercury, sil~er and lead. The electrodes should be rather highly purified, as is normally the case in electrochemistry. The form of the electrode is not important; it may be solid sheet, gauze or cloth, a basket of shot, or a fluidized bed of particles, with equally good results. The electrode may also be made of an inert substrate plated with the electrode metal, or it may be made in the form of a sheet of the electrode composition, wrapped with gauze of the same composition to increase the electrode area.
The auxiliary electrode does not participate in the reductive process, and so it may be made of any suitable substance which is not attacked by the oxi-dative side of the electrolytic process. Auxiliary electrodes are most often made of the noble metals, especially platinum, or of carbon. Platinum oxide, or platinum coated with platinum oxide, is the preferred anode composition. Lead oxide, silver oxide and such metallic oxides are also usable auxiliary electrode compositions.
It is most effective to arrange the cell so that the distance between the auxiliary electrode and the working electrode is everywhere the same, and i5 as small as possible. The relationship is desirable in all electrolytic processes, to maximize current flow and minimize temperature rise caused by the resistance of the fluid to the flow of current.
The process of this invention is carried out in an acidic working fluid, which is made acid by the addition of an acid having a PKa of 0 or less, deter-mined in water, preferably sulfuric acid or hydro-chloric acid. Other strong acids such as phosphoric acid, nitric acid, p-toluenesulfonic acid and the like may also be used.
~he acid is necessary to give up protons to the reaction at the working electrode, and also to keep the working fluid acid, because the products are unstable in basic conditions. Since the reduction is a ~-electron process, the working fluid must contain at least four ~oles of acid per mole of compound to be reduced~ Greater amounts of acid, even up to ten or twenty moles per mole of compound, may be used if desired.
If an undivided cell is used, the fluid in contact with both the working electrode and the auxiliary electrode will be the same. If the cell is divided, however, the working fluid will undoubtedly be different from the fluid in the auxiliary electrode compartment.
The working fluid used in this invention is a mixture containing up to about 50% water, preferably from about 10~ to about 50% water. The organic portions of the working fluid may be either wa~er-miscible or water-immiscible. It is preferred to use a water-miscible solvent, so that the working fluid is a homo-geneous solution.
Suitable water-miscible organic solvents include the amides, especially dimethylformamide and dimethylacetamide, acetone, the water-miscible alkanols, such as methanol, ethanol and propanol, and tetra-hydrofuran.
If a water-immiscible solvent is used in the working fluid, the choice of solvents is extremely broad, because any solvent may be used which is not reduced at the working electrode. Especially desirable solvents include the halogenated solvents, such as dichloromethane, 1,1,2-trichloroethane, chloroform, chlorobenzene, l,l,l-trichloroethane and the like.
Other immiscible sol~Jents which may advantageously be used include the ketones including methyl ethyl ketone, methyl butyl ketone and methyl isobutyl ketone, to mention only those which are economically available in commerce, the aromatic solvents such as benzene, toluene and the xylenes, the alkanes such as pentane, hexane and the octanes, the alcohols such as phenol, the butyl alcohols and the like, and ethers such as diethyl ether, diisopropyl ether and hexahydropyran.
When a water-immiscible solvent is used, the working fluid necessarily consists of two distinct phases. The acid remains in the aqueous phase, of course, and it is necessary to provide an electrolyte for the solvent phase of the working fluid, Such electrolytes are commonly used in the electrochemical art, and are preferably chosen from the class of tertiary amine salts~ Useful electrolytes for this purpose include, for example, tetraethylammonium perchlorate, tetrabutylammonium perchlorate, benzotri-butylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride, methyltributylammonium iodide, tribenzylethylammonium p-toluenesulfonate, and the like electrolytes.
The same organic electrolytes are used when the working fluid is non-aqueous, if the acid ls im-miscible with the solvent.
If the process of this invention is to be carried out in a divided cell, the divider may be made of any of the materials commonly used in electrochemistry for the purpose. Especially useful dividers are made from the ion exchange membranes, especially those which can pass cations. Dividers may also advantageously be made of finely porous substances such as ceramic mem-branes and sintered glass membranes. Such porous di~iders may be made permeable to ions, but not to the fluids themselves, by sealing the membranes with a conductive gel, of which a typical e~ample is agar gel saturated with an ionic substance such as, for example, potassium sulfate.
When the auxiliary electrode occupies a cell compartment by itself, it is immersed in a conductive fluid. If the divider is a porous membrane, it is advisable to provide an auxiliary electrode fluid which is compatible with the working fluid, such as an aqueous solution of the mineral acid used in the working fluid. If the cell divider is porous only to ions, then the au~iliary electrode fluid may be any convenient conductive fluid, such as dilute aqueous solutions of ionizable salts and acids.
The temperature of the process is from about 0C. to about 75C., preferably from about 0C. to about 30C.
The potential of the working electrode, or the potential between the working electrode and the auxiliary electrode, may be controlled in various ways.
The most effective and precise way to control the potential is to use a reference electrode, with its junction to the working fluid placed as physically close as possible to the working electrode. The desired potential for the process is determined from examination of a voltammogram of the system, and the potential between the working electrode and the auxiliary electrode is adjusted to give the desired constant potential between the reference electrode and the z working electrode. This method o~ control is much more effective than control by the overall voltage between the working electrode and the auxiliary electrode, because that voltage depends on the condition of the dividing membrane, if any, the concentration of the acid in the working fluid, and the concentration of the compound to be reduced in the working fluid.
Similarly it is relatively inefficient to control the system by means of the current flow between the auxiliary electrode and the working electrode, because the current flow is directly dependent on the concentration of the compound to be reduced, as well as upon the physical condition of the electrodes and of the divider. However, when an individual reduction has been thoroughly studied and the relationship between current, time and concentration is known, controlled-current electrolysis can be used for production of repeated batches.
Thus, the best way to control the system is by the potential between a reference electrode and the working electrode, and the con-trol most advantageously is provided by an automatic instrument which constantly senses that potential and adjusts the voltage between the workin~ electrode and auxiliary electrode accord-ingly. Such instruments are now readily available; onemaker of them is Princeton Applied Research, Inc., Princeton, M.J., U.S.A.
As has been briefly discussed above, the potential for operating the process of this invention with any given combination of electrodes, working fluid and compound is determined according to the routine method of the electrochemical art, by running a volt-ammogram of the system. It has been found, in per-forming voltammograms of many compounds of the formula described above, that the first current plateau cor-responds to the reduction of the nitro group of the p-nitrobenzyl group of these compounds. Accordingly, it is selectively possible to reduce that nitro group without affecting other portions of the compound. Once the nitro group has been reduced, the benzyl ester group spontaneously hydroly~es from the compound, producing the antibiotic cephalosporin acid.
It is not possible, of course, to name a precise potential range for the operation of the process of this invention, since the potential for every system will necessarily be different. It has been observed, however, that the potential of the working electrode for reductions accordin~ to this process is from about -0.3 volt to about -l volt, relative to a saturated calomel reference electrode, in the majority of systems which have been used.
The reduction of this invention appears to be a 4-electron process, and so the reduction of a gram-mole of compound requires 385,948 coulombs. The length of time necessary to pass this amount of current necessarily depends upon the overall resistance of the cell and the e~fective area of the electrodes.
Electrolytic cells usually require good agitation, and the process of this invention is typical in this respect. It has been found advisable to
4~;2 X-4509 -17~
provide enough agitation o the working fluid to keep the surface of the electrode thoroughly swept, so that a fresh supply of compound to be reduced is constantly supplied to the working electrode. Further, when a water-immiscible solvent is used in the working fluid, it is necessary to agitate the fluid sufficently well to keep the two phases of the working fluid intimately mixed in the form of fine droplet~.
The electrochemical art has long known that electrolytic processes are carried out more advanta geously in flow cells than in batch electrolytic cells, in general. A flow cell is an electrolytic cell arranged for the constant passage of the working fl~id through the cell. The cell volume may be quite small, and the current density rather high, to achieve the desired extent of reaction in a single pass through the cell, or the flow rate may be lower and the volume higher, with the expectation that a number of passes through the cell will be necessary. In either event, the Low cell is operated continuously with no inter-ruptions for filling and emptyin~ the cell, and the associated operations of product isolation and tem-perature control are carried on outside the cell.
Flow cells are set up just as are batch cells, except for the necessary provisions for entry and exit of the working fluid. A flow cell may be divided, if necess~ry, in the usual manner. It is often possible to design a flow cell with the elec-trodes spaced advantageously close to each other, because the agi~ation of the working fluld is orovided p~
by its own flow velocity and it is unnecessary to provide for mechanical agitatlon of the cell. For example, a flow cell is often built in the form of a plate-and-frame filter press, with the electrodes in sheet form, clamped between the frames.
The concentration of the compound to be reduced in the working fluid is widely variable and is limited only by the solubility of the compound. Of course, it is most economical to use relatively high concentrations, in order to obtain the maximum effect from the sol~ents used in the process. However, work-up of the ~luid and isolation of the product from it is frequently more difficult when highly concentrated working fluids are used. Accordingly, it has not been ad~-antageous in practice to use concentrations of compound in the working fluid higher than about 20 weight/volume.
The cephalosporin acid is recovered from th~
working fluid by a conventional isolation procedure.
Typically, the working ~luid is diluted with a large amount of dilute mineral acid, such as l-normal hydro-chloric acid, and the dilute solution is extracted with ethyl acetate. In some cases, it is advantageous to back-extract the organic layer with additional dilu~e acid, to remove as much as possible of the organic portions of the working fluid. The organic layer is then evaporated under vacuum to obtain the product, which may be further purified, as by recrystalli~ation, if desired.
In isolating the product, it is separated from an impurity which is believed to be composed of polymers of the aminobenzyl moiety removed i~ the reduction. This polymeric impurity is formed in deesterifications according to the prior art methods, as well. The use of dimethylformamide as the solvent in the working fluid makes the isolation problem much easier, and back-extraction of the first organic layer obtained in the isolation steps, with dilute aqueous acid, is very useful in removing the polymeric impurity.
The following examples are included to assist the reader in understanding the process of this in-vention, and to assure that a skilled electrochemist can carry out any desired process of this invention.
The products of the examples were identified by in-strumental analytical techniques, as will be explained in the individual examples. Some products were made repeatedly by different embodiments of the process of the invention, and in such cases, the products were often merely identified by thin-layer chromatography (TL~) or by nuclear magnetic resonance (NMR) analysis as identical to the original product, and were not otherwise isolated or identified.
Much of the data in the following e~amples has been tabulated, to condense the information, and the compounds made by the processes to be described will be identified by the following code. I t will be understood, of course, that in all cases the starting compound was the corresponding p-nitrobenzvl ester.
~t~
1. 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid 2. 7-(2-phenyl-2-aminoacetamido)-3-methyl-3-cephem-4-carboxylic acid 3. 7-phenoxyacetamido-3-(1-methyltetrazol-S-ylthio-methyl)-3-cephem-4-carboxylic acid 4. 7-(2-thienylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
provide enough agitation o the working fluid to keep the surface of the electrode thoroughly swept, so that a fresh supply of compound to be reduced is constantly supplied to the working electrode. Further, when a water-immiscible solvent is used in the working fluid, it is necessary to agitate the fluid sufficently well to keep the two phases of the working fluid intimately mixed in the form of fine droplet~.
The electrochemical art has long known that electrolytic processes are carried out more advanta geously in flow cells than in batch electrolytic cells, in general. A flow cell is an electrolytic cell arranged for the constant passage of the working fl~id through the cell. The cell volume may be quite small, and the current density rather high, to achieve the desired extent of reaction in a single pass through the cell, or the flow rate may be lower and the volume higher, with the expectation that a number of passes through the cell will be necessary. In either event, the Low cell is operated continuously with no inter-ruptions for filling and emptyin~ the cell, and the associated operations of product isolation and tem-perature control are carried on outside the cell.
Flow cells are set up just as are batch cells, except for the necessary provisions for entry and exit of the working fluid. A flow cell may be divided, if necess~ry, in the usual manner. It is often possible to design a flow cell with the elec-trodes spaced advantageously close to each other, because the agi~ation of the working fluld is orovided p~
by its own flow velocity and it is unnecessary to provide for mechanical agitatlon of the cell. For example, a flow cell is often built in the form of a plate-and-frame filter press, with the electrodes in sheet form, clamped between the frames.
The concentration of the compound to be reduced in the working fluid is widely variable and is limited only by the solubility of the compound. Of course, it is most economical to use relatively high concentrations, in order to obtain the maximum effect from the sol~ents used in the process. However, work-up of the ~luid and isolation of the product from it is frequently more difficult when highly concentrated working fluids are used. Accordingly, it has not been ad~-antageous in practice to use concentrations of compound in the working fluid higher than about 20 weight/volume.
The cephalosporin acid is recovered from th~
working fluid by a conventional isolation procedure.
Typically, the working ~luid is diluted with a large amount of dilute mineral acid, such as l-normal hydro-chloric acid, and the dilute solution is extracted with ethyl acetate. In some cases, it is advantageous to back-extract the organic layer with additional dilu~e acid, to remove as much as possible of the organic portions of the working fluid. The organic layer is then evaporated under vacuum to obtain the product, which may be further purified, as by recrystalli~ation, if desired.
In isolating the product, it is separated from an impurity which is believed to be composed of polymers of the aminobenzyl moiety removed i~ the reduction. This polymeric impurity is formed in deesterifications according to the prior art methods, as well. The use of dimethylformamide as the solvent in the working fluid makes the isolation problem much easier, and back-extraction of the first organic layer obtained in the isolation steps, with dilute aqueous acid, is very useful in removing the polymeric impurity.
The following examples are included to assist the reader in understanding the process of this in-vention, and to assure that a skilled electrochemist can carry out any desired process of this invention.
The products of the examples were identified by in-strumental analytical techniques, as will be explained in the individual examples. Some products were made repeatedly by different embodiments of the process of the invention, and in such cases, the products were often merely identified by thin-layer chromatography (TL~) or by nuclear magnetic resonance (NMR) analysis as identical to the original product, and were not otherwise isolated or identified.
Much of the data in the following e~amples has been tabulated, to condense the information, and the compounds made by the processes to be described will be identified by the following code. I t will be understood, of course, that in all cases the starting compound was the corresponding p-nitrobenzvl ester.
~t~
1. 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid 2. 7-(2-phenyl-2-aminoacetamido)-3-methyl-3-cephem-4-carboxylic acid 3. 7-phenoxyacetamido-3-(1-methyltetrazol-S-ylthio-methyl)-3-cephem-4-carboxylic acid 4. 7-(2-thienylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
5. 7-(2-t-butoxycarbonylamino-2-phenylacetamido)-7-methoxy-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
6. 7-(2-hydroxy-2-phenylacetamido)-3-(1-methyltetra-zol-5-ylthiomethylj-3-cephem-4-carboxylic acid
7. 7-phenoxyacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid
8. 7-(2-thienylacetamido)-3-(5-methyl-1,3,4-thia-diazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid
9. 7-(tetrazol-1-ylacetamido)-3-(S-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid
10. 7-[2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-exomethylenecepham-4-carboxylic acid
11. 7-phenylacetamido-3-chloro-3-cephem-4-carboxylic acid
12. 7-~2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid
13. 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid `U~
14. 7-(2-thienylacetamido)-3-benzoyloxymethyl-3-cephem-4-carboxylic acid
15. 7-(2-thienylacetamido)-3-(2 methyltetrazol-5-ylaminomethyl)-3-cephem-4-carboxylic acid
16. 7-(2-thienylacetamido)-3-(4-carbamoylpyridinio-methyl)-3-cephem-4-carboxylic acid, bromide
17. 7-(2-thienylacetamido)-3-(4-chlorophenylthio-methyl)-3-cephem-4-carboxylic acid
18. 7-(2-thienylacetamido)-3-(benzo[4,5-a]-1,2,3-trlazol-1-yloxymethyl)-3-cephem-4-carboxylic acid
19. 7-(2-thienylacetamido)-3-methoxycarbonylmethyl-thiomethyl-3-cephem-4-carboxylic acid
20. 7-(2-thienylacetamido)-3-t-butoxycarbonylmethyl-thiomethyl-3-cephem-4-carboxylic acid
21. 7-(2-thienylacetamido)-7-methoxy-3-carbamoylthio-methyl-3-cephem-4-carboxylic acid
22. 7-(2-thienylacetamido)-3-~luoromethyl-3-cephem~
4-ca~boxylic acid
4-ca~boxylic acid
23. 7-(2-thienylacetamido)-3-(1-carboxymethyltetrazGl-5-ylthiomethyl)-3-cephem-4-carboxylic acid
24. 7-(2-thienylacetamido)-3-(S-amino-4-cyanopyrimidin-2-ylthiomethyl)-3-cephem-4-c~rboxylic acid
25. 7-[2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-ylthiomethyl)-3-cephem-4-carboxylic acid, l-oxide ~6~ 7-(2-thienylacetamido)-3-(1~-pyrazoloL3,4-d]-pyrimidln-4-ylthiomethyl!-3-cephem-4-carboxylic acid 27. 7-(2-thienylacetamido)-3-(1~ pyrazolo[4,3-d]-pyri.-nidin-7-ylthiomethyl)-3-cephem-4-carboxylic acid X-4509 -~2-28. 7-(2-thienylacetamido)-3-(4-ben~ylcarbonyloxy-aminomethyl-1,2,4-t~iazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 29. 7-(2-thienylacetamldo)-3-(5-carbamoyl-4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-car boxylic acid 30. 7-(2-t-butoxycarbonylamino-2-phenylacetamido)-3-(5-carbamoyl-4-methyl-1,2,4-triazol-3-ylthio-methyl)-3-cephem-4-carboxylic acid 31. 7-[2-(2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-carbamoyl-4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-car-boxylic acid 32. 7-[2-~2-triphenylmethylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 33. 7-(2-thienylacetamido)-3-(5-aminomethyl-1,~,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 34. 7-(2-thienylacetamido)-3-(5-ethoxycarbonyl-4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid The examples which follow are arranged in groups, according to the variations in the operating conditions under which they were run. Most of the operating data are tabulated.
The first group of examples were run in small batch electrolytic cells, having volumes from about 10 to lOa ml.
l~t~
Examples 1-29 3_ In tnese examples, the working fluid was comprised of 90% by volume of dimethylformamide, and 10% by volume of 12~ sulfuric acid. The working electrode was a toroidal mercury pool having an area, in various experiments, of from 14 to 20 cm. . The auxiliary electrode was a loop o platinum wire, parallel to the surface of the working electrode, and separated from the working electrode by a fine glass frit. The reference electrode, in all experiments, was a saturated calomel electrode, with its junction placed physicall~r as close as possible to 'he surface of the working electrode. In some experiments, the cell was an H-type cell with the three electrodes in separate tubes, separated by fine glass frits. An automatic potentiostat was used to control the potential between the working electrode and the reference electrode, and in most cases no measurement of overall voltage o~ the cell was made. The current flows recorded in the table below indicate the approximate maximum current flow at the beginning or the experiment; the current flow, of course, declined steadily as the starting compound was used up.
Many experiments were run at controlled temperatures; room temperature experiments are indi-cated by R. T .
Operating conditions which were not recordedby the operator are indicated by N.R.
1~64~
~-4509 -24-ïn the tables below, the total time of the experiment is indicated, to the nearest 10 minutes, and the total amount of current passed is expressed in terms of a percentage of the theoretical amount o~
current necessary to accomplish a 4-electron reaction.
The products were isolated by diluting the working fluid with a large amount of dilute aqueous acid, usually hydrochloric acid, and extracting the diluted solution several times with portions of ethyl acetate. The organic layers were then back-e~tracted several times with additional portions of dilute aqueous acid, and evaporated to dryness under vacuum to obtain the product. In general, the products were not further purified. Physical-chemical characterizing data for the products is tabulated after the tables showing the operating conditions of the experiments.
The working fluid in all of the experiments was kept free of air by bubbling argon slowly through it.
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The following NMR features were observed in analysis of the compounds prepared in the examples above.
Compound 1, 60 mHz instrument in DMSOd6; ~ 2.12 (s);
3.53 (broad s); 5.15 (d, J = 4.5 Hz); 5.71 (dd, J = 8 Hz and 4.5 Hz); 8.98 (d, J = 8 Hz); 4.68 (s); 6.8-7.6 (m) Compound 3, 60 mHz instrument in DMSOd6; ~ 3.73 (broad s);
3.95 (s); 4.31 (broad s); 4.63 (s); 5.10 (d, J = 4.5 Hz); 5.75 (dd, J = 8 Hz and 4.5 Hz); 6.70-7.5 (m); 9.13 (d, J = 8 Hz) Compound 4, 100 mHz instrument in DMSOd6; ~ 3.70 (ABq), 3.77 (s); 3.93 (s) 4.31 (ABq); 5.08 (d, J = 4.5 Hz); 5.67 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.42 (m); 9.12 (d, J = 8 Hz) Compound 5, 100 mHz instrument in DMSOd6; ~ 1.91 (s);
3.~8 (s); 3.46 (ABq); 3.90 (s); 4.25 (ABq); 5.06 (s);
5.34 (d, J = 3Hz); 7.2-7.6 (m); 9.47 (broad s) Compound 6, 60 mHz instrument in D~SOd6; ~ 3.68 (broad s);
3.93 (s); 4.30 (broad s); 5.06 (d, J - 4.5 Hz); 5.11 (broad s); 5.71 (dd, ~- = 8 Hz and 4.5 Hz); 7.18-7.65 (m); 8.68 ~d, J = 8 Hz) Compound 9, 60 mHz instrument in DMSOd6; ~ 2.17 (s);
3.69 (ABq); 4.38 (ABq); 5.12 (d, J = 4.5 Hz); 5.37 (s);
5.72 (dd, J = 8 Hz and 4.5 Hz); 9.36 (s); 9.50 (d, J =
4.5 Hz) Compound 10, 100 mHz instrument in CDC13; ~ 3.45 (ABq); 4.23 (s); 5.10 (s); 5.23 (broad s); 5.38 (d, J = 4.5 Hz); 5.62 (dd, J = 8 Hz and 4.5 Hz); 6.6 (s), 7.1 (s); 7.35 (s); 8.03 (d, J = 8 Hz) Compound 11, 60 mHz instrument in CDC13 plus acetone d6; ~ 3.68; 3.75; 5.00; 5.80; 7.33; 7.85 Compound 12, 60 mHz instrument in CDC13; ~ 3.57 (ABq);
4.09 (s); 5.10 (d, J = 4O5 Hz); 5.78 (dd, J = 8 Hz and 4.5 Hz); 6.76 (s); 7.35 (m); 7.65 (d, J = 8 Hz) Compound 13, 60 mHz instrument in DMSOd6; ~ 2~03 (s);
3.60 (broad s); 4.63 (s); 4.90 (ABq); 5.10 (d, J = 4.5 Hz); 5.76 (dd, J = 8 Hz); 6.7-7.5 (m); 9.08 (d) Compound 14, 100 mHz instrument in acetone d6; ~ 3.77 (ABq); 3.90 (s); 5.19 (d, J = 4.5 Hz); 5.26 (ABq); 5.85 (dd, J = 8 Hz and 4.5 Hz); 6.85-8.15 (m); 8.05 (d, J =
8 Hz) Compound 18, 60 mHz instrument in DMSOd6; ~ 3.69 (broad s); 3.93 (broad s); 5.14 (d, J = 4.5 Hz); 5.39 (broad s); 5.72 (dd, J = 3 Hz and 4.5 Hz); 6.85-7.42 (m);
7.50-8.12 (m); 9.18 (d, J = 8 Hz) Compound 20, 100 mHz instrument in DMSOd6; ~ 1.41 (s);
3.22 (ABq); 3.51 (ABq); 3.67 (br~ad s); 3.76 (s); 5.09 (d, J = 4.5 Hz); 5.63 (dd, J = 8 Hz and 4.5 Hz); 6.95 (m); 7.35 (m); 9.09 (d, J = 8 Hz) Compound 21, no analysis Compound 22, 60 mHz instrument in acetone d6; ~ 3.71 (broad s); 3.98 (s); 5.36 (d, J = 48 Hz); 5.25 (d, J = 4.5 Hz); 5.78 (dd, J = 8 Hz and 4.5 ~z); 6.9-7.5 (m); 8.16 (d, J = 8 Hz~
Compound 23, 1~0 mHz instrument in DMSOd6; ~ 3.66 (ABq); 3.75 (s); 4.33 (ABq); 5.05 (d, J = 4.5 Hz); 5.3 (s); 6.95 (m!; 7.35 (m); 9.12 (d, J = 8 Hz) J~I ~
Compound 26, 60 mHz instrument in DMSOd6; ~ 3.53 (ABq);
3.78 (s); 4.53 (ABq); 5.13 (d, J = 4.5 Hz): 5.71 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 8.15 (s); 8.90 (s); 9.16 (d, J = 8 Hz);
Compound 28, 60 mHz instrument in DMSOd6; ~ 3.73 (broad s); 3.85 (s); 4.28 (ABq); 4.40 (d, J = 6 Hz); 5.13 (d, J = 4.5 Hz); 5.15 (s); 5.76 (dd, J = 8 Hz and 4.5 Hz);
7.41 (s); 7.78 (t, J = 6 Hz); 9.20 (J = 8 Hz);
Compound 29, 60 mHz instrument in DMSOd6; ~ 3.68 (broad s); 3.78 (s); 3.77 (s); 4.19 (ABq); 5.07 (d, J = 4.5 Hz);
5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.~0 (m); 7.83 (broad s); 8.17 (broad s); 9.14 (d = 8 Hz) Compound 30, 60 mHz instrument in DMSOd6; ~ 1.36 (s);
3.59 (broad 5); 3.77 (s); 4.14 (broad s); 4.98 (d, J = 4.5 Hz); 5.31 (d, J = 9 Hz); 5.67 (dd, J = 8 Hz and 4.5 Hz); 7.lS-7.50 (m); 7.82 (broad s) 8.16 (broad s); 9.17 (d, J = 8 Hz) Compound 31, 360 mHz instrument in DMSOd6; ~ 3.64 ~ (ABq); 3.77 (s); 3.81 (s); 4.18 (ABq); 5.09 (d, J = 4.5 Hz); 5.68 (dd, J = 8 Hz and 4.5 Hz); 6.71 (s); 7.2-7.4 (m); 7.86 (broad s); 8.21 (broad s); 8.84 (s); 9.58 (d, J = 8 Hz) Compound 33, no analysis Compound 34, 60 ~Hz instrument in DMSOd6; ~ 1.33 ~t, J = 7 E~z); 3.68 (broad s); 3.78 (q, J = 7 Hz); 4.23 (broad s); 4.39 (q, J = 7 Hz); 5.07 (d, J = 4.5 Hz);
5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 9.14 (d, J = 8 Hz) PZ' Examples 30-40 The following examples report experiments run according to the method described above, except that, in these examples, the auxiliary electrode was separated from the working electrode by a frit coated with an electrically conductive gel. In some experiments, the gel was formed from agar made with an ionizable salt solution, and in other e~:periments, the frit was coated with methyl cellulose gel made conductive in the same manner.
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Compound 7, 60 mHz instrument in DMSOd6; ~ 2.67 (s);
3.68 (ABq); 4.37 (ABq); 4.61 (s); 5.12 (d, J = 4.5 Hz);
5.71 (dd, J = 8 Hz and 4.5 Hz); 6.8-7.4 (m); 9.09 (d, J = 8 Hz) Compound 15, 100 mHz instrument in DMSOd6; ~ 3.51 (broad s); 3.76 (s); 4.09 (s); 4.22 (~Bq); 5.04 (d, J =
4.5 Hz); 5.62 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.4 (m);
9.07 (d, J = 8 Hz) Compound 16 identified only by TLC
Compound 17, 60 mHz instrument in acetone d6; ~ 3.71 (ABq); 3.93 (s); 4.23 (ABq); 5.13 (d, J = 4.5 Hz); 5.80 (dd, J = 8 Hz and 4.5 Hz); 6.83-7.73 (m); 8.08 (d, J =
8 Hz) Compound 19, 100 mHz instrumen-t in DMSOd6; ~ 3.34 (s);
3.61 (s); 3.67 (s); 3.76; 5.12 (d, J = 4.5 Hz); 5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 9.09 (d, J =
8 Hz) Compound 24, 60 mHz instrument in DMSOd6; ~ 3.68 (broad s); 3.78 (s); 4.20 (ABq); 5.13 (d, J = 4.5 Hz); 5.66 (dd, J = 8 Hz and 4.5 Hz); 6.95 (m); 7.35 (m); 7.93 (broad s); 8.40 (s) Compound 27, 60 mHz instrument in DMSOdS; ~ 3.5 (~road s); 5.63 ~dd, J = 8 Hz and 4.5 Hz); 6.98 (m); 7.37 (m);
8.45 (s); 8.78 (s); 9.08 (d, J = 8 Hz) Compound 8, 60 mHz instrument in DMSOd6; ~ 2 63 (s);
3.70 (ABq); 3.80 (s); 4.41 (ABq); 5.14 (d, J = 4.5 Hz);
5.73 (dd, J = 8 Hz and 4.5 Hz); 6.90-7~50 (m); 9.16 (d, J = ~
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Examples 41 42 The experiments reported in these examples were carried out in the same manner as the experiments of examples 1-29, except that the working and auxiliary electrodes were separated by an ion exchange membrane.
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Compound 25, no analysis Compound 32, 100 m~z instrument in CDC13; ~ 3.65 (s);
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Example 43 The experiment of this example was also carried out according to the methods described in the - text of examples 1-29, except that the working and auxiliary electrodes in this experiment were not separated.
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Example _ The experiment of this example was also carried out according to the process as described in the text of examples 1-29, except that the working electrode was lead, rather than mercury.
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Example 45 The method described in the text of Examples 1-29 was used for this experiment also, except that the working fluid was made up of 90~ dimethylformamide and 10~ of 24N sulfuric acid.
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~-4509 -43-Compound 2, 60 mHz instrument in TFAdl (trifluoro-acetic acid); ~ 2.31 (s); 5.18 (d, J = 4.5 Hz); 5~53 (s); 5.76 (d, J = 4.5 Hz); 7.60 (s) Example 51 The worklng fluid used in this example was composed of 40 ml. of dimethylformamide and lO ml. of pH 5.0 sodium acetate buffer, with sufficient p-toluenesulfonic acid added to the mixture to make it 1.8N. The working electrode was a pool of mercury, and the counter electrode was a platinum wire, immersed in the working fluid with no electrode separation. The reference electrode was saturated calomel.
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~-4509 -47-Example 53 The working fluid in this experiment was a mixture of 45~ of tetrahydrofuran and 55% of an O.lM
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The working electrode was mercury, and the auxiliary electrode was a platinum wire, separated from the working electrode by a fine glass frit coated with potassium sulfate-saturated agar. The reference electrode was saturated calomel, with the porous junction placed as close as possible to the working electrodei X-45~9 -a~8-r~
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Examples 1-29 3_ In tnese examples, the working fluid was comprised of 90% by volume of dimethylformamide, and 10% by volume of 12~ sulfuric acid. The working electrode was a toroidal mercury pool having an area, in various experiments, of from 14 to 20 cm. . The auxiliary electrode was a loop o platinum wire, parallel to the surface of the working electrode, and separated from the working electrode by a fine glass frit. The reference electrode, in all experiments, was a saturated calomel electrode, with its junction placed physicall~r as close as possible to 'he surface of the working electrode. In some experiments, the cell was an H-type cell with the three electrodes in separate tubes, separated by fine glass frits. An automatic potentiostat was used to control the potential between the working electrode and the reference electrode, and in most cases no measurement of overall voltage o~ the cell was made. The current flows recorded in the table below indicate the approximate maximum current flow at the beginning or the experiment; the current flow, of course, declined steadily as the starting compound was used up.
Many experiments were run at controlled temperatures; room temperature experiments are indi-cated by R. T .
Operating conditions which were not recordedby the operator are indicated by N.R.
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~-4509 -24-ïn the tables below, the total time of the experiment is indicated, to the nearest 10 minutes, and the total amount of current passed is expressed in terms of a percentage of the theoretical amount o~
current necessary to accomplish a 4-electron reaction.
The products were isolated by diluting the working fluid with a large amount of dilute aqueous acid, usually hydrochloric acid, and extracting the diluted solution several times with portions of ethyl acetate. The organic layers were then back-e~tracted several times with additional portions of dilute aqueous acid, and evaporated to dryness under vacuum to obtain the product. In general, the products were not further purified. Physical-chemical characterizing data for the products is tabulated after the tables showing the operating conditions of the experiments.
The working fluid in all of the experiments was kept free of air by bubbling argon slowly through it.
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The following NMR features were observed in analysis of the compounds prepared in the examples above.
Compound 1, 60 mHz instrument in DMSOd6; ~ 2.12 (s);
3.53 (broad s); 5.15 (d, J = 4.5 Hz); 5.71 (dd, J = 8 Hz and 4.5 Hz); 8.98 (d, J = 8 Hz); 4.68 (s); 6.8-7.6 (m) Compound 3, 60 mHz instrument in DMSOd6; ~ 3.73 (broad s);
3.95 (s); 4.31 (broad s); 4.63 (s); 5.10 (d, J = 4.5 Hz); 5.75 (dd, J = 8 Hz and 4.5 Hz); 6.70-7.5 (m); 9.13 (d, J = 8 Hz) Compound 4, 100 mHz instrument in DMSOd6; ~ 3.70 (ABq), 3.77 (s); 3.93 (s) 4.31 (ABq); 5.08 (d, J = 4.5 Hz); 5.67 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.42 (m); 9.12 (d, J = 8 Hz) Compound 5, 100 mHz instrument in DMSOd6; ~ 1.91 (s);
3.~8 (s); 3.46 (ABq); 3.90 (s); 4.25 (ABq); 5.06 (s);
5.34 (d, J = 3Hz); 7.2-7.6 (m); 9.47 (broad s) Compound 6, 60 mHz instrument in D~SOd6; ~ 3.68 (broad s);
3.93 (s); 4.30 (broad s); 5.06 (d, J - 4.5 Hz); 5.11 (broad s); 5.71 (dd, ~- = 8 Hz and 4.5 Hz); 7.18-7.65 (m); 8.68 ~d, J = 8 Hz) Compound 9, 60 mHz instrument in DMSOd6; ~ 2.17 (s);
3.69 (ABq); 4.38 (ABq); 5.12 (d, J = 4.5 Hz); 5.37 (s);
5.72 (dd, J = 8 Hz and 4.5 Hz); 9.36 (s); 9.50 (d, J =
4.5 Hz) Compound 10, 100 mHz instrument in CDC13; ~ 3.45 (ABq); 4.23 (s); 5.10 (s); 5.23 (broad s); 5.38 (d, J = 4.5 Hz); 5.62 (dd, J = 8 Hz and 4.5 Hz); 6.6 (s), 7.1 (s); 7.35 (s); 8.03 (d, J = 8 Hz) Compound 11, 60 mHz instrument in CDC13 plus acetone d6; ~ 3.68; 3.75; 5.00; 5.80; 7.33; 7.85 Compound 12, 60 mHz instrument in CDC13; ~ 3.57 (ABq);
4.09 (s); 5.10 (d, J = 4O5 Hz); 5.78 (dd, J = 8 Hz and 4.5 Hz); 6.76 (s); 7.35 (m); 7.65 (d, J = 8 Hz) Compound 13, 60 mHz instrument in DMSOd6; ~ 2~03 (s);
3.60 (broad s); 4.63 (s); 4.90 (ABq); 5.10 (d, J = 4.5 Hz); 5.76 (dd, J = 8 Hz); 6.7-7.5 (m); 9.08 (d) Compound 14, 100 mHz instrument in acetone d6; ~ 3.77 (ABq); 3.90 (s); 5.19 (d, J = 4.5 Hz); 5.26 (ABq); 5.85 (dd, J = 8 Hz and 4.5 Hz); 6.85-8.15 (m); 8.05 (d, J =
8 Hz) Compound 18, 60 mHz instrument in DMSOd6; ~ 3.69 (broad s); 3.93 (broad s); 5.14 (d, J = 4.5 Hz); 5.39 (broad s); 5.72 (dd, J = 3 Hz and 4.5 Hz); 6.85-7.42 (m);
7.50-8.12 (m); 9.18 (d, J = 8 Hz) Compound 20, 100 mHz instrument in DMSOd6; ~ 1.41 (s);
3.22 (ABq); 3.51 (ABq); 3.67 (br~ad s); 3.76 (s); 5.09 (d, J = 4.5 Hz); 5.63 (dd, J = 8 Hz and 4.5 Hz); 6.95 (m); 7.35 (m); 9.09 (d, J = 8 Hz) Compound 21, no analysis Compound 22, 60 mHz instrument in acetone d6; ~ 3.71 (broad s); 3.98 (s); 5.36 (d, J = 48 Hz); 5.25 (d, J = 4.5 Hz); 5.78 (dd, J = 8 Hz and 4.5 ~z); 6.9-7.5 (m); 8.16 (d, J = 8 Hz~
Compound 23, 1~0 mHz instrument in DMSOd6; ~ 3.66 (ABq); 3.75 (s); 4.33 (ABq); 5.05 (d, J = 4.5 Hz); 5.3 (s); 6.95 (m!; 7.35 (m); 9.12 (d, J = 8 Hz) J~I ~
Compound 26, 60 mHz instrument in DMSOd6; ~ 3.53 (ABq);
3.78 (s); 4.53 (ABq); 5.13 (d, J = 4.5 Hz): 5.71 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 8.15 (s); 8.90 (s); 9.16 (d, J = 8 Hz);
Compound 28, 60 mHz instrument in DMSOd6; ~ 3.73 (broad s); 3.85 (s); 4.28 (ABq); 4.40 (d, J = 6 Hz); 5.13 (d, J = 4.5 Hz); 5.15 (s); 5.76 (dd, J = 8 Hz and 4.5 Hz);
7.41 (s); 7.78 (t, J = 6 Hz); 9.20 (J = 8 Hz);
Compound 29, 60 mHz instrument in DMSOd6; ~ 3.68 (broad s); 3.78 (s); 3.77 (s); 4.19 (ABq); 5.07 (d, J = 4.5 Hz);
5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.~0 (m); 7.83 (broad s); 8.17 (broad s); 9.14 (d = 8 Hz) Compound 30, 60 mHz instrument in DMSOd6; ~ 1.36 (s);
3.59 (broad 5); 3.77 (s); 4.14 (broad s); 4.98 (d, J = 4.5 Hz); 5.31 (d, J = 9 Hz); 5.67 (dd, J = 8 Hz and 4.5 Hz); 7.lS-7.50 (m); 7.82 (broad s) 8.16 (broad s); 9.17 (d, J = 8 Hz) Compound 31, 360 mHz instrument in DMSOd6; ~ 3.64 ~ (ABq); 3.77 (s); 3.81 (s); 4.18 (ABq); 5.09 (d, J = 4.5 Hz); 5.68 (dd, J = 8 Hz and 4.5 Hz); 6.71 (s); 7.2-7.4 (m); 7.86 (broad s); 8.21 (broad s); 8.84 (s); 9.58 (d, J = 8 Hz) Compound 33, no analysis Compound 34, 60 ~Hz instrument in DMSOd6; ~ 1.33 ~t, J = 7 E~z); 3.68 (broad s); 3.78 (q, J = 7 Hz); 4.23 (broad s); 4.39 (q, J = 7 Hz); 5.07 (d, J = 4.5 Hz);
5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 9.14 (d, J = 8 Hz) PZ' Examples 30-40 The following examples report experiments run according to the method described above, except that, in these examples, the auxiliary electrode was separated from the working electrode by a frit coated with an electrically conductive gel. In some experiments, the gel was formed from agar made with an ionizable salt solution, and in other e~:periments, the frit was coated with methyl cellulose gel made conductive in the same manner.
~ ~ n 0'~ U~ U~ O CO ~ ~ O ~ ~ ~ ~D
o o ~ `o o Z o Z o o o ~ ~1 ~ a) 0~o 0~o ~ P oP 0~o 0,o 0~o 0~o o o ~ r~
o ~ . ~ ~ . . ~ o E~ ~ æ ~ æ z ,1 .,, .~I O O O O ~; O O O D; O O
~ ~ ~ ~ Z ~ ~ ~I Z ~ ~
~ r~
5~
~5 hP~ P; X O ~ ; O O
~ o r~ l O U~
C.; Z ~) Z ~ Z Z
In ~ er ~
~ o O
.,1 I I
~I
(O~ . . . . . ~; . . . .
O O O O O O O o O o o 1 P~ I I I I I Z I
.
o o ~ ~ o o o o o o o ~ O u~ ~ u7 n ,n u~ r u~
E~ ~ ~ X
o ~r o u~ Lr . o o ~ U~
u~ r . ~ ~ ~ o ~ ~ ~ o o o o ~
~s o O ~ ~ ~ ~1 ~1 ~ o ~ t~3 ~ ~r ;1~ ~ 1-- CO a~ o fi'~
Compound 7, 60 mHz instrument in DMSOd6; ~ 2.67 (s);
3.68 (ABq); 4.37 (ABq); 4.61 (s); 5.12 (d, J = 4.5 Hz);
5.71 (dd, J = 8 Hz and 4.5 Hz); 6.8-7.4 (m); 9.09 (d, J = 8 Hz) Compound 15, 100 mHz instrument in DMSOd6; ~ 3.51 (broad s); 3.76 (s); 4.09 (s); 4.22 (~Bq); 5.04 (d, J =
4.5 Hz); 5.62 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.4 (m);
9.07 (d, J = 8 Hz) Compound 16 identified only by TLC
Compound 17, 60 mHz instrument in acetone d6; ~ 3.71 (ABq); 3.93 (s); 4.23 (ABq); 5.13 (d, J = 4.5 Hz); 5.80 (dd, J = 8 Hz and 4.5 Hz); 6.83-7.73 (m); 8.08 (d, J =
8 Hz) Compound 19, 100 mHz instrumen-t in DMSOd6; ~ 3.34 (s);
3.61 (s); 3.67 (s); 3.76; 5.12 (d, J = 4.5 Hz); 5.66 (dd, J = 8 Hz and 4.5 Hz); 6.85-7.40 (m); 9.09 (d, J =
8 Hz) Compound 24, 60 mHz instrument in DMSOd6; ~ 3.68 (broad s); 3.78 (s); 4.20 (ABq); 5.13 (d, J = 4.5 Hz); 5.66 (dd, J = 8 Hz and 4.5 Hz); 6.95 (m); 7.35 (m); 7.93 (broad s); 8.40 (s) Compound 27, 60 mHz instrument in DMSOdS; ~ 3.5 (~road s); 5.63 ~dd, J = 8 Hz and 4.5 Hz); 6.98 (m); 7.37 (m);
8.45 (s); 8.78 (s); 9.08 (d, J = 8 Hz) Compound 8, 60 mHz instrument in DMSOd6; ~ 2 63 (s);
3.70 (ABq); 3.80 (s); 4.41 (ABq); 5.14 (d, J = 4.5 Hz);
5.73 (dd, J = 8 Hz and 4.5 Hz); 6.90-7~50 (m); 9.16 (d, J = ~
:1 ~fi ~
X-4509 ~33~
Examples 41 42 The experiments reported in these examples were carried out in the same manner as the experiments of examples 1-29, except that the working and auxiliary electrodes were separated by an ion exchange membrane.
o--l o ~
C~ o 0 a) ~ 0~o h er ~3 O h E~
., -~1 x a 0 S~
S~ O O
~1 r0~ 3 ~) er 1~') rl C
a~ ~ o o ~1 O
P~
r c~
~ U
~ o o a~ ~
~~ O
r~
O
~a O
U
r-l 1~ ~ ~
X-4509 -35~
Compound 25, no analysis Compound 32, 100 m~z instrument in CDC13; ~ 3.65 (s);
3.70 (ABq); 4.0 (s); 4.25 (broad s); 5.12 (d, J = 4.5 Hz); 5.82 (dd); 6.70 (s); 7.15-7.50 (m); 8.33 (s);
Example 43 The experiment of this example was also carried out according to the methods described in the - text of examples 1-29, except that the working and auxiliary electrodes in this experiment were not separated.
Z
t~
a) In o s~ ~
o a) .
5~ ~;
O h E~ ~ æ
C~
~I x ... .
E~ Z
~c a o O U~
er ~ ~r ~ .
O
~ o Q P~
E~
~ o a~ n E~ ~
o t~
~1 ol ~1 o I
`'~'I
X~
Example _ The experiment of this example was also carried out according to the process as described in the text of examples 1-29, except that the working electrode was lead, rather than mercury.
X-d,509 -38-rJ ~
~ r~
rrJ a~ ~
O ~ Z
P~
r r~ ¦
S~
Z
-O E~
1~ O
. r 1 x a) O
~ O
t) r-l .~
~n ~ co a.l r-l O O
E~
E o ~ U~
E~
r~l L(l c r3 P~
O
e c n~ ~
X-4509 -3~~
Example 45 The method described in the text of Examples 1-29 was used for this experiment also, except that the working fluid was made up of 90~ dimethylformamide and 10~ of 24N sulfuric acid.
o a o , o s~
E~ ~ Z
E~ Z
X 4~ E3 L~
O
~O C~
~ J ~J O
~ O
,4 aJ U~
E~
O
~ ~1 ~1 .
U
a)l ~1 ~! er ~1 Examples 46-50 In the following examples, the working fluids were mixtures of dimethylformamide and hydrochloric acid. Various amounts and concentrations of hydro-chloric acid were used in the various experiments, asdetailed in the table below. Tn other respects, the cells and methods were as described in the text intro-ducing Examples 1-29, except that in some experiments, the working and auxiliary electrodes were separated by a frit coated with a gel, as described in the intro-duction to Examples 30-40. The table below indicates the experiments in which a gel-coated frit was used.
.
C) O-rl Z Z ~
h >I o o ~1 ~
al c\ 0~o ~ 0~o 0~o s~ ~ u~
O ~ O ~1 Z ~ co ~: ~ X O o E~ . . ;_ ,_ ~ Z O z f~l E~ u~
~ 0 X ~ ~ U~
Z o ~ o Z
U~
~ ~D
,~
.
U~ ~ Ln ~ ~D U~
a) o o o ~ o O l l l l l ~4 . . C) ~ E~ o o O E~
~ U~ o U~ ~;
E~
I~
o o ~ ~ o ~ o o CO
Q E~ u~ ~ u~ u~
~ ~ ~ ~ ~ ~ U~
E~ I . ~ . u~ u~ ~
o o . . . .
t~ Z ~ ~ ~ Z
-I O O O
U ~ o ~ ~
--~ I o\O o\ o\ o\O o\
~) o o o o o I
,~
G~ 5-1 X X
~ l4 ~1 ~ ~ r~ o u~
~1 ~t3~
~-4509 -43-Compound 2, 60 mHz instrument in TFAdl (trifluoro-acetic acid); ~ 2.31 (s); 5.18 (d, J = 4.5 Hz); 5~53 (s); 5.76 (d, J = 4.5 Hz); 7.60 (s) Example 51 The worklng fluid used in this example was composed of 40 ml. of dimethylformamide and lO ml. of pH 5.0 sodium acetate buffer, with sufficient p-toluenesulfonic acid added to the mixture to make it 1.8N. The working electrode was a pool of mercury, and the counter electrode was a platinum wire, immersed in the working fluid with no electrode separation. The reference electrode was saturated calomel.
~16~
~
o ,r~ Q~ c~o r~o E~ ~ r r~
.,_1 o E~ r.~l r ,r~
x ~ e ra ~
5~ O
C?
,1 .~
c~ ~ c~
r~L~ ~ o ~ O
E~ ~ .
r o C~ u~
r,~
,_ C
O
r ~
~1 s I ,~
ra I u ~1 ~16~
The working fluid in the experiment of this example was dimethylformamide, which was 0.1-molar in tetraethylammonium perchlorate and contained about 35 mg./ml. of p-toluenesulfonic acid. The mercury pool working electrode was separated from the platinum auxiliary electrode by a glass frit.
X-4509 -4~;-U ~:;
3 r-l 11 5o~ O
~ I
h o O S~ Co r-X S~
:~ ~ O
a~ ~
C!) ~ O
r O
E~ ~
O
r~~
r~
n~ ,~
o a) I
rl¦
~-4509 -47-Example 53 The working fluid in this experiment was a mixture of 45~ of tetrahydrofuran and 55% of an O.lM
solution of pH 4.6 buffer. The measured pH of the working fluid, with the compound dissolved in it, was 5.5, and the pH of the working fluid was held at 5.5 throughout the experiment by the use of a pH controller which added 2N sulfuric acid as necessary.
The working electrode was mercury, and the auxiliary electrode was a platinum wire, separated from the working electrode by a fine glass frit coated with potassium sulfate-saturated agar. The reference electrode was saturated calomel, with the porous junction placed as close as possible to the working electrodei X-45~9 -a~8-r~
,~ , a~
O r1 O
o~
~`
~r~
O h ~ ::
E~ E~
.,1 O
E~ u~
x a S~
~n U
.~1 i O ~ r~
a~
a~ ~ o ~ O
P~
o ~ In E~ ~
O
~ cr~
L~7 .
U
o O r~) o O
a~
C
~ U~
X
Claims (10)
1. A process for removing the pNB ester protecting group from a cephalosporin 4-carboxylic acid pNB ester and thereby liberating the free cephalo-sporin 4-carboxylic acid;
characterized in that the pNB ester is electrolytically reduced in an acidic liquid medium comprising from about O to about 50% water, an acid having a PKa determined in water of O or below, the amount of said acid being at least four moles per mole of the compound to be reduced, and an organic solvent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, said working electrode sub-stantially comprising carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, at a temperature from about 0°C. to about 75°C., at a potential in a range from about the potential of the initial onset of current flow at which a first reduction takes place to about the potential of the initial onset of current flow at which a second reduction takes place.
characterized in that the pNB ester is electrolytically reduced in an acidic liquid medium comprising from about O to about 50% water, an acid having a PKa determined in water of O or below, the amount of said acid being at least four moles per mole of the compound to be reduced, and an organic solvent substantially inert to electrolytic reduction, at the working electrode of an electrolytic cell, said working electrode sub-stantially comprising carbon, mercury, tin, aluminum, silver, copper, lead, chromium, zinc, nickel or cadmium, at a temperature from about 0°C. to about 75°C., at a potential in a range from about the potential of the initial onset of current flow at which a first reduction takes place to about the potential of the initial onset of current flow at which a second reduction takes place.
2. A process according to claim 1 for pre-paring a compound of the formula or X-4509-(Canada) -50-wherein X is hydrogen;
m is 0 or 1;
R2 is hydrogen or methoxy;
R is hydrogen or -COR3;
R3 is hydrogen, C1-C3 alkyl, halomethyl, benzyloxy, 2,2,2-trichloroethoxy, t-butoxy, R4, R4-(O)n-CH2-, R4-CH(R5)-, R6-CH2-, or wherein R7 is hydrogen or C1-C3 alkyl and R8 is hydrogen or an amino-protecting group;
R4 is cyclohexadienyl or phenyl, or cyclohexadienyl or phenyl substituted with one or two halo, hydroxy, protected hydroxy, aminomethyl, protected amino-methyl, C1-C4 alkyl or C1-C4 alkoxy groups;
n is 0 or 1;
R5 is hydroxy, protected hydroxy, amino, protected amino, carboxy or protected carboxy;
R6 is 2-thienyl, 2-furyl, 5-tetrazolyl or 1-tetrazolyl;
R1 is chloro, C1-C3 alkyl or -CH2R ;
R9 is Cl-C4 alkanoyloxy, benzoyloxy, fluoro, chloro, carbamoyloxy, C1-C4 alkylcarbamoyloxy, X-4509-(Canada) pyridinio, pyridinio substituted with C1-C4 alkyl, C1-C4 alkanoyl, carbamoyl, C1-C4 alkyl-carbamoyl, chloro, fluoro, hydroxy or trifluoro-methyl, or the corresponding pyridinio chlorides or bromides, or -S-R10;
R10 is -CH2CO2(C1-C4 alkyl), carbamoyl, phenyl, phenyl substituted with one or two chloro, fluoro, C1-C4 alkyl, hydroxy, C1-C4 alkylsulfonamido or tri-fluoromethyl groups;
triazol-3-yl unsubstituted or substituted with one or two groups independently selected from C1-C3 alkyl, -CO2(C1-C4 alkyl), -CONH2 and -CH2NHOCO(benzyl or C1-C4 alkyl);
tetrazol-1-yl or tetrazol-5-yl substituted with one or two groups independently selected from C1-C4 alkyl and -CH2CO2(C1-C4 alkyl or hydrogen);
4-cyano-5-aminopyrimidin-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl;
provided that n is 0 when R4 is cyclohexadienyl;
by electrolytically reducing a compound of the above formula wherein X is p-nitrobenzyl.
m is 0 or 1;
R2 is hydrogen or methoxy;
R is hydrogen or -COR3;
R3 is hydrogen, C1-C3 alkyl, halomethyl, benzyloxy, 2,2,2-trichloroethoxy, t-butoxy, R4, R4-(O)n-CH2-, R4-CH(R5)-, R6-CH2-, or wherein R7 is hydrogen or C1-C3 alkyl and R8 is hydrogen or an amino-protecting group;
R4 is cyclohexadienyl or phenyl, or cyclohexadienyl or phenyl substituted with one or two halo, hydroxy, protected hydroxy, aminomethyl, protected amino-methyl, C1-C4 alkyl or C1-C4 alkoxy groups;
n is 0 or 1;
R5 is hydroxy, protected hydroxy, amino, protected amino, carboxy or protected carboxy;
R6 is 2-thienyl, 2-furyl, 5-tetrazolyl or 1-tetrazolyl;
R1 is chloro, C1-C3 alkyl or -CH2R ;
R9 is Cl-C4 alkanoyloxy, benzoyloxy, fluoro, chloro, carbamoyloxy, C1-C4 alkylcarbamoyloxy, X-4509-(Canada) pyridinio, pyridinio substituted with C1-C4 alkyl, C1-C4 alkanoyl, carbamoyl, C1-C4 alkyl-carbamoyl, chloro, fluoro, hydroxy or trifluoro-methyl, or the corresponding pyridinio chlorides or bromides, or -S-R10;
R10 is -CH2CO2(C1-C4 alkyl), carbamoyl, phenyl, phenyl substituted with one or two chloro, fluoro, C1-C4 alkyl, hydroxy, C1-C4 alkylsulfonamido or tri-fluoromethyl groups;
triazol-3-yl unsubstituted or substituted with one or two groups independently selected from C1-C3 alkyl, -CO2(C1-C4 alkyl), -CONH2 and -CH2NHOCO(benzyl or C1-C4 alkyl);
tetrazol-1-yl or tetrazol-5-yl substituted with one or two groups independently selected from C1-C4 alkyl and -CH2CO2(C1-C4 alkyl or hydrogen);
4-cyano-5-aminopyrimidin-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl;
provided that n is 0 when R4 is cyclohexadienyl;
by electrolytically reducing a compound of the above formula wherein X is p-nitrobenzyl.
3. A process according to claim 1 or 2, wherein the acidic liquid medium comprises from about 10% to about 50% water.
4. A process according to claim 1 wherein the organic solvent is water-miscible.
5. A process according to claim 1 wherein the working electrode comprises silver, lead or mercury.
6. A process according to claim 1 wherein the potential is controlled by means of a reference electrode.
7. A process according to claim 2 wherein the cephalosporin 4-carboxylic acid formed is a com-pound wherein R1 is chloro, methyl or -CH2SR10.
8. A process according to claim 7 wherein R10 is a triazol-3-yl, tetrazol-1-yl, tetrazol-5-yl or thiadiazol-2-yl group.
9. A process according to claim 1 for pre-paring 7-(D-2-amino-2-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid.
10. A process according to claim 1 for pre-paring 7-(D-2-amino-2-phenylacetamido)-3-chloro-3-cephem-4-carboxylic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13582980A | 1980-03-31 | 1980-03-31 | |
| US135,829 | 1980-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1164402A true CA1164402A (en) | 1984-03-27 |
Family
ID=22469892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000373328A Expired CA1164402A (en) | 1980-03-31 | 1981-03-18 | Electrolytic reduction of cephalosporin p-nitrobenzyl esters |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0038626A1 (en) |
| JP (1) | JPS56152982A (en) |
| KR (1) | KR830005237A (en) |
| CA (1) | CA1164402A (en) |
| GB (1) | GB2074607B (en) |
| HU (1) | HU185631B (en) |
| IL (1) | IL62427A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3632850A (en) * | 1969-03-18 | 1972-01-04 | Lilly Co Eli | Cephalexin synthesis |
| US4042472A (en) * | 1976-04-12 | 1977-08-16 | Eli Lilly And Company | Electrolytic process for 7-methoxy-3-exomethylenecepham compounds |
-
1981
- 1981-03-18 CA CA000373328A patent/CA1164402A/en not_active Expired
- 1981-03-19 EP EP81301187A patent/EP0038626A1/en not_active Ceased
- 1981-03-19 GB GB8108645A patent/GB2074607B/en not_active Expired
- 1981-03-19 IL IL62427A patent/IL62427A/en unknown
- 1981-03-20 HU HU81727A patent/HU185631B/en unknown
- 1981-03-20 KR KR1019810000929A patent/KR830005237A/en unknown
- 1981-03-24 JP JP4383581A patent/JPS56152982A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB2074607A (en) | 1981-11-04 |
| KR830005237A (en) | 1983-08-03 |
| IL62427A (en) | 1984-07-31 |
| HU185631B (en) | 1985-03-28 |
| GB2074607B (en) | 1983-02-16 |
| JPS56152982A (en) | 1981-11-26 |
| EP0038626A1 (en) | 1981-10-28 |
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