CA1171407A - Process for the manufacture of 6-aminopenicillanic derivatives - Google Patents
Process for the manufacture of 6-aminopenicillanic derivativesInfo
- Publication number
- CA1171407A CA1171407A CA000387840A CA387840A CA1171407A CA 1171407 A CA1171407 A CA 1171407A CA 000387840 A CA000387840 A CA 000387840A CA 387840 A CA387840 A CA 387840A CA 1171407 A CA1171407 A CA 1171407A
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- CA
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- Prior art keywords
- formula
- ester
- compound
- group
- pharmaceutically compatible
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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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- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
Abstract There is described a process for the manufacture of 6-aminopenicillanic acid derivatives of the general formula I
in which R represents hydrogen or a readily hydrolysable ester group, as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula II
in which R has the significance given above and R1 signifies a hydrogenolytically cleavable group, or a salt of such a compound, and, if desired, subjecting an ester of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, converting a compound of formula I obtained into a pharmaceutically compatible salt thereof. Novel intermediates of formula II and their salts used in the above process are also described. The 6-aminopenicillanic acid derivatives have antibacterial activity and is particularly useful for the treatment and prophylaxis of infectious diseases.
in which R represents hydrogen or a readily hydrolysable ester group, as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula II
in which R has the significance given above and R1 signifies a hydrogenolytically cleavable group, or a salt of such a compound, and, if desired, subjecting an ester of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, converting a compound of formula I obtained into a pharmaceutically compatible salt thereof. Novel intermediates of formula II and their salts used in the above process are also described. The 6-aminopenicillanic acid derivatives have antibacterial activity and is particularly useful for the treatment and prophylaxis of infectious diseases.
Description
~L~7JL~Ot7 The present invention is concerned with a novel - process for the manufacture of 6-aminopenicillanic acid derivatives of the general formula CN CH=N X ~OOR
in which R represents hydrogen or - a~readily hydrolysable ester groupj ; : as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula .
Mn/31.7.1981 : ' :
, H H
CN I ~C H II
O COOR
in which R has the significance given above and Rl signifies a hydrogenolytically cleavable group, such as benzhydryl or especially benzyl, or a salt of such a compound, and, if desired, subjecting an ester-of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, : converting a compound of formula I obtained into a pharma-ceutically compatible salt thereof.
It has been found that the catalytic hydrogenation o. the starting materials o formula II in accordance with the invention brings about not only the cleavage of the group Rl but also a decarboxylation, so that the end effect is the replacement of the group -COORl by a ~:
hydrogen atom.
:
::
:: : :
.
': :
, , ~'7~0~
The catalytic hydrogenation in accordance with the invention is preferably carried out in the presence of a noble metal catalyst such as Raney-nickel, Raney-cobalt, platinum dioxide or preferably palladium/carbon. The S catalytic hydrogenation is preferably carried out at atmospheric pressure in a polar solvent (e.g. in a lower alkanol such as methanol, ethanol or isopropanol) and in a temperature range of about 0 to 80C, preferahly at room temperature.
The compounds of formula I as well as their pharma-ceutically compatible salts have strong antibacterial activity, especially against gram-negative bacteria, and exhibit an especially low toxicity. They are accordingly especially suitable for the treatment and prophylaxis of infectious diseases.
, Examples of readily hydrolysable ester groups denoted by R are lower alkanoyloxyalkyl (e.gO acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and l-pivaloyloxyethyl), lower alkoxycarbonyloxyalkyl (e.g. methoxycarbonyloxy-~0 methyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyl-oxyethyl), lactonyl groups (e.g. phthalidyl and thio-phthalidyl), lower alkoxymethyl (e.g. methoxymethyl) and lower alkanoylaminomethyl (e.g. acetamidomethyl).
:
7~ 7 The novel starting materials of formula II can be obtained by reacting hexamethyleneimine [(CH2)6NH] with an oxalic acid monobenzyl ester halide [Hal-C0-COOC~2C6H5], preferably the chloride, treating the resulting oxalic, acid monoben~yl ester hexamethyleneimide [(CH2)6N-C0--COOCH2C6H5] with phosphorus pentasulphide and reacting the resulting hexamethyleneimino-thioxo-acetic acid benzyl ester [(CH2)6N-CS-COOCH2C6H5] with 6-aminopenicillanic acid or a readily hydrolysable ester thereof in the presence of an alkylating agent such as, for example, triethyloxonium tetrafluoroborate, preferably in the presence of an acid-binding agent such as triethylamine or diisopropylethylamine and in an inert organic solvent such as methylene chloride and at a temperature in the range of about -10C and +30C.
If desired, a thus-obtained base of formula II can be converted into the corresponding acid addition salt by the addition of acid (e.g. hydrochloric acid or p-toluene-sulphonic acid) or a thus-obtained carboxylic acid of formula II can be converted into the corresponding salt by the addition of base (e.g. sodium carbonate or potassium hydroxide).
.
l'he following Example illustrates the invention.
All temperatures are given in degrees Centigrade.
Pivaloyloxymethyl 6-[(hexahydro-lH-azepin-l-yl)--methyleneamino-penicillinate.
22.5 g (0.03 M) of methylene-(2S,5R,6R)-6-[[~(benzyl-oxy)carbonyl]-(hexahydro-lH-azepin-l-yl)methylene]aminol--7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate p-toluénesulphonate are converted into the free base in 250 ml of ethyl acetate with excess sodium bicarbonate solutlon with the addition of ice~ ~he ethyl acetate solution is washed with water, dried over magnesium sulphate and evaporated in vacuo at 25. The residue is hydrogenated in 300 ml of isopropanol with palladium/
carbon (5~), the catalyst being renewed once. The catalyst is filtered off under suction and the filtrate is evaporated at 30C in vacuo, crystallisation taking place. The substance is recrystallised from acetone/water. M.p~ 117-119.
[a]D =~+230 (c = 1 in ethanol). The NMR spectrum agrees with the structure.
The methylene-(2S,5R,6R)-6-[~(benzyloxy)carbonyl]--(hexahydro-lH-azepin-l-~l)methylenelamlno]-7-oxo-4-=hia-' -l-azabicyclo[3.2~0]heptane-2-carboxylate pivalate p--toluenesulphonate used as the starting material can be prepared as follows:
A solution of 19.9 g (0.1 M) of oxalic acid mono-~enzyl ester chloride in 70 ml of chloroform is addeddropwise while stirring within 45 minutes to a solution, cooled to 0, of 19.~ g (0.2 M) of hexamethvleneimine in 70 ml of chloroform and the mixture ,is subsequently stirred for 1 hour at 20. The solution is washed in each case twice with 3N a~ueous hydrochloric acid, water, 5~ aqueous sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated in vacuo. The oil remaining behind is distilled. There is obtained oxalic acid monobenzyl ester hexamethyleneimide of boiling point 165-170 (0.3 lS mm Torr); nD = 1.5328.
52.2 g (0.2 M) of oxalic acid monobenzyl ester hexamethyleneimide in 520 ml of absolute toluene are treated with 26.6 g (0.12 M) of phosphorus pentasulphide and the mixture is heated at 75 for 5 hours while stirring and excluding moisture. The cooled suspension is filtered in vacuo, the filtrate is evaporated in vacuo, the oil remaining behind is taken up in ehtyl acetate, the solution is washed with aqueous sodium bicarbonate solution, water, lN aqueous hydrochloric acid and water and, a~ter drying over magnesium sulphate, evaporated in vacuo. The oil remaining behind is ' ' ' - , ' , .
.
dissolved in benzene and chromatographed over silica gel with benzene. The fractions containing the hexamethylene-imino-thioxo-acetic acid benzyl ester are combined, evaporated in vacuo and dried at 40C in a hiyh vacuum.
The IR spectrum of the hexamethyleneimino-thioxo-acetic acid benzyl ester obtained agrees with the structure. The unreacted starting material can be regenerated and reacted again with phosphorus pentasulphide.
13.9 g (0.05 M) of hexamethyleneimino-thioxo-acetic acid benzyl ester are dissolved in 300 ml of absolute methylene chloride, treated with 9.5 g (0.05 M) of tri-ethyloxonium tetrafluoroborate and the mixture left to stand under a slight nitrogen stream overnight under a calcium chloride closure. To this solution, previously cooled to 0, is added dropwise within 10 minutes a solution, cooled to 0, of 16.5 g (0.05 M) of 6-amino--penicillanic acid pivaloyloxymethyl ester and 8.6 ml (0.05 M) of diisopropylethylamine and the mixture is subsequently stirred for a further 5 hours at 20 while gassing with nitrogen. The solution is evaporated in vacuo at 25~, the oil is taken up in ethyl acetate, the solution is washed with aqueous sodium bicarbonate solution and aqueous 5~ sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo at 25. The oil remaining behind is dissolved in 200 ml of ether and treated with a solution of 9 g of p-toluenesulphonic acid hydrate in lO0 ml , L4(~
of ethyl acetate and crystallised while stirring. There is obtained methylene-(2S,5R,6R)-6-[[[(benzyloxy)carbonyl]--(hexahydro-lH-azepin-l-yl)methylene]amino]-7-oxo-4-thia--l-azabicyclo[3,2,0]heptane-2-carboxylate pivalate p--toluenesulphonate of melting point 124-126(decomposition).
[a]D = 129.5 (c = l in dimethylformamide). The NMR
spectrum agrees with the structure.
.
in which R represents hydrogen or - a~readily hydrolysable ester groupj ; : as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula .
Mn/31.7.1981 : ' :
, H H
CN I ~C H II
O COOR
in which R has the significance given above and Rl signifies a hydrogenolytically cleavable group, such as benzhydryl or especially benzyl, or a salt of such a compound, and, if desired, subjecting an ester-of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, : converting a compound of formula I obtained into a pharma-ceutically compatible salt thereof.
It has been found that the catalytic hydrogenation o. the starting materials o formula II in accordance with the invention brings about not only the cleavage of the group Rl but also a decarboxylation, so that the end effect is the replacement of the group -COORl by a ~:
hydrogen atom.
:
::
:: : :
.
': :
, , ~'7~0~
The catalytic hydrogenation in accordance with the invention is preferably carried out in the presence of a noble metal catalyst such as Raney-nickel, Raney-cobalt, platinum dioxide or preferably palladium/carbon. The S catalytic hydrogenation is preferably carried out at atmospheric pressure in a polar solvent (e.g. in a lower alkanol such as methanol, ethanol or isopropanol) and in a temperature range of about 0 to 80C, preferahly at room temperature.
The compounds of formula I as well as their pharma-ceutically compatible salts have strong antibacterial activity, especially against gram-negative bacteria, and exhibit an especially low toxicity. They are accordingly especially suitable for the treatment and prophylaxis of infectious diseases.
, Examples of readily hydrolysable ester groups denoted by R are lower alkanoyloxyalkyl (e.gO acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and l-pivaloyloxyethyl), lower alkoxycarbonyloxyalkyl (e.g. methoxycarbonyloxy-~0 methyl, l-ethoxycarbonyloxyethyl and l-isopropoxycarbonyl-oxyethyl), lactonyl groups (e.g. phthalidyl and thio-phthalidyl), lower alkoxymethyl (e.g. methoxymethyl) and lower alkanoylaminomethyl (e.g. acetamidomethyl).
:
7~ 7 The novel starting materials of formula II can be obtained by reacting hexamethyleneimine [(CH2)6NH] with an oxalic acid monobenzyl ester halide [Hal-C0-COOC~2C6H5], preferably the chloride, treating the resulting oxalic, acid monoben~yl ester hexamethyleneimide [(CH2)6N-C0--COOCH2C6H5] with phosphorus pentasulphide and reacting the resulting hexamethyleneimino-thioxo-acetic acid benzyl ester [(CH2)6N-CS-COOCH2C6H5] with 6-aminopenicillanic acid or a readily hydrolysable ester thereof in the presence of an alkylating agent such as, for example, triethyloxonium tetrafluoroborate, preferably in the presence of an acid-binding agent such as triethylamine or diisopropylethylamine and in an inert organic solvent such as methylene chloride and at a temperature in the range of about -10C and +30C.
If desired, a thus-obtained base of formula II can be converted into the corresponding acid addition salt by the addition of acid (e.g. hydrochloric acid or p-toluene-sulphonic acid) or a thus-obtained carboxylic acid of formula II can be converted into the corresponding salt by the addition of base (e.g. sodium carbonate or potassium hydroxide).
.
l'he following Example illustrates the invention.
All temperatures are given in degrees Centigrade.
Pivaloyloxymethyl 6-[(hexahydro-lH-azepin-l-yl)--methyleneamino-penicillinate.
22.5 g (0.03 M) of methylene-(2S,5R,6R)-6-[[~(benzyl-oxy)carbonyl]-(hexahydro-lH-azepin-l-yl)methylene]aminol--7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate p-toluénesulphonate are converted into the free base in 250 ml of ethyl acetate with excess sodium bicarbonate solutlon with the addition of ice~ ~he ethyl acetate solution is washed with water, dried over magnesium sulphate and evaporated in vacuo at 25. The residue is hydrogenated in 300 ml of isopropanol with palladium/
carbon (5~), the catalyst being renewed once. The catalyst is filtered off under suction and the filtrate is evaporated at 30C in vacuo, crystallisation taking place. The substance is recrystallised from acetone/water. M.p~ 117-119.
[a]D =~+230 (c = 1 in ethanol). The NMR spectrum agrees with the structure.
The methylene-(2S,5R,6R)-6-[~(benzyloxy)carbonyl]--(hexahydro-lH-azepin-l-~l)methylenelamlno]-7-oxo-4-=hia-' -l-azabicyclo[3.2~0]heptane-2-carboxylate pivalate p--toluenesulphonate used as the starting material can be prepared as follows:
A solution of 19.9 g (0.1 M) of oxalic acid mono-~enzyl ester chloride in 70 ml of chloroform is addeddropwise while stirring within 45 minutes to a solution, cooled to 0, of 19.~ g (0.2 M) of hexamethvleneimine in 70 ml of chloroform and the mixture ,is subsequently stirred for 1 hour at 20. The solution is washed in each case twice with 3N a~ueous hydrochloric acid, water, 5~ aqueous sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated in vacuo. The oil remaining behind is distilled. There is obtained oxalic acid monobenzyl ester hexamethyleneimide of boiling point 165-170 (0.3 lS mm Torr); nD = 1.5328.
52.2 g (0.2 M) of oxalic acid monobenzyl ester hexamethyleneimide in 520 ml of absolute toluene are treated with 26.6 g (0.12 M) of phosphorus pentasulphide and the mixture is heated at 75 for 5 hours while stirring and excluding moisture. The cooled suspension is filtered in vacuo, the filtrate is evaporated in vacuo, the oil remaining behind is taken up in ehtyl acetate, the solution is washed with aqueous sodium bicarbonate solution, water, lN aqueous hydrochloric acid and water and, a~ter drying over magnesium sulphate, evaporated in vacuo. The oil remaining behind is ' ' ' - , ' , .
.
dissolved in benzene and chromatographed over silica gel with benzene. The fractions containing the hexamethylene-imino-thioxo-acetic acid benzyl ester are combined, evaporated in vacuo and dried at 40C in a hiyh vacuum.
The IR spectrum of the hexamethyleneimino-thioxo-acetic acid benzyl ester obtained agrees with the structure. The unreacted starting material can be regenerated and reacted again with phosphorus pentasulphide.
13.9 g (0.05 M) of hexamethyleneimino-thioxo-acetic acid benzyl ester are dissolved in 300 ml of absolute methylene chloride, treated with 9.5 g (0.05 M) of tri-ethyloxonium tetrafluoroborate and the mixture left to stand under a slight nitrogen stream overnight under a calcium chloride closure. To this solution, previously cooled to 0, is added dropwise within 10 minutes a solution, cooled to 0, of 16.5 g (0.05 M) of 6-amino--penicillanic acid pivaloyloxymethyl ester and 8.6 ml (0.05 M) of diisopropylethylamine and the mixture is subsequently stirred for a further 5 hours at 20 while gassing with nitrogen. The solution is evaporated in vacuo at 25~, the oil is taken up in ethyl acetate, the solution is washed with aqueous sodium bicarbonate solution and aqueous 5~ sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo at 25. The oil remaining behind is dissolved in 200 ml of ether and treated with a solution of 9 g of p-toluenesulphonic acid hydrate in lO0 ml , L4(~
of ethyl acetate and crystallised while stirring. There is obtained methylene-(2S,5R,6R)-6-[[[(benzyloxy)carbonyl]--(hexahydro-lH-azepin-l-yl)methylene]amino]-7-oxo-4-thia--l-azabicyclo[3,2,0]heptane-2-carboxylate pivalate p--toluenesulphonate of melting point 124-126(decomposition).
[a]D = 129.5 (c = l in dimethylformamide). The NMR
spectrum agrees with the structure.
.
Claims (4)
1. A process for the manufacture of 6-amino-penicillanic acid derivatives of the general formula I
in which R represents hydrogen or a readily hydrolysable ester group, as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula II
in which R has the significance given earlier in this claim and R1 signifies a hydrogenolytically cleavable group, or a salt of such a compound, and, if desired, subjecting an ester of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, converting a compound of formula I obtained into a pharmaceutically compatible salt thereof.
in which R represents hydrogen or a readily hydrolysable ester group, as well as of pharmaceutically compatible salts of these compounds, which process comprises catalytically hydro-genating a compound of the general formula II
in which R has the significance given earlier in this claim and R1 signifies a hydrogenolytically cleavable group, or a salt of such a compound, and, if desired, subjecting an ester of formula I obtained to an ester cleavage, if desired, treating a carboxylic acid of formula I obtained with an agent yielding the ester group R and, if desired, converting a compound of formula I obtained into a pharmaceutically compatible salt thereof.
2. A process according to claim 1, wherein R1 signifies a benzyl group.
3. A process according to claim 1, wherein palladium/carbon is used as the catalyst.
4. A process according to claim 1, 2 or 3, wherein a starting material of formula II in which R represents the pivaloyloxymethyl group is used and pivaloyloxymethyl 6-[(hexahydro-lH-azepin-l-yl)-methyleneamino-penicillinate or a pharmaceutically compatible salt thereof is isolated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH770080 | 1980-10-15 | ||
| CH7700/80 | 1980-10-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1171407A true CA1171407A (en) | 1984-07-24 |
Family
ID=4329211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000387840A Expired CA1171407A (en) | 1980-10-15 | 1981-10-14 | Process for the manufacture of 6-aminopenicillanic derivatives |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0049891B1 (en) |
| JP (1) | JPS5795991A (en) |
| KR (1) | KR830007668A (en) |
| AT (1) | ATE11540T1 (en) |
| CA (1) | CA1171407A (en) |
| DK (1) | DK456681A (en) |
| ES (1) | ES506236A0 (en) |
| FI (1) | FI813202L (en) |
| GR (1) | GR75822B (en) |
| PT (1) | PT73822B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5159077A (en) * | 1989-07-21 | 1992-10-27 | Hoffmann-La Roche Inc. | Penam antibacterial compounds |
| US5162523A (en) * | 1989-07-21 | 1992-11-10 | Hoffmann-La Roche Inc. | Cephalosporin antibacterial compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7216268A (en) * | 1971-12-16 | 1973-06-19 |
-
1981
- 1981-10-12 AT AT81108244T patent/ATE11540T1/en not_active IP Right Cessation
- 1981-10-12 EP EP81108244A patent/EP0049891B1/en not_active Expired
- 1981-10-13 GR GR66262A patent/GR75822B/el unknown
- 1981-10-14 KR KR1019810003874A patent/KR830007668A/en unknown
- 1981-10-14 ES ES506236A patent/ES506236A0/en active Granted
- 1981-10-14 PT PT73822A patent/PT73822B/en unknown
- 1981-10-14 CA CA000387840A patent/CA1171407A/en not_active Expired
- 1981-10-14 FI FI813202A patent/FI813202L/en not_active Application Discontinuation
- 1981-10-14 JP JP56162882A patent/JPS5795991A/en active Pending
- 1981-10-14 DK DK456681A patent/DK456681A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE11540T1 (en) | 1985-02-15 |
| EP0049891B1 (en) | 1985-01-30 |
| EP0049891A1 (en) | 1982-04-21 |
| DK456681A (en) | 1982-04-16 |
| ES8206529A1 (en) | 1982-08-16 |
| PT73822A (en) | 1981-11-01 |
| KR830007668A (en) | 1983-11-04 |
| ES506236A0 (en) | 1982-08-16 |
| JPS5795991A (en) | 1982-06-15 |
| GR75822B (en) | 1984-08-02 |
| PT73822B (en) | 1983-11-07 |
| FI813202L (en) | 1982-04-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEC | Expiry (correction) | ||
| MKEX | Expiry |