GB2095661A - Preparation of an ampicillin derivative - Google Patents
Preparation of an ampicillin derivative Download PDFInfo
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- GB2095661A GB2095661A GB8202662A GB8202662A GB2095661A GB 2095661 A GB2095661 A GB 2095661A GB 8202662 A GB8202662 A GB 8202662A GB 8202662 A GB8202662 A GB 8202662A GB 2095661 A GB2095661 A GB 2095661A
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- ampicillin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- 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
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- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
There is provided a process for preparing in high yields a 6-[D(-)- alpha-(4-C1-C4-alkyl-2,3-dioxo-1- piperazinocarbonylamino)- phenylacetamido]penicillanic acid, or pharmaceutically acceptable salt thereof, in which a 4-C1-C4-alkyl- 2,3-dioxo-1-piperazinocarbonyl halide is added under controlled pH conditions to a solution or suspension of ampicillin in a mixture of ethyl acetate and water in the presence of a base to form a reaction mixture, the resulting mixture is agitated until the reaction is completed, the reaction mixture is acidified, and the desired antibiotic is recovered as a crystalline product under controlled pH conditions and using controlled amounts of ethyl acetate as solvent.
Description
SPECIFICATION
Improved process for preparing 6-[D(-)-alpha- (C1 -C4-alkyl-2,3-dioxo- ioxo-l- piperazinocarbonyla mino)phenyl acetarnido]penicillanic acids
Background of the invention
Field of invention
The present invention relates to a novel improved process for the preparation of 6substituted penicillanic acids. More particularly, it relates to an improved process for the preparation of 6-[D(-)- alpha-(4-alkyl-2,3-dioxo-1 - piperazinocarboxylamino)phenyiacetamido] penicillanic acids of Formula (I)
wherein R represents C1C4 alkyl. These compounds are useful as antibiotics for the treatment of pneumonia, peritonitis, and blood system infections.
Description of prior art
Saikawa et al. disclose in U. S. Patent 4,1 12,090 a process for preparing 6-substituted penicillanic acids of formula (I) by reacting a 4 C1-C4 alkyl-2,3-dioxol piperazinocarbonyl chloride of Formula II
wherein R is C1-C4 alkyl, with 6-[D(-)-alpha- amino-phenylacetamido]penicillanic acid trihydrate, represented by Formula (III).
The anhydrous form of (III) is hereafter referred to as ampicillin. In example 23 of this reference, a suspension of (Ill) in a mixture of 10 parts water and 4.5 parts by weight of ethyl acetate per part by weight of compound Ill is cooled to 2 C, admixed with 2 molar equivalents of potassium carbonate at 2--30C for severai minutes admixed with 1 molar proportion of a compound of formala (II) wherein R is methyl at 2--3 OC over a period of 10 minutes and further reacted at said temperature for 15 minutes. The reaction mixture is clarified to remove some insolubles and the mother liquor is mixed with an additional 18 parts by weight of ethyl acetate per part by weight of compound Ill originally charged.The resulting mixture is then acidified with 1 molar equivalent of 2N HC1 at 20--220C over a period of 5 minutes, and stirred at 20--220C for 5 hours. The crystals which precipitate are collected, washed successively with water and isopropanol, and dried to obtain a dihydrate of 6-[D(-)-alpha-(4-methyl-2,3-dioxo1 -piperazinocarbonylimino)phenylacetamido]penicillanic acid in a yield of 75.4%. In a similar example, a monohydrate of 6-[D(-)-alpha- (4)ethyl-2,3-dioxo-1-piperazinocarbonylamino)- phenylacetamido]penicillanic acid is obtained in a yield of 84.8% with the compound of Formula (II) wherein R=ethyl.
There is a need for an improved process which significantly increases the yield obtained. The present invention provides such a process, with a final yield of about 95%.
Summary of the invention
The present invention provides an improvement in a process for preparing a alpha-(4-C1-C4 alkyl-2,3-dioxo-1 - piperazinocarbonylamino)phenylacetamido] penicillanic acid of Formula (I) wherein a 4-C,--C, alkyl-2,3-dioxo-1-piperazino- carbonyl halide is added to a solution or suspension of ampicillin in a mixture of ethyl acetate and water in the presence of a base to form a reaction mixture, the resulting mixture is agitated until the reaction is completed, the reaction mixture is acidified, and a crystalline product is recovered therefrom; said improvement comprising:
(1) adding about 1-1.5 molar proportions of a 4-C,--C, alkyl-2,3-dioxo-1-piperazinocarbonyl halide to an agitated suspension of about one molar proportion of ampicillin and an appropriate amount of a suitable base in a solvent mixture consisting of about 9-12 parts by weight of water and about 0.5-8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 minutes, at about 100- 250C, while maintaining a pH of about 6-8.3; (2) further agitating the reaction mixture at about 10 -25 C for at least 1 5 minutes upon completing the addition of the 4-C,--C, alkyl 2,3-dioxo-1 -piperazino-carbonyl halide in step (1);;
(3) adding to the reaction mixture about 0.05-0.2 part by weight each of an activated carbon and a filter-aid per part by weight of ampicillin charged in step (1), and agitating the resulting mixture at about 10 -25 C for at least 10 minutes;
(4) clarifying the resulting mixture, and washing the insoluble materials with about 0.62.5 parts by weight of water per part by weight of ampicillin charged in step (1);; (5) combining the mother liquor and wash liquor obtained in step (4) with about 2-12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in step (1), with the proviso that the total amount of ethyl acetate used in steps (1) and (5) is about 10-13 parts by weight per part by weight of said ampicillin, and warming the resulting mixture to about 150- 250C; (6) acidifying the mixture obtained in step (5) at about 150--250C to a pH of about 2.0-2.5;
(7) agitating the acidified mixture for at least one hour at about 1 5 0--25 OC, before collecting the resulting crystalline product; and
(8) optionally converting the product to a
pharmaceutically acceptable salt.
The process of the present invention results in
about a 95% yield of the product of Formula (I).
Detailed description of the invention
In carrying out the process of this invention, a stirred suspension of ampicillin in a mixture of water and ethyl acetate is prepared in amounts to provide about 9-12, preferably about 10-11, parts by weight of water and about 0.5-8, preferably about 4-6, parts by weight of ethyl acetate per part by weight of ampicillin. Ampicillin is defined as the anhydrous form of Compound Ill.
To this mixture is added an appropriate amount of a suitable base. In order to insure the high yields of the present invention, the amount of base must be sufficient to bring the pH of the initial mixture to about 6-8.3, preferably about 6.5-8, and to maintain the pH range during the subsequent addition of the 4-C,C4 alkyl-2,3dioxo-piperazinocarbonyl halide. The preferred method of adding base is to charge the initial mixture with about 2.1 3.0, prefereably about 2.5-2.7, molecular equivalents of a base such as sodium or potassium bicarbonate per mole of ampicillin charged. With this method the subsequent addition of the carbonyl halide wiil not induce a pH change.Alternatively, a base such as, e.g., potassium or sodium hydroxide or potassium or sodium carbonate may be used to bring the pH of the initial mixture to about 68.3, preferably about 6.5-8, but care must be taken thereafter to monitor the pH and to maintain this pH range during the subsequent addition of the carbonyl halide. The pH may be monitored by direct inspection and addition of appropriate acid or base or the pH may be maintained at the proper range by the addition to the initial reaction system of an appropriate noninterfering buffer system, which buffer system is readily determined by those skilled in the art.
The initial mixture is adjusted to a temperature of about 1 0-250C, preferably about 12-1 80C, to which is added about 1-1.5, preferably about
1.05-1.15, molecular proportions of a 4-C1-C4 alkyl-2,3-dioxo-1 -piperazinocarbonyl halide of the formula:
wherein R is C1 -C4 alkyl and X is fluoro, chloro, bromo, or iodo.The compound of Formula IV is added to the mixture over a period of at least 30 minutes, preferably over about 40-60 minutes, while maintaining the reaction mixture at the above-stated temperature and a pH of about 68.3, preferably about 6.5-8. In the preferred process the compound of Formula IV is 4-C1-C4 a Ikyl-2,3-dioxo-1 -piperazinocarbonyl chloride; 4- ethyl-2,3-dioxo- 1 -piperazinocarbonyl chloride is particularly preferred.
The resulting mixture is stirred at said temperature and pH for at least 1 5 minutes; and preferably for about 20-30 minutes, after completion of the addition of the compound of
Formula IV. The reaction mixture is then treated with about 0.05-0.2, preferably about 0.08- 0.1, part by weight of an activated carbon such as, e.g., activated charcoal or Type RB Activated
Carbon (Pittsburgh Coke and Chemical Co.), and about 0.05-0.2, preferably about 0.1-0.15, part by weight of a filter aid such as, e.g., Hyflo Super-Cel (Johns-Manville Sales Corp.), per part by weight of ampicillin originally charged. The resulting mixture is then stirred at said temperature for at least 10 minutes, and preferably for about 1 5-20 minutes.
The insolubles are then separated from the reaction mixture by conventional methods well known to those skilled in the art. The preferred method of separation is filtration. The filter cake is washed with about 0.6-2.5, preferably about 1.0-1.2, parts by weight of water per weight of ampicillin originally charged.The wash liquor is then combined with the mother liquor obtained from the filtration process and about 2-12.5, preferably about 6-7, parts by weight of ethyl acetate per part by weight of ampicillin originally charged is added thereto, with the proviso that the total amount of ethyl acetate used, including the ethyl acetate in the original reaction mixture, is about 10-13, preferably about 11-12, parts by weight per part by weight of ampiciilin originally charged.
The resulting mixture is warmed to about 1 5- 200 C, preferably to about 1 8-220C, and acidified at said temperature to a pH of about 2.0-2.5, preferably about 2.2-2.3, with dilute mineral acid, e.g. 2-5 N hydrochloric or sulfuric acid.
The acidified reaction mixture is then stirred at said temperature for at least one hour, preferably for about 2-3 hours, and the resulting crystals are collected by means well known to those skilled in the art, such as, e.g., by filtration or centrifugation. The crystals are then washed with water and dried to obtain the desired free acid product in a yield of about 9496%. This free acid may be hydrated in varying degrees.
The choice of ethyl acetate as a solvent is critical, as is the relative concentration of ethyl acetate during the crystallization step.
Controi of the pH during the reaction and crystallization stages is also critical. Variation of the stated ranges of these factors will either decrease the ultimate yield or result in an inferior crystallization structure, possibly even resulting in an amorphous mass with no crystalline structure at all, which makes isolation and purification of the final product time-consuming and expensive.
The free acid obtained above may be converted to a pharmaceutically acceptable salt by procedures well known to those skilled in the art.
Pharmaceutically acceptable salts include, e.g., alkali metal, alkaline earth metal, ammonium, Nmethylglucamine, etc. The sodium salt is preferred and is preferably obtained by treatment of the compound of Formula (I) obtained by the above process with an equivalent amount of sodium bicarbonate in water.
As used hereinabove and below unless expressly stated to the contrary, all temperatures and temperature ranges refer to the centigrade system. The term percent or (%) refers to the weight percent and the terms mole and moles refer to gram moles. The term equivalent refers to a quantity of reagent equal in moles to the moles of the preceding or succeeding reactant cited in that particular preparation or example in terms of moles of finite weight or volume.
Description of the preferred embodiment
The present invention also provides for a preferred improved process, wherein
(1) about 1.05-1.1 5 molar proportions of the 4-C1-C4 alkyl-2,3-dioxo- 1 -piperazinoca rbonyl halide of Formula IV is added to a suspension containing 2.5-2.7 molar equivalents of an appropriate base in a solvent mixture consisting of about 10-11 1 parts by weight of water and about 4-6 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of about 40-60 minutes at about 12-1 80C, while maintaining a pH of about 6.5-8; (2) the reaction mixture is further agitated at about 120--180C for about 20-30 minutes;;
(3) the reaction mixture is treated with about 0.08-0.1 part by weight of an activated carbon and about 0.1--0.15 part by weight of a filter-aid per part by weight of ampicillin originally charged and the resulting mixture is agitated at about 120--1$OC for about 15-20 minutes;
(4) after clarification, the insoluble materials are washed with about 1.0-1.2 parts by weight of water per part by weight of ampicillin;;
(5) the mother liquor and wash liquor are combined with about 6-7 parts by weight of ethyl acetate per part by weight of ampicillin originally charged, and the resulting mixture is warmed to about 180--220C, with the proviso that the total amount of ethyl acetate used in steps (1) and (5) is about 11-12 parts by weight of ampicillin originally charged;
(6) the reaction mixture is acidified at about 180--220C to a pH of about 2.2-2.3;
(7) the acidified reaction mixture is agitated at about 1 80-220C for about 2-3 hours, before collecting the crystalline free acid; and
(8) the free acid is optionally dissolved in water at a concentration of about 13.125% (weight of anhydrous free acid/volume of water), to which is gradually added about one molar equivalent of alkali metal bicarbonate; the reaction mixture is stirred for 3 4 hours at 60+40 until the pH drops to at least 6.5, before collecting the alkali metal salt of the product of Formula (I).
A further understanding of the invention can be had from the following non-limiting examples.
All parts are by weight unless otherwise indicated.
Example 1
Preparation of 6-[(-)-alpha-(4-Ethyl-2,3-dioxo 1 -piperazinocarbonylamino)phenylacetamido]penicillanic Acid Monohydrate
To an agitated slurry of 27.00 grams of ampicillin trihydrate (equivalent to 22.86 grams.
(0.0654 mole) of real anhydrous ampicillin), 14.50 grams (0.1726 mole) of sodium bicarbonate, 238 grams of water, and 119 grams of ethyl acetate, all at 15f20C, is added 14.73 grams (0.0720 mole) of 4-ethyl-2,3-dioxo-1 -piperazinocarbonyl chloride at a rate to maintain a pH greater than 6 and a temperature of 15+2 C. Upon completion of the addition, the reaction mixture is agitated at 1 5+20C for 20 minutes, and 2.1 grams of activated carbon (Type
RB Activated Carbon; Pittsburgh Coke and
Chemical Company), and 3.0 grams of a filter-aid (Hyflo Super-Cel; Johns-Manville Sales Corp.) are added thereto. The mixture is stirred for an additiona' 10 minutes, and the soiids are removed by filtration and washed with 26 grams of water.
The filtrate and wash liquor are combined and then mixed with 142.5 grams of ethyl acetate.
The temperature of the resulting mixture is adjusted to 20-220C, and the pH is adjusted to 2.3 by the addition of 2N hydrochloric acid thereto. The acidified mixture is agitated at 20220C for 2.5 hours and the crystalline precipitate is isolated by filtration, washed with 120 grams of water, and dried to obtain 33.49 grams (95.58% of theoretical) of the desired product.
Example 2
Preparation of 6-[(-)-alpha-(4-Ethyl-2,3-dioxo- 1 -piperazinocarbonylamino)phenylacetamido]penicillanic Acid, Sodium Salt
13.59. of the product of Example 1(0.025 moles, equivalent to 13.125 g. of the anhydrous free acid) is dissolved in 100 millileters of water, and to the stirred solution at 60+40C is added 2.06 grams of sodium bicarbonate (0.025 moles, equivalent to 1 5.685% W/W of the anhydrous free acid) in 10 increments of 0.206 grams each.
The reaction is allowed to proceed until the pH drops to at least 6.5, a period of 3-4 hours. The reaction mixture is sterilized by cold filtration, filled into asceptic vials and lyophilized to produce white or pale yellow crystals of 6-[D(-)-alpha-(4- ethyl-2,3-dioxo-1 -piperazinocarbonylamino)phenylacetamido]penicillanic acid, sodium salt.
Claims (6)
1. In a process for preparing a 6-[D(-)-alpha- (4-C1-C4 alkyl-2,3-dioxo-1 - piperazinocarbonylamino)-phenylacetamido penicillanic acid wherein a 4-C1-C4 alkyl-2,3 dioxo-1-piperazinocarbonyl halide is added to a solution or suspension of ampicillin in a mixture of ethyl acetate and water in the presence of a base to form a reaction mixture, the resulting mixture is agitated until the reaction is completed, the reaction mixture is acidified, and acrystalline product is recovered therefrom; the improvement which comprises:
(a) adding about 1-1.5 molar proportions of the 4-C1-C4 alkyl-2,3-dioxo-1piperazinocarbonyl halide to an agitated suspension of about one molar proportion of ampicillin and an appropriate amount of a suitable base in a solvent mixture consisting of about 912 parts by weight of water and about 0.5-8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 minutes at about 1 0-250C while maintaining a pH of about 6-8.3;; (b) further agitating the reaction mixture at about 100--250C for at least 1 5 minutes upon completing the addition of the 4-C1-C4alkyl- 2,3-dioxo-1-piperazino-carbonyl halide in step (a);
(c) adding to the reaction mixture about 0.05-0.2 part by weight each of an activated carbon and a filter-aid per part by weight of ampicillin charged in step (a), and agitating the resulting mixture at about 1 00--25 OC for at least 10 minutes;
(d) clarifying the resulting mixture, and washing the insoluble materials with about 0.62.5 parts by weight of water per part by weight of ampicillin charged in Step (a);;
(e) combining the mother liquor and wash liquor obtained in step (d) with about 2-12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in step (a), with the proviso that the total amount of ethyl acetate used in steps (a) and (e) is about 10-1 3 parts by weight per part by weight of said ampicillin, and warming the resulting mixture to about 150-- 250C; (f) acidifying the mixture obtained in step (e) at about 1 5 0--25 OC to a pH of about 2.0-2.5; and
(g) agitating the acidified mixture for at least one hour at about 1 5 0--25 OC before collecting the resulting crystalline free acid; and
(h) optionally converting the free acid to a pharmaceutically acceptable salt.
2. The improved process of Claim 1 wherein
(a) about 1.05-1.1 5 molar proportions of 4 C1C4 alkyl-2,3-dioxo-1-piperazinocarbonyl halide is added to the suspension containing 2.5-2.7 molar equivalents of base in a solvent mixture consisting of about 10-11 ? parts by weight of water and about 4-6 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of about 40-60 minutes at about 12-1 80C while maintaining a pH of about 6.58;
(b) the reaction mixture is further agitated at about 120--180C for about 20-30 minutes;;
(c) the reaction mixture is treated with about 0.08-0.1 part by weight of an activated carbon and about 0.1-0.1 5 part by weight of a filter-aid per part by weight of ampicillin charged in Step (a), and the resulting mixture is agitated at about 120--180C for about 1 5-20 minutes;
(d) the insoluble materials are washed with about 1.0-1.2 parts by weight of water per part by weight of ampicillin charged in Step (a);;
(e) the mother liquor and wash liquor are combined with about 6-7 parts by weight of ethyl acetate per part by weight of ampicillin charged in Step (a), and the resulting mixture is warmed to about 1 80--22 OC, with the proviso that the total amount of ethyl acetate used in steps (a) and (e) is about 11-12 parts by weight per part by weight of said ampicillin;
(f) the reaction mixture is acidified at about 180--220C to a pH of about 2.2-2.3;
(g) the acidified reaction mixture is agitated at about 1 80-220C for about 2-3 hours, before the crystalline free acid is collected, washed with water, and dried; and
(h) the free acid is optionally dissolved in water at a concentration of about 131.259. anhydrous free acid per liter of water to which is gradually added about one molar equivalent of alkali metal bicarbonate; the reaction mixture is stirred for about 3-4 hours at about 60+40C until the pH drops to at least 6.5, before collecting the alkali metal salt of the product of Formula (I).
3. The process of Claim 1 or 2, wherein the 4 C1-C4 a lkyl-2,3-dioxo- 1 -piperazinocarbonyl halide is 4-C1-C4 alkyl-2,3-dioxo-1 - piperazinocarbonyl chloride.
4. The process of Claim 1 or 2, wherein the 4 C1-C4 alkyl-2,3-d ioxo- 1 -piperazinocarbonyl halide is 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride.
5. The process of claim 1 or 2, wherein the product is converted to the sodium salt.
6. The product of the process of Claim 1, 2, 3, 4,or5.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24875481A | 1981-03-30 | 1981-03-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2095661A true GB2095661A (en) | 1982-10-06 |
GB2095661B GB2095661B (en) | 1985-02-27 |
Family
ID=22940531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8202662A Expired GB2095661B (en) | 1981-03-30 | 1982-01-29 | Preparation of an ampicillin derivative |
Country Status (23)
Country | Link |
---|---|
JP (1) | JPS57165391A (en) |
AT (1) | AT381706B (en) |
AU (1) | AU544896B2 (en) |
BE (1) | BE892586A (en) |
CA (1) | CA1200239A (en) |
CH (1) | CH654309A5 (en) |
DE (1) | DE3208506A1 (en) |
DK (1) | DK161079C (en) |
ES (1) | ES509424A0 (en) |
FR (1) | FR2502623A1 (en) |
GB (1) | GB2095661B (en) |
GR (1) | GR76054B (en) |
HK (1) | HK23590A (en) |
IE (1) | IE52907B1 (en) |
IL (1) | IL64981A (en) |
IT (1) | IT1148130B (en) |
LU (1) | LU84036A1 (en) |
NL (2) | NL192453A (en) |
NZ (1) | NZ199869A (en) |
PH (1) | PH19765A (en) |
PL (1) | PL235508A1 (en) |
SE (1) | SE452767B (en) |
ZA (1) | ZA82674B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BG46664A1 (en) * | 1985-08-16 | 1990-02-15 | Druzhestven N Izsledovatelski | Method for preparing of 6- /d (-)- alpha- (4- ethyl- 2, 3- dioxo- 1- piperazine carbonylamino)- phenylacetamido/- penicillanic acid |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL47168A (en) * | 1974-05-09 | 1979-07-25 | Toyama Chemical Co Ltd | Mono or dioxo piperazino(thio)carbonylamino derivatives ofpenicillins and cephalosporins and process for producing the same |
US4087424A (en) * | 1974-05-09 | 1978-05-02 | Toyama Chemical Co., Ltd. | Novel penicillins and cephalosporins and process for producing the same |
US4112090A (en) * | 1974-05-09 | 1978-09-05 | Toyama Chemical Co., Ltd. | Novel penicillins and cephalosporins and process for producing the same |
-
1982
- 1982-01-28 CA CA000395121A patent/CA1200239A/en not_active Expired
- 1982-01-29 GB GB8202662A patent/GB2095661B/en not_active Expired
- 1982-01-29 AU AU79964/82A patent/AU544896B2/en not_active Expired
- 1982-02-02 ZA ZA82674A patent/ZA82674B/en unknown
- 1982-02-03 GR GR67199A patent/GR76054B/el unknown
- 1982-02-04 DK DK048282A patent/DK161079C/en active
- 1982-02-08 ES ES509424A patent/ES509424A0/en active Granted
- 1982-02-11 IL IL64981A patent/IL64981A/en unknown
- 1982-02-17 PH PH26877A patent/PH19765A/en unknown
- 1982-02-22 JP JP57026170A patent/JPS57165391A/en active Granted
- 1982-03-01 NZ NZ199869A patent/NZ199869A/en unknown
- 1982-03-09 AT AT0093082A patent/AT381706B/en not_active IP Right Cessation
- 1982-03-09 DE DE19823208506 patent/DE3208506A1/en active Granted
- 1982-03-10 IT IT47962/82A patent/IT1148130B/en active
- 1982-03-17 FR FR8204497A patent/FR2502623A1/en active Granted
- 1982-03-18 PL PL23550882A patent/PL235508A1/xx unknown
- 1982-03-22 BE BE0/207631A patent/BE892586A/en not_active IP Right Cessation
- 1982-03-24 LU LU84036A patent/LU84036A1/en unknown
- 1982-03-26 CH CH1898/82A patent/CH654309A5/en not_active IP Right Cessation
- 1982-03-29 SE SE8201998A patent/SE452767B/en not_active IP Right Cessation
- 1982-03-29 IE IE746/82A patent/IE52907B1/en not_active IP Right Cessation
- 1982-03-29 NL NL192453D patent/NL192453A/xx not_active IP Right Cessation
- 1982-03-29 NL NL8201301A patent/NL192453C/en not_active IP Right Cessation
-
1990
- 1990-03-29 HK HK235/90A patent/HK23590A/en not_active IP Right Cessation
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