GB2183232A - Acetic acid thioesters as starting materials for cephalosporins - Google Patents
Acetic acid thioesters as starting materials for cephalosporins Download PDFInfo
- Publication number
- GB2183232A GB2183232A GB08627404A GB8627404A GB2183232A GB 2183232 A GB2183232 A GB 2183232A GB 08627404 A GB08627404 A GB 08627404A GB 8627404 A GB8627404 A GB 8627404A GB 2183232 A GB2183232 A GB 2183232A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- amino
- compounds
- optionally substituted
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Process for the production of known cephalosporin derivatives comprising reaction of 7-amino- cephalosporanic acid derivatives with novel acetic acid thioesters, as well as such thioesters and their production. The thioesters are of formula IV or IVa: <IMAGE> where R1'' is a 5-membered O, S or N containing heterocycle optionally substituted by optionally protected amino.
Description
SPECIFICATION
Process for the production of cephalosporin antibiotics and novel intermediates for use in such process and their production
The invention relates to a new process for the production of cephalosporines of formula
wherein
R1 is a 5-membered oxygen-, nitrogen- and/or sulphur-containing heterocyclic ring which is optionally substituted by amino,
R2 is hydrogen, acetoxy, methoxy, carbamoyloxy, a group -S-Y, wherein Y signifies an unsubstituted or substituted heterocyclic ring or R2 is an optionally substituted pyridinium of formula 11,
wherein R4 and R5 are each independently hydrogen, halogen, alkyl, hydroxy, carboxamido, alkoxycarbonyl, amino, monoalkylamino or dialkylamino, or together signify an optionally substituted, 5- or 6-membered carbocyclic ring and
R3 is carboxyl, carboxylate or a carboxylic acid ester group.
Compounds of formula I represent a known class of valuable cephalosporin antibiotics.
The heterocyclic ring in R1 contains, as indicated, one or more oxygen, sulphur and/or nitrogen atoms as heteroatom(s). Suitable heterocyclic rings include for example pyrazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl and oxadiazolyl. The heterocyclic ring may be unsubstituted or substituted by amino. Preferably R1 is thienyl or (1 H)-tetrazolyl.
R2 may be hydrogen. It can also be carbamoyloxy. However, it preferably signifies acetoxy, -S-Y or optionally substituted pyridinium. Suitable heterocycles as Y are known. Preferred heterocycles are for example thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl. These heterocyclic rings may be be unsubstituted, for example up to three times. Suitable substituents include (C1 4) alkyl, (C1 4) alkoxy, halogen, trihalo-(C1 4) alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C, 4) alkylamino, carboxymethyl, carbamoylmethyl, sulphomethyl and methoxycarbonylamino.Heterocyclic rings mentioned in the literature as particularly preferred include tetrazolyl, in particular 1-methyl-i H-tetrazol-5-yl, thiadiazolyl, in particular ,2,3-thiadiazol-5-yl, 2 methyl-1,3,4-thiadazol-5-yl and triazinyl, especially 1,2,5,6--tetrahydro-2-methyl-5,6-dioxo-as-tri- azin-3-yl, 2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl or 1 ,4,5,6-tetrahydro-4-methyl-5,6- dioxo-as-triazin-3-yl. R2 is preferably acetoxy, 1 -methyl-i H-tetrazol-5-ylthio, pyridinium or 2-me thyl- 1 ,3,4-thiadiazolyl-5-thio.
As is known in the field of cephalosporins, the compounds may exist in the form of free acids (R3=COOH) or of salts, for example alkali metal salts or alkaline earth metal salts, preferably alkali metal salts, such as sodium salts. Alternatively the compounds may be in the form of esters, e.g. in the form of pivaloyoxymethyl-ester. Examples of other ester-forming residues are acetoxymethyi, 1-acetoxyethyl, 1 -ethoxycarbonyloxyethyl, 5-indanoyl or preferably hexanoylmethyl, phthalidyl, carbethoxymethoxymethyl or 3-carbethoxy-1-acetonyl. If R2 is an optically substituted pyridinium group, the compounds of formula I can also exist as inner salts.
A particular preferred group of compounds of formula I are those of formula la,
wherein
R1, is 2-thienyl or 1(1 H)-tetrazolyl, R2, is hydrogen, acetoxy or -S-Y, wherein Y is 2-methyl-l ,3,4-thiadiazol-5-yl or 1 methyl-1Htetrazol-5-yl, and R3' is carboxyl or carboxylate.
As mentioned above, the compounds of formula I are known and various processes for their production have been proposed. One of these processes involves acylation of the corresponding optionally protected 7-aminocephalosporanic acid derivative with a reactive derivative of an acid of formula A,
R,-CH2-COOH A wherein
R1 is as defined above.
Such acylations has often to be carried out at low temperatures (-30 to 0 C). Formation of by-products and discoloration often occurs, requiring troublesome purification procedures. The prior art processes are further characterised by the disadvantage, that, if R1 is a heterocyclic ring bearing an amino substituent, the latter has to be protected prior to the activation of the acidic function, since otherwise competitive reactions may lead to great reductions in yield of the end product. The introduction of protecting groups prior to the acylation step, and their subsequent removal is in general accompanied by reduced yield and diminished purity of the end product and considerably increases the reaction time, energy, effort and costs.
The present invention provides an improved process for the production of compounds of formula I. The process is economical and provides compounds of formula I in high yield and high purity. In addition an optionally present amino substituent in the residue R1 need not be protected.
More particularly, the present invention provides a process for the production of compounds of formula I and their salts, comprising reacting a compound of formual IV or IVa,
wherein B1' is a 5-membered oxygen-, nitrogen- and/or sulphur containing heterocyclic ring which is optionally substituted by amino or protected amino, and
represents a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms, selected from oxygen, nitrogen and sulphur, and which may be substituted or fused to an optionally substituted benzene ring, with a compound of formula III,
wherein
R2 is as defined above, R6 is hydrogen or an amino-protective group, B2, is carboxyl, a protected carboxyl group, carboxylate or a carboxylic acid ester group, and where required, deprotecting the resulting compound, and, if desired, converting a resulting compound, wherein R3 is COOH into a salt thereof or vice versa.
The compounds of formula IV may also exist in the form of formula IVa, whereby the ratio of the two forms is dependent on the reaction components and the reaction conditions. For convenience, the above formula IV is considered to be embracive of the compounds having the structure of formula IVa.
The process is suitably effected in an inert solvent or in a mixture of such a solvent with water, e.g. in a lower alcohol such as ethanol, a chlorinated hydrocarbon, such as dichloromethane, or in an acid ester, such as ethyl acetate, or in acetone, dimethylformamide or dimethyl sulphoxide. The reaction temperature is suitably of -40 to +60"C in particular -15 to +25"C, and especially 0 to 20"C. The duration of the reaction is approximately few minutes to 48 hours. The reactants of formula Ill and IV may conveniently be used in stoichiometric quantities.
Alternatively an excess of up to 25% of the compound of formula IV is conveniently employed.
When compounds of formula I, wherein R3 is COOH (as well as salts thereof) are to be produced, the carboxylic acid group in the compound of formula Ill can be protected. Suitable protecting groups are well known and include not only those referred to above as possible significances for ester groups, but also silyl ester protecting groups, in particular the trimethysilyl protecting group, which may for example be introduced by reaction of the free acid with N,O- bis-trimethylsilylacetamide.
The 7-amino group of the starting material of formula ill may also be protected. Suitable protecting groups are known and include e.g. the trimethylsilyl group, which can be introduced for example simultaneously when protecting the carboxylic acid group.
If in compounds of formula IV R,'' is a heterocyclic ring bearing an amino substituent, the amino group in the starting material may be in free or in protected form. As mentioned above, protection of the amino group in the residue R," is not necessary. Should, however, protection be desired, this can be effective in known manner using conventional protecting groups.
Any deprotection following the reaction of formula III with compounds of formula IV may be effected in conventional manner. Similarly, conversion of the free acid (R3=COOH) into the salts can be effected in known manner.
The end products can be isolated and purified in conventional manner.
In the process according to the invention heterocyclic thioesters of formula IV are used as a reactive derivative of the acid of formula A. Compounds of formula IV are new and also form part of the invention. They are valuable intermediates which can be used for acylation of compounds of formula Ill, whereby cephalosporines of formula I are prepared in high yield and high purity. A further advantage of the present process is that the reactive intermediates of formula IV may be prepared in pure crystalline form and as such be employed for the reaction with compounds of formula Ill. If necessary, the compounds of formula IV may not be isolated, but may be allowed to react directly with compounds of formula Ill.Another advantage of the present process is that all process steps i.e. the process for the production of intermediates of formula IV as well as their reaction with compounds of formula Ill can be carried out at normal temperatures without employing low reaction temperatures.
Furthermore, it has surprisingly been found that when there is an amino group in the heterocyclic ring of these thioesters, the thioesters are not self-reacting. Accordingly, protection of this amino group in the subsequent reaction with compounds of formula Ill is not necessary. On the other hand, if required, the amino group may be protected if this is desirable for another reason.
determined by such factors as ease of formation and availability of the starting material. Preferably, however, the ring is 2-pyridyl or especially 2-benzothiazolyl. The ring may also be pyrimidinyl, triazolyl or thiazolyl.
The preferred compounds of formula IV are those of formula lVb,
wherein R,' and
are as defined above.
The compounds of formula IV can be produced by reacting a compound of formula V F 1"-CH2-COOH V wherein R," is as defined above, with a compound of formula VI,
in which the two groups
are the same and are as defined above.
This reaction is preferably effected in the presence of a tri(loweralkyl)- or tri(aryl)-phosphine or
-phosphite, especially triphenylphosphine, and preferably at a temperature of -30 to +50"C, especially -20 to +25"C, advantageously 0 to +25"C. Suitably an inert organic solvent which does not contain hydroxyl groups, e.g. a chlorinated hydrocarbon such as dichloromethane is employed. If a compound of formula IV is desired, wherein R," is a heterocycle substituted by a
protected amino group, the amino protecting group can be introduce prior or subsequent to the reaction.
The compounds of formula I are valuable antibiotics. They exhibit antibacterial activity as
indicated in vitro in the series dilution test, at a concentration for example of 0.01 to 50 ug/ml, and in vivo in the mouse at a dosage of for example from 0.1 to 100 mg/kg of animal body weight, using various strains, such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Escherichia coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Shigella dysenteria, Shigella sonnei, Shigella flexneri, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneunomiae, Serrata marcescens, Salmonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Neisseria gonorrhoae.
The compounds are therefore useful as antibacterially active antibiotics. For this usage, the dosage will of course vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 1 to 6 g conveniently given in divided dosages of from about 0.25 to about 3 g of the compound two to four times daily, or in sustained release form.
The compounds of formula I, wherein R3=COOH, may be administered in free acid form or in the form of their physiologically acceptable salts. Such salt forms have the same order of activity as the free acid forms. Suitable salt forms include alkali metal and alkaline earth metal salt forms, in particular alkali metal, such as sodium salt forms. The compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers and optionally other excipients and administered in such forms as capsules or injectable preparations.
The following Examples in which all temperatures are in degrees Centigrade, illustrate the invention.
Example 1: 7-(2-Thienylacetamido)cephalosporanic acid sodium salt [cefalotin]
a) 2-Thienylacetic acid 2-benzothiazolyl thioester
To a suspension of 14.3 g 2-thienylacetic acid and 30 g triphenylphosphine in 100 ml dichloromethane are added under stirring at room temperature 33 g 2,2'-dithiobis[benzothiazole].
A reddish coloured solid precipitates. The mixture is stirred at about 20 for 3 hours. Completion of reaction is determined by thin layer chromatography. The resulting reaction can then either be directly used for the following step or cooled to 0" and filtered to give the title compound; yield 27 g (93%).
b) 7-(2-Thienylacetamido)cephalosporanic acid sodium salt
To a suspension of 22 g 7-aminocephalosporanic acid in 200 ml dichloromethane are added 22 g N,O-bis(trimethylsilyl)acetamide. The mixture is stirred 2 hours at 250 to give a clear solution, which is then treated at about 20 either with the suspension of the title compound of
Example la) or the isolated title compound la). The temperature rises slightly and the mixture is stirred at about 20 for further 80 minutes. The mixture is then treated with 100 ml acetone and 2 ml water. Upon dropwise addition of a solution of 20 g sodium-2-ethylhexanoate in acetone the title compound precipitates in form of easily filterable crystals. After cooling to 0 the crystals are filtered, washed with acetone and dried.Yield 31 g (91.5%) of the title compound in pure form.
Example 2: 71 1-(1H)-TetrazolylacetamidoJ-3-[5-(2-methyl- 1,3,4-thiadia-zolyl)thiomethyl]-3-cephem 4-carboxylic acid [Cefazolin]
a) 1-(1 H)-Tetrazolylacetic acid 2-benzothiazolyl thioester
12.8 g 1-(1H)-tetrazolylacetic acid are suspended in 120 ml dichloromethane and treated with 30 g triphenylphosphine. The mixture is stirred vigorously and treated at 18 to 23 with 33 g 2,2'-dithiobis-[benzothiazole]. The reaction mixture is stirred 4 hours at about 20 , whereby pale yellow crystals precipitate. The resulting suspension can then either be directly used for the next step or cooled to 0 and filtered.The precipitate is washed with cold dichloromethane and dryied in vacuo to yield 25 g of the title compound (90%).
b) 7-[ 1 -(1 H)-Tetrazolylacetamido]-3-[5-(2-methyl- 1,3,4-thiadiazolyl) thiomethyl]-3-cephem-4-carboxylic acid
To a suspension of 27.8 g 7-amino-3-[5-(2-methyl-1,3,4-thiadiazolyl)-thiomethyl]-3-cephem-4- carboxylic acid in 250 ml dichloromethane are added 26 g N,O-bis(trimethylsilyl) acetamide. The mixture is stirred 2 hours at 25 and then treated at 18 to 23O either with the suspension of the title compound of step a) or with the isolated title compound of step a), whereby a mild exothermic reaction ensued. The reaction mixture is stirred for further 120 minutes at about 20 , then treated with 100 ml methanol and stirred 5 hours at room temperature, whereby the title compound precipitates in colourless crystals.Upon cooling for 2 hours at 0" the crystals are filtered off, washed with cold methanol and then with acetone. After drying in vacuo 32 g (87%) of the title compound are obtained.
Example 3: 7-(2- Thien ylacetamido)-3-[5-(2-methyl- 1,3, 4-thiadiazolyl) thiomethyl]-3-cephem-4-carboxylic acid sodium salt
To a suspension of 27.6 g 7-amino-3-[5-(2-methyl-1,3,4-thiadiazolyl)-thiomethyl]-3-cephem-4- carboxylic acid in 300 ml dichloromethane are added 26 g N,O-bis(trimethylsilyl)acetamide. The mixture is stirred 2 hours at 25 to 30 , cooled to 18 and then treated either with the suspension of the title compound of Example 1a) or with the isolated title compound of Example 1a), whereby a mild exothermic reaction ensued. The reaction mixture is stirred for further 100 minutes at about 20 , then treated with 150 ml acetone and 3 ml water.Under stirring a solution of 20 g sodium-2-ethylhexanoate in 50 ml acetone is added, whereby the title compound precipitates. The precipitate is filtered off and washed with acetone to give 36 g (93%) of the title compound. The product is purified by dissolving in 30 ml water, treatment with charcoal and addition of 750 ml ethanol to the pale-yellow filtrate, whereby the pure title compound crystallises in colourless needles.
NMR(D20): 7,3 and 7,0 (3H,2m; thienyl-protons);5,60 (1H,d,J=5 Hz, C7-H;5,02 (1H,d,J=5 Hz, Ce-H); 4,42 and 4,00 (2H,ABq,J=14 Hz, C3-CH2);3,88 (2H,S,thienyl-CH2); 3,66 and 3,30 (2H,ABq
J=18 Hz, C2-CH2);2,72 (3H,S,thiadiazolyl-CH3).
Example 4: 7-(2-Thienylacetamido)-3-[5-( 1-methyl- 2,3, 4-tetrazolyl) thiomethyl]-3-cephem-4-car- boxylic acid sodium salt
A suspension of 26.2 g 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-car- boxylic acid in 300 ml dichloromethane is treated with 26 g N,O-bis(trimethylsilyl)acetamide. The mixture is stirred for 2 hours at 25 to 30 , the obtained clear solution is cooled to about 18 and treated either with the suspension of the title compound of Example 1a) or with the isolated title compound lea). After stirring 1 hour at room temperature the clear reddish solution is treated with a solution of 20 g sodium-2-ethylhexanoate and 3 g water in 200 ml ethanol, whereby the title compound precipitates.After filtration, washing with ethanol and drying, 33.7 g (88%) of the title compound are obtained.
NMR(D20):7,3 and 7,0 (3H,2m, thienyl-protons); 5,45 (1H,d,J=5 Hz, C7-H);5,02 (1H,d,J=5 Hz, C6-H); 4,30 and 4,07 (2H,ABq, J=14 Hz, C3-CH2);4,00 (3H,S, N-CH3);3,86 (2H,S,thienyl
CH2);3,68 and 3,36 (2H,ABq,J=18 Hz, C2-CH2).
Example 5: 7-(2-Thienylacetamido)-3-methyl-3-cephem-4-carboxyllc acid sodium salt
A suspension of 17.2 g 7-amino-3-desacetoxycephalosporanic acid in 250 ml dichloromethane is treated with 26 g N,O-bis(trimethylsilyl)acetamide. After stirring 2 hours at 25 to 30O the resulting almost clear solution is cooled to 18 and treated with either the suspension of the title compound of Example la) or the isolated title compound of Example lea). After stirring 2 hours at room temperature 100 ml acetone and 3 g water are added and the mixture evaporated in vacuo. The residue is taken up in 100 ml acetone/water (1:1), treated with 3 g charcoal and filtered. The filtrate is treated with 300 ml acetone and 100 ml 20% solution of sodium-2ethylhexanoate in acetone, whereby the title compound precipitates. Yield 22 g (76%).
NMR(D20): 7,30 and 7,00 (3H, 2m; thienylproton); 5,56 (1H,d,J=5 Hz, C7-H); 5,00 (1H,d,J=5
Hz, C6-H); 3,85 (2H,S, thienyl-CH2); 3,47 and 3,10 (2H,ABq,J=18 Hz, C,-CH2); 1,93 (3H,S,C3
CH3).
Example 6: 7-(2-ThienylacetamidoJ-3-methoxymethyl-3-cephem-4-carboxylic acid sodium salt
In manner analogous to that described in Example 5, but using 19.5 g 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid instead of 7-amino-3-desacetoxycephalosporanic acid the title compound is obtained as colourless crystals, yield 26.5 g (83%).
NMR (D2G): 7,30 and 7,00 (3H,2m,thienylproton); 5,64 (lH,d,J=5 Hz, C7-H); 5,10 (1H,d,J=5 Hz,C6-H);4,25 (2H,S,C3-CH2);3,88 (2H,S,thienyi-CH2); 3,55 (2H,ABq,J=18 Hz,C2-CH2); 3,38 (3H,S,OCH3).
Claims (8)
1. A process for the production of compounds of formula
wherein
R1 is a 5-membered oxygen-, nitrogen- and/or sulphur-containing heterocyclic ring which is optionally substituted by amino,
R2 is hydrogen, acetoxy, methoxy, carbamoyloxy, a group -S-Y, wherein Y signifies an unsubstituted or substituted heterocyclic ring or R2 is an optionally substituted pyridinium of formula II,
wherein
R4 and R5 are each independently hydrogen, halogen, alkyl, hydroxy, carboxamido, alkoxycarbonyl, amino, monoalkylamino or dialkylamino, or together signify an optionally substituted, 5- or 6-membered carbocyclic ring and
R3 is carboxyl, carboxylate or a carboxylic acid ester group, and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula IV or IVa,
and/or
wherein R," is a 5-membered oxygen-, nitrogen- and/or sulphur containing heterocyclic ring which is optionally substituted by amino or protected amino, and
represents a 5- or 6-membered heterocyclic ring, which iri addition to the nitrogen atom may contain one or two further heteroatoms, selected from oxygen, nitrogen and sulphur, and which may be substituted or fused to an optionally substituted benzene ring, with a compound of formula Ill,
wherein
R2 is as defined above, R6 is hydrogen or an amino-protective group,
R3' is carboxyl, a protected carboxyl group, carboxylate or a carboxylic acid ester group, and where required, deprotecting the resulting compound, and, if desired, coverting a resulting compound, wherein R3 is COOH into a salt thereof or vice versa.
2. A process according to Claim 1 for the production of compounds of formula la,
wherein B1, is 2-thienyl or 1-(1H)-tetrazolyl, B2, is hydrogen, acetoxy or -S-Y, wherein Y is 2-methyl- 1 ,3,4-thiadiazol-5-yl or 1-methyl-1H- tetrazol-5-yl, and B3, is carboxyl or carboxylate, and pharmaceutically acceptable salts thereof.
3. A process according to Claim 1, in which the compound of formula IV,
is 2-benzothiazolyl.
4. A process for the production of a compound of formula IV, stated in Claim 1, comprising reacting a compound of formula V, B1,,-CH2-COOH V wherein
R," is as defined in Claim 1, with a compound of formula VI,
in which the two groups
are the same and are as defined in Claim 1.
5. Compounds of formula iV, stated in Claim 1.
6. Compounds of formula iVb,
wherein R,' is 2-thienyl or 1-(1H)-tetrazolyl, and
is as defined in Claim 1.
7. The compound of Claim 5 which is 2-thienylacetic acid 2-benzothiazolyl thioester.
8. The compound of Claim 5 which is 1-(1 H)-tetrazolylacetic acid 2-benzothiazolyl thioester.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0338185A AT383810B (en) | 1985-11-20 | 1985-11-20 | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8627404D0 GB8627404D0 (en) | 1986-12-17 |
| GB2183232A true GB2183232A (en) | 1987-06-03 |
| GB2183232B GB2183232B (en) | 1989-11-15 |
Family
ID=3549668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8627404A Expired GB2183232B (en) | 1985-11-20 | 1986-11-17 | Acetic acid thioesters as starting materials for cephalosporins |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS62135477A (en) |
| AT (1) | AT383810B (en) |
| BE (1) | BE905783A (en) |
| CH (1) | CH671228A5 (en) |
| DE (1) | DE3639410A1 (en) |
| ES (1) | ES2002912A6 (en) |
| FR (1) | FR2590257A1 (en) |
| GB (1) | GB2183232B (en) |
| IT (1) | IT1195841B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996020198A1 (en) * | 1994-12-23 | 1996-07-04 | Biochemie Gesellschaft Mbh | Production of cefotaxime and new sodium salts |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0231845B1 (en) * | 1986-02-07 | 1992-06-17 | F. Hoffmann-La Roche Ag | Process for the preparation of carboxylic-acid amides |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004570A1 (en) * | 1978-03-09 | 1979-10-17 | Asahi Kasei Kogyo Kabushiki Kaisha | Thiol esters, process for their preparation, pharmaceutical compositions containing them and a process for preparing cephalosporin compounds using the same |
| EP0047014A2 (en) * | 1980-09-02 | 1982-03-10 | Asahi Kasei Kogyo Kabushiki Kaisha | Novel thioesters and process for the preparation of the same |
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0060301B1 (en) * | 1980-09-19 | 1985-11-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Process for preparing cephalosporin compounds |
| DE3587866D1 (en) * | 1984-04-10 | 1994-07-28 | Biochemie Gmbh | Cephalosporin intermediates, processes for their preparation and their use. |
-
1985
- 1985-11-20 AT AT0338185A patent/AT383810B/en not_active IP Right Cessation
-
1986
- 1986-11-11 CH CH4494/86A patent/CH671228A5/de not_active IP Right Cessation
- 1986-11-17 GB GB8627404A patent/GB2183232B/en not_active Expired
- 1986-11-18 IT IT67857/86A patent/IT1195841B/en active
- 1986-11-18 DE DE19863639410 patent/DE3639410A1/en not_active Withdrawn
- 1986-11-18 FR FR8616024A patent/FR2590257A1/en not_active Withdrawn
- 1986-11-19 JP JP61276380A patent/JPS62135477A/en active Pending
- 1986-11-19 BE BE0/217434A patent/BE905783A/en not_active IP Right Cessation
- 1986-11-20 ES ES8603111A patent/ES2002912A6/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004570A1 (en) * | 1978-03-09 | 1979-10-17 | Asahi Kasei Kogyo Kabushiki Kaisha | Thiol esters, process for their preparation, pharmaceutical compositions containing them and a process for preparing cephalosporin compounds using the same |
| EP0047014A2 (en) * | 1980-09-02 | 1982-03-10 | Asahi Kasei Kogyo Kabushiki Kaisha | Novel thioesters and process for the preparation of the same |
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
Non-Patent Citations (7)
| Title |
|---|
| JP 55/122788 * |
| JP 56/63973 * |
| JP 58/172381 * |
| JP 58/172385 * |
| JP 60/136582 * |
| JP 60/34974 * |
| NIPPON NOGEI KAGAKU KAISHI 58 675-83(1984) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996020198A1 (en) * | 1994-12-23 | 1996-07-04 | Biochemie Gesellschaft Mbh | Production of cefotaxime and new sodium salts |
| AU711228B2 (en) * | 1994-12-23 | 1999-10-07 | Biochemie Gesellschaft Mbh | Production of cefotaxime and new sodium salts |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2590257A1 (en) | 1987-05-22 |
| IT1195841B (en) | 1988-10-27 |
| CH671228A5 (en) | 1989-08-15 |
| GB2183232B (en) | 1989-11-15 |
| AT383810B (en) | 1987-08-25 |
| JPS62135477A (en) | 1987-06-18 |
| IT8667857A0 (en) | 1986-11-18 |
| BE905783A (en) | 1987-05-19 |
| DE3639410A1 (en) | 1987-05-21 |
| GB8627404D0 (en) | 1986-12-17 |
| ATA338185A (en) | 1987-01-15 |
| ES2002912A6 (en) | 1988-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0037380B1 (en) | New process for the production of cephalosporin antibiotics, and novel intermediates used in such process and their production | |
| US4008246A (en) | Aminothiazole derivatives | |
| US4080498A (en) | 7-Alpha-(2-aminothiazole)-acetamido-cephalosporins | |
| EP0049118A2 (en) | Cephalosporin derivatives, their preparation and compositions containing them | |
| US4012382A (en) | α-Amino and α-formyl-α-(p-acyloxyphenyl)acetamidocephalosporanic acid derivatives | |
| JPS6153359B2 (en) | ||
| US3880848A (en) | 7-Trifluorome thylsulfinylacetamido cephalosporins | |
| GB2071654A (en) | Hydroxamic acid derivatives of 7-(2-amino-4-thiazolyl)oximino cephalosporins | |
| EP0053077B1 (en) | Salts of 7-aminocephalosporanic acids, soluble in organic solvents and their use in the preparation of cephalosporins | |
| US4145418A (en) | Thienopyridine substituted cephalosporins | |
| US3799924A (en) | Ester cleavage process | |
| GB2183232A (en) | Acetic acid thioesters as starting materials for cephalosporins | |
| JP2529093B2 (en) | Method for producing cephalosporin intermediate | |
| GB2146332A (en) | 2-Oxoimino acetic acid amides and their use in producing cephalosporin antibiotics | |
| CA1072949A (en) | Cephem compounds | |
| SU1037842A3 (en) | Process for preparing 3-thiovinyl cephalosporins | |
| US5585485A (en) | Cephalosporin intermediate products | |
| US3898221A (en) | Trifluoromethylmercaptoacetamidocephalosporins | |
| DE3043865A1 (en) | N-SUBSTITUTED THIAZOLYL DERIVATIVES OF OXY-IMINO-SUBSTITUTED CEPHALOSPORINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING PHARMACEUTICAL AND VETERINE MEDICAL AGENTS | |
| US4088761A (en) | 3-[(1,3-Dithiin-5-yl)-acetamido]-cephalosporins and antibacterial compositions containing them | |
| US4182868A (en) | 7-Methoxycephalosporin derivatives | |
| CA1064478A (en) | 7-methoxycephalosporin derivatives | |
| US4058609A (en) | 7-Dithioacetamido cephalosporins | |
| GB2165245A (en) | Chemical compounds | |
| US4481357A (en) | Process for the preparation of 3-substituted 7-aminocephalosporanic acids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |