GB2158432A - Process for the preparation of cephem derivatives - Google Patents
Process for the preparation of cephem derivatives Download PDFInfo
- Publication number
- GB2158432A GB2158432A GB08423207A GB8423207A GB2158432A GB 2158432 A GB2158432 A GB 2158432A GB 08423207 A GB08423207 A GB 08423207A GB 8423207 A GB8423207 A GB 8423207A GB 2158432 A GB2158432 A GB 2158432A
- Authority
- GB
- United Kingdom
- Prior art keywords
- process according
- formula
- acid
- mixture
- organic
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
Abstract
A novel process for preparing cephem derivatives is characterized in that an acylating agent, <IMAGE> wherein R<3> is benzotriazolyl, pyridyl, succinimidyl or phthalimidyl, and n is 1 or 2, is used in esterifying 2-(2-amino-thiazol-4-yl)-2-syn-methoxyiminoacetic acid: <IMAGE> The ester thus obtained is then reacted with 7-aminocephalosporanic acid of formula III below to give a desired cephem derivative. Use of such an acylating agent eliminates the awkward steps of protection and then deprotection of the amino radical of the starting organic acid. <IMAGE> wherein R' is H or alkali metal and R<2> is H, acetoxymethyl or heterocyclicthiomethyl.
Description
SPECIFICATION
Process for the Preparation of Cephem Derivatives
The present invention relates to a process for preparing plactam derivatives useful as antibitiotics, having the formula:
wherein R' is hydrogen or alkali metals, and R2 is hydrogen, acetoxymethyl, or 5- or 6-ring heterocyclic radical which may contain one or two or more nitrogen atoms, or be substituted by a lower alkyl.
Hitherto, various methods have been proposed for preparing sslactam series antibiotics in literatures and patents. These methods are in general directed to sslactam series antibiotics by condensing 7-aminodeoxycephalosporanic acid (7-ADCA) or 7-aminocephalosporanic acid (7
ACA) derivatives with a reactive derivative of an organic acid so as to give a peptide linkage between them.
In a typical method among the prior art methods for preparing an acyl compound (I) above, a protecting functional group which can readily be removed by an acid is introduced to the amine radical attached to an organic acid having the formula:
and then the organic acid must be converted to a reactive derivative thereof such as an acid chloride, a reactive ester or amide, a mixed acid anhydride or the like.
The methods for preparing Compound (I) via acid chlorides of Compound (II) above are disclosed in Japanese Laid-open Patent Publications (Sho) 52-102,096, 53-34,795, 53-68,796, 54-52,096 and 54-157,596, and British Patent 2,025,933. These methods generally comprise protecting the amino radical attached to the organic acid (II) with a protecting group, reacting the protected acid with thionyl chloride (SOCI2), phosphorous pentachloride (PCIs), phosphorous oxychloride (POCI3) or the like to give a corresponding acid chloride thereof, subjecting the acid chloride to acylation, and then removing the aminoprotecting group to afford Compound (I). However, these mothods have drawbacks in that the overall reaction must be carried out under severe conditions and the intermediate acid chloride is unstable.
Methods for preparing Compound (I) via the reactive derivatives of the organic acid (II) are disclosed in Japanese Laid-open Patent Publications (Sho) 52-102,293, 54-95,593 and 56-152,488. According to these publications, the organic acid (II) is converted to its corresponding 2-pyridine thioester, 2-benzothiazole ester or 1 -hydroxy-benzotriazole ester which is then subjected to acylation to give Compound (I). However, these methods also have defects in that undesirable side-reactions occurred during the process of obtaining the ester may cause a poor yield and the acylation requires a long period of time for completion.
Furthermore, in the methods via an acid amide or a mixed acid anhydride of the organic acid (II), there have also been found the drawbacks similar to those discussed above.
Therefore, the prior art methods require akward procedures for first protecting the amine radical of the organic acid (II) with a protecting group before acylating the acid to convert it into its corresponding acid chloride, reactive ester or amide, or the like, subjecting the intermediate to acylation with 7-ADCA or 7-ACA, and then removing the protecting group from the acylated compound.
The inventors have reached to the invention based on our discoveries that it is possible to increase the yield and the purity of the final product by omitting the steps of protection of the amino radical of the organic acid (II).
Accordingly, the object of the invention is to provide a new process for preparing Compound (I) in a more economical and convenient manner as compared against the prior art methods.
This object and advantageous effects can, in accordance with the invention, be achieved by providing a process comprising esterifying an organic acid having the formula:
with an esterifying agent having the formula:
wherein R3 is benzotriazolyl, pyridyl, succinimidyl or phthalimidyl, and n is an integer 1 or 2 in the presence of an organic amine to give a reactive ester of the acid having the formula:
wherein R3 has the same meaning as defined above, and reacting the ester with a compound having the formula:
wherein R1 and R2 each have the same meaning as defined above to afford a cephem derivative having the formula:
wherein R1 and R2 have the same meaning as defined above in the presence of an organic reaction solvent.
The process in accordance with the invention may schemetically be illustrated by the following reaction scheme:
As can be seen from the above scheme, in the invention, the organic acid (II) does not need protection of its amino group. The esterification for obtaining the reactive ester (V) in the scheme may in general be carried out in the presence of an organic reaction solvent.
Organic solvents suitable for the purpose include N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dichloromethane, 1,2,-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane and the like. Among these solvents; N,N-dimethylformamide and N,Ndimethylacetamide may preferably be used. The esterification may be conducted under weak organic amine basic conditions. Amine bases suitable for use in the esterification include pyridine, triethyl amine, N, N-dimethylaniline, N, N-dimethylaminopyridine, isopropyl amine and the like.
The ratios of the organic acid (II) and the base to the esterifying agent (IV) are preferably 1.2 equivalent and equimolar, respectively. This reaction may usually be carried out at room temperature and give quantitatively the reactive ester (V) after the lapse of a 10 to 1 5 hours period of time from the initiation thereof. The ester (V) can be precipitated when the reaction mixture is poured into water at once. At this time, the amount of water used is preferably about 20 to 30 times the amount of the solvent used.
The subsequent acylation of the ester (V) with Compound (III) may be conducted in a mixed solvent of basic solution-organic solvent. Suitable bases for this purpose include sodium hydrogen carbonate, potassium hydrogen carbonate, triethyl amine, caustic soda, sodium carbonate, potassium carbonate, ammonia water and the like. Sodium hydrogen carbonate is most preferably. As suitable organic solvents for the same purpose, there may be included acetonitrile, acetone, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane and the like. Acetonitrile, tetrahydrofuran and N,N-dimethylformamide are more preferably selected. In carrying out the acylation, a selected organic solvent is first added to a basic solution of Compound (III), and to the resulting mixture the reactive ester previously obtained is added in the crystalline form followed by stirring the mixture at room temperature for 6 to 7 hours. This reaction is quantitatively carried out. When the reaction is completed, the organic solvent is then removed by distilation in vacuo and the pH of the aqueous layer thus separated is adjusted to an isoelectric point to yield Compound (I) as precipitate. For this reaction, the amounts of water and the solvent are used are preferably about 20 to 30 times as much as the amount of the starting material of Compound (liy). The ratio of water to the solvent used may preferably be 1:1 or 1:2.The pH of the aqueous basic solution preferably ranges from 7.0 to 7.5.
As can be seen from the foregoing, the invention has advantages in that 1) it does not require the steps for protecting the amino radical of the organic acid (II) and then removing the aminoprotecting group; 2) it makes it possible to use a stable esterifying agent (acylating agent) which can be easily handled; 3) all of the reactions involved can be carried out at room temperature; and 4) it is possible to simply isolate the final product from an aqueous solution when the overall reaction is terminated. Accordingly, since the invention makes it possible to more simplify the procedures and the installation expense for preparing cephem compounds as compared with any of the prior art methods, a commercially valuable new process can be provided.
The invention will appear more fully described from consideration of the following examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope, and the appended claims.
Reference Example 1
To a suspension of 82 9 of 1-hydroxybenzotriazole in 400 ml of toluene, 36 ml of trichloromethyl chloroformate was added and the mixture was heated at reflux for 2.5 hours.
The resulting precipitate was filtered, washed with 1 50 ml of toluene and dried to give 71 g (yield 80%) of 1,1'-(carbonyldioxy)dibenzotriazole, melting at 150"C (dec.). IR (KBr, cm-'): 1800.
Reference Example 2
To a suspension of 27.3 g of 1-hydroxybenzotriazole in 300 ml of toluene, 8.6 ml of oxalyl chloride was added. The mixture was heated at reflux for 3 hours and cooled in an ice-bath. The resulting precipitate was filtered to give 21.7 g (yield 67%) of 1,1 '-dibenzotriazole oxalate, melting at 158-160"C (dec.).
IR (KBr, cm~'):1725.
Example 1
To a solution of 2.0 g of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid in 35 ml of
N,N-dimethylformamide, 0.8 ml of pyridine was added and the mixture was stirred for 10 minutes. Thereto, 6.0 g of 1,1 ,'-(carbonyldioxy)dibenzotriazole was added and the mixture was stirred at room temperature for 1 2 hours. The reaction mixture was slowly poured into 600 ml of water to produce precipitate. The reaction solution was stirred for 1 hour. The precipitate was taken through filtration and dried to give 3.2 g (yield 95%) of 2-(2-aminothiazol-4-yl)-2-syn methoxyiminoacetic acid benzotraizole ester as a reactive ester.
IR (KBr, cam~'): 1780 (ss-lactam carbonyl).
NMR (DMSO-d6, 8):4.0 (3H, s, -OCH3), 7.18 (1H, s, thiazole-proton), 7.21 (2H, s,-NH2), and 7.7-8.25 (4H, m, benzotriazole).
Example 2
The same procedure as was described in Example 1 was repeated, except that N,Ndimethylformamide was replaced with 32 ml of N,N-dimethylacetamide, to give 2.95 g (yield 93%) of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid benzotriazole ester, melting at 141-143"C.
Example 3
The same procedure as was described in Example 1 was repeated, except that N,Ndimethylformamide was replaced with 40 ml of N-methyl-2-pyrrolidone, to give 2.5 9 (yield 91%) of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid benzotriazole ester, melting at 141-143"C.
Example 4
To a suspension of 2.72 g of 7-aminocephalosporanic acid in 40 ml of water, 2.0 g of sodium hydrogen carbonate was added and the mixture was stirred for 1 5 minutes to obtain a solution. Thereto, 40 ml of acetonitrile was added and then the mixture was cooled to 1 0'C. To the cooled mixture, 3.18 g of the 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid benzotriazole ester from Example 1, 2, or 3 was added. The reaction mixture was stirred at room temperature for 6 hours until a clear solution was obtained (endpoint of the reaction).
Acetonitrile was evaporated in vacuo from the solution and the resulting aqueous layer was added with 40 ml of water and adjusted to pH 4.0 with 2N-HC1. After stirring for 1 hour, the resulting precipitate was filtered. The filtrate was saturated with sodium chloride and was treated with 80 ml of ethyl acetate. The mixture was adjusted to pH 2.5 with vigorously stirring to precipitate white crystals followed by filtering and drying to give 4.22 g (yield 93%) of 7-[[2-(2 aminothiazol-4-yl)-2-syn-methoxyimino]acetamido]cephalosporanic acid ("Ceftoaxime").
IR (KBr, cam~'): 1780 (fi-lactam carbonyl).
NMR (D20/NaHCO3, 8): 2.08 (3H, s,
3.53 (2H, d, C2-H), 4.02 (3H, s, -OCH3), 4.84 (2H, d, -S-CH2), 5-2 (1 H, d, C6-H), 5.83 (1 H, d, C7-H), and 6.97 (1 H, s, thiazole-proton).
Example 5
The same procedure as was described in Example 4 was repeated, except that acetonitrile was replaced with 40 ml of tetrahydrofuran, to give 4.1 3 g (yield 91 %) of 7-([2-(2-aminothiazol-4- yl)2-syn-methoxyimino]acetomido]cephalosporanic acid.
Example 6
A suspension of 2.72 g of 7-aminocepholosporanic acid in 40 ml of water and 20 ml of N,Ndimethylformamide was added with 2.0 g of sodium hydrogen carbonate and then stirred at room temperature for 10 minutes to obtain a solution. The solution was cooled to 10"C.
Thereto, a solution of 3.1 8 g of the 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid benzotriazole ester from Example 1, 2 or 3 in 20 ml of N,N-dimethylformamide was added over 10 minutes. The mixture was stirred at 10"C for 1 hour and at room temperature for 3 hours to complete the reation. The reaction mixture was extracted twice with 80 ml of ethyl acetate to remove the portions of N,N-dimethylformamide therefrom and then the resulting aqueous layer was saturated with sodium chloride. After cooling to 5'C, the mixture was adjusted to pH 4.0 with 2N-HCI and filtered to remove insoluble materials. The filtrate was adjusted to pH 2.5 to give white precipitate.After stirring for 2 hours, the mixture was filtered, washed with a small portion of water, and dried to yield 3.99 g (yield 88%) of 7-[2-(2-aminothiazolA-yl)-2-syn methoxyimino]acetamido]cephalosporanic acid.
Example 7
A suspension of 3.28 g of 7-amino-[3-( 1-methyl- 1 H-tetrazol-5-yl]thiomethyl]-3-cephem-4carboxylic acid in 35 ml of water was added with 2.0 g of sodium hydrogen carbonate and then stirred at room temperature for 20 minutes to obtain a solution. The solution was added with 40 ml of acetonitrile and cooled to 1 0,C. To this mixture, 3.81 g of 2-(2-aminothiazol-4-yl)-2-syn methoxyiminoacetic acid benzotriazole ester was added. The mixture was stirred for 5 hours until a clear solution was obtained (endpoint of the reaction). The solution was evaporated in vacuo to remove the portions of acetonitrile, and the resulting aqueous layer was added with additional 40 ml of water and adjusted to pH 3.8 with 2N-HC1. After stirring for 1 hour, the crystals produced were removed by filtration.The filtrate was saturated with NaCI and adjusted to pH 2.7 with 2N-HCI to precipitate crystals. The mixture was stirred at 5"C for 2 hours and filtered to afford 4.659 (yield 91%) of the desired product, 7-[[2-(2-aminothiazol-4-yl)-2-syn- methoxyi mino]acetamido]-3-[(1 1-methyl- 1 H-tetrazol-5-yl)-th iomethyl]-3-cephem-4-carboxylic acid (Cefmenoxine).
IR (KBr, cm-'): 1780 (ss-lactam carbonyl)
NMR (D2O/NaHCO3, S): 3.84 (2H, d, C2-H), 4.01 (3H, s, -OCH3), 4.05 (3H, s,
5.02 (1H, d, C6-H), 5.77 (1H, d, C7-H), and 7.01 (1H, s, thiazole-proton).
Example 8
The same procedure as was described in Example 7 as repeated, except that acetonitrile was replaced with 40 ml of ethyl acetate, to give 4.60 g (yield 90%) of 7-[[2-(2-aminothiazol-4-yl)-2- synmethoxyimino]acetamido-3-(( 1 -methyl- 1 H-tetrozol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid.
Example 9
To a suspension of 3.28 g of 7-amino-[3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl]-3-cephem-4carboxylic acid in 40 ml of water and 20 ml of N,N-dimethylformamide, 2.0 g of sodium hydrogen carbonate was added. The mixture was stirred at room temperature for 10 minutes to obtain a solution and cooled to 10"C. To the solution, another solution of 3.81 g of 2-(2 aminothiazol-4-yl)-2-syremethoxy-iminoacetic acid benzotriazole ester in 20 ml of N,N-dimethyl formamide was added over 10 minutes. The mixture was stirred at 10"C for 1 hour and at room temperature for 4 hours to complete the reaction. The reaction mixture was extracted twice with 80 ml of ethyl acetate to remove the portions of N,N-dimethylformamide and the resulting aqueous layer was saturated with sodium chloride.The solution was cooled to 5"C, adjusted to pH 4.0, and then filtered to remove insoluble materials. The filtrate was adjusted to pH 2.5 with 2N-HCI to give white precipitate. The mixture was stirred for 2 hours, filtered, washed with a small portion of water and dried to afford 4.1 9 g (yield 82%) of 7-{[2-aminothiazole-4-yl)-2-syn- methoxyiminoiacetamido-3- -methyl-l H-tetrazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acid.
Example 10
A suspension of 3.71 g of 7-amino-3-(2, 5-dihydro-2-methyl-6-hydrnxy-5-oxo-atriazin-3-yl)- thiomethyl-3-cephem-4-carboxylic acid in 40 ml of water and 30 ml of THF was treated with 2.7 g of sodium hydrogen carbonate to obtain a clear solution at pH 8.0-8.2. Thereto, 3.81 g of 2-(2-aminothiazol-4-yl)-2-symmethoxyiminoacetic acid benxotriaxole ester was added and the mixture was stirred at 5"C for 1 hour, then warmed to 25"C, and stirred for further 5 hours to complete the reaction. The reaction mixture was evaporated in vacuo to remove THF. The residue was added with 30 ml of water. The mixture was cooled to 5"C, adjusted to pH 4.2 with 2N-HCI and stirred for 30 minutes.Then, the mixture was filtered to remove insoluble materials, and the filtrate was saturated with sodium chloride and adjusted to pH 2.9-3.0 with 2N-HCI to produce precipitate. The mixture was stirred for 2 hours under a certain pH value, filter and dried to yield 4.7 g (yield 85%) of 7-((2-aminothiazol]-4-yl)-2-symethoxyimino]ace tamido]-3-[[2,5-dihydro-6-methoxy-2-methyl-5-oxo-atriazin-3-yl)thiomethyl]-3-cephem-4-car- boxylic acid (Cefatriaxone).
IR (KBr, cm-1):1780 (p-iactam carbonyl).
NMR (D2O/NaHCO3, 8):3.2 (2H, d, C2-H), 3.62 (3H, s, N-CH3), 3.95 (3H, s, -OCH3), 4.21 (2H, d, -S-CH2-), 5.17(1H, d, C6-H), 5.72 (1H, d, C7-H), and 6.95 (1H, s, thiazole-hydrogen).
Example 11
The same procedure as was described in Example 10 was repeated, except that THF was replaced with 40 ml of acetonitril, to give 4.5 g (yield 81%) of 7-[(2-(2-aminothiazol-4-yl)-2-syn methoxyimino]acetamido]-3-[2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-atriazin-3-yl)-thiomethyl] 3-cephem-4-carboxylic acid.
Example 12
To a suspension of 1.88 g of 7-amino-3-cephem-4-carboxylic acid in 20 ml of water and 20 ml of tetrahydrofuran, 2.0 g of sodium hydrogen carbonate was added to obtain a solution. The solution was cooled to 5'C. To the cooled solution, 3.1 8 g of 2-(2-aminoth iazol-4-yl)-2-syrr methoxyiminoacetic acid benzotriazole ester was added over 10 minutes. The mixture was subsequently stirred at 5"C for 1 hour and 25"C for 2 hours to complete the reaction. The reaction mixture was evaporated in vacuo to remove the tetrahydrofuran portions therefrom and the residue was treated with 15 ml of water. The mixture was cooled to 5"C and adjusted to pH 4.2 with 2N-HCI stirring for 30 minutes.The reaction mixture was filtered to remove insoluble materials, and the filtrate was saturated with sodium chloride and adjusted pH 2.8 with 2N-HCl to obtain precipitate. The mixture was stirred for 2 hours in an ice-bath under a certain pH value and filtered. Washing with saline salt-saturated water and then cooled water and drying gave 3.48 g (yield 91%) of 7-[[2-(2-aminothiazole-4-yl)methoxyimino]acetamido]-3-cephem-4-car- boxylic acid (Ceftizoxime).
IR (KBr, cm-1): 1780 (plactam carbonyl).
NMR (DMSO-d6,8):3.60 (2H, broad s), 3.84 (3H, s), 5.12(1H, d, J-5Hz), 5.84 (1H, dd,
J = 5HZ), 6.52 (1H, s), 6.76 (1 H, s), 7.26 (2H, broad s), and 9.65 (1H, d, J = 8Hz).
Example 13
The same procedure as was described in Example 12 was repeated, except that tetrahydrofuran was replaced with 20 ml of acetone, to give 3.4 g (yield 90%) of 7-[((2-amino-thiazol-4- yl)methoxyiminojacetamidoj-3-cephem-4-carboxylic acid.
Example 14
The same procedure as was described in Example 6 was repeated, except that tetrahydrofuran used in Example 12 was replaced with N,N-dimethylformamide, to give 3.26 g (yield 86%) of 7-[[(2-aminothiazol-4-yl)methoxyimino]acetamido]-3-cephem-4-carboxylic acid.
Claims (11)
1. A process for the preparation of cephem derivative having the formula:
wherein R1 represents a hydrogen or alkali metal atom, and R2 represents a hydrogen atom, acetoxymethyl radical or a 5- or 6-membered ring heterocyclic radical, which process comprises:
esterifying an organic acid having the formula:
with a compound having the formula:
wherein R3 represents a benzotriazolyl, pyridyl, succinimidyl or phthalimidyl radical, and n is 1 or 2, in the presence of an organic amine to give a corresponding reactive ester thereof having the formula:
wherein R3 has the same meaning as defined above; and reacting the corresponding reactive ester of formula (V) with a compound having the formula:
wherein R' and R2 each have the meaning defined above, in the presence of an organic solvent.
2. A process according to Claim 1, wherein R2 represents a 5- or 6-membered ring heterocyclic radical containing one, two or more nitrogen atoms.
3. A process according to Claim 1 or 2 wherein R2 represents a 5-or 6-membered ring heterocyclic radical substituted by a lower alkyl group.
4. A process according to Claim 1, 2 or 3, wherein the esterification is carried out at room temperature for a period of time in the range of from 3 to 6 hours.
5. A process according to any one of the preceding claims, wherein the esterification is carried out in the presence of a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone.
6. A process according to any one of the preceding claims wherein the said organic solvent is selected from aceton itrile, tetrahydrofuran, ethyl acetate, acetone, N, N-dimethylformamide,
N,N-dimethylacetamide and dioxan.
7. A process according to any one of the preceding claims wherein the acylation is carried out in the presence of a base selected from sodium hydrogen carbonate, potassium hydrogen carbonate and triethylamine.
8. A process according to any one of the preceding claims, wherein the said organic amine is selected from pyridine, triethyl amine, N,N-dimethylaniline, N, N-dimethylaminopyridine and isoproylamine.
9. A process for the preparation of cephem derivative, substantially as hereinbefore described in any one of Examples 1 to 3 in combination with any one of Examples 4 to 14.
10. A cephem derivative whenever obtained by a process in accordance with any one of the preceding claims.
11. Any novel feature or combination of features described herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019840002267A KR850001206B1 (en) | 1984-04-27 | 1984-04-27 | Process for preparing cephem derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8423207D0 GB8423207D0 (en) | 1984-10-17 |
| GB2158432A true GB2158432A (en) | 1985-11-13 |
| GB2158432B GB2158432B (en) | 1987-10-28 |
Family
ID=19233668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08423207A Expired GB2158432B (en) | 1984-04-27 | 1984-09-14 | Process for the preparation of cephem derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS60233090A (en) |
| KR (1) | KR850001206B1 (en) |
| CH (1) | CH667458A5 (en) |
| ES (1) | ES540544A0 (en) |
| GB (1) | GB2158432B (en) |
| IT (1) | IT1185509B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8816002B2 (en) | 1999-12-22 | 2014-08-26 | Nektar Therapeutics | Method involving 1-benzotriazolyl carbonate esters of poly(ethylene glycol) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2051788A (en) * | 1979-05-23 | 1981-01-21 | Rhone Poulenc Ind | 3 - thiovinyl - cephalosporins their preparation and compositions containing them |
| GB2081256A (en) * | 1980-01-17 | 1982-02-17 | Rhone Poulenc Ind | Heterocyclic thiols and processes for their preparation |
| GB2084144A (en) * | 1980-09-17 | 1982-04-07 | Lilly Co Eli | Bis-tetrazoylmethyl substituted cephalosporin antibiotics |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS591490A (en) * | 1982-06-29 | 1984-01-06 | Dai Ichi Seiyaku Co Ltd | 3-cephem-4-carboxylic acid derivative |
-
1984
- 1984-04-27 KR KR1019840002267A patent/KR850001206B1/en not_active IP Right Cessation
- 1984-09-14 GB GB08423207A patent/GB2158432B/en not_active Expired
- 1984-12-25 JP JP59272168A patent/JPS60233090A/en active Pending
-
1985
- 1985-02-18 IT IT19547/85A patent/IT1185509B/en active
- 1985-02-20 ES ES540544A patent/ES540544A0/en active Granted
- 1985-04-16 CH CH1615/85A patent/CH667458A5/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2051788A (en) * | 1979-05-23 | 1981-01-21 | Rhone Poulenc Ind | 3 - thiovinyl - cephalosporins their preparation and compositions containing them |
| GB2081256A (en) * | 1980-01-17 | 1982-02-17 | Rhone Poulenc Ind | Heterocyclic thiols and processes for their preparation |
| GB2084144A (en) * | 1980-09-17 | 1982-04-07 | Lilly Co Eli | Bis-tetrazoylmethyl substituted cephalosporin antibiotics |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8816002B2 (en) | 1999-12-22 | 2014-08-26 | Nektar Therapeutics | Method involving 1-benzotriazolyl carbonate esters of poly(ethylene glycol) |
| US9346917B2 (en) | 1999-12-22 | 2016-05-24 | Nektar Therapeutics | Method involving 1-benzotriazolyl carbonate esters of poly(ethylene glycol) |
| US9839695B2 (en) | 1999-12-22 | 2017-12-12 | Nektar Therapeutics | Polymer-active agent conjugate |
| US10456476B2 (en) | 1999-12-22 | 2019-10-29 | Nektar Therapeutics | Method involving 1-benzotriazolyl carbonate esters of poly(ethylene glycol) |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1185509B (en) | 1987-11-12 |
| KR850001206B1 (en) | 1985-08-20 |
| GB8423207D0 (en) | 1984-10-17 |
| IT8519547A0 (en) | 1985-02-18 |
| ES8602018A1 (en) | 1985-11-16 |
| CH667458A5 (en) | 1988-10-14 |
| JPS60233090A (en) | 1985-11-19 |
| ES540544A0 (en) | 1985-11-16 |
| GB2158432B (en) | 1987-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20030078882A (en) | Novel thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds | |
| HU191683B (en) | Process for production of cefem compounds | |
| JPH02311483A (en) | Preparation of ceftriaxone | |
| US6384215B1 (en) | Preparation of new intermediates and their use in manufacturing of cephalosporin compounds | |
| EP0175814B1 (en) | Process for preparing cephem derivatives | |
| US5567813A (en) | Process for preparing cephalosporin compounds from reactive organic acid derivatives | |
| GB2158432A (en) | Process for the preparation of cephem derivatives | |
| EP1268488B1 (en) | A process for preparing cephalosporin derivatives using new thiazole compound | |
| US4297279A (en) | Imidazoledicarboxylic acid derivative | |
| WO2003059908A1 (en) | Novel thioester derivatives and process for preparation of cephalosporin | |
| JPH07108896B2 (en) | Amino-beta-lactamate and method for producing the same | |
| US5739346A (en) | Dimethyl formiminium chloride chlorosulphate derivatives useful as intermediates for producing cephalosporins | |
| JPS62103092A (en) | Beta-lactam derivative | |
| HU200184B (en) | Process for producing 3-(alkanoyloxymethyl)-3-cefem-4-carboxilic acid derivatie | |
| KR890001489B1 (en) | Process for the preparation of 1-oxa-1-dethia-cephalosporin derivatives and new intermediates compounds therefor | |
| JP2549494B2 (en) | Pyridone isoxazole cephem compound and method for producing the same | |
| US4091214A (en) | De-esterification process for cephalosporins | |
| KR870001333B1 (en) | Process for preparing cephem derivatives | |
| CA1161429A (en) | 2-(2-aminothiazol-4-yl)-n-(imidazolidin-2-on-1-yl)-2- imino-acetylaminocephalosporanic acids in pure syn- form, a process for their production and syn-acid used in such a process | |
| US4304909A (en) | Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof | |
| US5416081A (en) | Cephalosporin compounds | |
| KR0129567B1 (en) | The process for preparation of cephalosporins | |
| KR870001984B1 (en) | Process for preparing cephem derivatives | |
| JPS61186391A (en) | Manufacture of cephem derivative | |
| KR100213442B1 (en) | Novel process for preparing cephem derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920914 |