GB1566515A - Intermediate products for the preparation of antibiotics from cephalosporin c - Google Patents
Intermediate products for the preparation of antibiotics from cephalosporin c Download PDFInfo
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- GB1566515A GB1566515A GB17409/77A GB1740977A GB1566515A GB 1566515 A GB1566515 A GB 1566515A GB 17409/77 A GB17409/77 A GB 17409/77A GB 1740977 A GB1740977 A GB 1740977A GB 1566515 A GB1566515 A GB 1566515A
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- cephalosporin
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- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 title claims description 26
- 239000013067 intermediate product Substances 0.000 title claims description 14
- 239000003242 anti bacterial agent Substances 0.000 title description 4
- 229940088710 antibiotic agent Drugs 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 3
- 239000000243 solution Substances 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 23
- HOKIDJSKDBPKTQ-GLXFQSAKSA-M cephalosporin C(1-) Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H]([NH3+])C([O-])=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-M 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- -1 5 - benzoylamino - adipamido Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 238000000855 fermentation Methods 0.000 claims description 7
- 230000004151 fermentation Effects 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002329 infrared spectrum Methods 0.000 claims description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- CNTJTTQDXPPSOX-UHFFFAOYSA-I O.O.O.O.O.O.O.O.O.O.O.O.[O-]P([O-])(=O)OP(=O)([O-])OP(=O)([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+] Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[O-]P([O-])(=O)OP(=O)([O-])OP(=O)([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+] CNTJTTQDXPPSOX-UHFFFAOYSA-I 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 150000002537 isoquinolines Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000003248 quinolines Chemical class 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- RQSCFNPNNLWQBJ-UHFFFAOYSA-N 2-methyl-1,3,4-thiadiazole Chemical compound CC1=NN=CS1 RQSCFNPNNLWQBJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- LLCOQBODWBFTDD-UHFFFAOYSA-N 1h-triazol-1-ium-4-thiolate Chemical compound SC1=CNN=N1 LLCOQBODWBFTDD-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- GRWAIJBHBCCLGS-UHFFFAOYSA-N 2-(tetrazol-1-yl)acetic acid Chemical compound OC(=O)CN1C=NN=N1 GRWAIJBHBCCLGS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000005239 aroylamino group Chemical group 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
(54) INTERMEDIATE PRODUCTS FOR THE
PREPARATION OF ANTIBIOTICS FROM CEPHALOSPORIN C
(72) We, PROTER S.P.A., an Italian Joint Stock Company of Via Lambro 38, Opera, Milan, Italy, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to intermediate products for the preparation of antibiotics from Cephalosporin C. The invention relates also to a process for obtaining said intermediate products from an aqueous Cephalosporin C containing liquor called fermentation broth or resin eluate.
The Cephalosporin C having the following formula
is the main product of fermentation processes completed in aqueous solutions in which many impurities are also contained.
In order to obtain from said solutions the intermediate products for preparing the corresponding antibiotics, the Cephalosporin C is to be separated from the aqueous fermentation solutions in the maximum purity grade. In such a separation process several difficult operations are involved which are time consuming and of low yield. Equally difficult and low yield reactions are involved for obtaining the desired intermediate products from the separated Cephalosporin C and particularly the requested steps for obtaining said intermediates in the desired purity grade.
These are technical and economical serious drawbacks.
In order to overcome said drawbacks and according to this invention there are provided new intermediate products obtained from aqueous Cephalosporin C fermentation liquors which have the following formula
in which:
Ar is phenyl or substituted phenyl
R is a heterocyclic radical with a 5 or 6 membered ring and having 1 to 4 heteroatoms consisting of S, N or O
Q is quinoline, isoquinoline or dicyclohexylamine.
According to this invention, there is provided a process for obtaining said intermediate products from an aqueous Cephalosporin C containing solution, such a process comprising the following steps:
a) an aroylating reaction of said Cephalosporin C by adding to said aqueous solution a reactive derivative of an acid of the formula Ar--COOH in which Ar is phenyl or substituted phenyl, said aroylating reaction occurring at a temperature from OOC to 300C, at a pH between 7 and 10;
b) a substituting reaction of the N-aroyl Cephalosporin C thus formed by a compound having the formula R-SH in which:
R is a heterocyclic radical with a 5 or 6 membered ring having 1 to 4 heteroatoms consisting of S, N or O, said substituted reaction occurring at a temperature from 500C to 100 C, at a pH between 5 and 8 whereby 3-substituted N-aroyl-Cephalosporin C is obtained
c) a salifying reaction of said 3-substituted N-aroyl-Cepalosporin C by adding quinoline, isoquinoline or dicyclohexy]amine to the aroylated aqueous solution;
d) crystallisation of the quinoline, isoquinoline or dicyclohexylamine salt of the 3-substituted N-aroyl-Cephalosporin C thus obtained at a temperature from 0 C to 309C, at a pH between 2.5 and 4;
e) recovering, solvent washing and drying said crystalline product having formula
in which Ar, R and Q are the same as above cited.
The preferred reactive derivatives of an acid for said aroylating reaction are the chloride of the acid (Ar-COCI) or the anhydride having the formula
or the mixed anhydride having the formula
in which Ar is as above indicated and R, is C1-C5 alkylgroup.
Since, the pH during the aroylation reaction tends to decrease, it is maintained at the indicated value by adding a base or a suitable buffer such as sodium phosphate.
The quantity of the aroylating reagent to be used depends on the fermentation broth or resin eluate composition.
When a broth partially purified by means of ionic resins exchange is used, from 1.5 to 4 moles of aroylating reagent for each mole of Cephalosporin C are needed.
When a filtered broth is used, about 2 to 5 moles of the aroylating reagent for each mole of Cephalosporin C are used.
In the substituting reaction the preferred R-SH compound is selected from:
2 - methyl - 5 - mercapto - 1,3,4 - thiadiazole; 1H - 5 - mercapto - 1,2,3 triazole; 1 - methyl - 5 - mercapto - 1,2,3,4 - tetrazole.
The most preferred R-SH compound is 2 - methyl - 5 - mercapto - 1,3,4 thiadiazole.
At the end of the aroylating reaction, 2 - methyl - 5 - mercapto - 1,3,4 thiadiazole is added in a quantity equivalent to 1.2-1.5 moles of the thiol for each mole of N-aroyl Cephalosporin C present in the aqueous solution. The pH is adjusted at a value between 5 and 8, preferably between 6.5 and 6.8; successively the solution is warmed at a temperature from 500C to 1000C, preferably between 80"C and 85"C, for a time from 15 minutes to 6 hours, preferably between 30 minutes and 45 minutes.
After cooling, quinoline, or isoquinoline in a quantity of from about 2 to j moles for each mole of 3-substituted N-aroyl-Cephalosporin C present in the solution are added.
The pH is adjusted between 2 and 3.5, preferably between 2.5 and 3 with an acid, e.g. sulphuric acid, hydrochloric acid, nitric acid or phosphoric acid.
The solution is stirred for about one hour at a temperature from OOC to 300 C, preferably between 10"C and 200 C, in order to obtain the complete precipitation in crystalline form of the quinoline salt or of isoquinoline salt of the 7 - (5 aroylamino - adipamido)- 3- (2 - methyl - 1,3,4 - thiadiazol- 5 yl)thiomethyl - 3 - cephem - 4 - carboxylic acid, having the following structural formula
The crystalline salt is recovered and washed with water to remove impurities, most of which are water soluble, and successively with ethyl acetate to remove organic soluble impurities. The cake can be dried in a fluid bed dryer at about 40"C for 2 to 4 hours.
The invention is further illustrated by the following detailed examples, which are not intended to be limiting.
EXAMPLE 1
An aqueous solution containing 430.8 g (1.037 moles) of Cephalosporin C is treated with 600 g of sodium triphosphate dodecahydrate.
This solution is chilled to 100C and aroylated with 333.5 ml (2.87 moles) of benzoyl chloride solution in 1040 ml of ethyl acetate.
The pH of the solution is maintained between 7 and 7.5 by adding sodium phosphate buffer; the temperature is maintained at 100C to 150C.
At the end of the reaction, the solution is stirred for 90 minutes.
164 g (1.24 moles) of 2 - methyl - 5 - mercapto - 1,3,4 - thiadiazole are added and the pH is adjusted to 6.8-7.
The solution is warmed and stirred for 45 minutes at 800--830C.
The solution is cooled in an ice bath and 110 ml of quinoline are added; successively the pH is adjusted to 3.3 with 105 ml of concentrated HCI.
The acidified solution is stirred for 2 hours at room temperature to ensure completion of the crystallisation, and refrigerated overnight (5"C).
The crystalline product is filtered, washed with 500 ml of cold water, 800 ml of ethyl acetate and dried in a fluid bed dryer for 2 hours at about 40"C.
Weight: 424 g (92 percent purity) of the quinoline salt of the 7 - (5 benzoylamino - adipamido)- 3 - (2 - methyl - 1,3,4 - thiadiazol - 5 yl)thiomethyl - 3 - cephem - 4 - carboxylic acid, resulting in a yield of 52 percent.
The NMR and IR spectra were consistent with the desired structure. M.P.
108--110"C dec.
Analysis calculated for C24H25N5O7S3.C9H7N. 1 .5H2O (percent):
C 53.00; H 4.71; N 11.23; S 12.86.
Found (percent):
C 53.25; H 4.68; N 11.21: S 12.90.
Quinoline (GLC): calculated 17.27%; found 17.24%.
Water (KF): calculated 3.61 ,'; found 3.66%
To the solution of 115 g (0.146 moles) of the quinoline salt of the 7 - (5 benzoylamino - adipamido) - 3 - (2 - methyl - 1,3,4 - thiadiazol - 5 yl)thiomethyl - 3 - cephem - 4 - carboxylic acid (920to purity) in 750 ml of dichloromethane are added 131 ml of N,N - dimethyl - aniline at 250C to 270C, and successively 153 ml of trimethylchlorosilane.
The solution is heated at gentle reflux for one hour. Upon cooling at --50"C, 46 g of PCl5 are added and the slurry is stirred for one hour and a half at -400C to -50"C; the solution is maintained at -600C during 10 minutes and 63 ml of methanol are added. During the addition of methanol the temperature rose to -500C. After stirring for one hour at --50qC to 600 C, the solution is warmed to 15"C, evaporated to a yellow syrup. The residue is taken up with 875 ml of dichloromethane; next with cooling, 175 ml of triethylamine is added.
The solution is coupled at -300C with a mixed anhydride solution, obtained by reacting 29.1 g of 1H-tetrazole-l-acetic acid, 32 ml of triethylamine and 28.2 g of pivaloyl chloride in tetrahydrofurane.
After stirring for 30 minutes at -300C to 350C and successively for 2 hours at -20"C, the solution is allowed to attain room temperature during a further one hour's stirring.
The reaction mixture is poured into 300 ml of water and the two phases are allowed to separate.
The organic phase is extracted with 2x 150 ml portions of water.
The combined aqueous extracts are acidified to pH 3.5 with 20 percent HCI.
After addition of 200 ml of isopropyl alcohol, the aqueous solution is acidifed to pH 1.8 and refrigerated overnight (5"C).
The crystalline product is filtered, washed with 100 ml of cold water, 150 ml of ethyl acetate and dried.
Weight: 42 g of cefazolin. M.P. l980-2000C dec.
The NMR and IR spectra were consistent with the desired structure.
EXAMPLE 2
An aqueous solution containing 450 g (1.065 moles) of Cephalosporin C was treated according to Ex. 1 in order to obtain a solution of N - benzoyl cephalosporin C at 100--150C. The pH of said solution was maintained in the range of 7-7.5 by adding a buffer, such as sodium phosphate.
136 g (1.35 moles) of 5 mercapto - 1H - 1,2,3 - triazole were added to the solution and the pH was adjusted to 6.56.8.
The temperature of the solution was raised to 820C and at this temperature the solution was stirred for 30 minutes.
The solution is cooled in an ice bath and 110 ml of isoquinoline are added, successively the pH was adjusted to 3.0 with concentrated H2SO4.
After stirring (2 hours) at room temperature and cooling (50C) overnight, from this solution a crystalline product was obtained and their NMR and IR spectra were consistent with the desired structure:
isoquinoline salt of 7(5 - benzoylamino - adipamido) - 3 - (1H - 1,2,3 - triazol 5 - yl) - thiomethyl - 3 - cephem - 4 - carboxylic acid.
EXAMPLE 3
An aqueous solution containing 129 g (0.311 moles) of Cephalosporin C is treated with 180 g of sodium triphosphate dodecahydrate.
This solution is chilled to 100C and aroylated with 170 g (0.86 moles) of the mixed anhydride of 4 - chlor - benzoic acid and acetic acid in 310 ml of ethyl acetate.
The pH of the solution is maintained at 7.5-8 by adding sodium phosphate buffer and the temperature at 10 to 150C.
The solution is then stirred for 90 minutes and 64.8 g (0.372 moles) of the sodium salt of the 1 - methyl - 5 - mercapto - 1,2,3,4-tetrazole is added.
The solution is warmed and stirred for 45 minutes at 800--850C.
The temperature of the mixture was lowered to 100C and 85 ml of dicyclohexylamine are added; successively the pH of the solution was adjusted to 3.5 with 10 N phosphoric acid.
After stirring (3 hours) at room temperature and cooling (5"C) overnight, from this solution a crystalline product was obtained and their IR and NMR spectra were consistent with the desired structure:
bis - dicyclohexylamine salt of 7 - (5 - (4 - chlorbenzoylamino)adipamido) - 3 (1 - methyl - 1,2,3,4, - tetrazol - 5 - yl) - thiomethyl - 3 - cephem - 4 carboxylic acid.
WHAT WE CLAIM IS:
1. Intermediate product obtained from aqueous cephalosporin C fermentation solutions which have the following formula
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (9)
1. Intermediate product obtained from aqueous cephalosporin C fermentation solutions which have the following formula
in which:
Ar is phenyl or substituted phenyl
R is a heterocyclic radical with a 5 or 6 membered ring and having 1 to 4 heteroatoms consisting of S, N or O
Q is quinoline, isoquinoline or dicyclohexylamine.
2. Intermediate product of Claim 1, in which R is selected from 2 - methyl
1,3,4 - thiadiazol - 5 - yl; 1H - 1,2,3 - triazol - 5 - yl; 1 - methyl - 1,2,3,4 tetrazol - 5 - yl.
3. Intermediate product of Claim 1, in which Ar is phenyl and R is 2 - methyl 1,3,4 - thiadiazol - 5 - yl.
4. Intermediate product of Claim 1 in which Ar is phenyl and R is I H - 1,2,3 triazol - 5 - yl.
5. Process for obtaining the intermediate product of Claim 1 from an aqueous
Cephalosporin C containing solution, comprising the following steps:
a) an aroylating reaction of said Cephalosporin C by adding to said aqueous solution a reactive derivative of an acid of the formula Ar-COOH in which Ar is phenyl or substituted phenyl said aroylating reaction occurring at a temperature from OOC to 300C, at a pH between 7 and 10;
b) a substituting reaction of the N-aroyl-Cephalosporin C thus obtained by means of a compound having the formula R-SH in which R is a heterocyclic radical with a 5 or 6 membered ring and having 1 to 4 heteroatoms consisting of S,
N or O, said substituting reaction occurring at a temperature from 500C to 1000C and at a pH between 5 and 8, whereby 3 - substituted - N - aroyl - Cephalosporin C is obtained
c) a salifying reaction of said 3 - substituted - N - aroyl - Cephalsporin C by adding quinoline, isoquinoline or dicyclohexylamine to the aroylated aqueous solution;
d) crystallisation of the quinoline, isoquinoline or dicyclohexylamine salt of the 3 - substituted - N - aroyl - Cephalosporin C thus obtained at a temperature from 0 C to 300C and at a pH between 2.5--4 and recovering of a crystalline compound having the following formula
in which Ar, R and Q are as above cited.
6. Process of Claim 5, in which the said substituting reaction RSH compound used is selected from
2 - methyl - 5 - mercapto - 1,3,4 - thiadiazole; 1H - 5 - mercapto - 1,2,3
triazole and I - methyl - 5 - mercapto - 1,2.3.4 - tetrazole.
7. Process of Claim 5 in which the said aroylating reaction the reactive derivative is benzoylchloride and in the said substituting reaction 2 - methyl - 5 mercapto - 1,3,4 - thiadiazole is used.
8. Process of Claim 5 in which in the aroylating reaction the said reactive derivative is benzoylchloride and in the said substituting reaction 1H - 5 mercapto - 1,2,3 - triazole is used.
9. Process of Claim 5 in which in the aroylating reaction the said derivative is benzoylchloride and in the said substituting reaction 1 - methyl - 5 - mercapto 1,2,3,4 - tetrazole is used.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB17409/77A GB1566515A (en) | 1977-04-26 | 1977-04-26 | Intermediate products for the preparation of antibiotics from cephalosporin c |
| JP8305977A JPS53132591A (en) | 1977-04-26 | 1977-07-13 | Intermediate of antibiotics production from cephalospoline c |
| IT7822042A IT1235673B (en) | 1977-04-26 | 1978-04-06 | INTERMEDIATE PRODUCT FOR THE PREPARATION OF ANTIBIOTICS FROM CEPHALOSPORIN C |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB17409/77A GB1566515A (en) | 1977-04-26 | 1977-04-26 | Intermediate products for the preparation of antibiotics from cephalosporin c |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1566515A true GB1566515A (en) | 1980-04-30 |
Family
ID=10094694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB17409/77A Expired GB1566515A (en) | 1977-04-26 | 1977-04-26 | Intermediate products for the preparation of antibiotics from cephalosporin c |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS53132591A (en) |
| GB (1) | GB1566515A (en) |
| IT (1) | IT1235673B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6642020B2 (en) | 2001-04-19 | 2003-11-04 | Bioferma Murcia S.A. | Process for preparing cephalosporin derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5422998B2 (en) * | 1972-04-21 | 1979-08-10 | ||
| JPS5246237B2 (en) * | 1971-12-04 | 1977-11-22 | ||
| JPS5525194B2 (en) * | 1972-06-27 | 1980-07-04 |
-
1977
- 1977-04-26 GB GB17409/77A patent/GB1566515A/en not_active Expired
- 1977-07-13 JP JP8305977A patent/JPS53132591A/en active Pending
-
1978
- 1978-04-06 IT IT7822042A patent/IT1235673B/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6642020B2 (en) | 2001-04-19 | 2003-11-04 | Bioferma Murcia S.A. | Process for preparing cephalosporin derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| IT7822042A0 (en) | 1978-04-06 |
| IT1235673B (en) | 1992-09-21 |
| JPS53132591A (en) | 1978-11-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |