NO822870L - PROCESS FOR THE PRODUCTION OF PENICILLIN AND CEPHALOSPORIN DERIVATIVES - Google Patents
PROCESS FOR THE PRODUCTION OF PENICILLIN AND CEPHALOSPORIN DERIVATIVESInfo
- Publication number
- NO822870L NO822870L NO822870A NO822870A NO822870L NO 822870 L NO822870 L NO 822870L NO 822870 A NO822870 A NO 822870A NO 822870 A NO822870 A NO 822870A NO 822870 L NO822870 L NO 822870L
- Authority
- NO
- Norway
- Prior art keywords
- compound
- general formula
- following general
- dioxo
- phenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 229940124587 cephalosporin Drugs 0.000 title claims description 9
- 229940049954 penicillin Drugs 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 229930186147 Cephalosporin Chemical class 0.000 title claims description 6
- 229930182555 Penicillin Natural products 0.000 title claims description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical class N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 title claims description 6
- 150000001780 cephalosporins Chemical class 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 10
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 8
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000543 intermediate Substances 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 239000007806 chemical reaction intermediate Substances 0.000 claims description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 125000005208 trialkylammonium group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000004471 Glycine Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000002906 microbiologic effect Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000005051 trimethylchlorosilane Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical class C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- ZBEKOEYCWKIMGU-UHFFFAOYSA-N 1-ethylpiperazine-2,3-dione Chemical compound CCN1CCNC(=O)C1=O ZBEKOEYCWKIMGU-UHFFFAOYSA-N 0.000 description 2
- QQKAZZAULUMMKR-UHFFFAOYSA-N 2-n-hydroxybenzene-1,2-dicarboxamide Chemical class NC(=O)C1=CC=CC=C1C(=O)NO QQKAZZAULUMMKR-UHFFFAOYSA-N 0.000 description 2
- AGEUQNZXCIVHPB-UHFFFAOYSA-N 4-(hydroxyamino)-4-oxobutanoic acid Chemical class ONC(=O)CCC(O)=O AGEUQNZXCIVHPB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000001632 acidimetric titration Methods 0.000 description 2
- -1 alkali metal salt Chemical class 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical class C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Chemical class O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical class NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- KIYRSYYOVDHSPG-UHFFFAOYSA-N 2-amino-2-phenylacetamide Chemical compound NC(=O)C(N)C1=CC=CC=C1 KIYRSYYOVDHSPG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical compound C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 229960003311 ampicillin trihydrate Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- IGNBIZWNICXNAG-UHFFFAOYSA-N n'-hydroxypentanediamide Chemical compound NC(=O)CCCC(=O)NO IGNBIZWNICXNAG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- XQXPVVBIMDBYFF-UHFFFAOYSA-N para-hydroxyphenylacetic acid Natural products OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 1
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 description 1
- AKGSNUOZGBDODP-UHFFFAOYSA-N piperazine-1-carbonyl chloride Chemical compound ClC(=O)N1CCNCC1 AKGSNUOZGBDODP-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- LAYPMCGIWDGYKX-UHFFFAOYSA-N trichloromethyl hydrogen carbonate Chemical compound OC(=O)OC(Cl)(Cl)Cl LAYPMCGIWDGYKX-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
Den foreliggende oppfinnelsen vedrører en prosess for framstilling av penicillin og cephalosporinderivater repre-sentert ved følgende generelle formel (I) The present invention relates to a process for the production of penicillin and cephalosporin derivatives represented by the following general formula (I)
Antibiotika med formel (I) er en kjent forbindelse fra belgisk patent No. 828.629, fransk patent nr. 7.514.159, Antibiotics of formula (I) are a known compound from Belgian patent No. 828,629, French Patent No. 7,514,159,
• S os• S os
japansk patent nr.N<oV52-106,883 og er rapportert å ha et bredt antibakteriologisk spekter mot Gram-positive og Gram-negative bakterier. Japanese patent no. N<oV52-106,883 and is reported to have a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria.
Framstillingsprosess ifølge disse kjente patentene er som følger: I. organisk løsningsmiddel reagerer l-alkyl-2,3-diokso-piperazin med følgende generelle formel (II) med fosgen med følgende generelle formel (Illa) eller triklormetyl-klor-karbonat med følgende generelle formel (Illb) og danner 4-alkyl-2,3-diokso-pvperazin^karbonyl-klorid med følgende generelle, formel (IV) via forskjellige kompliserte rensingstrinn. Deretter reagerer denne forbindelsen med formel (IV) med ampicillin, amoksicillin eller cephalosporinderivater med følgende generelle formel (V) ved lav temperatur og danner forbindelsen med den ovenfor viste formelen (I) Production process according to these known patents is as follows: I. organic solvent reacts l-alkyl-2,3-dioxo-piperazine of the following general formula (II) with phosgene of the following general formula (Illa) or trichloromethyl-chloro-carbonate of the following general formula (IIIb) and forms 4-alkyl-2,3-dioxo-pvperazine^carbonyl chloride of the following general formula (IV) via various complicated purification steps. Then this compound of formula (IV) reacts with ampicillin, amoxicillin or cephalosporin derivatives of the following general formula (V) at low temperature to form the compound of formula (I) shown above
hvor R^, R, M og Z representerer det samme som ovenfor. where R^, R, M and Z represent the same as above.
En annen kjent prosess er som følger: Another known process is as follows:
4-alkyl-2,3-diokso pipérazinokarbonyl klorid med den generelle formelen (IV) ovenfor reagerer med alkalimetallsalt av D-(-)-fenyl (eller para-hydroksy fenyl) glycin med følg-ende generelle formel (VI) og danner D-(-)-a-(4-alkyl-2,3-diokso-piperazinø-karbonyl)-fenyl (eller para-hydroksy-fenyl) glycin med følgende generelle formel (VII). Denne forbindelsen med formel (VII) blir separert og reagerer med etyl-klor-karbonat og danner et syreanhydrid med følgende gene-.reile formel (VIII). Denne forbindelse med formel (VIII) blir uten separa-sjon ac>~ylert ved lav temperatur med 6-amino-penicillin-syre-ester eller 7-amino-cephalosporinderivat med følgende generelle formel (IX) og danner forbindelse med den ovenfor nevnte generelle formelen (I)J 4-alkyl-2,3-dioxo piperazinocarbonyl chloride with the general formula (IV) above reacts with alkali metal salt of D-(-)-phenyl (or para-hydroxy phenyl) glycine with the following general formula (VI) and forms D -(-)-α-(4-alkyl-2,3-dioxo-piperazine-carbonyl)-phenyl (or para-hydroxy-phenyl) glycine of the following general formula (VII). This compound of formula (VII) is separated and reacts with ethyl chlorocarbonate to form an acid anhydride of the following general formula (VIII). This compound of formula (VIII) is acylated without separation at low temperature with 6-amino-penicillin acid ester or 7-amino-cephalosporin derivative of the following general formula (IX) and forms a compound with the above said general formula (I)J
hvor Rj,, R, M og Z representerer det samme som ovenfor. where Rj, R, M and Z represent the same as above.
I de ovenfor nevnte framstillingsmetodene er prosedyr-en for dannelsen av 4-alkyl-2,3-diokso-piperazinøkarbonyl-klorid med den generelle formelen (IV) betraktelig kompli-sert på grunn av de mange rensingstrinnene og resulterer i høye kostnader. In the above-mentioned production methods, the procedure for the formation of 4-alkyl-2,3-dioxo-piperazinecarbonyl chloride of the general formula (IV) is considerably complicated due to the many purification steps and results in high costs.
For å unngå ulempene nevnt ovenfor, blir i denne oppfinnelsen, istedenfor å danne forbindelsen med formel (IV) karbonylgruppen i ampillicin, amoksycillin eller cephalosporinderivatet beskyttet, og reagerer med fosgen eller triklor-metylklorkarbonat og danner forbindelsen som er vist ved de følgende generelle formlene (X), (XI) eller (XII). Denne forbindelsen med formel (X), (XI) eller (XII) ifølge oppfinnelsen som reagerer med 4-alkyl-2,3-diokso piperazin er aktivert med trimetylklorsilan med følgende generelle formel (XIII). In order to avoid the disadvantages mentioned above, in this invention, instead of forming the compound of formula (IV), the carbonyl group of ampillicin, amoxicillin or the cephalosporin derivative is protected, and reacts with phosgene or trichloromethylchlorocarbonate to form the compound shown by the following general formulas ( X), (XI) or (XII). This compound of formula (X), (XI) or (XII) according to the invention which reacts with 4-alkyl-2,3-dioxo piperazine is activated with trimethylchlorosilane of the following general formula (XIII).
Ved hjelp av framstillingsmetoden som hittil er be-skrevet, dannes enkelt forbindelsen med den generelle formelen (I) ovenfor. By means of the production method described so far, the compound with the general formula (I) above is easily formed.
I framgangsmåten er forbindelsen med formel (X), (XI) eller (XII) som mellomprodukt i reaksjonen den nye forbindelsen som enkelt danner sluttproduktet med den generelle formelen In the method, the compound with formula (X), (XI) or (XII) as an intermediate in the reaction is the new compound that easily forms the final product with the general formula
(I). (IN).
hvor R, R^, M og Z representerer det samme som ovenfor. where R, R^, M and Z represent the same as above.
For å lage D-(-)-a-(4-alkyl-2,3-diokso-piperazinøkarbonyl)-fenyl (eller parahydroksy fenyl) glycin med den generelle formelen (VII) lar en istedenfor å danne l-alkyl-2,3-diokso-piperaziho-karbonylklorid med den ovennevnte formelen (IV) ved å la l-alkyl-2,3-diokso-piperazin med den generelle formelen (II) oven med fosgen eller triklormetyl-karbonat, reagerer D-(-)-fenyl (eller parahydroksy fenyl) glycin med den ovenfor viste generelle formelen (VI) direkte med fosgen eller triklormetylklorkarbonat og danner reaksjons-mellomproduktet med den følgende generelle formelen (XIV) eller (XV), og dette mellomproduktet reagerer med forbindelsen som er aktivert ved reaksjonen av l-alkyl-2,3-diokso piperazin med den ovenfor viste generelle formelen (XIII) med trimetylklorsilan og danner enkelt forbindelsen med den generelle formelen (VII) ovenfor, hvor R^og M representerer det samme som ovenfor.. To make D-(-)-α-(4-alkyl-2,3-dioxo-piperazinecarbonyl)-phenyl (or parahydroxy phenyl) glycine of the general formula (VII) instead of forming 1-alkyl-2, one allows 3-dioxo-piperaziho-carbonyl chloride of the above formula (IV) by adding 1-alkyl-2,3-dioxo-piperazine of the general formula (II) above with phosgene or trichloromethyl carbonate, reacts D-(-)- phenyl (or parahydroxy phenyl) glycine of the general formula (VI) shown above directly with phosgene or trichloromethyl chlorocarbonate to form the reaction intermediate of the following general formula (XIV) or (XV), and this intermediate reacts with the compound activated by the reaction of 1-alkyl-2,3-dioxo piperazine of the general formula (XIII) shown above with trimethylchlorosilane and simply forms the compound of the general formula (VII) above, where R^ and M represent the same as above..
Ved prosessen for dannelse av penicillin eller cephalo-acylerings- In the process for the formation of penicillin or cephalo-acylation-
spormderivater er ■ " vTreaksjonen av syreanhydrider eller syrehalider med 6-amino-penicillin-syre eller 7-amino-cephalosporin-derivater allerede en alminnelig kjent metode. sporm derivatives are ■ " vThe reaction of acid anhydrides or acid halides with 6-amino-penicillin acid or 7-amino-cephalosporin derivatives is already a commonly known method.
Selv om syreanhydridene enkelt kan lages ved reaksjon av karboksyl-gruppen av organisk syre med alkylklorkarbonater eller alkylhalider så som metyl-klor-karbonat, etylklor-karbonat eller pivalklorid, ifølge oppfinnelsen, kan syreanhydrider dannes enklere ved å bruke N-hydroksy-ravsyre-amider, N-hydroksyftalamider eller N-hydroks\X glutaramider som ikke tidligere er brukt ved syntese av penicillin eller cephalosporin-derivater. Although the acid anhydrides can easily be made by reaction of the carboxyl group of an organic acid with alkyl chlorocarbonates or alkyl halides such as methyl chlorocarbonate, ethyl chlorocarbonate or pival chloride, according to the invention, acid anhydrides can be formed more easily by using N-hydroxysuccinic acid amides , N-hydroxyphthalamides or N-hydroxy\X glutaramides which have not previously been used in the synthesis of penicillin or cephalosporin derivatives.
Det vil si, D-(-)-a-(4-alkyl-2,3-diokso-piperazinO karbonyl) fenyl (eller para-hydroksy-fenyl) glycin med den generelle formelen (VII) reagerer med N-hydroksy-ravsyreamid, N-hydroksy ftalamid eller N-hydroksy glutaramid og danner et nytt syreanhydrid med følgende generelle formel (XVI). Og deretter, ved reaksjon av dette nye anhydridet med 6-amino-penicillin-syreester eller 7-amino-cephalosporin-derivat, dannes enkelt forbindelse med den generelle formelen (I) ovenfor. That is, D-(-)-α-(4-alkyl-2,3-dioxo-piperazineO carbonyl)phenyl (or para-hydroxy-phenyl)glycine of the general formula (VII) reacts with N-hydroxysuccinamide , N-hydroxy phthalamide or N-hydroxy glutaramide and forms a new acid anhydride with the following general formula (XVI). And then, upon reaction of this new anhydride with 6-amino-penicillin acid ester or 7-amino-cephalosporin derivative, simple compound of general formula (I) above is formed.
Syreanhydridet som brukes ved ac,>*yl er ingen og som er esteren av ravsyreamid, ftalamid eller glutaramid av D(-)-a-(4-alkyl-2,3-diokso-piperazinokarbonyl)-fenyl (eller para-hydroksyl fenyl) glycin, reagerer med forbindelsen med den generelle formelen (IX) ovenfor, ved bruk av den nye forbindelsen (som til nå ikke har vært kjent) for enkelt å danne forbindelsen med den generelle formelen (I) ovenfor. hvor R og R^representerer det samme som ovenfor, R2representerer The acid anhydride used at ac,>*yl is none and which is the ester of succinamide, phthalamide or glutaramide of D(-)-a-(4-alkyl-2,3-dioxo-piperazinecarbonyl)-phenyl (or para-hydroxyl phenyl ) glycine, reacts with the compound of general formula (IX) above, using the new compound (which has not been known until now) to readily form the compound of general formula (I) above. where R and R^ represent the same as above, R 2 represents
Ifølge oppfinnelsen er det beste løsningsmidlet metylenklorid, aceton, acetonitril eller tetrahydrofuran, According to the invention, the best solvent is methylene chloride, acetone, acetonitrile or tetrahydrofuran,
og maksimalt utbytte er oppnådd ved temperaturer på -20°Cand maximum yield is achieved at temperatures of -20°C
til -30°C, 0 til 5°C, 10 til 15°C eller romtemperatur.to -30°C, 0 to 5°C, 10 to 15°C or room temperature.
Den foreliggende oppfinnelsen beskrives nærmere i det følgende: The present invention is described in more detail in the following:
Eksempel 1:Example 1:
7,56 g D-(-)-fenyl glycin blir suspendert i 50 ml metylenklorid, og temperaturen i suspensjonen reguleres til 0°C. 7 ml trietylamin blir tilsatt suspensjonen og reagerer ved samme temperatur i 30 minutter. 7.56 g of D-(-)-phenylglycine are suspended in 50 ml of methylene chloride, and the temperature in the suspension is regulated to 0°C. 7 ml of triethylamine is added to the suspension and reacted at the same temperature for 30 minutes.
5,4 ml trimetylklorsilan blir tilsatt suspensjonen og ristet ved 0°C i 30 minutter, og reaksjonstemperaturen nås ved -25°C, 7,3 g l-etyl-2,3-diokso-piperazin smeltes i 50 ml metylenklorid og 5,55 ml trimetylklorsilan tilsettes, og dette reagerer ved 0°C i 30 minutter. 5.4 ml of trimethylchlorosilane is added to the suspension and shaken at 0°C for 30 minutes, and the reaction temperature is reached at -25°C, 7.3 g of 1-ethyl-2,3-dioxo-piperazine is melted in 50 ml of methylene chloride and 5, 55 ml of trimethylchlorosilane is added, and this reacts at 0°C for 30 minutes.
Til fenyl-glycin-løsningen som er laget ovenfor tilsettes dråpevis i 30 minutter og ved -25°C 16,82 ml (30,3°a løsning av tetrahydrofuran) fosgen og løsning av aktivert l-etyl-2,3-diokso-piperazin. Temperaturen i reaksjonsblandingen er regulert til 0-5°C, og reaksjonstiden er to timer. Deretter blir løsningsmidlet fullstendig fjernet ved lav temperatur og redusert trykk. To the phenyl-glycine solution prepared above, 16.82 ml (30.3°a solution of tetrahydrofuran) of phosgene and a solution of activated l-ethyl-2,3-dioxo- piperazine. The temperature in the reaction mixture is regulated to 0-5°C, and the reaction time is two hours. The solvent is then completely removed at low temperature and reduced pressure.
Deretter blir suspensjonen ved tilsats av 50 ml vann ogThe suspension is then made by adding 50 ml of water and
50 ml etylacetat, fullstendig oppløst og deretter ristet i tolv timer, og krystallene felles ut. Krystallene filtreres fra, vaskes med vann og tørkes ved 40°C i 2-3 timer. Deretter oppnås 13>1 g D-(-)-a-(4-etyl-2,3-diokso-piperazin karbonyl amido) fenyl eddiksyre. 50 ml of ethyl acetate, completely dissolved and then shaken for twelve hours, and the crystals precipitated. The crystals are filtered off, washed with water and dried at 40°C for 2-3 hours. 13>1 g of D-(-)-α-(4-ethyl-2,3-dioxo-piperazine carbonyl amido)phenylacetic acid is then obtained.
Analyseresultater:Analysis results:
Smeltepunktstemperatur: -136 -138°C.Melting point temperature: -136 -138°C.
Spesifikk rotasjon [a]D 2 0 er -53~-56°.Specific rotation [a]D 2 0 is -53~-56°.
Acidimetrisk titrering: 102,1%Acidimetric titration: 102.1%
Eks empe1 2:Ex empe1 2:
Ved samme prosedyre som i eksempel 1, men med-8,32 g D-(-)-a-para-hydroksy-fenyl-glycin, oppnås 12,3 g D-(-)-a-(4-etyl-2,3-diokso-piperazin karbonyl amido)-para-hydroksy-fenylacetat. By the same procedure as in example 1, but with 8.32 g of D-(-)-α-para-hydroxy-phenyl-glycine, 12.3 g of D-(-)-α-(4-ethyl-2) are obtained ,3-dioxo-piperazine carbonyl amido)-para-hydroxy-phenylacetate.
Analyseresultater: 0Analysis results: 0
Smeltepunktstemperatur: 210 CMelting point temperature: 210 C
Spesifikk rotasjon [a]p°: -87°Specific rotation [a]p°: -87°
Acidimetrisk titrering: 98,9%Acidimetric titration: 98.9%
Tynnsjiktkromatografi brukes for å påvise at en har fått det ønskete produktet. Thin-layer chromatography is used to demonstrate that one has obtained the desired product.
Eksempel 3:Example 3:
1,5 g D-(-)-a-(4-etyl-2 ,3-diokso-l-piperazin>-karbonyl-acetamid)-fenyl eddiksyre suspenderes i 20 ml tetrahydofuran. Til denne suspensjonen tilsettes 0,5 g N-hydroksy-ravsyre-imid og 0,9 g cyklo-hexyl-karbo-di-imid. Den resulterende klare løsningen blir ristet ved romtemperatur i to timer, og da dannes bunnfall. Bunnfallet filtreres fra, og filtratet holdes på 5°C. 1.5 g of D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazine>-carbonyl-acetamide)-phenylacetic acid are suspended in 20 ml of tetrahydofuran. 0.5 g of N-hydroxysuccinic acid imide and 0.9 g of cyclohexyl carbodiimide are added to this suspension. The resulting clear solution is shaken at room temperature for two hours, and then a precipitate forms. The precipitate is filtered off, and the filtrate is kept at 5°C.
1,1 g 6-amino penicillinsyre suspenderes i 20 ml metylenklorid. Til denne suspensjonen tilsettes 0,5 ml trietylamin og 0,7 ml dietylamin og løses fullstendig. 1.1 g of 6-amino penicillin acid is suspended in 20 ml of methylene chloride. To this suspension, 0.5 ml of triethylamine and 0.7 ml of diethylamine are added and dissolved completely.
Til denne løsningen tilsettes syreanhydridløsning dråpevis ved -25°C i 30 minutter, og reaksjonsblandingen kondenseres fullstendig ved lav temperatur og redusert trykk. Deretter tilsettes og oppløses 20 ml vann og 20 ml etylacetat, og pH-verdien for reaksjonsblandingen er justert til 1,5. Krystallene felles da ut. Etter risting av reaksjonsblandingen i 5 timer, filtreres krystallene fra, vaskes med vann og tørkes ved 40°C og under redusert trykk i 2 timer. To this solution, acid anhydride solution is added dropwise at -25°C for 30 minutes, and the reaction mixture is condensed completely at low temperature and reduced pressure. 20 ml of water and 20 ml of ethyl acetate are then added and dissolved, and the pH value for the reaction mixture is adjusted to 1.5. The crystals then fall out. After shaking the reaction mixture for 5 hours, the crystals are filtered off, washed with water and dried at 40°C and under reduced pressure for 2 hours.
Da oppnås 1,9 g 6-[D-(-)-a-(4-etyl-2,3-diokso-piperazin#~karbonyl) amino-fenyl-acetamid]-penicillinsyre. Analyseresultater: 1.9 g of 6-[D-(-)-α-(4-ethyl-2,3-dioxo-piperazine#~carbonyl)amino-phenyl-acetamide]-penicillinic acid is then obtained. Analysis results:
Spesifikk rotasjon [a] D er +167,5°Specific rotation [a] D is +167.5°
Svovelinnhold : 6,1%Sulfur content: 6.1%
Fuktighetsinnhold: 3,6%Moisture content: 3.6%
Mikrobiologisk Assay: 928 ug/mgMicrobiological Assay: 928 ug/mg
Eksempel 4Example 4
Ved samme prosedyre som i eksempel 3, men med 1,8 g D- (-) - a- (4-etyl-2 ,3-diokso-l-piperazinerkarbonyl-acetamid) - para-hydroksy-fenyl-eddiksyre) oppnås 1,75 g 6-[D-(-)-a-(4-etyl-2,3-diokso-l-piperazin-karbonyl)-amino-para-hydroksy - fenyl-acetamido] penicillinsyre. By the same procedure as in example 3, but with 1.8 g of D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarbonyl-acetamide) - para-hydroxy-phenyl-acetic acid) 1 is obtained .75 g of 6-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazine-carbonyl)-amino-para-hydroxy-phenyl-acetamido]penicilic acid.
Analyseresultater:Analysis results:
Spesifikk rotasjon [ct]p° er +171,5° Specific rotation [ct]p° is +171.5°
Fuktighetsinnhold: 4,2%Moisture content: 4.2%
Svovelinnhold: 5,7%Sulfur content: 5.7%
Mikrobiologisk Assay 899 ,4 g/mgMicrobiological Assay 899 .4 g/mg
Eksempel 5Example 5
4,0 g ampicillintrihydrat suspenderes i 50 ml metylenklorid og temperaturen i suspensjonen reguleres til 5°C. 4.0 g of ampicillin trihydrate is suspended in 50 ml of methylene chloride and the temperature in the suspension is regulated to 5°C.
Til suspensjonen tilsettes og løses 2,3 ml trietylamin, og IQ g<y>annfritt magnesiumsulfat tilsettes og reagerer ved samme temperatur i 30 minutter. Reaksjonsblandingen filtreres, og filtratet kjøles til -20°C. To the suspension, 2.3 ml of triethylamine is added and dissolved, and IQ g<y>an-free magnesium sulfate is added and reacted at the same temperature for 30 minutes. The reaction mixture is filtered, and the filtrate is cooled to -20°C.
Det avkjølte filtratet tilsettes 9,8 ml 12% fosgen-løsning (tetra-hydrofuran-løsning) og reaksjonen går. ved'-5°C i 30 minutter. The cooled filtrate is added to 9.8 ml of 12% phosgene solution (tetrahydrofuran solution) and the reaction proceeds. at -5°C for 30 minutes.
Løsningsmiddel fjernes fra reaksjonsblandingen ved 30°C under redusert trykk. Da framkommer blekgule krystaller. Den utfelte krystallen løses i 50 ml metylenklorid, og tempera- Solvent is removed from the reaction mixture at 30°C under reduced pressure. Pale yellow crystals then appear. The precipitated crystal is dissolved in 50 ml of methylene chloride, and temperature
turen reguleres til -5^ -10°C.the trip is regulated to -5^ -10°C.
1,5 g 4-etyl-2,3-diokso-piperazin løses i 10 ml metylenklorid, og denne løsningen tilsettes den ovenfor nevnte løsningen ved samme temperaturen i løpet av 30 min, og en lar reaksjonen gå i 1,5 timer. 50 ml destillert vann settes til reaksjonsløsningen, og blandingen ristes i 30 minutter. 1.5 g of 4-ethyl-2,3-dioxo-piperazine is dissolved in 10 ml of methylene chloride, and this solution is added to the above-mentioned solution at the same temperature over the course of 30 minutes, and the reaction is allowed to proceed for 1.5 hours. 50 ml of distilled water is added to the reaction solution, and the mixture is shaken for 30 minutes.
Deretter separeres vannfasen fra og vaskes tre ganger The water phase is then separated from and washed three times
hver gang med 320 ml metylenklorid. Til vannfasen tilsettes 30 ml etylacetat, pH^verdien justeres til 1,5 med 101 saltsyre, og krystallene felles ut. each time with 320 ml of methylene chloride. 30 ml of ethyl acetate are added to the water phase, the pH value is adjusted to 1.5 with 101 hydrochloric acid, and the crystals are precipitated.
Ved risting ved romtemperatur i 5 timer, og vasking med vann og tørking ved 40°C i 5 timer, oppnås 4,9 g 6-[D-(-)-a-(4-etyl-2,3-diokso-piperazinøkarbonyl) amino-fenyl-acetamido] penicillinsyreo By shaking at room temperature for 5 hours, and washing with water and drying at 40°C for 5 hours, 4.9 g of 6-[D-(-)-a-(4-ethyl-2,3-dioxo-piperazinecarbonyl) are obtained ) amino-phenyl-acetamido] penicillin acido
Analyseresultater:Analysis results:
Spesifikk rotasjon [a]-2Q 0 er +167,5o Fuktighetsinnhold: 3,2% Specific rotation [a]-2Q 0 is +167.5o Moisture content: 3.2%
Svovelinnhold: 5,89%Sulfur content: 5.89%
Mikrobiologisk Assay 934,1 yg/mgMicrobiological Assay 934.1 yg/mg
Eksempel 6Example 6
Ved samme prosedyre som i eksempel 5, men med 3,12 g amoksycillintrihydrat, oppnås 4,5.g.6-[D-(-)-a-(4-etyl-2,3-diokso-piperazinø-karbonyl) -amino-para-hydroksy-fenyl-acetamido] penicillinsyre. Analyseresultater: By the same procedure as in example 5, but with 3.12 g of amoxicillin trihydrate, 4.5 g of 6-[D-(-)-a-(4-ethyl-2,3-dioxo-piperazine-carbonyl)- amino-para-hydroxy-phenyl-acetamido] penicillin acid. Analysis results:
Spesifikk rotasjon [ot]n 20er + 172,5Specific rotation [ot]n 20er + 172.5
Svovelinnhold 5,6%Sulfur content 5.6%
Mikrobiologisk Assay 912,5 yg/mgMicrobiological Assay 912.5 yg/mg
Eksempel 7Example 7
4;,2 g 6-[D-(-) -a-(4-etyl-2 ,3-diokso-l-piperazin«-karbonyl)-amino-fenyl-acetamido] penicillinsyre suspenderes i 20 ml vann, og natriumbikarbonat (0,62 g løst i 5 ml vann) tilsettes og løses fullstendig. 4.2 g of 6-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazine-carbonyl)-amino-phenyl-acetamido]penicilic acid is suspended in 20 ml of water, and sodium bicarbonate (0.62 g dissolved in 5 ml of water) is added and completely dissolved.
Ved aseptisk filtrering og frysetørking oppnås 3,8 g na-triumsalt av 6-[D-(-)-a-(4-etyl-2,3-diokso-l-piperazihb-karbonyl)Tamino-fenyl-acetamido] penicillinsyre. By aseptic filtration and freeze-drying, 3.8 g of the sodium salt of 6-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazihb-carbonyl)-amino-phenyl-acetamido] penicillin acid is obtained.
Analyseresultater:Analysis results:
Spesifikk rotasjon tajj^ er + 185,5°. Specific rotation tajj^ is + 185.5°.
Eksempel 8 Example 8
1,44 g D-(-)-a- (4-etyl-2,3-diokso-l-piperazincT-karbonyi-amino) -p-hydroksy-fenyl-eddiksyre suspenderes i 20 ml tetrahydrofuran. 1.44 g of D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazincT-carbonylamino)-p-hydroxy-phenyl-acetic acid are suspended in 20 ml of tetrahydrofuran.
0,5 g N-hydroksy-ravsyr.eamid og 0,9 g dicykloheksylkarbodi-imid tilsettes til suspensjonen. En klar løsning oppnås. Ved å riste løsningen ved romtemperatur i 2 timer, dannes bunnfall. Bunnfallet filtreres og filtratet holdes på 5°C. 0.5 g of N-hydroxysuccinic acid amide and 0.9 g of dicyclohexylcarbodiimide are added to the suspension. A clear solution is obtained. By shaking the solution at room temperature for 2 hours, a precipitate forms. The precipitate is filtered and the filtrate is kept at 5°C.
1,34 g 7-amino-3-[5-(l-metyl-l,2,3,4-tetrazonyl) thiometyl]-- A-3c£pham-karboksylsyre suspenderes i 15 ml vann og temperaturen regulerCStil 5°C. 1.34 g of 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazonyl) thiomethyl]- A-3 c£pham-carboxylic acid is suspended in 15 ml of water and the temperature regulated to 5°C .
Til suspensjonen tilsettes og oppløses 1 ml trietylamin.Add and dissolve 1 ml of triethylamine to the suspension.
Til denne løsningen tilsettes på en gang syreanhydridløsning laget som vist ovenfor, temperaturen heves til 10°C og fargen på løsningen blir rød, men etter en tid blir fargen blek gul. To this solution is added at once the acid anhydride solution made as shown above, the temperature is raised to 10°C and the color of the solution becomes red, but after some time the color becomes pale yellow.
Denne løsningen reagerer ved romtemperatur i 2,5 timer, og løsningsmiddel fjernes under redusert trykk. This solution is reacted at room temperature for 2.5 hours, and solvent is removed under reduced pressure.
Til denne resten tilsettes og oppløses 20 ml etylacetat og 20 ml vann. Ved 5°C blir pH-verdien justert til 1,5 med for-tynnet saltsyre. Etylacetat-fasen blir separert fra og vas-ket med vann to ganger. Den organiske fasen tilsettes y-ann-'fritt natriumsulfat og filtreres, og filtratet fordamper ved redusert trykk. 20 ml of ethyl acetate and 20 ml of water are added to this residue and dissolved. At 5°C, the pH value is adjusted to 1.5 with dilute hydrochloric acid. The ethyl acetate phase is separated from and washed with water twice. The organic phase is added with y-other-'free sodium sulfate and filtered, and the filtrate evaporates at reduced pressure.
Til resten tilsettes 30 ml eter.30 ml of ether is added to the residue.
Etter omkrystallisering fås 2,2 g 7-[D-(-)(4-etyl-2,3-diokso-l-piperazifl-karbonyl-amino)-p-hydroksy-fenyl-acetamido] -3- [ 5- (1-metyl-l ,2,3,4-tetrazonyl) ^-thiometyl ] cepham-4-karboksylsyre. After recrystallization, 2.2 g of 7-[D-(-)(4-ethyl-2,3-dioxo-1-piperazifl-carbonyl-amino)-p-hydroxy-phenyl-acetamido]-3- [ 5- ( 1-methyl-1 ,2,3,4-tetrazonyl) ^-thiomethyl ] cepham-4-carboxylic acid.
Analyseresultater:Analysis results:
Spesifikk rotasjon [a]^° er -34,1°Specific rotation [a]^° is -34.1°
Eksempel 9 Example 9
6,3 g 7-[D-(-)-a-(4-etyl-2 ,3-diokso-l-piperazinc>-karbonylamino)-p-hydroksy-fenyl-acetamido]-3-[5-(1-metyl-1,2,3,4-tetrazonyl)-thiometyl]-A -cepham-4-karboksylsyre suspenderes i 30 ml destillert vann. 6.3 g 7-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazinc>-carbonylamino)-p-hydroxy-phenyl-acetamido]-3-[5-(1 -methyl-1,2,3,4-tetrazonyl)-thiomethyl]-A-cepham-4-carboxylic acid is suspended in 30 ml of distilled water.
Til denne suspensjonen tilsettes og løses fullsten-To this suspension, full stone is added and dissolved.
dig en løsning av natriumbikarbonat (0,8 g løst i 10 ml destillert vann). a solution of sodium bicarbonate (0.8 g dissolved in 10 ml of distilled water).
Ved aseptisk filtrering og frysetørking oppnås 6,1 g av natriumsaltet av 7-[D-(-)-a-(4-etyl-2,3-diokso-l-pipera-zinivkarbonyl-amino-p-hydroksy-fenyl-acetamido ]-3-[5-(1-mety1-1,2,3,4-tetrazonyl)-thiometyl]-A<*->cepham-4-karboksyl- By aseptic filtration and freeze-drying, 6.1 g of the sodium salt of 7-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonyl-amino-p-hydroxy-phenyl-acetamido) are obtained ]-3-[5-(1-methyl-1,2,3,4-tetrazonyl)-thiomethyl]-A<*->cepham-4-carboxyl-
syre.acid.
Analyseresultater:Analysis results:
Spesifikk rotasjon [<*]j^ er -36,2°Specific rotation [<*]j^ is -36.2°
Mikrobiologisk Assay er 946,5 ug/mg Microbiological Assay is 946.5 ug/mg
Claims (3)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019810003767A KR830001969B1 (en) | 1981-10-06 | 1981-10-06 | 6- {D-(-) α- (4-ethyl-2.3-dioxo-1 piperazinocarbonylamino) phenyl (or hydroxyphenyl) acetamido peniclanic acid and a method for preparing the salt thereof |
KR1019810003768A KR830001970B1 (en) | 1981-10-06 | 1981-10-06 | Method for preparing cephalosporin derivative |
KR1019810004869A KR830000272B1 (en) | 1981-12-12 | 1981-12-12 | Process for preparing D-(-)-α- (4-alkyl-2,3-dioxopiperazino carbonyl amino) phenyl (or hydroxyphenyl) acetic acid |
Publications (1)
Publication Number | Publication Date |
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NO822870L true NO822870L (en) | 1983-04-07 |
Family
ID=27348356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO822870A NO822870L (en) | 1981-10-06 | 1982-08-24 | PROCESS FOR THE PRODUCTION OF PENICILLIN AND CEPHALOSPORIN DERIVATIVES |
Country Status (7)
Country | Link |
---|---|
AU (1) | AU8267582A (en) |
DK (1) | DK435682A (en) |
ES (3) | ES8307816A1 (en) |
FI (1) | FI820760L (en) |
IN (1) | IN155630B (en) |
IT (1) | IT1157064B (en) |
NO (1) | NO822870L (en) |
-
1982
- 1982-03-04 FI FI820760A patent/FI820760L/en not_active Application Discontinuation
- 1982-04-16 AU AU82675/82A patent/AU8267582A/en not_active Abandoned
- 1982-04-26 ES ES511709A patent/ES8307816A1/en not_active Expired
- 1982-05-05 IN IN502/CAL/82A patent/IN155630B/en unknown
- 1982-08-24 NO NO822870A patent/NO822870L/en unknown
- 1982-10-01 DK DK435682A patent/DK435682A/en not_active Application Discontinuation
- 1982-10-05 IT IT68169/82A patent/IT1157064B/en active
-
1983
- 1983-03-28 ES ES521035A patent/ES8404792A1/en not_active Expired
- 1983-03-28 ES ES521036A patent/ES521036A0/en active Granted
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FI820760L (en) | 1983-04-07 |
ES521035A0 (en) | 1984-05-16 |
AU8267582A (en) | 1983-04-14 |
ES8504742A1 (en) | 1985-04-16 |
IT8268169A0 (en) | 1982-10-05 |
IN155630B (en) | 1985-02-16 |
IT1157064B (en) | 1987-02-11 |
DK435682A (en) | 1983-04-07 |
ES511709A0 (en) | 1983-08-01 |
ES8404792A1 (en) | 1984-05-16 |
ES521036A0 (en) | 1985-04-16 |
ES8307816A1 (en) | 1983-08-01 |
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