HRP970713A2 - 7-bromo- and 7,7 dibromo-cepham and cephem derivatives - Google Patents
7-bromo- and 7,7 dibromo-cepham and cephem derivativesInfo
- Publication number
- HRP970713A2 HRP970713A2 HR970713A HRP970713A HRP970713A2 HR P970713 A2 HRP970713 A2 HR P970713A2 HR 970713 A HR970713 A HR 970713A HR P970713 A HRP970713 A HR P970713A HR P970713 A2 HRP970713 A2 HR P970713A2
- Authority
- HR
- Croatia
- Prior art keywords
- bromine
- hydrogen
- methyl
- bromo
- dibromo
- Prior art date
Links
- UYFNNBZKYYUODW-RXMQYKEDSA-N (6r)-7,7-dibromo-5-thia-1-azabicyclo[4.2.0]octan-8-one Chemical class S1CCCN2C(=O)C(Br)(Br)[C@H]21 UYFNNBZKYYUODW-RXMQYKEDSA-N 0.000 title claims description 7
- 150000001782 cephems Chemical class 0.000 title description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 39
- 229910052794 bromium Inorganic materials 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- -1 bromo, hydroxy Chemical group 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 23
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000741 silica gel Substances 0.000 claims description 15
- 229910002027 silica gel Inorganic materials 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- OSORMYZMWHVFOZ-UHFFFAOYSA-N phenethyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCC1=CC=CC=C1 OSORMYZMWHVFOZ-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 10
- 238000003818 flash chromatography Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 7
- KDIXCGXBTQBLOU-RXMQYKEDSA-N (6r)-7,7-dibromo-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class S1CC=CN2C(=O)C(Br)(Br)[C@H]21 KDIXCGXBTQBLOU-RXMQYKEDSA-N 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- DAVPSCAAXXVSFU-ALEPSDHESA-N (2s,5r,6r)-6-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2[C@H](Br)C(=O)N21 DAVPSCAAXXVSFU-ALEPSDHESA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 108091005804 Peptidases Proteins 0.000 claims description 3
- 102000035195 Peptidases Human genes 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 19
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 107
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000011877 solvent mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 2
- 102100033174 Neutrophil elastase Human genes 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001781 cephams Chemical class 0.000 description 2
- 239000003602 elastase inhibitor Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LFMBIMXJWIQULB-SSDOTTSWSA-N (6r)-3-methyl-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1CC(C)=CN2C(=O)C[C@H]21 LFMBIMXJWIQULB-SSDOTTSWSA-N 0.000 description 1
- HHOUIMZXVJMFGE-NQPNHJOESA-N (6r)-3-methyl-5-thia-1-azabicyclo[4.2.0]octan-8-one Chemical compound C1C(C)CS[C@@H]2CC(=O)N21 HHOUIMZXVJMFGE-NQPNHJOESA-N 0.000 description 1
- HTFTURZHXAWZPC-SSDOTTSWSA-N (6r)-3-methylidene-5-thia-1-azabicyclo[4.2.0]octan-8-one Chemical class C1C(=C)CS[C@@H]2CC(=O)N21 HTFTURZHXAWZPC-SSDOTTSWSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- AOPRXJXHLWYPQR-UHFFFAOYSA-N 2-phenoxyacetamide Chemical group NC(=O)COC1=CC=CC=C1 AOPRXJXHLWYPQR-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 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
- QWAIEVYMYMARFH-GVHYBUMESA-N [(5r)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptan-3-yl] acetate Chemical compound S1C(OC(=O)C)(C)CN2C(=O)C[C@H]21 QWAIEVYMYMARFH-GVHYBUMESA-N 0.000 description 1
- FDNASFLFTOCYHY-QFSRMBNQSA-N [(6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]octan-3-yl] acetate Chemical compound C1C(OC(=O)C)CS[C@@H]2CC(=O)N21 FDNASFLFTOCYHY-QFSRMBNQSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940096017 silver fluoride Drugs 0.000 description 1
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Predmet ovog izuma se odnosi na nove 7-bromo-, i 7,7-dibromo-cefam i cefem derivate, na postupak za njihovu pripravu i na farmaceutske i veterinarske formulacije, koje ih sadrže. Prema tom izumu su novi spojevi potencijalno korisni kao inhibitori proteaza, posebno human leukocyte elstaza (HLE) i za prevenciju , kontrolu i liječenje bolesti uključujući nekontrolirano otpuštanje proteolitičkih enzima, posebno emphysema, metastasis, cystic fibrosis.
Metil 7,7-dibromo-3-metil cef-3-em-4-karboksilat se dobiva kao jedini produkt pregrađivanja metil 6,6- dibromo penicillanata-1-beta sulfoksida u refluksirajućem ksilenu uz dodatak malo p-toluen-sulfonske kiseline. (R.B. Morin, B. G. Jackson, R. A. Mueller, E.R. Lavagnino, W.B. Sconlin i S.L. Andrews (J. Am. Chem. Soc. 1969,21, 1401).
Pummerovo pregrađivanje u acetanhidridu je primjenjeno na metil 6,6-dibromopenicillanatu-1-beta sulfoksidu, kada nastaje smjesa 2-acetoksi-metilpenama, 3-acetoksicefama i metil 7,7-dibromo-3-metil cef-3-em-4-karboksilata. (J. Peter Clayton, John H.C. Nayler, Michael J. Pearson i Robert Soughte, Beacham Research Laboratories: J. Chem. Soc. Perkin. Trans I 1974, 22-25).
Elektrolizom Kamiya's disulfida t.j. 3-fenilacetamido-4-(2-benzotiazolil-ditio)-azetidinona s natrijevim jodidom dobiven je 7-fenilacetamido-3-beta-jodo-3-alfa-metil cefam, koji se dehidrohalogenira u 3-metil cefem (Torii, Sigeru; Tanaka, Hideo; Siroi, Takashi; Sasaoka, Michio; Saitoh, Norio; Nokami, Junzo; Tada, Nobuhito: Chem. Lett. 1982 (11) 1829-32).
Reakcijom metalnih fluorida s nesimetričnim azetidinon disulfidom u metilen kloridu i nakon toga oksidacijom dobiveni su 3-beta fluoro-3-alfa-metil cefami odnosno 1-oksidi, ali s fenoksiacetamidnom grupom u položaju 7. Međutim reakcijom 2-beta-halometilpenama sa srebrnim fluoridom dobiveni su 3-beta fluoro-3-alfa-metil 7-fenoksiacetamido cefami. (Micetich, Roland, G.; Betageri, Sucheta; Singh, Rajeshwar; Payne, Pamela: J. Org. Chem. 1987, 52(5) 915-18).
Esteri 3-bromo-3-metil 7-fenilacetamido i 7-fenoksiacetamido cefama su pripravljeni od Fujisawa grupe (Kamiya T., Teraji T., Saito Y., Hashimoto M., Nakaguchi O., i Oku T.,Tetrahedron Lett. 1973, 3001.; Brit. pat. 1453301), a njegovo egzocikličko dehidrobromiranje je primjenjeno na pripravu cefaklora.
Ekspanzija 6-fenoksiacetamido-2-beta-bromometil-penama u 3-metil-cefam provedena je sa trifenil kositrenim hidridom (Baldwin, Jack E.; Adlington Robert M; Kang, Tae Won; Lee, Eun; Scofield; Christopher J.: Tetrahedron 1988, 44 (18)5953-7). Isti je produkt pripravljen homolitičkim debromi-ranjem 3-beta -bromo-3-alfa-metil 7-fenoksiacetamido cefama sa trifenil kositrenim hidridom (Baldwin, Jack E.; Adlington Robert M; Kang, Tae Won; Lee, Eun; Scofield; Christopher J.: J. Chem. Soc. Chem. Commun. 1987, (2) 104-6).
3-Metil-3-halo-7-fenoksiacetamido cefam sulfoksidi u reakcijama sa metalnim solima, posebno živinim solima daju 3-metilen-cefam spojeve.(Corfield J. R. i Taylor, C.G. 1978, Tetrahedron Lett. 2915.).
Spojevi sličnih struktura su opisani u literaturi kao inhibitori elastaza (Bissolino, P.; Alpegiani, M.; Corigli, R.; Perrone, E.; Phamacia &Upjohn S.P.A.; WO 97/02268, 23.01. 1997., PCT/EP 96/02883; Grigory Veinberg et al.: Bioorganic & Medicinal Chemistry Letters. vol.7, 843-6, 1997.; Alpegiani M. et al.: Bioorganic & Medicinal Chemistry Letters vol.2, 1127-1132, 1992.; Paul E Finke et al.: Journal of Medicinal Chemistry, 1992, vol 35, 3731-3744.)
Prema našim saznanjima o stanju tehnike 7-bromo-, i 7,7-dibromo-cefam i cefem derivati nisu poznati.
Predmet ovog izuma se odnosi na 7-bromo-, i 7,7-dibromo-cefam derivate opće formule I u kojoj
[image]
R1 je vodik ili brom
R2 je vodik ili brom
R3 je brom, hidroksi
R4 je metil
R5 je –OR6 ili-NR7 R8 gdje su R6, R7 i R8 vodik, alkil, alkilaril
n=0,1,2
odnosno na 7-bromo-, i 7,7-dibromo-cefem derivate opće formule II u kojoj
[image]
R1 je vodik ili brom
R2 je vodik ili brom
R3 je metil
R4 je vodik, -COOR5 ili CONR6 R7
gdje su R5, R6 i R7 vodik, alkil, alkilaril
n=0,1,2
Daljnji predmet ovog izuma je postupak za pripravu 7-bromo-, i 7,7-dibromo-cefam derivata opće formule I i 7-bromo-, i 7,7-dibromo-cefem derivata opće formule II u kojima radikali imaju gore navedeno značenje, a koji se mogu pripraviti polazeći od estera ili amida sulfoksida 6-bromo-, odnosno 6,6-dibromopenicilanske kiseline opće formule III
[image]
u kojoj
R1 je vodik ili brom
R2 je vodik ili brom
R3 je OR4 ili NR5 R6, gdje su R4 ,R5 i R6 vodik, alkil, alkilaril
n= 1
grijanjem na temperaturi vrenja u nekom organskom otapalu napr. acetonitrilu, toluenu ili nekom drugom otapalu s ili bez dodatka tetrabutilamonijeva bromida, nakon čega se reakcijska smjesa upari do suhog ostatka, koji se nakon obrade pročišćava flash kromatografijom ili kromatografijom na koloni silikagela ili kristalizira iz pogodnog ili iz pogodne smjese otapala te se izolira produkt ili se odmah dobiveni produkt oksidira uobičajenim sredstvima napr. vodikovim peroksidom ili kalijevim permanganatom s ili bez dodatka ledene octene ili mravlje kiseline pri čemu nastaju 7-bromo-, i 7,7-dibromo-cefam derivati opće formule I u kojoj
R1 je vodik ili brom
R2 je vodik ili brom
R3 je brom, hidroksi
R4 je metil
R5 je -OR6 ili-NR7 R8 gdje su R6, R7 i R8 vodik, alkil, alkilaril
n=0,1,2
odnosno na 7-bromo-, i 7,7-dibromo-cefem derivate opće formule II u
kojoj
R1 je vodik ili brom
R2 je vodik ili brom
R3 je metil
R4 je vodik, -COOR5 ili CONR6 R7
gdje su R5, R6 i R7 vodik, alkil, alkilaril
n=0,1,2
Derivati 6,6-dibromopenicilanske kiseline su priređeni iz 6-amino-pe nicilanske kiseline prema poznatim postupcima (R. A. Volkmann, R. D. Carroll, R. B. Drolet, M. L. Elliott, i B. S. Moore. J. Org. Chem. 47, (1982) 3344-5; i Wayne E. Barth, US pat. 4,234,579, 18. Nov. 1980). Amidi su pripravljeni prema Mascaretti O. at al. (J. Chem. Research (14) 1988, 1501-36).
Sulfoksidi amida su pripravljeni u jednoj fazi metodom kiselinskog klorida ili mješovitog anhidrida, zatim amidiranjem, i oksidacijom dobivenog produkta m-klorperbenzojevom kiselinom ili vodikovim peroksidom uz dodatak octene kiseline (R. Micetich: Heterocycles 22. 531, (1984).
Predmet ovog izuma su novo sintetizirane supstancije koje se pripravljaju polazeći od estera ili amida sulfoksida 6-bromo-, odnosno 6,6-dibromopenicilanske kiseline. Predmet ovog izuma je i novi postupak, koji je jednostavan i lako provediv.
Daljnji predmet ovog izuma se odnosi na upotrebu ovih spojeva kao aktivnih komponenata u farmaceutskim preparatima s antibakterijskim ili sinergističkim djelovanjem ili kao inhibitori elastaza.
Izum je ilustriran sljedećim primjerima koji ni u čemu ne ograničavaju širinu izuma.
Primjer 1
Benzilamid 6,6-dibromopenicilanske kiseline
U ledom ohlađenu otopinu 6,6-dibromopenicilanske kiseline (7.2g; 0.02 mola) u metilen kloridu (100 ml, suhi) na 0°C doda se trietilamin (2.8 ml; 0.02 mola) i miješa na 0°C pola sata. Zatim se doda etil kloroformijat (2.1 ml; 0.02) mola i miješa u ledu još pola sata. Zatim se dokapava otopina benzilamina (4.8 ml; 0.044mola; u metilen kloridu /50 ml/) do pH 7.5 (utrošeno 3.74 ml; 0.034 mola) i miješa se na sobnoj temperaturi još dva sata. Talog je odsisan, a lug pran 1N HCl, vodom, sušen i uparen do suha (9.8 g). Dobiveni ostatak je čišćen flash kromatografijom sa sistemom otapala petroleter-metilen klorid (7:3), zatim petroleter-metilen klorid (1:1), i zatim metilen kloridom, kad je izolirano 1.98 g (22.1%) produkta.
Tt 156-158°C
Rf 0.3 (metilen klorid)
IR (KBr) v max (CDCl3): 1810(β-laktam) i 1660(amid) cm-1.
1H NMR (CDCl3, 300 MHz): 1.48 (3H, s,13 Me), 1.67 (3H, s,14 Me), 4.34 (1H, s, 3-H), 4.35 and 4.57 (svaki 1H, ABX svstem, J gem. 14.5 Hz, J vic 5.7 and 6.0 Hz resp.11H), 5.66 (1H, s, 5-H) 6.66 (1H, br t, NH), 7.31 (5H, s, Ph) ppm.
13C NMR (CDCl3, 300 MHz) δ: 26.2 (C-10) 30.3 (C-9), 43.4(C-11), 55.0(C-6), 64.6(C-2) 71.3 (C-3) 78.5(C-5), 127.6 and 128.7 C-2' to C-6') 137.0 (C-1') 165.9 (C-7) and 166.4(C-8) ppm.
Nađeno: C, 40.1; H 3.5; N 6.3
C15H16Br2N2O2S: C, 40.2; H 3.6; N 6.2
Primjer 2
Benzilamid sulfoksida 6,6-dibromopenicilanske kiseline
Benzilamid 6,6-dibromopenicilanske kiseline (4.48g, 0.01 mol) se otopi u metilen kloridu (140 ml) zatim doda ledena octena kiselina (22.8 ml; 0.400 mola) i vodikov peroksid (12.5 ml, 0.120 mola) i miješa na sobnoj temperaturi 20 sati. Kad je reakcija gotova, pere se vodom, NaHCO3, slanom vodom, suši i upari do suha. Dobiveno je 4.2 g produkta koji je obrađen metanolom, talog je odsisan (2.2 g), a upareni lug je čišćen flash kromatografijom metilen kloridom i metilen kloridom-acetonom (10:0.3) čime je dobiveno još bijelih kristala (0.39 g). Ukupno je dobiveno 2.59 g; (55.75%) produkta.
Tt 158-160°C (MeOH)
Rf 0.20 u sistemu metilen klorid-aceton (10:0.3)
IR (KBr) νmax: 3305 (s),1810 (vs), 1670 (s), 1535(s), 1275(vs), 1065(vs) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.41 (3H, s, Me), 1.69 (3H, s, Me), 4.42 (1H, s, 3-H), 4.38 and 4.61(svaki 1H, ABX sistem, J gem. 14.8 Hz, J vic 5.9 and 6.0 Hz resp. 11H), 5.04 (1H, s, 5-H) 6.75 (1H, br s, NH), 7.32 (5H, s, Ph) ppm.
Nađeno: C, 39.2; H 3.5; N 6.1
C15H16Br2N2O3S: C, 38.9; H 3.5; N 6.0
Primjer 3
Benzilamid sulfoksida 6,6-dibromopenicilanske kiseline
U ledom ohlađenu otopinu 6,6-dibromopenicilanske kiseline (14.4g; 0.04 mola) u metilen kloridu (200 ml, oprani, suhi) na 0°C doda se trietilamin (5.6 ml; 0.04 mola) i miješa na 0°C pola sata.
Zatim se doda etil kloroformijat (4.2 ml; 0.04 mola ) i miješa u ledu još pola sata. Zatim se dokapa 67 ml otopine benzilamina (9.6 ml; 0.088mola benzilamina; u 100 ml metilen klorida) do pH 7.5 i miješa na sobnoj temperaturi još dva sata.
Talog se odsiše, a lugu opranom 1N HCl, vodom, sušenom (Na2SO4 se doda ledena octena kiselina (91.2 ml) i vodikov peroksid (50 ml) i miješa se na sobnoj temperaturi. Kad je reakcija gotova, reakcijska smjesa se pere vodom, otopinom natrijevog hidrogen karbonata, slanom vodom, suši i upari do suha. Prekristalizacijom uparenog ostatka iz metanola dobiven je produkt (8.2g).
Upareni metanolni lug nakon kristalizacije (4.5 g) je čišćen flash kromatografijom s metilen kloridom i metilen kloridom-acetonom (10:0.3). Dobiveno je još 1.2 g produkta. Ukupno je dobiveno: 9.3 g (50.2%), Tt 158-160°C (MeOH).
Rf 0.2 metilen klorid-aceton (10:0.3)
Spektroskopski podaci su identični onima u Primjeru 2.
Primjer 4
Benzilni ester 3-bromo-, 7,7-dibromo -3-metil- cefam-4-karboksilne kiseline
Sulfoksid benzilnog estera 6,6-dibromopeničileanske kiseline (13.95 g;0.03 mola) u acetonitrilu (100 ml) se miješa pod povratnim hladilom na temperaturi vrenja. Kad je reakcija gotova (10 sati), što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid), reakcijska smjesa se upari do suhog ostatka i čisti flash kromatografijom po redu sistemima otapala a) petroleter-metilen klorid (8:2) b) petroleter-metilen klorid (6:4), c) metilen klorid nakon čega je izoliran produkt Tt 93-95°C.
Rf 0.60 (metilen klorid)
IR(KBr) ν max: 1787 (vs), 1740 (s), 1333 (m), 1296 (m), 1228 (m), 1188(m), 1122 (m) cm-1.
1H NMR (CDCl3, 300 MHz) δ:1.79 (3H, s, Me), 2.79 i 3.53 (2H, ABq J=15 Hz, H-C2-H), 4.87 (1H, s, C4-H), 5.15 i 5.28 (svaki 1H d, J=12 Hz, CH2Ph), 5.55 (1H, s, C6-H), 7.32- 7.33 (5H, 2s, Ar) ppm.
13C NMR (CDCl3, 300 MHz) APT 8 : 29.80 (Me), 38.58 (C-4), 54.63 (C-3), 56.68 (C-7), 62.41 (C-2), 65.92 (C-6), 68.24 (CH2Ph), 128.78-129.23(Ph), 133.90 (C-Ph), 158.63 (C-8) i 165.84 (COO)
m/e M+ 525 (3 Br), 312 (2Br), 91
Primjer 5
7,7-Dibromo-3-metil cef-3-em
Sulfoksid benzilnog estera 6,6-dibromopenicilanske kiseline (13.95; 0.03 mola) otopi se u acetonitrilu (150 ml) i doda se tetrabutilamonijev bromid 19.32 g (0.06 mola). Reakcijska smjesa se miješa pod povratnim hladilom na temperaturi vrenja i kad nestane početna supstanca na tankom sloju silkagela (10 sati) reakcijska smjesa se upari do suha. Suhom ostatku se doda metilen klorid i voda, slojevi se dobro izmućkaju i odvoje. Sloj metilen klorida se pere vodom, otopinom natrijevog hidrogen karbonata i vodom, suši i upari do suha. Reakcijska smjesa je čiščena flash kromatografijom sa smjesom otapala petroleter-metilen klorid (7:3) kod čega je dobiven produkt Tt 101-103°C (eter). Rf 0.55 metilen klorid.
IR(KBr) ν max: 1794 (vs), 1771 (vs), 1747 (s), 1390 (s), 1375(s) 1261 (w), 1107 (w), 609 (s) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.83 (3H, s, Me), 3.11. i 3.51 (2H, Abq J=18 Hz, C2-H), 5.16 (1H, s, C4-H), 6.53 (1H, s, C6-H) ppm.
13C NMR (CDCl3, 300 MHz) APT δ : 20.95 (Me), 29.96 (C-2), 53.51 (C-7), 67.34 (C-6), 116.34(C-4), 119.93 (C-3), 200.60 (C-8).
Primjer 6
7,7-Dibromo-3-metil cef-3-em
Sulfoksid benzilnog estera 6,6-dibromopenicilanske kiseline (13.95; 0.03 mola) otopi se u toluenu (150 ml) i doda se tetrabutilamonijev bromid 19.32 g (0.06 mola). Reakcijska smjesa se miješa pod povratnim hladilom na temperaturi vrenja dok ne nestane početna supstanca (2 sata) što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid), i zatim se reakcijska smjesa se upari do suha.
Suhom ostatku se doda metilen klorid i voda, slojevi se dobro izmućkaju i odvoje. Sloj metilen klorida se pere vodom, otopinom natrijevog hidrogen karbonata i vodom, suši i upari do suha. Reakcijska smjesa je čišćena flash kromatografijom sa smjesom otapala petroleter-metilen klorid (7:3) kod čega je dobiven produkt 101-103°C (eter).
Rf 0.55 metilen klorid
Spektroskopski podaci su identični onima u Primjeru 5.
Primjer 7
7,7-Dibromo-3-methyl ceph-3-em-1-oxide
7,7-Dibromo-3-metil cef-3-em (0.460 g; 1.48 mmol) se otopi u metilen kloridu (15 ml) doda 6.8 ml ledene octene kiseline i reakcijskoj smjesi se dokapa 30%-tni vodikov peroksid (3.6 ml) i miješa na sobnoj temperaturi dok na tankom sloju silikagela u sistemu otapala metilen klorid-aceton (9:1) ne nestane početna supstanca (6 sati). Kad je reakcija gotova, reakcijska se otopina pere vodom, otopinom natrijevog hidrogen karbonata, vodom, suši i upari do suha. Dobiveni je produkt smjesa izomera, a čisti se kromatografijom na koloni silikagela sa sistemom otapala metilen klorid-aceton (9:1) pri čemu je prvo izoliran prvi izomer obzirom na sumpor Tt 153-5°C.
Rf 0.40 metilen klorid - aceton (9:1)
IR (KBr) ν max: 3422 (m), 1788 (vs), 1382 (m), 1371 (s), 1264 (s), 1064 (vs), 737 (vs) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.86 (3H, s, Me),3.56 i 3.91 (2H, ABq, J 16 Hz, C2-H), 4.89 (1H, s, C4-H), 6.52 (1H, s, C6-H) ppm.
13C NMR,CDCl3,300MHz) APT δ: 20.11 (Me), 50.53 (C-7) 53.80 (C-2), 81.62 (C-4), 117.07 (C-3), 117.27 (C-6). 154.70 (C=O) ppm.
Nakon toga je izoliran drugi izomer obzirom na sumpor
Tt 188-190°C
Rf 0.30 metilen klorid-acetn (9:1)
IR (KBr) ν max: 3422 (vs), 1773 (s),1644 (vs), 1382 (m), 1371 (s), 1033 (vs) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.88 (3H, s, Me),3.27 i 3.60 (2H, ABq, J 17.5 Hz, C2-H), 4.64 (1H, s, C4-H), 6.52 (1H, s, C6-H) ppm.
Primjer 8
Benzilni ester 7,7-dibromo-3-metil cef-3-em-4-karboksilne kiseline
Sulfoksid benzilnog estera 6,6-dibromopenicilanske kiseline (13.95; 0.03 mola) otopi se u acetonitrilu (150 ml) i doda se tetrabutilamonijev bromid 19.32 g (0.06 mola). Smjesa se miješa pod povratnim hladilom na temperaturi vrenja i kad nestane početna supstanca (10 sati) što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid), reakcijska smjesa se upari do suha. Suhom ostatku se doda metilen klorid i voda, slojevi se dobro izmućkaju i odvoje. Sloj metilen klorida se pere vodom, otopinom natrijevog hidrogen karbonata i vodom, suši i upari do suha. Reakcijska smjesa je ci scena flash kromatografijom sa smjesom otapala 1) petroleter-metilen klorid (1:1) i 2.) metilen klorid, kad je izoliran produkt Tt 111-113°C (eter). Rf 0.50 (metilen klorid)
IR (KBr) ν max: 3070-2920(vs), 1790(vs),1740(vs), 1375(m), 1365(m),1215(m), 740(s) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 2.24 (3H, s, Me), 3.20 i 3.29 (svaki 1H, d, J=16.6 Hz, C2-H), 5.25 (1H, s, C6-H), 5.27 i 5.31 (svaki 1H, d, J=12Hz, CH2Ph), 7.30-7.43 (5H, m, Ar) ppm.
13C NMR (CDCl3, 300 MHz) APT δ : 19.77 (Me), 31.62 (C-2), 56.42 (C -7), 67.33 (CH2Ph), 70.52 (C-6),123. 06; 128.23-128.55(Ph), 135.10(C-Ph), 141.04; 157.72 (C=O), 161.55(COO).
m/e M+ 445 (79Br2), 356 (79Br2), 270 (79Br2)
Primjer 9
Benzilni ester 7,7-dibromo-3-β-hidroksi-3-α-metil cefam -4-karboksilna kiselina
Sulfoksid benzilnog estera 6,6-dibromopenicilanske kiseline (13.95; 0.03 mola) otopi se u acetonitrilu (150 ml) i reakcijska smjesa se miješa pod povratnim hladilom na temperaturi vrenja dok ne nestane početna supstanca (10 sati), što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid) i zatim se reakcijska smjesa upari do suha. Suhom ostatku se doda metilen klorid i voda, slojevi se dobro izmućkaju i odvoje. Sloj metilen klorida se pere vodom, otopinom natrijevog hidrogen karbonata i vodom, suši i upari do suha. Reakcijska smjesa je čišćena flash kromatografijom po redu sa smjesom otapala 1.) petroleter-metilen klorid (8:2), 2.) petroleter-metilen klorid (6:4) i 3.) metilen klorid, kad je izoliran produkt u 50 %-tnom iskorištenju Tt 138-9°C (i-PrOH).
Rf0.40(CH2Cl2).
IR (KBr) ν max: 3446(m), 1784(vs) 1736(vs), 1394(m), 1375(m), 1333(s), 1282(m), 1149(m), 1138(m), 945(m) cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.23 (3H, s, Me), 2.57 i 3.50 (2H, ABq, J=14Hz, CH2), 3.76 (1H, s, OH, nestaje sa D2O), 4.46 (1H, s, C4-H), 5.13 i 5.25 (svaki 1H, d, J=12Hz, CH2Ph), 7.37 (5H, s, Ar) ppm.
13C NMR (CDCl3, 300 MHz) APT δ: 24.14 (Me), 36.53 (C-2) 53.82 (C-7), 61.38 (C-4), 62.89 (C-3), 66.33 (C-6), 67.82 (CH2Ph), 128.57-128.94 (Ph), 134.12 (C-Ph) 158.74 (C-8), 167.4 (COO).
m/e M+ 463 (2Br), 384 (Br), 91(CH2Ph)
Primjer 10
Benzilamid 3-β-bromo-7,7-dibromo-3-α-metil cefam -4-karboksilne kiseline
Benzilamidu sulfoksida 6,6-dibromopenicilanske kiseline (4.60 g; 0.01 mol) otopljenom u acetonitrilu (100 ml) dodan je tetrabutilamonijev bromid (6.4 g; 0.04 mola) i reakcijska smjesa refluksira 12 sati. Kad je reakcija gotova, što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid) reakcijska smjesa se upari do suhog ostatka i propusti kroz kolonu silikagela sa smjesom otapala metilen klorid-aceton (10:0.3), pri čemu se izolira produkt Tt 58-60°C (n-heksan).
Rf 0.7 (metilen-klorid-aceton (10:0.3)
IR (KBr) ν max: 3336(m), 1785(vs) 1677(s),1655(s), 1540(m) , 1452(m), 1399(m), 1340(m), 1222(m), 1050 (m), 648 (m) cm'1.
1H NMR( (CDCl3, 300 MHz) δ: 1.89 (3H, s, Me), 2.77 i 4.06 (2H, ABq, J=14.5 Hz, H-C2-H), 4.28 i 4.56 (2H, svaki 1H ABX sistem, J gem. 14,6 Hz, J vic 5.0 and 6.2 Hz, NCH2Ph), 4.83 (1H, s, C4-H), 5.61 (1H, s, C6-H), 7.30-7.36 (5H, m, Ar), 7.43 (1H, m, NH) ppm.
13C NMR (CDCl3, 300 MHz) APT δ: 29.69 (Me), 38.91 (C-2), 43.64 (N-CH2Ph), 54.34 (C-7), 59.23 (C-3), 62.66 (C-4), 66.15 (C-6), 127.77-128.84(Ph), 159.52 (C=O), 164.92 (CO-N).
m/e M+ 524 (79Br3), 445 (79Br2)
Primjer 11
Benzilamid 3-β-bromo-7,7-dibromo-3-α-metil cefam-4-karboksilne kiseline
Benzilamidu sulfoksida 6,6-dibromopenicilanske kiseline (4.60 g; 0.01 mol) otopljenom u toluenu (100 ml) dodan je tetrabutilamonijev bromid (6.4 g; 0.04 mola) i reakcijska smjesa se miješa pod povratnim hladilom na temperaturi vrenja. Kad je reakcija gotova (2 sata), što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid) reakcijska smjesa se upari do suhog ostatka i propusti kroz kolonu silikagela sa smjesom otapala metilen klorid-aceton (10:0.3), peri čemu se izolira produkt Tt 58-60°C (n-heksan).
Rf 0.7 metilen klorid-aceton (10:0.3)
Spektroskopski podaci su identični onima u Primjeru 10.
Primjer 12
Benzilamid 7,7-dibromo-3-metil-cef-3-em-4-karboksilne kiseline
Benzilamid sulfoksida 6,6-dibromopenicilanske kiseline (4.60 g; 0.01 mol) se miješa u acetonitrilu (100 ml) pod povratnim hladilom na temperaturi vrenja. Kad je reakcija gotova, što se utvrdi tankoslojnom kromatografijom na sloju silikagela (metilen klorid) reakcijska smjesa se upari do suhog ostatka i propusti kroz kolonu silikagela sa smjesom otapala metilen klorid-aceton (10:0.3), peri čemu se izolira produkt Tt 57-59°C (n-heksan).
Rf 0.60 (metilen-klorid-aceton (10:0.3)
IR(KBr) ν max: 3330(m), 1785(vs), 1660(s), 1535(m), 700(m)cm-1.
1H NMR (DMSO-d6, 300 MHz) δ: 1.88 (3H, s, Me), 3.35 i 3.57 (2H, ABq J 17 Hz, H-C2-H), 4.32 i 4.48 (2H, svaki 1H ABX sistem, J gem. 13.7 Hz, J vic 4.9 i 5.9 Hz;
NCH2Ph), 5.56 (1H, s, C6-H) 7.20-7.40 (5H, m, Ar), 9.07 (1H, m, NH) ppm.
1H NMR (DMSO-d6+D2O,300 MHz) δ:J.85 (3H, s, Me), 3.32 i 3.55 (2H, svaki 1H d, J=17.4 Hz, H-C2-H), 4.32 i 4.43 (2H, svaki 1H d, J=15 Hz, NCH2Ph), 5.52 (1H, s, C6-H) 7.20-7.33 (5H, m, Ar) ppm.
13C NMR (DMSO-d6,300 MHz)APT δ : 18.80 (Me), 29.88 (C-2),57.01, 67.64, 116.62, 127.14-128.71(Ph)139.25(C-Ph)), 156.48, 161.50
m/e M+ 444 (2Br), 365 (Br), 106, 91
Primjer 13
Benzilamid 3-β-bromo-7,7-dibromo-3-α-metil cefam-1,1-dioksid-4-karboksiIne kiseline
Smjesa sulfoksida benzilamida 6,6-dibromopenicilanske kiseline (4.6g; 0.01 mol) i tetrabutilamonijeva bromida (6.4 g; 0.02 mola) miješa se u acetonitrilu (100 ml) pod povratnim hladilom na temperaturi vrenja dok ne nestane početna supstanca. Kad je reakcija gotova (12 sati), što se utvrdi tankoslojnom kromatografijom na sloju silikagela u sistemu otapala metilen klorid-aceton (10:0.3), reakcijska smjesa je je uparena do suha. Upareni ostatak je podvrgnut oksidaciji u mravljoj kiselini (28 ml) sa vodikovim peroksidom (11.2 ml), tako da reakcijska smjesa refluksira pola sata. Smjesi se doda metilen klorid, slojevi se odijele, sloj metilen klorida se pere vodom, sodom bikarbonom, vodom, suši i upari do suha. Upareni ostatak je čišćen na kromatografijom na koloni sistemom metilen klorid-aceton (9:1) pri čemu je izoliran produkt 1.75 g (svjetlo žuta pjena, 31% ) Tt 163-165°C . Rf 0.45 metilen klorid- aceton (9:1)
IR(KBr) ν max : 3260-90(vs), 1797 (vs), 1670(vs), 1560(s), 1425(m), 1394(m), 1332(m), 1051(vs), 752(s), 702(s)cm-1.
1H NMR (CDCl3, 300 MHz) δ: 1.90 (s, 3H, Me), 3.69 i 4.25 (2H, ABq J=13 Hz, H-C2-H) 4.37 i 4.56 (2H, svaki 1H ABX sistem, J gem. 14.6 Hz, J vic 5.0 i 6.0 Hz, NCH2Ph), 4.56 (1H, s, C4-H), 5.35 (1H, s, C6-H), 7.14 (m, 1H, NH), 7.28-7.38 (5H, m, Ar) ppm.
13C NMR (CDCl3,300 MHz) APT 8: 30.1 (Me) 43.90 (C-2), 50.74 (C-3), 59.17 (CH2N), 59.48 (C-7), 61.62 (C-6), 84.16 (C-4), 127.91-129.03 (Ph), 136.41 (C-Ph), 158.48 (C=O), i 164.21 ( CONH).
m/e 540 (3Br), 461 (2Br), 91
Claims (13)
1. 7-Bromo-, i 7,7-dibromo-cefam derivati opće formule I
[image]
naznačen time, da radikali imaju značenje
R1 je vodik ili brom
R2 je vodik ili brom
R3 je brom, hidroksi
R4 je metil
R5 je -OR6 ili-NR7 R8 gdje su R6 ,R7 i R8 vodik, alkil, alkilaril
n=0,1,2
2. 7-bromo-, i 7,7-dibromo-cefem derivati opće formule II
[image]
naznačen time, da radikali imaju značenje
R1 je vodik ili brom
R2 je vodik ili brom
R3 je metil
R4 je vodik, -COOR5 ili CONR6 R7
gdje su R5, R6 i R7 vodik, alkil, alkilaril
n=0,1,2
3. Spoj prema zahtjevu 1, naznačen time, da je R1 brom, R2 brom, R3 brom, R4 metil, R5 -OR6, gdje je R6 benzil, n=0
4. Spoj prema zahtjevu 1, naznačen time, da je R1 brom, R2 brom, R3 hidroksi, R4 metil, R5 -OR6, gdje je R6 benzil, n=0
5. Spoj prema zahtjevu 1, naznačen time, da je R1 brom, R2 brom, R3 brom, R4 metil, R5 -NHCH2Ph, n=0
6. Spoj prema zahtjevu 1, naznačen time, da je R1 brom, R2 brom, R3 brom, R4 metil, R5 -NHCH2Ph, n=2
7. Spoj prema zahtjevu 2, naznačen time, da je R1 brom, R2 brom, R3 metil, R4 vodik, n=0
8. Spoj prema zahtjevu 2, naznačen time, da je R1 brom, R2 brom, R3 metil, R4 vodik, n=1
9. Spoj prema zahtjevu 2, naznačen time, da je R1 brom, R2 brom, R3 metil, R4 COOR5, R5 benzil, n=0
10. Spoj prema zahtjevu 2, naznačen time, da je R1 brom, R2 brom, R3 metil, R4 CONR6R7 gdje su R6 vodik, R7 CH2Ph, n=0
11. Postupak za pripravu novih 7-bromo-, i 7,7-dibromo-cefam derivata opće formule I u kojoj radikali imaju značenje
[image]
R1 je vodik ili brom
R2 je vodik ili brom
R3 je brom, hidroksi
R4 je metil
R5 je -OR6 ili-NR7 R8 gdje su R6 R7 i R8 vodik, alkil, alkilaril
n=0,1,2 kao i
7-bromo-, i 7 ,7-dibromo-cefem derivata opće formule II u kojoj radikali imaju značenje
[image]
R1 je vodik ili brom
R2 je vodik ili brom
R3 je metil
R4 je vodik, -COOR5 ili CONR6 R7
gdje su R5 R6 i R7 vodik, alkil, alkilaril
n=0,1,2
naznačen je time, da polazi od estera ili amida sulfoksida 6-bromo-, odnosno 6,6-dibromo-penicilanske kiseline opće formule III
[image]
u kojoj radikali imaju značenje
R1 je vodik ili brom
R2 je vodik ili brom
R3 je OR4 ili NR5 R6, gdje su R4, R5 i R6 vodik, alkil alkilaril
n= 1
grijanjem na temperaturi vrenja u nekom organskom otapalu napr. acetonitrilu, toluenu s ili bez dodatka tetrabutilamonijeva bromida, nakon čega se reakcijska smjesa upari do suhog ostatka, koji se nakon obrade pročišćava flash kromatografijom ili kromatografijom na koloni silikagela ili kristalizira izbogodnog otapala ili pogodne smjese otapala te se izolira produkt ili se oamah dobiveni produkt oksidira uobičajenim sredstvima napr. vodikovim peroksidom uz ili bez dodatka ledene octene ili mravlje kiseline ili kalijevim permanganatom uz ili bez dodatka ledene octene kiseline.
12. Farmaceutska ili veterinarska smjesa djelotvorna u antibakterijskoj terapiji, naznačen time, da sadrži kao aktivnu supstanciju spoj naveden u patentnim zahtjevima od 1. do 10., pogodan nosač i adjuvante.
13. Spoj naveden u patentnim zahtjevima 1. do 10. naznačen time, da se koristi u terapiji inflamatornih ili degenerativnih bolesti uzrokovanih proteolitičkim enzimima kod sisavaca uključujući i ljude.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR970713A HRP970713A2 (en) | 1997-12-30 | 1997-12-30 | 7-bromo- and 7,7 dibromo-cepham and cephem derivatives |
| SK1779-98A SK177998A3 (en) | 1997-12-30 | 1998-12-22 | 7-bromo- and 7,7-dibromo-cepham and cephem derivatives, preparation process thereof and pharmaceutical and veterinary compositions them containing |
| CZ984310A CZ431098A3 (cs) | 1997-12-30 | 1998-12-23 | 7-Brom- a 7,7-dibrom-cefamové a cefemové deriváty, způsob jejich přípravy a je obsahující farmaceutické a veterinární prostředky |
| JP10369396A JPH11255771A (ja) | 1997-12-30 | 1998-12-25 | ７―ブロモ及び７，７―ジブロモ―セファム及びセフェム誘導体、その製造方法及びこれらの化合物を含有する医薬及び獣医薬用製剤 |
| EP98124764A EP0934944A1 (en) | 1997-12-30 | 1998-12-28 | 7-bromo- and 7,7-dibromo-cepham and cephem derivatives and their use as protease inhibitors |
| NO986185A NO986185L (no) | 1997-12-30 | 1998-12-29 | 7-brom- og 7,7-dibrom-cefam- og -cefem-derivater |
| HU9803035A HUP9803035A3 (en) | 1997-12-30 | 1998-12-29 | 7-bromo- and 7,7-dibromo-cepham and cephem derivatives |
| PL98330590A PL330590A1 (en) | 1997-12-30 | 1998-12-29 | Novel derivatives of 7-bromo- and 7,7-dibromocephame and cepheme |
| CA002256002A CA2256002A1 (en) | 1997-12-30 | 1998-12-29 | 7-bromo- and 7,7-dibromo-cepham and cephem derivatives |
| BG103044A BG103044A (en) | 1997-12-30 | 1998-12-30 | 7-bromo- and 7,7-dibromo-cepham and -cephem derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR970713A HRP970713A2 (en) | 1997-12-30 | 1997-12-30 | 7-bromo- and 7,7 dibromo-cepham and cephem derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP970713A2 true HRP970713A2 (en) | 1999-10-31 |
Family
ID=10946679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR970713A HRP970713A2 (en) | 1997-12-30 | 1997-12-30 | 7-bromo- and 7,7 dibromo-cepham and cephem derivatives |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0934944A1 (hr) |
| JP (1) | JPH11255771A (hr) |
| BG (1) | BG103044A (hr) |
| CA (1) | CA2256002A1 (hr) |
| CZ (1) | CZ431098A3 (hr) |
| HR (1) | HRP970713A2 (hr) |
| HU (1) | HUP9803035A3 (hr) |
| NO (1) | NO986185L (hr) |
| PL (1) | PL330590A1 (hr) |
| SK (1) | SK177998A3 (hr) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2337472A1 (de) * | 1973-07-24 | 1975-02-13 | Hoechst Ag | Alpha-halogenazetidinone und verfahren zu ihrer herstellung |
| KR927003605A (ko) * | 1989-10-06 | 1992-12-18 | 산파아 레버러토리즈, 인크. | 신규한 2-스피로사이클로프로필세파로스포린설폰유도체 및 이의 제조방법 |
| GB2266526A (en) * | 1992-03-17 | 1993-11-03 | Merck & Co Inc | Substituted cephalosporin sulfones useful in the treatment of leukemia |
| GB9513818D0 (en) * | 1995-07-06 | 1995-09-06 | Pharmacia Spa | 7,7-Disubstituted cephem-4-ketones |
-
1997
- 1997-12-30 HR HR970713A patent/HRP970713A2/hr not_active Application Discontinuation
-
1998
- 1998-12-22 SK SK1779-98A patent/SK177998A3/sk unknown
- 1998-12-23 CZ CZ984310A patent/CZ431098A3/cs unknown
- 1998-12-25 JP JP10369396A patent/JPH11255771A/ja active Pending
- 1998-12-28 EP EP98124764A patent/EP0934944A1/en not_active Withdrawn
- 1998-12-29 NO NO986185A patent/NO986185L/no not_active Application Discontinuation
- 1998-12-29 CA CA002256002A patent/CA2256002A1/en not_active Abandoned
- 1998-12-29 HU HU9803035A patent/HUP9803035A3/hu unknown
- 1998-12-29 PL PL98330590A patent/PL330590A1/xx unknown
- 1998-12-30 BG BG103044A patent/BG103044A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2256002A1 (en) | 1999-06-30 |
| JPH11255771A (ja) | 1999-09-21 |
| HUP9803035A2 (hu) | 1999-09-28 |
| BG103044A (en) | 1999-09-30 |
| CZ431098A3 (cs) | 1999-07-14 |
| NO986185L (no) | 1999-07-01 |
| HUP9803035A3 (en) | 2001-04-28 |
| SK177998A3 (en) | 2000-04-10 |
| HU9803035D0 (en) | 1999-02-01 |
| NO986185D0 (hr) | 1998-12-29 |
| PL330590A1 (en) | 1999-07-05 |
| EP0934944A1 (en) | 1999-08-11 |
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