DK162055B - 6-TRIMETHYLSILYLOXYCARBONYLAMINOPENICILLANIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF - Google Patents
6-TRIMETHYLSILYLOXYCARBONYLAMINOPENICILLANIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF Download PDFInfo
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- DK162055B DK162055B DK143990A DK143990A DK162055B DK 162055 B DK162055 B DK 162055B DK 143990 A DK143990 A DK 143990A DK 143990 A DK143990 A DK 143990A DK 162055 B DK162055 B DK 162055B
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- 238000000034 method Methods 0.000 title claims description 11
- NADCPIRWMLBTKX-RSPBLZPZSA-N (2S,5R)-3,3-dimethyl-7-oxo-6-(trimethylsilyloxycarbonylamino)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical class OC(=O)[C@H]1C(C)(C)S[C@@H]2C(NC(=O)O[Si](C)(C)C)C(=O)N21 NADCPIRWMLBTKX-RSPBLZPZSA-N 0.000 title 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000001569 carbon dioxide Substances 0.000 claims description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 36
- -1 p-hydroxyphenyl Chemical group 0.000 description 36
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 34
- 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 29
- 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 27
- 239000002253 acid Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 19
- 239000005051 trimethylchlorosilane Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 229930182555 Penicillin Natural products 0.000 description 13
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound 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 13
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound 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 13
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 13
- 229960003022 amoxicillin Drugs 0.000 description 12
- 229960000723 ampicillin Drugs 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 238000005917 acylation reaction Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 230000010933 acylation Effects 0.000 description 8
- 238000006884 silylation reaction Methods 0.000 description 8
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound 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 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229940049954 penicillin Drugs 0.000 description 7
- 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 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 6
- 150000002960 penicillins Chemical class 0.000 description 6
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- YLHCHEBQIHXSIW-SSDOTTSWSA-N (2r)-2-amino-2-(4-hydroxyphenyl)acetyl chloride Chemical compound ClC(=O)[C@H](N)C1=CC=C(O)C=C1 YLHCHEBQIHXSIW-SSDOTTSWSA-N 0.000 description 4
- MEAZEHJUPLREOQ-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetyl chloride Chemical compound ClC(=O)[C@H](N)C1=CC=CC=C1 MEAZEHJUPLREOQ-SSDOTTSWSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229960003884 hetacillin Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 229910014571 C—O—Si Inorganic materials 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229930195708 Penicillin V Natural products 0.000 description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 3
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000021523 carboxylation Effects 0.000 description 3
- 238000006473 carboxylation reaction Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- 229940056367 penicillin v Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- 150000004684 trihydrates Chemical class 0.000 description 3
- PKUPAJQAJXVUEK-UHFFFAOYSA-N 2-phenoxyacetyl chloride Chemical compound ClC(=O)COC1=CC=CC=C1 PKUPAJQAJXVUEK-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 229960001585 dicloxacillin Drugs 0.000 description 2
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 229960004273 floxacillin Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- QTQPGZVDUCMVLK-ZXFNITATSA-N methoxymethyl (2s,5r,6r)-6-[(4r)-2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC)=CC=CC=C1 QTQPGZVDUCMVLK-ZXFNITATSA-N 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 229960000515 nafcillin Drugs 0.000 description 2
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229960001019 oxacillin Drugs 0.000 description 2
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 2
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical class OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- XMNFWSAYWSUJMH-ZXFNITATSA-N sarmoxicillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC)=CC=C(O)C=C1 XMNFWSAYWSUJMH-ZXFNITATSA-N 0.000 description 2
- 229950004779 sarmoxicillin Drugs 0.000 description 2
- 229950002532 sarpicillin Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 2
- 229960004659 ticarcillin Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000006000 trichloroethyl group Chemical group 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 238000006227 trimethylsilylation reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FRUAVHAXMXYUGM-NFFDBFGFSA-N (2s,5r,6r)-6-[[(2r)-2-(furan-2-carbonyloxy)-4-methylpentanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O([C@H](CC(C)C)C(=O)N[C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=CC=CO1 FRUAVHAXMXYUGM-NFFDBFGFSA-N 0.000 description 1
- BSIJLJGDLNRGBY-NXWNEQKCSA-N (2s,5r,6r)-6-[[(2r)-2-[[2-(4-chlorophenoxy)-2-methylpropanoyl]amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C=1C=CC=CC=1)C(=O)C(C)(C)OC1=CC=C(Cl)C=C1 BSIJLJGDLNRGBY-NXWNEQKCSA-N 0.000 description 1
- WRFCGBVLTRJBKN-QSNWEANLSA-N (2s,5r,6r)-6-[[(2r)-2-[[2-[[amino(pyridin-4-yl)methylidene]amino]acetyl]amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)CN=C(N)C1=CC=NC=C1 WRFCGBVLTRJBKN-QSNWEANLSA-N 0.000 description 1
- XRCKXULNIUSXFZ-HYSWKAIVSA-N (2s,5r,6r)-6-[[2-(2,6-dichlorophenyl)-4-methylpyrazole-3-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)C=NN1C1=C(Cl)C=CC=C1Cl XRCKXULNIUSXFZ-HYSWKAIVSA-N 0.000 description 1
- YTJRZMJLBUOVBK-JHGBVSNDSA-N (2s,5r,6r)-6-[[2-[[2-(4-formylpiperazin-1-yl)-5-oxo-8h-pyrido[2,3-d]pyrimidine-6-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C=1C=CC(O)=CC=1)NC(=O)C(C(C1=CN=2)=O)=CNC1=NC=2N1CCN(C=O)CC1 YTJRZMJLBUOVBK-JHGBVSNDSA-N 0.000 description 1
- PRHFOBHERXQTKK-UHFFFAOYSA-N 2-(hydroxyamino)-2-phenylacetyl chloride Chemical compound ONC(C1=CC=CC=C1)C(=O)Cl PRHFOBHERXQTKK-UHFFFAOYSA-N 0.000 description 1
- VLOIVYPDUSVCLZ-UHFFFAOYSA-N 2-[2-(azaniumylmethyl)phenyl]acetate Chemical compound NCC1=CC=CC=C1CC(O)=O VLOIVYPDUSVCLZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- KEKPAPJXCXKIDQ-UHFFFAOYSA-N 4-methylpentan-2-one Chemical compound CC(C)CC(C)=O.CC(C)CC(C)=O KEKPAPJXCXKIDQ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229910017917 NH4 Cl Inorganic materials 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229950008560 almecillin Drugs 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- DIGBQDMXLUJMHN-FSWJYKAZSA-M apalcillin sodium Chemical compound [Na+].C1([C@@H](NC(=O)C=2C(=C3N=CC=CC3=NC=2)O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 DIGBQDMXLUJMHN-FSWJYKAZSA-M 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- ODFHGIPNGIAMDK-NJBDSQKTSA-N azidocillin Chemical compound C1([C@@H](N=[N+]=[N-])C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 ODFHGIPNGIAMDK-NJBDSQKTSA-N 0.000 description 1
- 229960004328 azidocillin Drugs 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- UVOCNBWUHNCKJM-XFAPPKAWSA-M azlocillin sodium Chemical compound [Na+].N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O UVOCNBWUHNCKJM-XFAPPKAWSA-M 0.000 description 1
- 229960002699 bacampicillin Drugs 0.000 description 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000003990 capacitor Substances 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- NZDASSHFKWDBBU-KVMCETHSSA-N carfecillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C=1C=CC=CC=1)C(=O)OC1=CC=CC=C1 NZDASSHFKWDBBU-KVMCETHSSA-N 0.000 description 1
- 229960002543 carfecillin Drugs 0.000 description 1
- 229960000717 carindacillin Drugs 0.000 description 1
- JIRBAUWICKGBFE-MNRDOXJOSA-N carindacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(=O)OC=1C=C2CCCC2=CC=1)C1=CC=CC=C1 JIRBAUWICKGBFE-MNRDOXJOSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- JKXQBIZCQJLVOS-GSNLGQFWSA-N clometocillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(OC)C1=CC=C(Cl)C(Cl)=C1 JKXQBIZCQJLVOS-GSNLGQFWSA-N 0.000 description 1
- 229960001351 clometocillin Drugs 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 description 1
- 229960004244 cyclacillin Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960002457 epicillin Drugs 0.000 description 1
- RPBAFSBGYDKNRG-NJBDSQKTSA-N epicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CCC=CC1 RPBAFSBGYDKNRG-NJBDSQKTSA-N 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229950006401 fibracillin Drugs 0.000 description 1
- 229950001615 furbucillin Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- QULKGELYPOJSLP-WCABBAIRSA-N penicillin O Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2[C@H](NC(=O)CSCC=C)C(=O)N21 QULKGELYPOJSLP-WCABBAIRSA-N 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229950004791 pirbenicillin Drugs 0.000 description 1
- 229960003342 pivampicillin Drugs 0.000 description 1
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 description 1
- 238000010935 polish filtration Methods 0.000 description 1
- 229950007249 prazocillin Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1896—Compounds having one or more Si-O-acyl linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
iin
DK 162055 BDK 162055 B
Den foreliggende opfindelse angår hidtil ukendte 6-trimethylsilyl-oxycarbonylaminopenicillansyrederivater med formlen (I) og en fremgangsmåde til fremstilling deraf, hvilke penicillansyrederivater anvendes som udgangsmaterialer ved en hidtil ukendt fremgangsmåde til 5 fremstilling af konventionelle penicilliner. Forbindelserne med formlen (I) er ejendommelige ved det i krav l's kendetegnende del angivne.The present invention relates to novel 6-trimethylsilyl-oxycarbonylaminopenicillanic acid derivatives of formula (I) and a process for the preparation thereof, which penicillanic acid derivatives are used as starting materials in a novel process for the preparation of conventional penicillins. The compounds of formula (I) are characterized by the characterizing portion of claim 1.
Det første kommercielle penicillin med en α-aminogruppe på 6-acylamidosidekaden var ampicillin, som er 6-(D-o!-amino-a-phenylacet-amido)penicillansyre (se U.S.A. patentskrift nr. 2.985.648).The first commercial penicillin with an α-amino group on the 6-acylamidoside chain was ampicillin, which is 6- (D-o-amino-α-phenylacetamido) penicillanic acid (see U.S. Patent No. 2,985,648).
10 Amoxicillin er et antibakterielt middel, som anvendes i humanterapien og markedsføres som trihydratet af den frie syre (dvs. zwitter-ionen). Forbindelsen er f.eks. beskrevet i britisk patentskrift nr.Amoxicillin is an antibacterial agent used in human therapy and marketed as the trihydrate of the free acid (i.e., the zwitter ion). The compound is e.g. disclosed in British Pat.
978.178, J.Chem.Soc. (London), side 1920-1922 (1971) og Antimicrobial Agents and Chemotherapy - 1970, side 407-430 (1971). Dens kemiske navn 15 er 6-[D-a-amino-a-(p-hydroxyphenyl)acetamido]peniciliansyre.978,178, J.Chem.Soc. (London), pages 1920-1922 (1971) and Antimicrobial Agents and Chemotherapy - 1970, pages 407-430 (1971). Its chemical name 15 is 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] penicilic acid.
Anvendelsen af aminosyrechlorid,hydrochlorider til fremstilling af sådanne penicilliner var omhandlet i patentlitteraturen, f.eks. i britisk patentskrift nr. 938.321 og 959.853 under vandfri betingelser (sidstnævnte anvendte beskyttelse under acyleringen af 6-aminopeni-20 cillansyrens carboxyl gruppe med en silylgruppe, såsom også omhandlet i britisk patentskrift nr. 1.008.468 og U.S.A. patentskrift nr. 3.249.622) samt i britisk patentskrift nr. 962.719 i kold vandig acetone. Disse penicilliner er amfotere aminosyrer, og der anvendtes derfor til deres isolering (f.eks. som omhandlet i U.S.A. patentskrift nr. 3.157.640 og 25 3.271.389) visse alifatiske usymmetriske forgrenede sekundære aminer (ofte kaldet flydende aminharpikser), der tidligere havde været anvendt til isolering af 6-aminopenicillansyre, som også er en amfoter aminosyre (se U.S.A. patentskrift nr. 3.008.956). Forbedrede fremgangsmåder til isolering og rensning af sådanne penicilliner var omhandlet i f.eks.The use of amino acid chloride, hydrochlorides for the preparation of such penicillins has been disclosed in the patent literature, e.g. in British Patent Nos. 938,321 and 959,853 under anhydrous conditions (the latter used protection during the acylation of the carboxyl group of 6-aminopenicillic acid with a silyl group, as also disclosed in British Patent Nos. 1,008,468 and U.S. Patent Nos. 3,249,622) and in British Patent Specification No. 962,719 in cold aqueous acetone. These penicillins are amphoteric amino acids and therefore were used for their isolation (e.g., in U.S. Patent Nos. 3,157,640 and 3,271,389) to certain aliphatic asymmetric branched secondary amines (often called liquid amine resins) which had previously has been used to isolate 6-aminopenicillanic acid, which is also an amphoteric amino acid (see United States Patent No. 3,008,956). Improved methods for isolating and purifying such penicillins have been disclosed in e.g.
30 U.S.A. patentskiift nr. 3.180.862 via Ø-naphthalensulfonater og i U.S.A. patentskrift nr. 3.198.804 via mellemliggende isolering og efterfølgende let hydrolyse af hetacillin.30 U.S.A. U.S. Patent No. 3,180,862 through Naphthalene sulfonates and in U.S.A. Patent No. 3,198,804 via intermediate isolation and subsequent light hydrolysis of hetacillin.
Anvendelsen af en silylgruppe til beskyttelse af carboxyl gruppen i et naturligt penicillin under kemisk spaltning til 6-aminopenicillansyre 35 var omhandlet i U.S.A. patentskrift nr. 3.499.909. Anvendelsen af sily-leret 6-aminopenicillansyre under vandfri acylering med aminosyre-chlorid,hydrochlorider var omhandlet i talrige patentskrifter, f.eks.The use of a silyl group to protect the carboxyl group in a natural penicillin during chemical cleavage to 6-aminopenicillanic acid 35 was disclosed in U.S.A. U.S. Patent No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochlorides has been disclosed in numerous patents, e.g.
U.S.A. patentskrift nr. 3.478.018, U.S.A. patentskrift nr. 3.595.855,U.S.A. U.S. Patent No. 3,478,018, U.S.A. U.S. Patent No. 3,595,855,
DK 162055BDK 162055B
2 U.S.A. patentskrift nr. 3.654.266, U.S.A. patentskrift nr. 3.479.338 og U.S.A. patentskrift nr. 3.487.073. Nogle af disse patentskrifter omhandler også brugen af flydende aminharpikser. Se også U.S.A. patentskrifter nr. 3.912.719, 3.980.637 og 4.128.547.2 U.S.A. U.S. Patent No. 3,654,266, U.S.A. U.S. Patent No. 3,479,338 and U.S.A. U.S. Patent No. 3,487,073. Some of these patents also deal with the use of liquid amine resins. See also U.S.A. U.S. Patent Nos. 3,912,719, 3,980,637 and 4,128,547.
5 Britisk patentskrift nr. 1.339.605 indeholder forskellige speci fikke og detaljerede eksempjer på fremstillingen af amoxicillin ved omsætning af et silyleret derivat af 6-aminopeniciliansyre med et reak-tionsdygtigt derivat (herunder chlorid,hydrochloridet) af D-(-)-a-amino-p-hydroxyphenyleddikesyre, hvori aminogruppen er beskyttet, derefter 10 fjernelse af silylgruppen eller -grupperne ved hydrolyse eller alkoho-lyse og derefter, om muligt, udvinding af amoxicillin, sædvanligvis som det krystallinske tri hydrat. Således opnåedes krystallinsk amoxicillin i eksempel 1 ved isoelektrisk fældning fra en vandig opløsning, f.eks. ved pH-værdi 4,7. Rensning opnåedes formentlig i dette eksempel ved opløs-15 ning af det rå produkt (før isoelektrisk fældning) i vand ved en sur pH-værdi, såsom 1,0 (f.eks. i vandig hydrogenchloridsyre) i nærværelse af et med vand ublandbart organisk opløsningsmiddel, såsom methyliso-butylketon (4-methylpentan-2-on). I væsentlig grad samme fremgangsmåde anvendtes i U.S.A. patentskrift nr. 3.674.776.British Patent Specification 1,339,605 contains various specific and detailed examples of the preparation of amoxicillin by reacting a silylated derivative of 6-aminopenicilic acid with a reactive derivative (including the chloride, the hydrochloride) of D - (-) - a- amino-β-hydroxyphenylacetic acid in which the amino group is protected, then removal of the silyl group or groups by hydrolysis or alcoholysis and then, if possible, recovery of amoxicillin, usually as the crystalline trihydrate. Thus, crystalline amoxicillin in Example 1 was obtained by isoelectric precipitation from an aqueous solution, e.g. at pH 4.7. Purification was probably achieved in this example by dissolving the crude product (before isoelectric precipitation) in water at an acidic pH such as 1.0 (e.g., in aqueous hydrochloric acid) in the presence of a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one). Substantially the same approach was used in U.S.A. U.S. Patent No. 3,674,776.
20 Ifølge den foreliggende opfindelse tilvejebringes hidtil ukendte forbindelser med formlen O c .CH_.According to the present invention there are provided novel compounds of formula O c.
or , , II , , 25 (CH~)-Si-0-C-NH-CH—CH · C.- (i) ^ ^ Il I ^or,, II,, (CH ~) -Si-O-C-NH-CH-CH · C.- (i)
λ-N-CHλ-N-CH
tf Itf I
υ C-O-Bυ C-O-B
II- 0 30 hvori B betegner en let fraspaltelig ester-beskyttende gruppe udvalgt blandt gruppen bestående af trimethylsilyl, benzhydryl, benzyl, p-nitro-benzyl, p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxy-35 methyl, 5-indanyl, 3-phthalidyl, l-[(ethoxycarbonyl)oxy]ethyl, pi.valoyl-oxymethyl og acetoxymethyl. Til fremstilling af et konventionelt penicillin omsættes omhandlede forbindelser med formlen (I) i et vandfrit inert organisk opløsningsmiddel, og fortrinsvis i methylenchlorid,II-0 30 wherein B represents an easily leaving ester protecting group selected from the group consisting of trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pyvaloyl-oxymethyl and acetoxymethyl. To prepare a conventional penicillin, the compounds of formula (I) are reacted in an anhydrous inert organic solvent, and preferably in methylene chloride.
DK 162055 BDK 162055 B
3 fortrinsvis i nærværelse af en svag base, der fortrinsvis er propylen-oxid, og fortrinsvis ved en temperatur over -10°C, og mere foretrukket i området fra -8°C til 20°C, og endnu mere foretrukket i området fra 0°C til 20°C, og mest foretrukket ved ca. 20°C, med omtrentlig en ækvimolær 5 vægtmængde af et syrechlorid eller chloridhydrogenchlorid, hvor sidstnævnte fortrinsvis tilsættes portionsvis til opløsningen af førstnævnte, hvorefter man om ønsket omdanner gruppen B til hydrogen.3 preferably in the presence of a weak base which is preferably propylene oxide, and preferably at a temperature above -10 ° C, and more preferably in the range of -8 ° C to 20 ° C, and even more preferably in the range of 0 ° C to 20 ° C, and most preferably at approx. 20 ° C, with approximately an equimolar 5 weight amount of an acid chloride or chloride hydrogen chloride, the latter being preferably added portionwise to the solution of the former, and if desired, group B is converted to hydrogen.
Med "konventionelt penicillin" menes i det foreliggende et penicillin, der tidligere har været beskrevet i patentlitteraturen eller 10 den videnskabelige litteratur, herunder sammendrag deraf.By "conventional penicillin" herein is meant a penicillin previously described in the patent literature or the scientific literature, including summaries thereof.
Ifølge den foreliggende opfindelse tilvejebringes endvidere en fremgangsmåde til fremstilling af forbindelsen med formlen 15 O yClL· H / P (i) (CH,),Si-0-C-NH-CH— CH C^r„ v 3'3 || I CH3Further, according to the present invention, there is provided a process for the preparation of the compound of the formula 15 O yClL · H / P (i) (CH,), Si-O-C-NH-CH-CH C In CH3
i-n-CHi-N-CH
tf 1tf 1
u C-O-Bu C-O-B
20 II -II -
OISLAND
hvori B betegner en let fraspaltelig ester-beskyttende gruppe udvalgt blandt gruppen bestående af trimethylsilyl, benzhydryl, benzyl, p-nitro-25 benzyl, p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxy-methyl, 5-indanyl, 3-phthalidyl, l-[(ethoxycarbonyl)oxy]ethyl, pivaloyloxymethyl og acetoxymethyl, hvilken fremgangsmåde er ejendommelig ved, at man sætter tør carbondioxid som en gas til en opløsning af en forbindelse med formlen 30 /CH5 (CH^Si-NH-CH-CH C^CHj (h)wherein B represents an easily leaving ester-protecting group selected from the group consisting of trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl and acetoxymethyl, which is characterized by adding dry carbon dioxide as a gas to a solution of a compound of formula 30 / CH5 (CH2 Si-NH-CH-CH C (CH)
/ ” ?H/ "? H
« 0 C-O-B«0 C-O-B
35 ||35 ||
OISLAND
DK 162055BDK 162055B
4 hvor B har samme betydning som ovenfor anført, i et vandfrit inert organisk opløsningsmiddel, fortrinsvis methylenchlorid, ved stuetemperatur eller ved en temperatur i intervallet fra 0°C til 100°C, indtil reaktionen er løbet til ende.4 wherein B has the same meaning as above, in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or at a temperature ranging from 0 ° C to 100 ° C until the reaction is complete.
5 Til fremstilling af en 6-a-aminoarylacetamidopenicillansyre, for trinsvis ampici1 lin eller amoxicillin, omsætter man således en forbindelse med formlenThus, to prepare a 6-α-aminoarylacetamidopenicillanic acid, for stepwise ampicillin or amoxicillin, a compound of the formula is reacted
0 Q0 Q
|| / \ yCYU|| / \ yCYU
10 (CH,),Si-0-C-KH-CH—CH C J {Ia)(CH,), Si-O-C-KH-CH-CH C J {Ia)
^ I I I^CH^ I I I ^ CH
i-N-CH ^ / i U l-O-SiiCH^)^i-N-CH ^ / i U l-O-SiiCH ^) ^
OISLAND
15 i et vandfrit, inert organisk opløsningsmiddel, fortrinsvis i methylen-chlorid, og fortrinsvis i nærværelse af en svag base, der fortrinsvis er propylenoxid, og fortrinsvis ved en temperatur over -10°C, mere foretrukket i intervallet fra -8°C til 20°C, endnu mere foretrukket i inter-20 vallet fra 0°C til 20°C, og mest foretrukket ved ca. 20°C, med omtrentlig en ækvimolær mængde af et D-(-)-a-aminoarylacetylchlorid,hydro-chlorid, fortrinsvis D-(-)-2-phenylglycylchlorid,hydrochlorid eller D-(-)-2-p-hydroxyphenylglycylchlorid,hydrochlorid, hvor sidstnævnte reaktant fortrinsvis tilsættes portionsvis til opløsningen af førstnævnte 25 reaktant.15 in an anhydrous, inert organic solvent, preferably in methylene chloride, and preferably in the presence of a weak base, which is preferably propylene oxide, and preferably at a temperature above -10 ° C, more preferably in the range of -8 ° C to 20 ° C, even more preferably in the range of 0 ° C to 20 ° C, and most preferably at approx. 20 ° C, with approximately an equimolar amount of a D - (-) - α-aminoarylacetyl chloride, hydrochloride, preferably D - (-) - 2-phenylglycyl chloride, hydrochloride or D - (-) - 2-p-hydroxyphenylglycyl chloride, hydrochloride, wherein the latter reactant is preferably added portionwise to the solution of the former reactant.
Et af de overraskende· træk ved anvendelsen af de hidtil ukendte mellemprodukter er stabiliteten af den vandfrie acyleringsopløsning.One of the surprising features of the use of the novel intermediates is the stability of the anhydrous acylation solution.
Denne kan holdes i lange tidsrum, selv ved stuetemperatur, uden at nogen mærkbar dekomponering af penicillinmolekylet finder sted. Dette står i 30 kontrast til opførslen af acyleringsopløsninger ved fremgangsmåder kendt i teknikken. Denne stabilitetsfordel muliggør, at man kan udføre acyle-ringsreaktionen ved langt højere temperaturer (f.eks. stuetemperatur) end normalt anvendt ved ampicillinfremstillingen, hvor temperaturen normalt er under 0°C og typisk ca. -10°C.This can be kept for long periods of time, even at room temperature, without any appreciable decomposition of the penicillin molecule. This contrasts with the behavior of acylation solutions by methods known in the art. This stability advantage enables the acylation reaction to be carried out at much higher temperatures (e.g. room temperature) than normally used in the ampicillin preparation, where the temperature is usually below 0 ° C and typically approx. -10 ° C.
35 Der tilvejebringes også som en foretrukket udførelsesform en, frem gangsmåde til fremstilling af forbindelsen med formlenAlso provided, as a preferred embodiment, is a process for preparing the compound of the formula
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5 0 nr5 0 no
i) / Sice
5 (CI^i-jSi-O-C-MH-CH CH j^cH^ <Ia) }-*' f O· C-O-SiCCIU)^5 (C1-6Si-O-C-MH-CH CH2 ^ cH ^ <Ia)} - * 'f O · C-O-SiCCIU) ^
IIII
o 10 ved hvilken man sætter tør carbondioxid som en gas til en opløsning af trimethylsilyl-6-trimethylsilylaminopenicillanat i et vandfrit inert organisk opløsningsmiddel, fortrinsvis methylenchlorid, ved stuetemperatur, eller ved en temperatur i intervallet fra 0°C til 100°C, indtil 15 reaktionen er løbet til ende.Dry carbon dioxide is added as a gas to a solution of trimethylsilyl-6-trimethylsilylaminopenicillanate in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature, or at a temperature in the range of 0 ° C to 100 ° C. the reaction has ended.
Den foretrukne forbindelse ifølge opfindelsen har formlen il /S\ /CH, 20 (CHj^Si-O-C-ira-CH-CH C^CH da) i— N-CH 5The preferred compound of the invention has the formula I / S \ / CH, 20 (CH2 Si-O-C-ira-CH-CH C
°\ C-0-Si(CH,U° C-O-Si (CH, U
II ^ ^ o 25II ^^ o 25
Denne forbindelse omtales her ved forskellige trivialnavne, såsom bis-si lyleret carbamat af 6-APA, SCA, 6-trimethylsilyloxycarbonyl-penicillansyre TMS-ester og TMS02C,APA,TMS.This compound is referred to herein by various trivial names, such as bis-silylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonyl-penicillanic acid TMS ester and TMSO2C, APA, TMS.
Selve eksistensen af denne forbindelse er overraskende i betragt-30 ning af den velkendte kendsgerning, at omsætning af 6-APA med carbondioxid ødelægger 6-APA og giver 8-hydroxypenicillansyre som omhandlet f.eks. i U.S.A. patentskrift nr. 3.225.033.The very existence of this compound is surprising considering the well-known fact that reacting 6-APA with carbon dioxide destroys 6-APA and yields 8-hydroxypenicillanic acid as contemplated e.g. in USA. U.S. Patent No. 3,225,033.
Et middel til opnåelse af kvantitative udbytter af 6-trimethyl-s ilyloxycarbonylami nopeni ci11ansyre tri methyl s i 1ylester (TMS01C,APA,TMS) 35 ligger i fuldstændigt at fremstille 6-APA bis-TMS-prækursoren i første omgang. Dette er blevet opnået ved, at man omsætter 6-APA med hexa-methyldisilazan (HMDS) som i følgende reaktionsskema:An agent for obtaining quantitative yields of the 6-trimethyl-s ilyloxycarbonylamino nepi-cilanic acid tri-methyl s in 1-ester (TMS01C, APA, TMS) 35 is in the complete preparation of the 6-APA bis-TMS precursor in the first place. This has been achieved by reacting 6-APA with hexa-methyldisilazane (HMDS) as in the following reaction scheme:
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6 6-APA + HMDS + Imidazol- Tilbagesvaling 1 mol 1,1 mol katalysator 6-8 timer 3-5 mol% 56 6-APA + HMDS + Imidazole- Reflux 1 mole 1.1 mole catalyst 6-8 hours 3-5 mole% 5
Fuldstændig carboxyl Tilsæt 5 mo1% TMCS og "silylering" & ca. tilbagesvaling natten 40-65% 6-NH2 over 10 "silylering" _ TMSNH s - \-S "NC (6-APA,bis-TMS) lo ..... — __ yd N-\ cr *co2™sComplete carboxyl Add 5 ml of 1% TMCS and "silylation" & approx. reflux overnight 40-65% 6-NH 2 over 10 "silylation" _ TMSNH s - \ -S "NC (6-APA, bis-TMS) lo ..... - __ yd N- \ cr * co2 ™ s
Afslutningen af bis-trimethylsilyleringsreaktionen kan let følges 20 ved anvendelse af NMR. 3-trimethylsilyloxycarbonylgruppen viser en methyl silyl-singlet ved 0,31 ppm (tetramethylsilan = 0), medens 6-tri-methylsilylamingruppen viser en methyl silyl-singlet ved 0,09 ppm.The termination of the bis-trimethylsilylation reaction can be readily followed using NMR. The 3-trimethylsilyloxycarbonyl group shows a methyl silyl singlet at 0.31 ppm (tetramethylsilane = 0), while the 6-trimethylsilylamine group shows a methyl silyl singlet at 0.09 ppm.
6-APA-trimethylsilyleringsreaktionen er hidtil kun blevet udført i methylenchlorid. Andre opløsningsmidler kan imidlertid anvendes, som 25 f.eks. acetonitril, dimethyl formamid eller endog selve HMDS.The 6-APA trimethylsilylation reaction has so far been carried out only in methylene chloride. However, other solvents may be used, such as e.g. acetonitrile, dimethyl formamide or even HMDS itself.
Omdannelse af trimethylsilylaminogruppen til trimethyl silyloxy-carbonylaminogruppen opnås let ved at boble tør C02 i reaktionsopløsningen. Omdannelsen følges let ved hjælp af NMR, fordi trimethylsilyl-amino-singletten ved 0,09 ppm deklinerer efterhånden, som der optræder 30 en ny singlet for trimethylsilyloxycarbonylaminogruppen ved 0,27 ppm.Conversion of the trimethylsilylamino group to the trimethyl silyloxy-carbonylamino group is readily achieved by bubbling dry CO 2 in the reaction solution. The conversion is readily followed by NMR because the trimethylsilyl amino singlet at 0.09 ppm declines as a new trimethylsilyloxycarbonylamino group occurs at 0.27 ppm.
Når fremgangsmåden anvendes til fremstilling af ampicillin, ampicillinanhydrat, ampici 11 intrihydrat, amoxicillin og amoxicillin·^ tri hydrat, isoleres slutprodukterne og renses i henhold til konventionelle metoder, der er velkendte inden for tek-nikken, som belyst af 35 U.S.A. patentskrifter nr. 3.912.719, 3.980.637 og 4.128.547, samt andre deri angivne patentskrifter og publikationer.When used in the preparation of ampicillin, ampicillin anhydrate, ampicillin intrihydrate, amoxicillin and amoxicillin trihydrate, the final products are isolated and purified according to conventional methods well known in the art as illustrated by 35 U.S.A. Patent Nos. 3,912,719, 3,980,637 and 4,128,547, as well as other patents and publications therein.
De i de følgende eksempler anvendte syrechlorider kan erstattes af en lang række andre syrechlorider til fremstilling af konventionelleThe acid chlorides used in the following examples can be replaced by a wide variety of other acid chlorides to produce conventional
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7 penicilliner.7 penicillins.
Således kan acylhalogenidet udvælges til indføring af en vilkårlig ønsket acylgruppe i 6-aminosti11 ingen, som velkendt i teknikken, f.eks.Thus, the acyl halide can be selected to introduce any desired acyl group into the 6-amino acid, as is well known in the art, e.g.
U.S.A. patentskrift nr. 3.741.959.U.S.A. U.S. Patent No. 3,741,959.
5 Når acylgruppen, som skal indføres, indeholder en aminogruppe, kan det være nødvendigt at beskytte denne under de forskellige reaktionsstadier. Den beskyttende gruppe er hensigtsmæssigt en, som kan fjernes ved hydrolyse uden at påvirke resten af molekylet, især lactam- og 7-amido-bindingerne. Den amin-beskyttende gruppe og den esterificerende 10 gruppe i 4-C00H-sti11 ingen kan fjernes under anvendelse af samme reagens. En fordelagtig fremgangsmåde består i at fjerne begge grupper i det sidste trin i sekvensen. Beskyttede amin-grupper omfatter urethan, arylmethyl (f.eks. tri tyl)-ami no, arylmethylenamino, sul phenyl amino eller enamin-typer. Enamin-blokerende grupper er særligt værdifulde i 15 tilfælde af o-aminomethylphenyleddikesyre. Sådanne grupper kan i almindelighed fjernes ved hjælp af et eller flere reagenser udvalgt blandt fortyndede mineralsyrer, f.eks. fortyndet saltsyre, koncentrerede organiske syrer, f.eks. koncentreret eddikesyre, tri fluoreddikesyre og flydende hydrogenbromid ved meget lave temperaturer, f.eks. -80°C. En 20 hensigtsmæssig beskyttende gruppe er t-butoxycarbonylgruppen, der let fjernes ved hydrolyse med fortyndet mineralsyre, f.eks. fortyndet saltsyre, eller fortrinsvis med en stærk organisk syre (f.eks. myresyre eller tri fluoreddikesyre), f.eks. ved en temperatur på 0-40°C, fortrinsvis ved stuetemperatur (15-25°C). En anden hensigtsmæssig beskyttende 25 gruppe er 2,2,2-trichlorethoxycarbonylgruppen, der kan fraspaltes med et middel, såsom zink/eddikesyre, zink/myresyre, zink/lavere alkoholer eller zink/pyridin.When the acyl group to be introduced contains an amino group, it may be necessary to protect it during the various reaction stages. The protecting group is conveniently one that can be removed by hydrolysis without affecting the rest of the molecule, especially the lactam and 7-amido bonds. The amine protecting group and the esterifying group in the 4-C00H pathway can be removed using the same reagent. An advantageous method consists of removing both groups in the last step of the sequence. Protected amine groups include urethane, arylmethyl (e.g., triethyl) amine, arylmethylenamino, sul phenyl amino or enamine types. Enamine blocking groups are particularly valuable in 15 cases of o-aminomethylphenylacetic acid. Such groups can generally be removed by one or more reagents selected from dilute mineral acids, e.g. dilute hydrochloric acid, concentrated organic acids, e.g. concentrated acetic acid, trifluoroacetic acid and liquid hydrogen bromide at very low temperatures, e.g. -80. A convenient protecting group is the t-butoxycarbonyl group which is readily removed by dilution with dilute mineral acid, e.g. diluted hydrochloric acid, or preferably with a strong organic acid (e.g. formic acid or trifluoroacetic acid), e.g. at a temperature of 0-40 ° C, preferably at room temperature (15-25 ° C). Another suitable protecting group is the 2,2,2-trichloroethoxycarbonyl group which can be cleaved off with an agent such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohols or zinc / pyridine.
M^-gruppen kan også beskyttes som NH3+ ved anvendelse af ami nosy rehal ogen i det som et syreadditionssalt under betingelser, hvor amino-30 gruppen forbliver protoni seret.The M 2 group can also be protected as NH 3 + by using the amino acid halide in it as an acid addition salt under conditions where the amino group remains protonated.
Den til dannelse af syreadditionssaltet anvendte syre er fortrinsvis en syre med en pK,-værdi (i vand ved 25°C) på >X+1, hvor X er pK - d d værdien (i vand ved 25°C) af aminosyrens carboxygrupper. Syren er fortrinsvis monovalent. I praksis vil syren HQ (se nedenfor) i almin-35 delighed have en pK. <3, fortrinsvis <1.The acid used to form the acid addition salt is preferably an acid having a pK, value (in water at 25 ° C) of> X + 1, where X is the pK - d d value (in water at 25 ° C) of the amino acid carboxy groups. The acid is preferably monovalent. In practice, the acid HQ (see below) will generally have a pK. <3, preferably <1.
d Særligt fordelagtige resultater har vist sig at blive opnået, når syrehal ogenidet er et salt af et aminosyrehalogenid. Aminosyrehalogeni der har formlend Particularly advantageous results have been found when the acid tail ogenide is a salt of an amino acid halide. Amino acid halogen having the formula
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88
HgN-R^COHal hvori R* betyder en divalent organisk gruppe, og Hal betyder chlorid 5 eller bromid. Salte af sådanne aminosyrehalogenider har formlen [H3N-R1-C0Hal]+Q" hvori R* og Hal har den ovenfor anførte betydninger, og Q" betyder 10 anionen af syren, idet HQ har en pK. som defineret ovenfor. Syren HQ er fortrinsvis en stærk mineralsyre, som f.eks. en hydrohalogenidsyre, såsom saltsyre eller hydrogenbromidsyre. Et vigtigt aminosyrehalogenid er, på grund af de værdifulde penicillinantibiotika, som indeholder den deraf afledte gruppe, D-N-(a-chlorcarbonyl-a-phenyl)methylammonium- 15 chlorid, D-[PhCH(NH3)COCl]+Cl, der her af nemheds grunde omtales som D- α-phenylgiycylchlori d,hydrochlorid.HgN-R 2 COHal wherein R * represents a divalent organic group and Hal represents chloride 5 or bromide. Salts of such amino acid halides have the formula [H3N-R1-COHal] + Q "wherein R * and Hal have the above meanings, and Q" means the anion of the acid, with HQ having a pK. as defined above. The acid HQ is preferably a strong mineral acid, e.g. a hydrohalic acid such as hydrochloric or hydrobromic acid. An important amino acid halide is, because of the valuable penicillin antibiotics containing the resulting group, DN- (α-chlorocarbonyl-α-phenyl) methylammonium chloride, D- [PhCH (NH 3) COCl] + Cl reasons of convenience are referred to as D-α-phenylglycyl chloride d, hydrochloride.
Penicilliner, som har en acylamidogruppe RuCH(NH«)-CONH-, hvor Ru L 2 3 har den ovenfor anførte betydning, kan omsættes med en keton R .R CO, 2 3 hvori R og R betyder lavere al kyl grupper (Cj-C^), til dannelse af 20 forbindelser, som antages at indeholde gruppenPenicillins having an acylamido group RuCH (NH 4) - CONH-, where Ru L 2 3 has the meaning given above, can be reacted with a ketone R 1 R 2 CO, 2 3 wherein R and R mean lower alkyl groups (C C ^) to form 20 compounds believed to contain the group
COCO
» . /\ R--CH N- 1_I,». / \ R - CH N- 1_I,
HN__RZHN__RZ
A3 30A3 30
Forbindelser af denne type omfatter hetacillin, sarpicillin, p-hydroxy-35 hetacillin og sarmoxicillin.Compounds of this type include hetacillin, sarpicillin, p-hydroxy-hetacillin and sarmoxicillin.
Opfindelsen illustreres nærmere under henvisning til tegningen, hvor:The invention is further illustrated with reference to the drawing, in which:
Figur 1 viser 80 MHz NMR-spektret for si lyleret 6-APA i området 0-2Figure 1 shows the 80 MHz NMR spectrum of silylated 6-APA in the range 0-2
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9 ppm indeholdende det geminale signal for de to methylgrupper i 2-stil-1 ingen og signalet for 100% silylering af 3-carboxylgruppen og 100% silylering af 6-aminogruppen (foruden triethylamin,HCl (TEA-HC1), tri-methylchlorsilan (TMCS) og spor af hexamethyldisiloxan (HMDSO)), og 5 figur 2 viser 80 MHz NMR-spektret i området 0-2 ppm for produktet ifølge opfindelsen opnået ved ^-behandling af det i figur 1 viste silylerede 6-APA. 6-aminotrimethylsignalet er fuldstændigt forsvundet og et nyt signal fremkommet som følge af 6-trimethylsilylcarbonylamino-gruppen. Integration af 6-trimethylsilylcarbonylaminosignalet mod det 10 geminale dimethyl signal viser at omdannelsen til 6-trimethylsilyl-carbonylamino er 100%.9 ppm containing the geminal signal for the two methyl groups in 2-style-1 gene and the signal for 100% silylation of the 3-carboxyl group and 100% silylation of the 6-amino group (in addition to triethylamine, HCl (TEA-HCl), trimethylchlorosilane ( TMCS) and traces of hexamethyldisiloxane (HMDSO)), and Figure 2 shows the 80 MHz NMR spectrum in the range 0-2 ppm of the product of the invention obtained by β-treatment of the silylated 6-APA shown in Figure 1. The 6-aminotrimethyl signal has completely disappeared and a new signal has emerged as a result of the 6-trimethylsilylcarbonylamino group. Integration of the 6-trimethylsilylcarbonylamino signal against the geminal dimethyl signal shows that the conversion to 6-trimethylsilylcarbonylamino is 100%.
Fremgangsmåden ifølge opfindelsen belyses nærmere i de følgende eksempler.The process according to the invention is illustrated in more detail in the following examples.
15 Eksempel 1Example 1
Til en blanding af 6-aminopenicillansyre (6-APA) og 10 ml CDgC^ og 1,13 ml trimethylchlorsilan ved en temperatur på 25-27°C sattes dråbevis 1,23 ml tri ethylamin over et tidsrum af 30 minutter. Omrøring fortsattes i yderligere 2 timer. Tør carbondioxidgas bobledes dernæst i blandingen 20 i ca. 3 timer. Ved slutningen af dette tidsrum viste NMR (kernemagnetisk resonans) tilstedeværelsen af 60% silyleret carboxy-6-APA (SCA) med strukturen 25 8 ^ ^ (CH^Si-O-C-HN-i-p \CH5To a mixture of 6-aminopenicillanic acid (6-APA) and 10 ml of CD 2 Cl 2 and 1.13 ml of trimethyl chlorosilane at a temperature of 25-27 ° C was added dropwise 1.23 ml of triethylamine over a period of 30 minutes. Stirring was continued for another 2 hours. Dry carbon dioxide gas is then bubbled into the mixture 20 for approx. 3 hours. At the end of this time, NMR (nuclear magnetic resonance) showed the presence of 60% silylated carboxy-6-APA (SCA) with the structure 258 ^ (CH2 Si-O-C-HN-i-p \ CH5
i— Ni— N
O C-0-Si(CH UO C-O-Si (CH U
Il 5 * 30 . 0Il 5 * 30. 0
Blandingen holdtes i køleskab natten over. Næste morgen tilsattes 0,77 35 ml Ν,Ν-dimethylanilin, og blandingen afkøledes til -8°C. Dernæst tilsattes 1,2 g D-(-)-p-hydroxy-2-phenylglycylchlorid,hydrochlorid (79% renhed) i portioner som følger:The mixture was kept in the refrigerator overnight. The next morning, 0.77 ml of Ν, Ν-dimethylaniline was added and the mixture was cooled to -8 ° C. Next, 1.2 g of D - (-) - p-hydroxy-2-phenylglycyl chloride, hydrochloride (79% purity) was added in portions as follows:
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ίοίο
Tid i Temperatur Gram, tilsatTime in Temperature Gram, added
minutter °Cminutes ° C
0 -8 0,30 5 20 -4 0,30 40 -4 0,30 60 -4 0,30 120 +8 220 +15 10 310 +200 -8 0.30 5 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +15 10 310 +20
Ved afslutningen af de 310 minutters reaktionsperiode viste tyndt-1agskromatografi (TLC) foretaget på en prøve af reaktionsblandingen under anvendelse af et opløsningsmiddel system, som var 60% ethyl acetat, 15 20% eddikesyre og 20% vand, tilstedeværelsen af amoxicillin.At the end of the 310 minute reaction period, thin layer chromatography (TLC) performed on a sample of the reaction mixture using a solvent system which was 60% ethyl acetate, 15 20% acetic acid and 20% water, showed the presence of amoxicillin.
Til en kold, 2 ml prøve af den endelige reaktionsblanding sattes 1,0 ml D20. Efter adskillelse ved centrifugering viste den vandige fase sig ved NMR at indeholde 78% amoxicillin og ca. 20% 6-APA. Tilstedeværelsen af amoxicillin bekræftedes også ved TLC.To a cold 2 ml sample of the final reaction mixture was added 1.0 ml of D 2 O. After separation by centrifugation, the aqueous phase was found by NMR to contain 78% amoxicillin and ca. 20% 6-APA. The presence of amoxicillin was also confirmed by TLC.
2020
Eksempel 2Example 2
En blanding af 5,4 g (0,025 mol) 6-aminopenicillansyre og 6,2 ml 93% hexamethyldisilazan (HMDS; 0,0275 mol) samt 0,07 g (ca. 0,001 mol) imidazol i 40 ml CH2C12 tilbagesval edes under nitrogenskylning i ca.A mixture of 5.4 g (0.025 mol) of 6-aminopenicillanic acid and 6.2 ml of 93% hexamethyldisilazane (HMDS; 0.0275 mol) as well as 0.07 g (about 0.001 mol) of imidazole in 40 ml of CH 2 Cl 2 was refluxed under nitrogen rinsing. for approx.
25 17,5 timer. Ved slutningen af denne periode tilsattes 0,13 ml (ca. 0,001 mol) trimethylchlorsilan (TMCS). Opløsningen blev uklar. Tilbagesvaling fortsattes i yderligere 7 timer, og afsætninger af NH^Cl iagttoges i kondensatoren. På dette tidspunkt viste NMR ca. 100% silylering af både amino- og carboxylgruppen i 6-APA. Der tilsattes dernæst 0,2 ml HMDS 30 (0,00125 mol; ca. 5 molprocent) og 0,06 ml TMCS (ca. 0,0005 mol), og tilbagesvaling med nitrogenskylning fortsattes i yderligere 17 timer. På dette tidspunkt var NMR-spektret det samme som før med tilføjelsen af små mængder HMDS og TMCS. Tør carbondioxid bobledes dernæst i reaktions-blandingen ved stuetemperatur i 75 minutter, hvorefter NMR ikke viste 35 HMDS og mere end 92% silyleret carboxy-6-APA (SCA). Der tilsattes dernæst 4,45 ml Ν,Ν-dimethylanilin (DMA) (0,035 mol), og blandingen afkøledes til -3°C. Der tilsattes dernæst 5,65 g D-(-)-2-phenylglycylchlorid (95% renhed; 0,026 mol) i portioner som følger:25 17.5 hours. At the end of this period, 0.13 ml (about 0.001 mol) of trimethyl chlorosilane (TMCS) was added. The solution became fuzzy. Reflux was continued for a further 7 hours and deposits of NH 2 Cl were observed in the capacitor. At this point, the NMR showed approx. 100% silylation of both the amino and carboxyl group of 6-APA. 0.2 ml of HMDS 30 (0.00125 mol; about 5 mol%) and 0.06 ml of TMCS (about 0.0005 mol) were then added and reflux with nitrogen rinsing continued for an additional 17 hours. At this point, the NMR spectrum was the same as before with the addition of small amounts of HMDS and TMCS. Dry carbon dioxide was then bubbled into the reaction mixture at room temperature for 75 minutes, after which NMR did not show 35 HMDS and more than 92% silylated carboxy-6-APA (SCA). Then, 4.45 ml of Ν, Ν-dimethylaniline (DMA) (0.035 mol) was added and the mixture was cooled to -3 ° C. Then 5.65 g of D - (-) - 2-phenylglycyl chloride (95% purity; 0.026 mol) was added in portions as follows:
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1111
Tid i Temperatur Gram, tilsatTime in Temperature Gram, added
minutter °Cminutes ° C
5 O -3 1,05 20 O 1,30 40 O 1,30 50 O 1,00 60 O 1,00 105 O -3 1.05 20 O 1.30 40 O 1.30 50 O 1.00 60 O 1.00 10
Reaktionen fulgtes ved NMR, som viste meget lille ændring ca. 5 timer efter starten af reaktionen. Temperaturen var da 3°C. Reaktionsblandingen holdtes pakket i is i de næste 16 timer. Den fjernedes dernæst fra køling og omrørtes i 3,5 timer ved stuetemperatur (ca. 20-15 24°C). En stor mængde fast materiale var stadig tilstede. Reaktionsblandingen omrørtes dernæst ved stuetemperatur (22-24°C) i ca. 63 timer.The reaction was followed by NMR which showed very little change approx. 5 hours after the start of the reaction. The temperature was then 3 ° C. The reaction mixture was kept packed in ice for the next 16 hours. It was then removed from cooling and stirred for 3.5 hours at room temperature (about 20-15 24 ° C). A large amount of solid material was still present. The reaction mixture was then stirred at room temperature (22-24 ° C) for approx. 63 hours.
Ved slutningen af dette tidsrum var der kun let uklarhed. Ved DgO-ekstraktion af en prøve viste NMR ampicillin og 6-APA.At the end of this time, there was only slight obscurity. Upon DgO extraction of a sample, NMR showed ampicillin and 6-APA.
Reaktionsblandingen afkøledes til ca. 0°C og omrørtes 5 minutter i 20 kulden efter tilsætning af 35 ml isvand. Efter poleringsfiltrering vaskedes blandingen med koldt vand og CHgClg. Den vandige fase viste efter fraskillelse, ved hjælp af TLC en stor zone, som var langsommere end ampici11 in og 6-APA, og som repræsenterede nyt mellemprodukt X.The reaction mixture was cooled to ca. 0 ° C and stirred for 5 minutes in the cold after adding 35 ml of ice water. After polishing filtration, the mixture was washed with cold water and CH 2 Cl 2. After separation, the aqueous phase showed a large zone slower than ampici11 in and 6-APA, which represented new intermediate X.
Den vandige fase indstilledes på pH-værdi 3,0 med NH40H og podedes 25 med ampicillin. Methyl isobutylketon (MIBK; 35 ml) tilsattes, og blandingen omrørtes, indstilledes på pH-værdi 5,2 med mere NH^OH, omrørtes ved 20°C i 1 time, omrørtes i et isbad i yderligere 1 time og køledes natten over. Bundfaldet af ampicillin opsamledes ved filtrering, vaskedes først med 25 ml koldt vand og dernæst med 40 ml MIBK og endelig med 40 ml af 30 en blanding af 85 dele isopropyl al kohol og 15 dele vand, tørredes ved 50°C og viste sig at veje 4,5 g med dets identitet som ampicillin bekræftet ved TLC.The aqueous phase was adjusted to pH 3.0 with NH 4 OH and inoculated with ampicillin. Methyl isobutyl ketone (MIBK; 35 ml) was added and the mixture was stirred, adjusted to pH 5.2 with more NH 3 OH, stirred at 20 ° C for 1 hour, stirred in an ice bath for an additional 1 hour and cooled overnight. The precipitate of ampicillin was collected by filtration, washed first with 25 ml of cold water and then with 40 ml of MIBK and finally with 40 ml of 30 a mixture of 85 parts of isopropyl alcohol and 15 parts of water, dried at 50 ° C and weighed 4.5 g with its identity as ampicillin confirmed by TLC.
Eksempel 3 35 En blanding af 5,4 g 6-APA, 6,2 ml HMDS (93%) og 0,06 g imidazol i 50 ml ^Clg til bagesval edes under nitrogenskylning i 18 timer. Dernæst tilsattes 0,1 ml TMCS, som bevirkede uklarhed. Tilbagesvaling i yderligere 2 timer gav en klar opløsning med NH^Cl i kondensatoren. Der 12Example 3 A mixture of 5.4 g of 6-APA, 6.2 ml of HMDS (93%) and 0.06 g of imidazole in 50 ml of Clg for reflux is added under nitrogen rinsing for 18 hours. Next, 0.1 ml of TMCS was added which caused turbidity. Reflux for a further 2 hours gave a clear solution of NH4 Cl in the condenser. There 12
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tilsattes dernæst yderligere 0,1 ml TMCS, som kun efterlod meget ringe uklarhed. Tilbagesvaling fortsattes uden nitrogenskylning i de næste 65 timer. Blandingen afkøledes dernæst til ca. 22°C, og tilsætning af tør carbondioxid påbegyndtes. Efter 75 minutter viste NMR dannelsen af mere 5 end 90% bis-silyleret carbamat (SCA). Der tilsattes dernæst 4,45 ml DMA og dernæst 5,6 g D-(-)-2-phenylglycylchlorid,hydrochlorid (97% renhed) i portioner som følger:a further 0.1 ml of TMCS was then added, leaving only very slight turbidity. Reflux was continued without nitrogen rinsing for the next 65 hours. The mixture was then cooled to ca. 22 ° C and addition of dry carbon dioxide was started. After 75 minutes, the NMR showed the formation of more than 90% bis-silylated carbamate (SCA). Then 4.45 ml of DMA and then 5.6 g of D - (-) - 2-phenylglycyl chloride, hydrochloride (97% purity) were added in portions as follows:
Tid i Temperatur Gram, tilsatTime in Temperature Gram, added
10 minutter °C10 minutes ° C
0 20 1,35 20 20 1,30 32 20 1,00 15 48 20 1,00 75 20 1,000 20 1.35 20 20 1.30 32 20 1.00 15 48 20 1.00 75 20 1.00
Efter at denne blanding var blevet omrørt i yderligere 17 timer foretoges TLC på prøver af reaktionsblandingen og på fortyndet reak-20 tionsblanding (1 ml af reaktionsblandingen fortyndet med 2 ml CHgClg) og viste i hver en lille zone af ampicillin og en stor zone af nyt mellemprodukt X.After this mixture was stirred for an additional 17 hours, TLC was performed on samples of the reaction mixture and on diluted reaction mixture (1 ml of the reaction mixture diluted with 2 ml CHgCl 2) and showed in each a small zone of ampicillin and a large zone of new intermediate X.
Reaktionsblandingen afkøledes dernæst til 0°C, 40 ml isvand tilsattes, og blandingen omrørtes i 5 minutter, poleringsfiltreredes og 25 vaskedes med vand og med CHgCl^ Den vandige fase fraskiltes, 10% fjernedes til prøvning, og resten indstilledes på pH-værdi 3,0 med NH^OH, podedes med ampicillin og omrørtes. Efter tilsætning af yderligere 40 ml MIBK omrørtes blandingen, og pH-værdien indstilledes på 5,2 med NH40H og omrørtes ved stuetemperatur i i time oq dernæst på et isbad i yderligere 30 1 time. Krystaller udfældede. Efter afkøling natten over opsamledes det krystallinske produkt ved filtrering, vaskedes successivt med MIBK, vand og MIBK Og dernæst med 40 ml isopropanol-vand (85-15) og tørredes ved 45°C til dannelse af 6,25 g ampicillin (6,8 g korrigeret for prøvning eller et udbytte på 68%).The reaction mixture was then cooled to 0 ° C, 40 ml of ice water was added and the mixture stirred for 5 minutes, polished filtered and washed with water and with CH 2 Cl 2. The aqueous phase was separated, 10% removed for testing and the residue adjusted to pH 3. 0 with NH 2 OH, inoculated with ampicillin and stirred. After adding an additional 40 ml of MIBK, the mixture was stirred and the pH was adjusted to 5.2 with NH 4 OH and stirred at room temperature for 1 hour and then on an ice bath for a further 30 1 hour. Crystals precipitated. After cooling overnight, the crystalline product was collected by filtration, washed successively with MIBK, water and MIBK And then with 40 ml of isopropanol-water (85-15) and dried at 45 ° C to give 6.25 g of ampicillin (6.8 g corrected for testing or 68% yield).
Eksempel 4Example 4
Til en blanding af 1,0 g 6-APA og 1,13 ml TMCS i 10 ml CDgClg sattes dråbevis 1,23 ml TEA over 30 minutter, og blandingen omrørtes i 35To a mixture of 1.0 g of 6-APA and 1.13 ml of TMCS in 10 ml of CDgClg was added dropwise 1.23 ml of TEA over 30 minutes and the mixture was stirred for 35 minutes.
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13 yderligere 2 timer. Tør carbondioxid tilbobledes dernæst i 4 timer. På dette tidspunkt viste NMR ca. 55-60% carboxysilylering. Blandingen holdtes i køleskab natten over. Om morgenen tilsattes 0,77 ml DMA, blandingen omrørtes, afkøledes til -8°C, og der tilsattes 1,2 g D-(-)-p-5 hydroxy-2-phenylglycylchlorid,hydrochlorid i portioner som følger:13 additional 2 hours. Dry carbon dioxide was then refluxed for 4 hours. At this point, the NMR showed approx. 55-60% carboxysilylation. The mixture was kept in the refrigerator overnight. In the morning, 0.77 ml of DMA was added, the mixture was stirred, cooled to -8 ° C and 1.2 g of D - (-) - p-5 hydroxy-2-phenylglycyl chloride, hydrochloride in portions were added as follows:
Tid i Temperatur Gram, tilsatTime in Temperature Gram, added
minutter °Cminutes ° C
10 0 -8 0,30 20 -4 0,30 40 -4 0,30 60 -4 0,30 120 8 15 220 15 310 2010 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 15 220 15 310 20
Ved slutningen af 310 minutters perioden viste NMR ca. 78% amoxicillin og ca. 20% 6-APA.At the end of the 310 minute period, NMR showed approx. 78% amoxicillin and approx. 20% 6-APA.
2020
Eksempel 5 Tør 6-aminopenicillansyre (10,0 g, 46,24 mmol, 1,0 ækv.) suspenderedes i vandfri methylenchlorid (175 ml) under omrøring ved 25°C. Tri-ethylamin (10,76 g, 106,36 mmol, 2,30 ækv.) tilsattes ved 25°C efter-25 fulgt af tilsætning af trimethylchlorsilan (11,70 g, 107,75 mmol, 2,33 ækv.) over et 10-15 minutters tidsrum, idet temperaturen holdtes under ca. 32°C ved hjælp af tilsætningshastigheden for trimethylchlorsilan.Example 5 Dry 6-aminopenicillanic acid (10.0 g, 46.24 mmol, 1.0 eq) was suspended in anhydrous methylene chloride (175 ml) with stirring at 25 ° C. Triethylamine (10.76 g, 106.36 mmol, 2.30 eq) was added at 25 ° C followed by addition of trimethyl chlorosilane (11.70 g, 107.75 mmol, 2.33 eq) over a 10-15 minute period, keeping the temperature below ca. 32 ° C using the addition rate of trimethyl chlorosilane.
Efter omrøring i 20-30 minutter analyseredes blandingen, som indeholdt udfældet triethylamin,hydrochlorid, for fuldstændig silylering ved 80 30 MHz NMR. Blandingen forgassedes dernæst med carbondioxid ved 20°C i ca.After stirring for 20-30 minutes, the mixture containing precipitated triethylamine hydrochloride was analyzed for complete silylation at 80 30 MHz NMR. The mixture was then gasified with carbon dioxide at 20 ° C for approx.
2 timer og analyseredes for fuldstændig carboxylering ved 80 MHz NMR. Yderligere gastilsætning var undertiden nødvendig. Volumenet af carboxyleringsblandingen genindstilledes om nødvendigt til ca. 175 ml med tør methylenchlorid. Da carboxyleringen var fuldstændig, behandledes 35 opslæmningen med propylenoxid (2,95 g, 3,56 ml, 50,87 mmol, 1,1 ækv.) og afkøledes til 0-5°C. D-(-)-2-(p-hydroxyphenyl)glycylchlorid,hydrochlorid hemidioxansolvat tilsattes i 5 X 2,71 g portioner ved ca. 2°C [i alt 13,54 g (50,87 mmol, 1,1 ækv.) tilsattes]. Hver portion syrechlorid fik2 hours and analyzed for complete carboxylation at 80 MHz NMR. Additional gas addition was sometimes needed. If necessary, the volume of the carboxylation mixture was reset to approx. 175 ml with dry methylene chloride. When the carboxylation was complete, the slurry was treated with propylene oxide (2.95 g, 3.56 ml, 50.87 mmol, 1.1 eq) and cooled to 0-5 ° C. D - (-) - 2- (p-hydroxyphenyl) glycyl chloride, hydrochloride hemidioxane solvate was added in 5 x 2.71 g portions at ca. 2 ° C [a total of 13.54 g (50.87 mmol, 1.1 eq) was added]. Each serving of acid chloride was given
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14 lov at opløse, før den næste portion ti Isattes. (Omrørinq blev afbrudt og blandingen undersøgt for eventuelt fast stof på bunden af kolben. Opslæmningen må ikke opvarmes under 5°C til denne test, da resultaterne kan blive fejlagtige). Dette krævede ca. 20 minutter pr. portion. Denne 5 portionsvise tilsætning var meget vigtig. Den endelige acyleringsblånding undersøgtes for eventuelt uopløst syrechlorid,hydrochlorid. Blandingen holdtes ved 0-5°C i 30 minutter og behandledes med koldt (0-5°C) deioniseret vand (DI) (100 ml) under meget hurtig omrøring i 10 minut ter. Blandingen fik lov at separere, og den nedre methylenchloridfase 10 fjernedes. Den vandrige fase poleringsfiltreredes (meget ringe mængde fast stof) gennem en tynd (Dicalite) forbelægning af diatoméjord, og kagen vaskedes med koldt (0-5°C) DI vand (15 ml). Eventuel nedre fase af organisk lag fjernedes før krystallisering. Den klare, lysegule vandige opløsning (pH 2-2,5) indstilledes på pH-værdi 3,5 ved 0-5°C og podedes 15 om nødvendigt. Opslæmningen holdtes ved 0-5°C i 40 minutter, og pH-værdien indstilledes på 4,8-5,0 med 6N ammoniumhydroxid og krystalliseredes i 2 timer. Opslæmningen filtreredes, og det således opsamledes faste amoxicillin vaskedes med en blanding af kold (0-5°C) 1:1 isopropanol/vand, og kagen vaskedes med methylenchlorid (30 ml), hvilket 20 gav ca. 13,5 g (ca. 70%) snehvid amoxicillin,tri hydrat.14 allowed to dissolve before the next batch of ten Isattes. (Stirring was discontinued and the mixture examined for any solid on the bottom of the flask. The slurry must not be heated below 5 ° C for this test as the results may be erroneous). This required approx. 20 minutes per portion. This 5 portion addition was very important. The final acylation mixture was investigated for any undissolved acid chloride, hydrochloride. The mixture was kept at 0-5 ° C for 30 minutes and treated with cold (0-5 ° C) deionized water (DI) (100 ml) with very rapid stirring for 10 minutes. The mixture was allowed to separate and the lower methylene chloride phase 10 was removed. The aqueous phase was polished (very low solids) filtered through a thin (Dicalite) coating of diatomaceous earth and the cake washed with cold (0-5 ° C) DI water (15 ml). Any lower layer of organic layer was removed before crystallization. The clear, pale yellow aqueous solution (pH 2-2.5) was adjusted to pH 3.5 at 0-5 ° C and seeded if necessary. The slurry was kept at 0-5 ° C for 40 minutes and the pH was adjusted to 4.8-5.0 with 6N ammonium hydroxide and crystallized for 2 hours. The slurry was filtered and the thus obtained solid amoxicillin was washed with a mixture of cold (0-5 ° C) 1: 1 isopropanol / water and the cake washed with methylene chloride (30 ml) to give ca. 13.5 g (about 70%) of snow white amoxicillin, tri hydrate.
Eksempel 6 6-aminopenicillansyre (108 g, 0,5 mol), 1,0 g imidazol (0,017 ml), 800 ml tør methylenchlorid og 120 ml (0,56 mol) HMDS (ca. 98% renhed) 25 omrørtes og opvarmedes til tilbagesvaling i 3,3 timer. Reaktionsblandingen skylledes med tør nitrogengas under tilbagesvalingen for at ' fjerne NH^ dannet under reaktionen. Dernæst tilsattes 2,0 ml trimethyl-chlorsilan (TMCS) (0,016 mol). Tilbagesvaling fortsattes med Ng-skylning i yderligere 19 timer, og dernæst var det i kondensatoren sublimerede 30 NH^Cl fjernet, og 2,6 ml TMCS (0,0206 mol) tilsattes til reaktionen. Tilbagesvaling med Ng-skylning fortsattes i yderligere 34 timer. Volumenet af reaktionsblandingeri bragtes til 1000 ml med tør methylenchlorid.Example 6 6-Aminopenicillanic acid (108 g, 0.5 mol), 1.0 g imidazole (0.017 ml), 800 ml dry methylene chloride and 120 ml (0.56 mol) HMDS (about 98% purity) was stirred and heated. for reflux for 3.3 hours. The reaction mixture was rinsed with dry nitrogen gas under reflux to remove NH 2 formed during the reaction. Next, 2.0 ml of trimethyl chlorosilane (TMCS) (0.016 mol) was added. Reflux was continued with Ng rinsing for a further 19 hours, then the 30 NH 3 Cl sublimated in the condenser was removed and 2.6 ml of TMCS (0.0206 mol) was added to the reaction. Reflux with Ng rinsing was continued for an additional 34 hours. The volume of reaction mixture was brought to 1000 ml with dry methylene chloride.
NMR viste da 100% silylering af amino- og carboxyl gruppen på 6-amino-penicillansyren. Opløsningen dækkedes med Ng-gas og holdtes i 9 dage.NMR then showed 100% silylation of the amino and carboxyl group of the 6-amino-penicillanic acid. The solution was covered with Ng gas and held for 9 days.
35 NMR bekræftede ovenstående og stabiliteten. Opløsningen omrørtes, og C02 tilbobledes i ca. 90 minutter. Temperatur 20-22°C. NMR viste 100% omdannelse af bis-trimethylsilyl-6-aminopenicillansyren til bis-trimethyl-silylcarboxy-6-aminopenicillansyre (SCA).35 NMR confirmed the above and the stability. The solution was stirred and CO 2 refluxed for approx. 90 minutes. Temperature 20-22 ° C. NMR showed 100% conversion of bis-trimethylsilyl-6-aminopenicillanic acid to bis-trimethylsilylcarboxy-6-aminopenicillanic acid (SCA).
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Denne basisblanding anvendtes til de nedenfor beskrevne acylerings-forsøg. Den kemiske forbindelse i denne opløsning havde formlen 5 '8 (CH})3Si-0-C-HH-1-ζ P'CHjThis basic mixture was used for the acylation experiments described below. The chemical compound in this solution had the formula 5 '8 (CH}) 3 Si-O-C-HH-1-ζ P'CH 2
)-*—I)-*-IN
o C-0-Si(CE, 10 II ^ 3 O.o C-O-Si (CE, 10 II ^ 3 O.)
NMR viste, at bis-trimethylsilylcarboxy-6-aminopenicillansyren var stabil efter 9 dage.NMR showed that the bis-trimethylsilylcarboxy-6-aminopenicillanic acid was stable after 9 days.
15 100 ml af basisblandingen (SCA ækvivalent med 10,8 g 6-aminopeni- cillansyre, 0,05 mol) omrørtes ved 22°C, og 0,0 g TEA,HC1 (0,058 mol) og 4,2 ml propylenoxid (0,06 mol) (se U.S.A. patentskrift nr. 3.741.959) tilsattes. Noget TEA,HC1 bundfældede. Blandingen omrørtes og afkøledes til +3°C. 15,5 g D-(-)-p-hydroxyphenylglycylchlorid,hydrochlorid hemi- 20 dioxansolvat (79% renhed, 0,055 mol) tilsattes reaktionsblandingen i portioner som følger:100 ml of the basic mixture (SCA equivalent of 10.8 g of 6-aminopencillanic acid, 0.05 mol) was stirred at 22 ° C and 0.0 g TEA, HCl (0.058 mol) and 4.2 ml of propylene oxide (0 , 06 mol) (see U.S. Patent No. 3,741,959) was added. Some TEA, HC1 precipitated. The mixture was stirred and cooled to + 3 ° C. 15.5 g of D - (-) - p-hydroxyphenylglycyl chloride, hydrochloride hemidioxane solvate (79% purity, 0.055 mol) were added to the reaction mixture in portions as follows:
Gram, tilsat Tid i TemperaturGram, added Time in Temperature
minutter °Cminutes ° C
25 ..............-..............................25 ..............-..............................
3.0 0 +3 3.0 7 +2 3.0 20 +2 6,5 33 +2 30 15,53.0 0 +3 3.0 7 +2 3.0 20 +2 6.5 33 +2 30 15.5
Efter yderligere 70 minutter tilsattes ca. 50 ml tør methylen-chlorid til reaktionsblandingen for at reducere viskositeten.After another 70 minutes, approx. 50 ml of dry methylene chloride to the reaction mixture to reduce the viscosity.
Efter yderligere 160 minutter fjernedes en 2 ml prøve og sattes til 35 1,0 ml DgO. Efter centrifugering viste NMR-analyse af den vandige fase ca. 6% uacyleret 6-aminopenicillansyre.After another 160 minutes, a 2 ml sample was removed and 1.0 ml of DgO was added. After centrifugation, NMR analysis of the aqueous phase showed ca. 6% unacylated 6-aminopenicillanic acid.
10 minutter senere overførtes reaktionsb]andingen til et 600 ml bægerglas, og overføringen afsluttedes ved vaskning med 50 ml methyl en- 16Ten minutes later, the reaction mixture was transferred to a 600 ml beaker and the transfer was terminated by washing with 50 ml methyl en 16
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1,0 ml D2O. Efter centrifugering viste NMR-analyse af den vandige fase ca. 6% uacyleret 6-aminopenicillansyre.1.0 ml D2O. After centrifugation, NMR analysis of the aqueous phase showed ca. 6% unacylated 6-aminopenicillanic acid.
10 minutter senere overførtes reaktionsb]åndingen til et 600 ml bægerglas, og overføringen afsluttedes ved vaskning med 50 ml methylen-5 chlorid. Under omrøring i et isbad tilsattes 60 ml koldt deioniseret isvand til frembringelse af en opløsning af to faser uden indhold af faste stoffer og med en pH-værdi på 1,0.Ten minutes later, the reaction mixture was transferred to a 600 ml beaker and the transfer was terminated by washing with 50 ml of methylene chloride. While stirring in an ice bath, 60 ml of cold deionized ice water was added to give a solution of two phases without solids content and having a pH of 1.0.
15,0 ml flydende anionbytterharpiks ("LA-1") sattes til tofase-systemet under omrøring og podning ved pH-værdi 2,0. Krystallisation 10 beqyndte. Yderligere 10,0 ml LA-1 tilsattes langsomt over ca. 5 minutter. pH-værdien var 3,0. Der tilsattes dernæst 0,15 g NaBH4. Dernæst tilsattes 5,0 ml LA-1; pH-værdien var 4,5. Omrøring fortsattes, og der tilsattes 1,0 g NaHS03 (natriumbi sul fit) i 4,0 ml vand dråbevis. Der tilsattes dernæst 10,0 ml LA-1; pH-værdien fortsatte med at stige. I alt 15 40 ml LA-1, den endelige pH-værdi var 5,6. Der tilsattes dernæst 5 ml acetone. På dette tidspunkt tilsattes 1,5 g NaHSOg opløst i 6,0 ml vand, over 30 minutter. Omrøring i isbad fortsattes. Det udfældede produkt opsamledes ved filtrering, og kagen vaskedes successivt med 50 ml methylenchlorid, 40 ml vand, 100 ml isopropyl al kohol-vand (80:20) og 100 20 ml methylenchlorid. Kagen tørredes dernæst ved atmosfæretryk og 45°C til opnåelse af 18,2 g amoxicillin,trihydrat, der var et udbytte på 87% baseret på 6-aminopenicillansyre; korrigeret for 1% til prøVning var det samlede udbytte ca. 88%.15.0 ml of liquid anion exchange resin ("LA-1") was added to the two-phase system with stirring and grafting at pH 2.0. Crystallization 10 accelerated. An additional 10.0 ml of LA-1 was added slowly over ca. 5 minutes. The pH was 3.0. 0.15 g of NaBH 4 was then added. Next, 5.0 ml of LA-1 was added; The pH was 4.5. Stirring was continued and 1.0 g of NaHSO 3 (sodium sulphite) in 4.0 ml of water was added dropwise. 10.0 ml of LA-1 was then added; The pH value continued to rise. A total of 15 40 ml of LA-1, the final pH was 5.6. Then 5 ml of acetone was added. At this point, 1.5 g of NaHSOg dissolved in 6.0 ml of water was added over 30 minutes. Stirring in ice bath was continued. The precipitated product was collected by filtration and the cake was washed successively with 50 ml of methylene chloride, 40 ml of water, 100 ml of isopropyl alcohol (80:20) and 100 ml of methylene chloride. The cake was then dried at atmospheric pressure and 45 ° C to give 18.2 g of amoxicillin trihydrate, which was 87% yield based on 6-aminopenicillanic acid; corrected for 1% for testing, the total yield was approx. 88%.
"LA-1" flydende anionbytterharpiks er en blanding af 10 sekundære 25 aminer, hvori hver sekundær amin har formlen R1 CH3C(CH3)2CH2C(CH3)2CH2CH=CH-CH2NHC-R2 30 R3 hvori hver af R , R og R er en alifatisk carbonhydridgruppé, og hvori R , R og R i aggregatet indeholder fra 11 til 14 carbonatomer; denne særlige blanding af sekundære aminer, der undertiden omtales som "Liquid Amine Mixture No. I", er en klar ravgul væske med følgende fysiske 35 egenskaber: viskositet ved 25°C på 70 cps; specifik vægtfylde ved 20°C på 0,845; brydningsindeks ved 45°C på 1,467; destillationsinterval ved 10 mm: indtil 160°C 4%, 160 til 210°C - 5%, 210 til 220°C - 74%, over 220°C - 17%."LA-1" liquid anion exchange resin is a mixture of 10 secondary 25 amines wherein each secondary amine has the formula R1 CH3C (CH3) 2CH2C (CH3) 2CH2CH = CH-CH2NHC-R2 30 R3 wherein each of R, R and R is a aliphatic hydrocarbon group and wherein R, R and R in the aggregate contain from 11 to 14 carbon atoms; this particular mixture of secondary amines, sometimes referred to as "Liquid Amine Mixture No. I", is a clear amber liquid having the following physical properties: viscosity at 25 ° C at 70 cps; specific gravity at 20 ° C of 0.845; refractive index at 45 ° C of 1.467; distillation range at 10 mm: up to 160 ° C 4%, 160 to 210 ° C - 5%, 210 to 220 ° C - 74%, above 220 ° C - 17%.
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Eksempel 7Example 7
En methylenchlondopløsning (5,0 ml) af trimethylsilyl-6-trimethylsilyloxycarbonylaminopenicillinat (0,54 g, 2,497 mmol) behandledes med tri ethylamin,hydrochlorid (0,20 g, 1,45 mmol) efterfulgt 5 af propylenoxid (0,162 g, 2,75 mmol) ved 25°C. Blandingen omrørtes ved 25°C i 20 minutter for at lette opløsning af det meste af tri ethyl -amin,hydrochloridet. Phenoxyacetylchlorid (0,43 g, 2,75 mmol) tilsattes dråbevis ved 25°C, og blandingen omrørtes ved 25°C i 30 minutter. En prøve fjernedes og analyseredes ved CMR ved 20,0 MHz. CMR (carbon-13 10 kernemagnetisk resonans-spektroskopi)-data viste fuldstændig forsvinden af phenoxyacetylchlorid samt APA-carbamatet og forekomsten af penicillin V trimethylsilylester. Tilstedeværelsen af penicillin V trimethylsilyl-ester påvistes ved spektralsammenligning med en identisk prøve fremstillet ved silylering af den frie penicillin V syre med triethylamin og 15 trimethylchlorsilan. Udbyttet skønnedes ud fra CMR-spektret at være 85-90%.A methylene chloride solution (5.0 ml) of trimethylsilyl-6-trimethylsilyloxycarbonylaminopenicillinate (0.54 g, 2.497 mmol) was treated with triethylamine hydrochloride (0.20 g, 1.45 mmol) followed by propylene oxide (0.162 g, 2). 75 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 20 minutes to facilitate dissolution of most of the triethylamine, the hydrochloride. Phenoxyacetyl chloride (0.43 g, 2.75 mmol) was added dropwise at 25 ° C and the mixture was stirred at 25 ° C for 30 minutes. A sample was removed and analyzed by CMR at 20.0 MHz. CMR (carbon-13 nuclear magnetic resonance spectroscopy) data showed complete disappearance of phenoxyacetyl chloride as well as the APA carbamate and the presence of penicillin V trimethylsilyl ester. The presence of penicillin V trimethylsilyl ester was detected by spectral comparison with an identical sample prepared by silylation of the free penicillin V acid with triethylamine and trimethylchlorosilane. The yield was estimated from the CMR spectrum to be 85-90%.
På tilsvarende måde fremstilledes under anvendelse af de samme molære mængder reagenser og det passende syrechlorid cl oxacillin, dicloxacillin, staphcillin og nafcillin. CMR data på disse acylerings-20 blandinger viste en ekstremt ren acyleringsblånding med udbytter skønnet til mindst 85%.Similarly, using the same molar amounts of reagents and the appropriate acid chloride, cl oxacillin, dicloxacillin, staphcillin and nafcillin, were prepared. CMR data on these acylation mixtures showed an extremely pure acylation blend with yields estimated at least 85%.
Eksempel 8Example 8
Omsætning i henhold til de foregående fremgangsmåder af en forbin-25 del se med formlen n }J i? g = = c ,ch3 ,Λ (CH,) -.Si-O-C-NH— 30 3 3 J-l- CH3 ° 35 hvori B er en let fraspaltelig ester-beskyttende gruppe udvalgt fra gruppen bestående af trimethyl silyl, benzhydryl, benzyl, p-nitrobenzyl,Reaction according to the foregoing methods of a compound of formula n} J i? g = = c, ch3, Λ (CH,) -Si-OC-NH-30 3 3 J1-CH3 ° 35 wherein B is an easily cleavable ester-protecting group selected from the group consisting of trimethyl silyl, benzhydryl, benzyl, p-nitrobenzyl,
DK 162055 BDK 162055 B
18 p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, l-[(ethoxycarbonyl)oxyl]ethyl, pivaloyloxy-methyl og acetoxymethyl med et reagens, som et det passende syrechlorid eller syrechlorid,hydrochlorid, hvilket reagens indeholder blokerende 5 grupper efter behov, efterfulgt af fjernelse af eventuelle blokerende grupper, hvis fjernelse er ønskelig, giver følgende forbindelser: almecillin, armecillin, azidocillin, azlocillin, bacampicillin, Bay K 4999 med formlen Η0”ΐ^\_18 p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxyl] ethyl, pivaloyloxymethyl and acetoxymethyl with a reagent as the appropriate acid chloride or acid chloride, hydrochloride, which reagent contains blocking groups as required, followed by removal of any blocking groups whose removal is desirable, yields the following compounds: almecillin, armecillin, azidocillin, azlocillin, bacampicillin, Bay K 4999 of the formula Η0 ”ΐ ^ \ _
15 ^ 0 o COOH15% COOH
J il BL-P1654 med formlen 20 /——» CH_J-BL-P1654 of formula 20
(r °i-cori,yrYcL(r ° i-cori, yrYcL
25 NH O C00K25 NH 0 C00K
0=C-NH-C^ 2 30 BL-P1908 med formlen Η0Ί^ΐ1 L>1-ch - com—r-f γ, 35 *0 = C-NH-C ^ 2 BL-P1908 of the formula Η0Ί ^ ΐ1 L> 1-ch - com — r-f γ, 35 *
IH OH 0 COOHIH OH 0 COOH
0=C-tjAh 'K,0 = C-tjAh 'K,
HH
carfeeillin, carindacillin, cyclacillin, clometocillin, cloxacillin, 40carfeeillin, carindacillin, cyclacillin, clometocillin, cloxacillin, 40
DK 162055 BDK 162055 B
19 dicloxacillin, EMD-32412 med formlen CH-CONH \ r„ i ^Ln—119 dicloxacillin, EMD-32412 of the formula CH-CONH \ r
NH 0 oH ' C00HNH0 and OH C00H
ίο 1 i 0=C-NH I „= 1 in 0 = C-NH
uQuQ
15 epicillin, floxacillin (flucloxacillin), furbucillin, hetacillin, I.S.F.-2664 med formlen 20 CH_Epicillin, floxacillin (flucloxacillin), furbucillin, hetacillin, I.S.F.-2664 of formula 20 CH
/ Λ— CH - CONH—i-K/ Λ— CH - CONH — i-K
! 33—rCBJs N-CH^ o 0=C-CCH20C-C(CH^)_! 33-rCBJs N-CH 2 O 0 = C-CCH 20 C-C (CH
25 I25 I
nh2 · 30 isopropici1 lin, methicillin, mezlocillin, nafcillin, oxacillin, phenbenici11 in, PC-455 med formlen 35nh2 · 30 isopropicline lin, methicillin, mezlocillin, nafcillin, oxacillin, phenbenici11in, PC-455 of formula 35
DK 162055BDK 162055B
20 CH^20 CH2
5 UH 0-^ COOH5 UH 0- ^ COOH
: oiY) 10 aparcillin (PC-904) med formlen 15 /-v /CH3 V 'V-CH-CONH—r— \=/ I >-K- CH3.: oIY) aparcillin (PC-904) of formula 15 / -v / CH3 V 'V-CH-CONH-r- \ = / I> -K- CH3.
NH 0 COOHNHO COOH
I ' -HO - - .I '-HO - -.
2° 25 piperacillin, 3,4-dihydroxypiperacillin, pirbenicillin, pivampicillin, PL-385 med formlen 30 H°Y\ _WS<CH3 l^JLcH-coirH--pr I · OH ^—K-- 52 ° 25 piperacillin, 3,4-dihydroxypiperacillin, pirbenicillin, pivampicillin, PL-385 of the formula 30 H ° Y \ _WS <CH3 l ^ JLcH-coirH - pr I · OH ^ -K-- 5
HH COOHHH COOH
0=C-X ί A-i \ - CEO0 = C-X ί A-i \ - CEO
35 \_/35 \ _ /
DK 162055 BDK 162055 B
21 prazocillin, sarmoxicillin, sarpici11 in, ticarcillin, cresylnatrium, ticarcillin, carbenicillin, carfecillin, fibracillin og Bay-e-6905 med formlen 5 CH_21 prazocillin, sarmoxicillin, sarpicillin, ticarcillin, cresyl sodium, ticarcillin, carbenicillin, carfecillin, fibracillin and Bay-e-6905 of formula 5
Oc" '”τχ!^4.Oc "'" τχ! ^ 4.
m cook 10 c=o N xO I-HH 'm cook 10 c = o N xO I-HH '
Claims (5)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US97070478A | 1978-12-18 | 1978-12-18 | |
US97070478 | 1978-12-18 | ||
US478079A | 1979-01-19 | 1979-01-19 | |
US06/021,852 US4240960A (en) | 1979-03-19 | 1979-03-19 | Trimethylsilyl substituted penicillins |
US2185279 | 1979-03-19 | ||
US478079 | 1990-02-09 |
Publications (4)
Publication Number | Publication Date |
---|---|
DK143990D0 DK143990D0 (en) | 1990-06-13 |
DK143990A DK143990A (en) | 1990-06-13 |
DK162055B true DK162055B (en) | 1991-09-09 |
DK162055C DK162055C (en) | 1992-02-10 |
Family
ID=27357705
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK213779A DK160613C (en) | 1978-12-18 | 1979-05-23 | PROCEDURE FOR PREPARING CONVENTIONAL PENICILLINES |
DK143990A DK162055C (en) | 1978-12-18 | 1990-06-13 | 6-TRIMETHYLSILYLOXYCARBONYLAMINOPENICILLANIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK213779A DK160613C (en) | 1978-12-18 | 1979-05-23 | PROCEDURE FOR PREPARING CONVENTIONAL PENICILLINES |
Country Status (20)
Country | Link |
---|---|
AR (1) | AR225898A1 (en) |
AT (1) | AT364849B (en) |
AU (1) | AU531779B2 (en) |
CA (1) | CA1141752A (en) |
CH (1) | CH642972A5 (en) |
DK (2) | DK160613C (en) |
ES (2) | ES482986A1 (en) |
FI (1) | FI69846C (en) |
FR (1) | FR2444683A1 (en) |
GB (1) | GB2037275B (en) |
GR (1) | GR73899B (en) |
IE (1) | IE48521B1 (en) |
IL (1) | IL57909A (en) |
IT (1) | IT1117760B (en) |
LU (1) | LU81432A1 (en) |
NL (1) | NL171271C (en) |
NO (1) | NO158541C (en) |
PH (1) | PH16327A (en) |
SE (2) | SE436281B (en) |
YU (1) | YU221082A (en) |
-
1979
- 1979-05-22 SE SE7904483A patent/SE436281B/en not_active IP Right Cessation
- 1979-05-23 DK DK213779A patent/DK160613C/en not_active IP Right Cessation
- 1979-05-29 GR GR59209A patent/GR73899B/el unknown
- 1979-05-29 CA CA000328553A patent/CA1141752A/en not_active Expired
- 1979-05-30 FI FI791732A patent/FI69846C/en not_active IP Right Cessation
- 1979-05-31 NO NO791823A patent/NO158541C/en unknown
- 1979-06-01 GB GB7919231A patent/GB2037275B/en not_active Expired
- 1979-06-05 AU AU47774/79A patent/AU531779B2/en not_active Ceased
- 1979-06-12 FR FR7915037A patent/FR2444683A1/en active Granted
- 1979-06-13 AT AT0421579A patent/AT364849B/en not_active IP Right Cessation
- 1979-06-13 CH CH554179A patent/CH642972A5/en not_active IP Right Cessation
- 1979-06-19 NL NLAANVRAGE7904805,A patent/NL171271C/en not_active IP Right Cessation
- 1979-06-27 LU LU81432A patent/LU81432A1/en unknown
- 1979-07-16 PH PH22784A patent/PH16327A/en unknown
- 1979-07-26 AR AR277486A patent/AR225898A1/en active
- 1979-07-27 IL IL57909A patent/IL57909A/en not_active IP Right Cessation
- 1979-07-30 ES ES482986A patent/ES482986A1/en not_active Expired
- 1979-08-01 IT IT49919/79A patent/IT1117760B/en active
- 1979-08-08 IE IE1283/79A patent/IE48521B1/en not_active IP Right Cessation
-
1980
- 1980-04-16 ES ES490644A patent/ES490644A0/en active Granted
-
1982
- 1982-10-01 YU YU02210/82A patent/YU221082A/en unknown
-
1984
- 1984-03-02 SE SE8401182A patent/SE448630B/en not_active IP Right Cessation
-
1990
- 1990-06-13 DK DK143990A patent/DK162055C/en not_active IP Right Cessation
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