CA2648178A1 - Process for preparing linezolid - Google Patents
Process for preparing linezolid Download PDFInfo
- Publication number
- CA2648178A1 CA2648178A1 CA002648178A CA2648178A CA2648178A1 CA 2648178 A1 CA2648178 A1 CA 2648178A1 CA 002648178 A CA002648178 A CA 002648178A CA 2648178 A CA2648178 A CA 2648178A CA 2648178 A1 CA2648178 A1 CA 2648178A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- chloro
- benzylidene
- amino
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims abstract description 27
- 229960003907 linezolid Drugs 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 230000010933 acylation Effects 0.000 claims abstract description 4
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 12
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 7
- 125000004799 bromophenyl group Chemical group 0.000 claims description 7
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 7
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- OMPURGCNIGTEBA-SFHVURJKSA-N (5s)-5-[[(4-chlorophenyl)methylideneamino]methyl]-3-(3-fluoro-4-morpholin-4-ylphenyl)-1,3-oxazolidin-2-one Chemical compound FC1=CC(N2C(O[C@@H](CN=CC=3C=CC(Cl)=CC=3)C2)=O)=CC=C1N1CCOCC1 OMPURGCNIGTEBA-SFHVURJKSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- QUIRMPBFJNOJKI-SECBINFHSA-N (2s)-1-chloro-3-[(2,4-dichlorophenyl)methylideneamino]propan-2-ol Chemical compound ClC[C@@H](O)CN=CC1=CC=C(Cl)C=C1Cl QUIRMPBFJNOJKI-SECBINFHSA-N 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- LFVZLCKHDSVJFP-KUKWCLJQSA-N ClC[C@@H](O)C\N=C\C1=CC=C(Cl)C=C1 Chemical compound ClC[C@@H](O)C\N=C\C1=CC=C(Cl)C=C1 LFVZLCKHDSVJFP-KUKWCLJQSA-N 0.000 claims 2
- QZNSUKJDFNQCRL-KUKWCLJQSA-N ClC[C@@H](O)C\N=C\c1ccc(Br)cc1 Chemical compound ClC[C@@H](O)C\N=C\c1ccc(Br)cc1 QZNSUKJDFNQCRL-KUKWCLJQSA-N 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- -1 morpholinyl fluorophenyl carbamate Chemical compound 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 150000002466 imines Chemical class 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 101150041968 CDC13 gene Proteins 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 239000002002 slurry Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000003828 vacuum filtration Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 5
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- XKGUZGHMWUIYDR-UHFFFAOYSA-N benzyl n-(3-fluoro-4-morpholin-4-ylphenyl)carbamate Chemical compound C=1C=C(N2CCOCC2)C(F)=CC=1NC(=O)OCC1=CC=CC=C1 XKGUZGHMWUIYDR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- QZNSUKJDFNQCRL-SNVBAGLBSA-N (2s)-1-[(4-bromophenyl)methylideneamino]-3-chloropropan-2-ol Chemical compound ClC[C@@H](O)CN=CC1=CC=C(Br)C=C1 QZNSUKJDFNQCRL-SNVBAGLBSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
- 241000694440 Colpidium aqueous Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- LFVZLCKHDSVJFP-SNVBAGLBSA-N (2s)-1-chloro-3-[(4-chlorophenyl)methylideneamino]propan-2-ol Chemical compound ClC[C@@H](O)CN=CC1=CC=C(Cl)C=C1 LFVZLCKHDSVJFP-SNVBAGLBSA-N 0.000 description 1
- AOQXLDPYOYBFHZ-SNVBAGLBSA-N (2s)-1-chloro-3-[(4-nitrophenyl)methylideneamino]propan-2-ol Chemical compound ClC[C@@H](O)CN=CC1=CC=C([N+]([O-])=O)C=C1 AOQXLDPYOYBFHZ-SNVBAGLBSA-N 0.000 description 1
- QUIRMPBFJNOJKI-UHFFFAOYSA-N 1-chloro-3-[(2,4-dichlorophenyl)methylideneamino]propan-2-ol Chemical compound ClCC(O)CN=CC1=CC=C(Cl)C=C1Cl QUIRMPBFJNOJKI-UHFFFAOYSA-N 0.000 description 1
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 description 1
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- LSYOFPBORRARMF-UHFFFAOYSA-N 5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical class OCC1CNC(=O)O1 LSYOFPBORRARMF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000004703 alkoxides Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- BTUYOSMJKPGOSS-UHFFFAOYSA-N chlorocarbamic acid Chemical class OC(=O)NCl BTUYOSMJKPGOSS-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
- HBTVZPMDLRPWKZ-UHFFFAOYSA-N n-(oxiran-2-ylmethyl)acetamide Chemical compound CC(=O)NCC1CO1 HBTVZPMDLRPWKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
- C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a new process for preparing the oxazolidinone antibacterial agent linezolid which comprises the reaction of an (S)-I -chloro-3- (benzyIidenylamino)-propan-2-ol with a morpholinyl fluorophenyl carbamate to afford a protected imine intermediate which, upon hydrolysis and acylation, yields linezolid in high yield.
Description
PROCESS FOR PREPARING LINEZOLID
FIELD OF INVENTION
The present invention relates to a novel process to prepare an oxazolidinone antibacterial agent. Particularly, the present invention relates to a novel process to prepare linezolid.
BACKGROUND OF THE INVENTION
Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. As a result, structurally novel antibacterial agents with a new mode of action have become increasingly important in the treatment of bacterial infections.
Among newer antibacterial agents, linezolid is a recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. Linezolid [(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is disclosed in U.S. Patent No. 5,688,792. It is marketed in the United States by Pfizer, Inc.
as an injection, tablets, and oral suspensions under the name ZYVOX . Processes for preparation of linezolid are described in U.S. Patent No. 5,688,792, U.S. Patent No. 5,837, 870, PCT
publication WO 99/24393, PCT publication WO 2006/004922, J. Med. Chem. 39(3), 679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
We have discovered and developed a novel process to prepare linezolid. The process has the potential to significantly lower the cost of commercial production of linezolid. It is a highly convergent three-step process with a much shorter cycle time. It is environmentally friendly because it reduces the large solvent volumes used in the currently known processes.
We also discovered rapidly crystallized key intermediates for the process of the present invention.
INFORMATION DISCLOSURE
US 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the synthesis of 5-hydroxymethyloxazolidinones from amines.
J. Med. Cltern., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and US Patent 4,948,801 disclose a method of producing oxazolidinones.
PCT Publications W093/09103, W093109103, W095/07271 and W093/23384;
PCT applications PCT/US95/12751 and PCT/US95/10992 disclose the reaction of a carbamate with n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.
International Publication W095/07271 discloses the ammonolysis of 5R-methylsuifonyloxymethyl substituted ox.azolidinones.
US Patent 4,476,136 discloses a method of transforming 5-hydroxymethyl substituted oxazolidinones to the corresponding 5(S)-aminomethyl substituted oxazolidinones.
US patent 5,332,754 discloses racemic oxazolidinone-CH2-NH-Ac can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide.
US patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
1.0 SUMMA.RY OF THE INVENTION
The present invention provide a process to prepare linezolid F o o N ! ~ ~O H
N,,jr Linezolid which comprises:
a) reacting a compound of structure (1) HO
Cl N~~~ x (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) p N / \ NO_R
(2) at a temperature in a range from ambient temperature to about 65 C, wherein R
is benzyl or CI.8alkyl to provide a compound of structure (3);
O lN N~O
N4~X
FIELD OF INVENTION
The present invention relates to a novel process to prepare an oxazolidinone antibacterial agent. Particularly, the present invention relates to a novel process to prepare linezolid.
BACKGROUND OF THE INVENTION
Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. As a result, structurally novel antibacterial agents with a new mode of action have become increasingly important in the treatment of bacterial infections.
Among newer antibacterial agents, linezolid is a recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. Linezolid [(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is disclosed in U.S. Patent No. 5,688,792. It is marketed in the United States by Pfizer, Inc.
as an injection, tablets, and oral suspensions under the name ZYVOX . Processes for preparation of linezolid are described in U.S. Patent No. 5,688,792, U.S. Patent No. 5,837, 870, PCT
publication WO 99/24393, PCT publication WO 2006/004922, J. Med. Chem. 39(3), 679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
We have discovered and developed a novel process to prepare linezolid. The process has the potential to significantly lower the cost of commercial production of linezolid. It is a highly convergent three-step process with a much shorter cycle time. It is environmentally friendly because it reduces the large solvent volumes used in the currently known processes.
We also discovered rapidly crystallized key intermediates for the process of the present invention.
INFORMATION DISCLOSURE
US 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the synthesis of 5-hydroxymethyloxazolidinones from amines.
J. Med. Cltern., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and US Patent 4,948,801 disclose a method of producing oxazolidinones.
PCT Publications W093/09103, W093109103, W095/07271 and W093/23384;
PCT applications PCT/US95/12751 and PCT/US95/10992 disclose the reaction of a carbamate with n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.
International Publication W095/07271 discloses the ammonolysis of 5R-methylsuifonyloxymethyl substituted ox.azolidinones.
US Patent 4,476,136 discloses a method of transforming 5-hydroxymethyl substituted oxazolidinones to the corresponding 5(S)-aminomethyl substituted oxazolidinones.
US patent 5,332,754 discloses racemic oxazolidinone-CH2-NH-Ac can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide.
US patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
1.0 SUMMA.RY OF THE INVENTION
The present invention provide a process to prepare linezolid F o o N ! ~ ~O H
N,,jr Linezolid which comprises:
a) reacting a compound of structure (1) HO
Cl N~~~ x (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) p N / \ NO_R
(2) at a temperature in a range from ambient temperature to about 65 C, wherein R
is benzyl or CI.8alkyl to provide a compound of structure (3);
O lN N~O
N4~X
(3) where X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
b) hydrolyzing the compound of structure (3) and subsequent acylation to provide linezolid.
Other aspects of the present invention are the compounds of structures (1) and (3) as shown above, their crystal structures, and their methods of crystallizations.
DETAILED DESCRIi'TION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C;_j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive.
Thus, for example, Ci_$ alkyl refers to alkyl of one to eight carbon atoms, inclusive.
The term alkyl refers to both straight and branched groups, but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Specifically, alkyl is C14alkyl.
More specifically, alkyl is tert-butyl.
The term "ambient temperature" refers to a temperature in a range from about to 30 C.
SCHEME I
ON OH ~N ~ O ~
X + ~ i JL .R F N O
F ~ O
(1) (3) X
~ O N
--=
~ ~ (i ~
F N O ~'N O
1__~NH2 t.inezoiici 1__~NH
HCI O
As shown in Scheme I (wherein X and R are defined above), the synthesis begins with coupling the substituted imine moiety (1) (preferably 1 to 3 eq, most preferably 1.5 to 2 eq) with a carbamate (2) to provide the corresponding (S)-oxazolidinone imine (3). The reaction is carried out preferably at a temperature in a range from ambient temperature to about 65 C in the presence of a base with pKa greater than 12, preferably a tertiary alkoxide base, most preferably lithium t-butoxide and an aprotic non-nucleophilic solvent (preferably DMF, DMAc, THF, Acetonitrile, C1.6 linear, branched and cyclic ethers and/ or chlorinated solvents and/ or mixtures of these solvents, most preferably MTBE or methylene chloride).
Most preferably, the temperature is from about 30-60 C and the reaction time is 2 to 24 hours. Preferably, the (S)-oxazolidinone imine (2), after an aqueous extractive workup, is crystallized and isolated by filtration from a weakly polar organic solvent, such as an alcohol (including C1.6 branched and linear alcohols and polyols) or ether (including MTBE, THF, and other Cl_6 linear, branched and cyclic ethers); most preferably isopropanol. Hydrolysis of compound (3) with an aqueous acidic solution and subsequent acylation provides crude linezolid. Compound (3) is best hydrolyzed with a mixture of water and a strong acid such as hydrochloric acid and the substituted benzaldehyde byproduct removed by extraction with a water immiscible organic solvent (preferably toluene, MTBE, methylene chloride and ethyl acetate), most preferably ethyl acetate. The resulting aqueous solution of Amine hydrochloride (4) is preferably acylated with acetic anhydride, preferably in the presence of water and a water immiscible organic solvent (most preferably methylene chloride), The conversion of Amine hydrochloride (4) to linezolid is well known in the literature (Brickner, S.J.; et. al. J. Med. Chem. 1996 39 (3) 673-679, US Patent 5,837,870, US
Other aspects of the present invention are the compounds of structures (1) and (3) as shown above, their crystal structures, and their methods of crystallizations.
DETAILED DESCRIi'TION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C;_j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive.
Thus, for example, Ci_$ alkyl refers to alkyl of one to eight carbon atoms, inclusive.
The term alkyl refers to both straight and branched groups, but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to. Specifically, alkyl is C14alkyl.
More specifically, alkyl is tert-butyl.
The term "ambient temperature" refers to a temperature in a range from about to 30 C.
SCHEME I
ON OH ~N ~ O ~
X + ~ i JL .R F N O
F ~ O
(1) (3) X
~ O N
--=
~ ~ (i ~
F N O ~'N O
1__~NH2 t.inezoiici 1__~NH
HCI O
As shown in Scheme I (wherein X and R are defined above), the synthesis begins with coupling the substituted imine moiety (1) (preferably 1 to 3 eq, most preferably 1.5 to 2 eq) with a carbamate (2) to provide the corresponding (S)-oxazolidinone imine (3). The reaction is carried out preferably at a temperature in a range from ambient temperature to about 65 C in the presence of a base with pKa greater than 12, preferably a tertiary alkoxide base, most preferably lithium t-butoxide and an aprotic non-nucleophilic solvent (preferably DMF, DMAc, THF, Acetonitrile, C1.6 linear, branched and cyclic ethers and/ or chlorinated solvents and/ or mixtures of these solvents, most preferably MTBE or methylene chloride).
Most preferably, the temperature is from about 30-60 C and the reaction time is 2 to 24 hours. Preferably, the (S)-oxazolidinone imine (2), after an aqueous extractive workup, is crystallized and isolated by filtration from a weakly polar organic solvent, such as an alcohol (including C1.6 branched and linear alcohols and polyols) or ether (including MTBE, THF, and other Cl_6 linear, branched and cyclic ethers); most preferably isopropanol. Hydrolysis of compound (3) with an aqueous acidic solution and subsequent acylation provides crude linezolid. Compound (3) is best hydrolyzed with a mixture of water and a strong acid such as hydrochloric acid and the substituted benzaldehyde byproduct removed by extraction with a water immiscible organic solvent (preferably toluene, MTBE, methylene chloride and ethyl acetate), most preferably ethyl acetate. The resulting aqueous solution of Amine hydrochloride (4) is preferably acylated with acetic anhydride, preferably in the presence of water and a water immiscible organic solvent (most preferably methylene chloride), The conversion of Amine hydrochloride (4) to linezolid is well known in the literature (Brickner, S.J.; et. al. J. Med. Chem. 1996 39 (3) 673-679, US Patent 5,837,870, US
5,688,792).
SCHEME II
o,,, OH
~~ GI + XNr'O ----~- CI~~N X
H
il) As shown in Scheme IT (wherein X is defined above), the key strating material (1) can be prepared by reacting (S)-epichlorohydrin with a mixture of the appropriately substituted benzaldehyde derivative (preferably 0.5 to 2 eq, most preferably I
eq) and aqueous ammonia (preferably 0.5 to 3 eq, most preferably 1.5 eq). The reaction is best performed in both protic and aprotic non-nucleophilic and non-electrophilic solvents such as alcohols (including C1.6 branched and linear alcohols and polyols), ethers (including MTBE, THF, and other C1.6 linear, branched and cyclic ethers) as well as chlorinated solvents such as methylene chloride. MTBE is a preferred solvent. Temperatures can be in a range from about 15 to about 60 C are preferred, preferably between 30 to 50 C most preferred. After extractive isolation and concentration, the imine moiety (1) is obtained. It is then crystallized from a second liquid phase, in the presence of non-polar aprotic hydrocarbon solvents such as, but not limited to, alkanes, mixtures of alkanes (hexane, heptane, octane, isooctane and commercially available alkane mixtures), optionally in the presence of aprotic polar solvents, preferably ethereal solvents such as MTBE or aromatic solvents such as toluene or chlorinated solvents such as methylene chloride or mixtures thereof. Preferred solvents are a mixture of MTBE and heptane or a mixture of toluene and heptane. The crystallization process can be conducted in a temperature in a range from ambient temperature (about 18-25 C) to about 55 C, preferably in a range of 30 to 50 C, more preferably in a range of 38 to 45 C. This crystallization provides surprisingly high yield and with significantly improved 5 enantiomeric purity after isolation by filtration.
EXAMPLES
In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
bm - broad multiplet BOC tert-butoxycarbonyl bd -- broad doublet bs = broad singlet iS CDI -- 1, 1 0-carbodiimidazole d - doublet dd -- doublet of doublets dq = doublet of quartets dt = doublet of triplets DMF dimethylformamide DMAP dimethylaminopyridine DMSO - dimethyl sulfoxide eq. - equivalents g grams h hours HPLC - high pressure liquid chromatography HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide LG - leaving group m - multiplet M - molar M% - mole percent max maximum meq = milliequivalent mg = milligram mL - milliliter mm = millimeter mmol - millimol MTBE = methyl t-butyl ether q = quartet s - singlet t or tr -- triplet TBS -- tributylsilyl TFA = trifluoroacetic acid THF - tetrahydrofuran TLC ~ thin layer chromatography p-TLC - preparative thin layer chromatography L - microliter N normality MeOH methanol DCM -- dichloromethane HCl = hydrochloric acid ACN - acetonitrile MS _ mass spectrometry rt - room temperature EtOAc ethyl acetate EtO = ethoxy Ac - acetate NMP - 1-methyl-2-Pyrrolidinone L - microliter J - coupling constant NMR - Nuclear magnetic resonance MHz - megahertz Hz = hertz m/z - mass to charge ratio min = minutes Boc tert-butoxycarbonyl CBZ - benzyloxycarbonyl DCC - 1,3-dicyclohexylcarbodiimide PyBop -- benzotriazole-l-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate Example 1 Preparation of (S)=1-chloro-3-[(4-chloro-E-benzylidene)-aminol-propan-2-ol cI CI
o NN3 ,` FIO i I
+
a Method A
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (351. g, 2.5 mol, 1.0 eq.). MTBE (1.5 L) is then charged into the round bottom to give a homogeneous solution. Aqueous ammonia (28 wt%, 252.98 mL, 3.75 mol, 1.5 eq.) is added in a single portion resulting in a white precipitate that turned into a thin slurry within 15 minutes of stirring. (S)-(+)-epichlorohydrin (> 99 % ee, 196.0 mL, 2.5 mol, 1.0 eq.) is then slowly charged into the vessel. After 40 minutes, the contents are then slowly heated to 43 C. The reaction is stirred at 40 C for 18 hours at which time 8.4% area of epichorohydrin remained by GC. Upon cooling to rt, the reaction mixture is transferred to a separatory funnel and the layers are separated. The lower aqueous layer is discarded. The organic layer is transferred to a 3L round bottom flask, concentrated in vacuo to about half the volume (800-900 mL) at which time iso-octanes is slowly added from a feed tube (-750 mL) until cloudiness is observed. The biphasic mixture is seeded with - 4 mgs of the title compound.
The reaction is cooled with an ice bath for 45 minutes while stirring. The precipitate is collected and rinsed with cold iso-octane (500 mL). The solid is dried for 18 hours at 50 C
SCHEME II
o,,, OH
~~ GI + XNr'O ----~- CI~~N X
H
il) As shown in Scheme IT (wherein X is defined above), the key strating material (1) can be prepared by reacting (S)-epichlorohydrin with a mixture of the appropriately substituted benzaldehyde derivative (preferably 0.5 to 2 eq, most preferably I
eq) and aqueous ammonia (preferably 0.5 to 3 eq, most preferably 1.5 eq). The reaction is best performed in both protic and aprotic non-nucleophilic and non-electrophilic solvents such as alcohols (including C1.6 branched and linear alcohols and polyols), ethers (including MTBE, THF, and other C1.6 linear, branched and cyclic ethers) as well as chlorinated solvents such as methylene chloride. MTBE is a preferred solvent. Temperatures can be in a range from about 15 to about 60 C are preferred, preferably between 30 to 50 C most preferred. After extractive isolation and concentration, the imine moiety (1) is obtained. It is then crystallized from a second liquid phase, in the presence of non-polar aprotic hydrocarbon solvents such as, but not limited to, alkanes, mixtures of alkanes (hexane, heptane, octane, isooctane and commercially available alkane mixtures), optionally in the presence of aprotic polar solvents, preferably ethereal solvents such as MTBE or aromatic solvents such as toluene or chlorinated solvents such as methylene chloride or mixtures thereof. Preferred solvents are a mixture of MTBE and heptane or a mixture of toluene and heptane. The crystallization process can be conducted in a temperature in a range from ambient temperature (about 18-25 C) to about 55 C, preferably in a range of 30 to 50 C, more preferably in a range of 38 to 45 C. This crystallization provides surprisingly high yield and with significantly improved 5 enantiomeric purity after isolation by filtration.
EXAMPLES
In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
bm - broad multiplet BOC tert-butoxycarbonyl bd -- broad doublet bs = broad singlet iS CDI -- 1, 1 0-carbodiimidazole d - doublet dd -- doublet of doublets dq = doublet of quartets dt = doublet of triplets DMF dimethylformamide DMAP dimethylaminopyridine DMSO - dimethyl sulfoxide eq. - equivalents g grams h hours HPLC - high pressure liquid chromatography HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide LG - leaving group m - multiplet M - molar M% - mole percent max maximum meq = milliequivalent mg = milligram mL - milliliter mm = millimeter mmol - millimol MTBE = methyl t-butyl ether q = quartet s - singlet t or tr -- triplet TBS -- tributylsilyl TFA = trifluoroacetic acid THF - tetrahydrofuran TLC ~ thin layer chromatography p-TLC - preparative thin layer chromatography L - microliter N normality MeOH methanol DCM -- dichloromethane HCl = hydrochloric acid ACN - acetonitrile MS _ mass spectrometry rt - room temperature EtOAc ethyl acetate EtO = ethoxy Ac - acetate NMP - 1-methyl-2-Pyrrolidinone L - microliter J - coupling constant NMR - Nuclear magnetic resonance MHz - megahertz Hz = hertz m/z - mass to charge ratio min = minutes Boc tert-butoxycarbonyl CBZ - benzyloxycarbonyl DCC - 1,3-dicyclohexylcarbodiimide PyBop -- benzotriazole-l-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate Example 1 Preparation of (S)=1-chloro-3-[(4-chloro-E-benzylidene)-aminol-propan-2-ol cI CI
o NN3 ,` FIO i I
+
a Method A
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (351. g, 2.5 mol, 1.0 eq.). MTBE (1.5 L) is then charged into the round bottom to give a homogeneous solution. Aqueous ammonia (28 wt%, 252.98 mL, 3.75 mol, 1.5 eq.) is added in a single portion resulting in a white precipitate that turned into a thin slurry within 15 minutes of stirring. (S)-(+)-epichlorohydrin (> 99 % ee, 196.0 mL, 2.5 mol, 1.0 eq.) is then slowly charged into the vessel. After 40 minutes, the contents are then slowly heated to 43 C. The reaction is stirred at 40 C for 18 hours at which time 8.4% area of epichorohydrin remained by GC. Upon cooling to rt, the reaction mixture is transferred to a separatory funnel and the layers are separated. The lower aqueous layer is discarded. The organic layer is transferred to a 3L round bottom flask, concentrated in vacuo to about half the volume (800-900 mL) at which time iso-octanes is slowly added from a feed tube (-750 mL) until cloudiness is observed. The biphasic mixture is seeded with - 4 mgs of the title compound.
The reaction is cooled with an ice bath for 45 minutes while stirring. The precipitate is collected and rinsed with cold iso-octane (500 mL). The solid is dried for 18 hours at 50 C
under vacuum to give the title compound as a white crystalline in solid. GC
assay: 100%, 99,7% ee by Chiral SFC). GC (conditions: column - 30 meter HP-1, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.0 l injection size; T;,,; = 70 C, ramp of 20 C/min) Ta (epichlorohydrin) = 2.4 min, Ta (4-chlorobenzaldehyde) = 4.8 min and TR
(title compound) = 9.7min; HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO.2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound]
= 3.9 min; TR (enantiomer of title compound) = 2.8 min; 'H NMR (400 MHz, CDC13) S
3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41. (d, J= 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, I H);
"C NMR (CDCI3) 8 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30;
IR (KBr Pellet) 1630 cm``;
X-ray crystal structure: crystal system = monoclinic, space group = P2(l), unit cell dimensions a 8.791(2) A, b = 4.6556(11) A, c = 14.372(3) A, oc= 90 , (3=
106.819(4) , y=
90 , Volume = 563.0(2) A3; Z =2; F(000) = 240; Ortep' Drawing:
: =r~, f.=...
õ Qlt C2 '''.....r C4 r.iu = .. C10 CS
Ce r. =>.t \/~K1iJ
`..../
Method B
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.). Methanol or THF is added and mixture warmed from 10 to 23 C.
Aqueous ammonia (28.4 wt%, 264 mL, 3.95 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 C. (S)-(+)-epichlorohydrin ( 99.3 % ee, 207 mL, 2.64 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 C for 18 h, then warmed to 40 to 45 C
and stirred for 2.5 h at which time 0.26% area of S-epichorohydrin remains by GC (GC conditions, 0.050 ml reaction mixture in 1 ml acetonitrile, inject 1 microliter; 15 M DB-1 column, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.0p1 injection size; T; = 38 C, ramp of 10 C/min) TR (epichlorohydrin) = 1.1 min, TR (4-chlorobenzaldehyde) = 6.9 min and Ta (title compound) = 16.0 min). The mixture is concentrated in vacuo to a total volume of 1250 ml.
Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1250 ml. Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1145 ml. Toluene (355 m.l) is added and the mixture concentrated in vacuo to a total volume of 900 ml. Toluene (600 ml) is added and the mixture concentrated in vacuo to a total volume of 1120 ml. While maintaining 45 to 50 C, heptane (1500 ml) is added.
The resulting biphasal solution is cooled to 45 C and seeded. The mixture is then further cooled to 38 C over 1/2 h while seeding after every I degree of cooling. The mixture is then further allowed to slowly cool to 23 C over 16 h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. IAPLC 95 area% [Kromasil 150 mm X
4.6 mm column, 254 nm, flow rate 1.5 ml! m'rn; A=1000 ml water + 0.52 ml trifluoroacetic acid +
1.20 ml triethylamine; B = acetonitrile; Isocratic 47: 53 A: B for 5 min then gradient to 100%
B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3 min];
99.72% ee by Chiral SFC. Chiral BPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO2/ 30%MeOH at 3.0 mLlmin, detecting at 255 nm. TR
[title compound] = 3.9 min; TR (enantiomer of title compound) = 2.8 m.in;'H NMR (400 MHz, CDCl3) & 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, 1 H); "C IVMR (CDC13) & 47.05, 63.09, 70.82, 128.93, .129.39, 134.08, 137.07, 162.30.
Method C
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1..0 eq.). MTBE (1.50 L) is then added to give a homogeneous solution after warming from 9 to 24 C. Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stixring for 15 minutes at 23 to 26 C. (S)-(+)-epichlorohydrin ( 99.3 % ee, 209 mL, 2.67 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 C for 3 days. The phases are separated and the upper phase concentrated under atmospheric pressure from 2000 to 1000 ml total volume (boiling point 58 to 67 C). While maintaining 45 to 50 C, heptane (1700 ml) is added. The resulting biphasal solution is cooled to 45 C and seeded.
The mixture is then further cooled to 38 C over 1/2 h while seeding after every i degree of cooling. The mixture is then further allowed to slowly cool to 23 C over I h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. HPLC 94 area% [Kromasil 150 nm X 4.6 nm column, 254 nm, flow rate 1.5 ml/ min; A = 1000 ml water +
0.52 ml trfluoroacetic acid + 1.20 ml triethylamine; B = acetonitrile Isocratic 47: 53 A: B for 5 min then gradient to 100% B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3 min]; 99.92% ee by Chiral SFC. Chiral HPLC
conditions:
Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% COZ/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.9 min; Tk (enantiomer of title compound) = 2.8 min; EH NMR (400 MHz, CDC13) S 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, I
H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, i H); 13C NMR
(CDCI3) S 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.
Example 2 Preparation of (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-ph.enyl)-oxazolidin-2-one Ao-' ~H cl ~N \ O
F + cl ,~irv F ! ~' N,~, C) . \ ~
Method A
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (20 g, 60.05 mmoles, 1 eq) is added lithium t-butoxide (12.11 g, 151.4 mmoles, 2.5 eq), followed by methylene chloride (80 mL) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-chloro-3-[(4-chloro-benzylidene)-amino]-propan-2-ol (21.07 g, 90.81 mmoles, 1.5 eq) in methylene chloride (40 mL) in one portion. The resulting thin suspension is heated to reflux (41 C) for 5h. After cooling to room temperature, the organic layer is washed with water (1 x 100 mL, 1 x 50 mL), these aqueous washes are then discarded. The organic phase is concentrated in vacuo to about 1/2 volume, at which time isopropy). alcohol (200 mL) is added and the concentration continued to a volume of less than 200 mL. The resultant suspension is cooled to -i0 C to -20 C and the solids isolated by filtration and washed with cold isopropyl alcohol (less than 100 mL) then dried at 55 C under vacuum to afford the title compound as a crystalline in solid. SFC achiral assay indicates a purity of 99.4 area% and SFC chiral assay identified 0.11 % of the (R) enantiomer. HPLC
conditions: YMC 5 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water +
0.1%
TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
[(3-fluoro-4-morpholin-4-yl-phenyi)-carbamic acid benzyl ester] = 8.5 min; TR
(title compound) = 7.9 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 75%
C02/ 25%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.8 min; TR
(enantiomer of title compound) = 4.4 min; tH NMR (400 MHz, CDC13) $ 3.05 (d, J= 4 Hz, 4 H), 3.87 (d, J= 4 Hz, 4 H), 3.90 (m, 2 H), 4.12 (m, 2 H), 4.95 (m, I H), 6.92 (t, J= 8 Hz, 1 H), 7.12 (d, J= 2 Hz, I H), 7.36 (d, J= 8 Hz, 2 H), 7.44 (dd, J= 16, 4 Hz, I
H); 7.63 (d, J= 8 Hz, 2 H), 8.34 (s, 1 H); "C NMR (CDC13) S 48.23, 51.00, 63.19, 66.94, 71.69, 107.42 (d, J =
27 Hz), 113.88, 118.74, 128.93, 129.50, 133.36 (d, J= 11 Hz),133.94, 136.30,137.22, 154.46, 155.48 (d, J = 244 Hz), 163.46.
Method B
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (372 g, 1.13 mol, 1 eq) is added lithium t-butoxide (225 g, 2.81 mol, 2.5 eq), followed by methylene chloride (2.2 L) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-5 chloro-3-[(4-chloro-benzylidene)-amino.]-propan-2-ol (400 g, 1.72 mol, 1.5 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 10 h.
The resultant slurry is added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq) in methanol (800 ml) while maintaining reflux and rinsed in with methanol (40 ml). The resultant slurry is concentrated via atmospheric distillation to a total volume of 3200 ml.
Methanol (2500 ml) l0 is added while concentrating via atmospheric distillation to maintain a total volume of 3200-3800 ml. The resultant slurry is cooled to 3 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. (HPLC conditions: Kromasil C18 3.5 micron 250 mm X 4.6 mm column, mobile phase A = 0.52 ml TFA, 1.20 ml~ triethylamine, 1000 ml water; mobile phase B
acetonitrile, isocratic 53: 47 A:B for 5 min then gradient to 100% B over 5 min at 1.5 mL/min, detecting at 254 nm; TR [title compound] = 6.66 min.
Example 3 Preparation of (S)-N-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (Linezolid) o N)~ 0 vN I ~
~FN~
\ GI F NNH I I
NH
Method A
To (S)-5-{ [(4-chloro-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 rnL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCI (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic.
After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HFLC conditions: YMC 5 ODS-AM 150 nm X
4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. Retention time of (S)-N-[3-(3-fluor.o-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL).
CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with - 25 mL aq. 50%
aq. NaOH.
With constant stirring, Ac20 (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CH2,CI2 (800 mL) and the organics are combined and concentrated to -IL in volume. Ethyl acetate (1L) is added and the volume is reduced to 1.5 L under vacuum. Another 1L of ethyl acetate is added and volume is reduced again to 1L under vacuum. The resultant slurry is cooled to 0 C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 50 C for 2 hours to give the title compound as linezolid crystalline Form I.
Method B
N ~
F I/N~_-~ CI F'~ kNH2 HCF`: NCI
NH
a Following the general procedure of method A and making non-critical variations, but substituting (S)-5-{ [2,4-dichloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (example 11.) for (S)-5-{ [(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin 2-one, the title compound is obtained.
Method C
N N
/ 8r F N
N HCI
O
Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (example 9) for (S)-5- { [(4-chloro-benzylidene)-arnino]-methyl}-3-(3-luoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.
Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form Ii) The product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 50 C. A
slight exotherm of 3 C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 50 C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes. The contents are then cooled to 3 C for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resultant solids are dried under vacuum at 50 C for 18 hours to give Linezolid (78.12 g) Form R by XRD, 99.8 wt%, 99.9% ee. HPLC
conditions:
YMC 511 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA
from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
(Linezolid) =
4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% C02/
assay: 100%, 99,7% ee by Chiral SFC). GC (conditions: column - 30 meter HP-1, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.0 l injection size; T;,,; = 70 C, ramp of 20 C/min) Ta (epichlorohydrin) = 2.4 min, Ta (4-chlorobenzaldehyde) = 4.8 min and TR
(title compound) = 9.7min; HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO.2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound]
= 3.9 min; TR (enantiomer of title compound) = 2.8 min; 'H NMR (400 MHz, CDC13) S
3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41. (d, J= 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, I H);
"C NMR (CDCI3) 8 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30;
IR (KBr Pellet) 1630 cm``;
X-ray crystal structure: crystal system = monoclinic, space group = P2(l), unit cell dimensions a 8.791(2) A, b = 4.6556(11) A, c = 14.372(3) A, oc= 90 , (3=
106.819(4) , y=
90 , Volume = 563.0(2) A3; Z =2; F(000) = 240; Ortep' Drawing:
: =r~, f.=...
õ Qlt C2 '''.....r C4 r.iu = .. C10 CS
Ce r. =>.t \/~K1iJ
`..../
Method B
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.). Methanol or THF is added and mixture warmed from 10 to 23 C.
Aqueous ammonia (28.4 wt%, 264 mL, 3.95 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 C. (S)-(+)-epichlorohydrin ( 99.3 % ee, 207 mL, 2.64 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 C for 18 h, then warmed to 40 to 45 C
and stirred for 2.5 h at which time 0.26% area of S-epichorohydrin remains by GC (GC conditions, 0.050 ml reaction mixture in 1 ml acetonitrile, inject 1 microliter; 15 M DB-1 column, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.0p1 injection size; T; = 38 C, ramp of 10 C/min) TR (epichlorohydrin) = 1.1 min, TR (4-chlorobenzaldehyde) = 6.9 min and Ta (title compound) = 16.0 min). The mixture is concentrated in vacuo to a total volume of 1250 ml.
Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1250 ml. Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1145 ml. Toluene (355 m.l) is added and the mixture concentrated in vacuo to a total volume of 900 ml. Toluene (600 ml) is added and the mixture concentrated in vacuo to a total volume of 1120 ml. While maintaining 45 to 50 C, heptane (1500 ml) is added.
The resulting biphasal solution is cooled to 45 C and seeded. The mixture is then further cooled to 38 C over 1/2 h while seeding after every I degree of cooling. The mixture is then further allowed to slowly cool to 23 C over 16 h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. IAPLC 95 area% [Kromasil 150 mm X
4.6 mm column, 254 nm, flow rate 1.5 ml! m'rn; A=1000 ml water + 0.52 ml trifluoroacetic acid +
1.20 ml triethylamine; B = acetonitrile; Isocratic 47: 53 A: B for 5 min then gradient to 100%
B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3 min];
99.72% ee by Chiral SFC. Chiral BPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO2/ 30%MeOH at 3.0 mLlmin, detecting at 255 nm. TR
[title compound] = 3.9 min; TR (enantiomer of title compound) = 2.8 m.in;'H NMR (400 MHz, CDCl3) & 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, 1 H); "C IVMR (CDC13) & 47.05, 63.09, 70.82, 128.93, .129.39, 134.08, 137.07, 162.30.
Method C
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1..0 eq.). MTBE (1.50 L) is then added to give a homogeneous solution after warming from 9 to 24 C. Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stixring for 15 minutes at 23 to 26 C. (S)-(+)-epichlorohydrin ( 99.3 % ee, 209 mL, 2.67 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 C for 3 days. The phases are separated and the upper phase concentrated under atmospheric pressure from 2000 to 1000 ml total volume (boiling point 58 to 67 C). While maintaining 45 to 50 C, heptane (1700 ml) is added. The resulting biphasal solution is cooled to 45 C and seeded.
The mixture is then further cooled to 38 C over 1/2 h while seeding after every i degree of cooling. The mixture is then further allowed to slowly cool to 23 C over I h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. HPLC 94 area% [Kromasil 150 nm X 4.6 nm column, 254 nm, flow rate 1.5 ml/ min; A = 1000 ml water +
0.52 ml trfluoroacetic acid + 1.20 ml triethylamine; B = acetonitrile Isocratic 47: 53 A: B for 5 min then gradient to 100% B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3 min]; 99.92% ee by Chiral SFC. Chiral HPLC
conditions:
Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% COZ/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.9 min; Tk (enantiomer of title compound) = 2.8 min; EH NMR (400 MHz, CDC13) S 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, I
H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, i H); 13C NMR
(CDCI3) S 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.
Example 2 Preparation of (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-ph.enyl)-oxazolidin-2-one Ao-' ~H cl ~N \ O
F + cl ,~irv F ! ~' N,~, C) . \ ~
Method A
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (20 g, 60.05 mmoles, 1 eq) is added lithium t-butoxide (12.11 g, 151.4 mmoles, 2.5 eq), followed by methylene chloride (80 mL) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-chloro-3-[(4-chloro-benzylidene)-amino]-propan-2-ol (21.07 g, 90.81 mmoles, 1.5 eq) in methylene chloride (40 mL) in one portion. The resulting thin suspension is heated to reflux (41 C) for 5h. After cooling to room temperature, the organic layer is washed with water (1 x 100 mL, 1 x 50 mL), these aqueous washes are then discarded. The organic phase is concentrated in vacuo to about 1/2 volume, at which time isopropy). alcohol (200 mL) is added and the concentration continued to a volume of less than 200 mL. The resultant suspension is cooled to -i0 C to -20 C and the solids isolated by filtration and washed with cold isopropyl alcohol (less than 100 mL) then dried at 55 C under vacuum to afford the title compound as a crystalline in solid. SFC achiral assay indicates a purity of 99.4 area% and SFC chiral assay identified 0.11 % of the (R) enantiomer. HPLC
conditions: YMC 5 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water +
0.1%
TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
[(3-fluoro-4-morpholin-4-yl-phenyi)-carbamic acid benzyl ester] = 8.5 min; TR
(title compound) = 7.9 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 75%
C02/ 25%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.8 min; TR
(enantiomer of title compound) = 4.4 min; tH NMR (400 MHz, CDC13) $ 3.05 (d, J= 4 Hz, 4 H), 3.87 (d, J= 4 Hz, 4 H), 3.90 (m, 2 H), 4.12 (m, 2 H), 4.95 (m, I H), 6.92 (t, J= 8 Hz, 1 H), 7.12 (d, J= 2 Hz, I H), 7.36 (d, J= 8 Hz, 2 H), 7.44 (dd, J= 16, 4 Hz, I
H); 7.63 (d, J= 8 Hz, 2 H), 8.34 (s, 1 H); "C NMR (CDC13) S 48.23, 51.00, 63.19, 66.94, 71.69, 107.42 (d, J =
27 Hz), 113.88, 118.74, 128.93, 129.50, 133.36 (d, J= 11 Hz),133.94, 136.30,137.22, 154.46, 155.48 (d, J = 244 Hz), 163.46.
Method B
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (372 g, 1.13 mol, 1 eq) is added lithium t-butoxide (225 g, 2.81 mol, 2.5 eq), followed by methylene chloride (2.2 L) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-5 chloro-3-[(4-chloro-benzylidene)-amino.]-propan-2-ol (400 g, 1.72 mol, 1.5 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 10 h.
The resultant slurry is added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq) in methanol (800 ml) while maintaining reflux and rinsed in with methanol (40 ml). The resultant slurry is concentrated via atmospheric distillation to a total volume of 3200 ml.
Methanol (2500 ml) l0 is added while concentrating via atmospheric distillation to maintain a total volume of 3200-3800 ml. The resultant slurry is cooled to 3 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. (HPLC conditions: Kromasil C18 3.5 micron 250 mm X 4.6 mm column, mobile phase A = 0.52 ml TFA, 1.20 ml~ triethylamine, 1000 ml water; mobile phase B
acetonitrile, isocratic 53: 47 A:B for 5 min then gradient to 100% B over 5 min at 1.5 mL/min, detecting at 254 nm; TR [title compound] = 6.66 min.
Example 3 Preparation of (S)-N-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (Linezolid) o N)~ 0 vN I ~
~FN~
\ GI F NNH I I
NH
Method A
To (S)-5-{ [(4-chloro-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 rnL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCI (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic.
After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HFLC conditions: YMC 5 ODS-AM 150 nm X
4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. Retention time of (S)-N-[3-(3-fluor.o-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL).
CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with - 25 mL aq. 50%
aq. NaOH.
With constant stirring, Ac20 (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CH2,CI2 (800 mL) and the organics are combined and concentrated to -IL in volume. Ethyl acetate (1L) is added and the volume is reduced to 1.5 L under vacuum. Another 1L of ethyl acetate is added and volume is reduced again to 1L under vacuum. The resultant slurry is cooled to 0 C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 50 C for 2 hours to give the title compound as linezolid crystalline Form I.
Method B
N ~
F I/N~_-~ CI F'~ kNH2 HCF`: NCI
NH
a Following the general procedure of method A and making non-critical variations, but substituting (S)-5-{ [2,4-dichloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (example 11.) for (S)-5-{ [(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin 2-one, the title compound is obtained.
Method C
N N
/ 8r F N
N HCI
O
Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (example 9) for (S)-5- { [(4-chloro-benzylidene)-arnino]-methyl}-3-(3-luoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.
Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form Ii) The product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 50 C. A
slight exotherm of 3 C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 50 C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes. The contents are then cooled to 3 C for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resultant solids are dried under vacuum at 50 C for 18 hours to give Linezolid (78.12 g) Form R by XRD, 99.8 wt%, 99.9% ee. HPLC
conditions:
YMC 511 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA
from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
(Linezolid) =
4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% C02/
10%MeOH at 3.0 mLlmin, detecting at 255 nm. Tx [title compound] = 3.6 min; TR
(enantiomer of title compound) = 4.1 min.
Example 5 Preparation of (S)-1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-ol Br A + + NH3 ,= HO =~ ~
Cl To a solution of 4-bromobenzaldehyde (20,8 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated.
The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 m.l) is added to the filtrate. The solution is concentrated- in vacuo to 75 ml total volume and the resultant precipitate collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream afforded the title compound as crystalline in solid. 'H NMR (400 MHz, CDC13) S 3.69 (m, 2 H), 3.77 (dd, J =
6,13 Hz, I H), 3.84 (dd, J = 13, 5 Hz, 1 H), 4.15 (m, 1 H), 7.57 (d, J= 8 Hz, 2 H), 7.62 (d, J= 8 Hz, 2 H), 8.31 (s, I H);13C NMR (CDC13) 5 47.05, 63.11, 70.80, 129.60, 131.89, 134.49, 137.36, 162.41.
Example 6 Preparation of (S)-I-chloro-3-[(4-nitro-benzylidene)-amino]-propan-2-ol / I
~ + NO* NH3 ~-~- WO NO2 CI~_,N
O
To a mixture of 4-nitrobenzaldehyde (2.69 g, 17.8 mmol), THF (10 ml), and aqueous ammonia (28%, 1.80 ml, 26.7 mmol, 1.5 eq) at 18 C is added (S)-(+)-epichlorohydrin (> 99 % ee, 1.39 mL, 17.8 mmol, 1.0 eq.). The mixture is stirred at 40 C for 18 h then concentrated to in vacuo to provide the title compound as oil. GC (column - 30 meter HP-1, 0.25mm ID and 0.25 micron film and 15 psi head pressure, I.0 1 injection size;
Tir,; = 70 C, ramp of 20 C/min) Ta (title compound) =11.16 min, 64 area%.
Example 7 Preparation of (S)-1-chloro-3-[(2,4-dimethoxy-benzylidene)-aminol-propan-2-ol / OMe OMe HO / I
0 + \ ~ + NH3 30 CI~,N ~ \
I
0 OMe OMe To a solution of 2,4-dimethoxybenzaldehyde (18.0 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSO4(2 g) clarified with an MTBE
rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to 75 ml total volume. The resultant biphasal mixture is allowed to stand at room temperature for 24 hours. The resultant waxy solid is collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream to provide the title compound 1H NMR (400 MHz, CDC13) 8 3.74 (rn, 4 H), 3.85 (s, 6 H), 4.11 (m, 1 H), 6.44 (s, I H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J= 8 Hz, 1 H), 8.68 (s, 1 H); "C NMR (CDC13) S
47.11, 55.44, 55.46, 63.39; 13C NMR (CDC13) 8 71.07, 97.94, 105.32, 117.40, 128.45, 159.1.3, 1.60.20, 163.35.
Example 8 Preparation of (S)-1-chloro-3-[(2,6-dichloro-benzylidene)-aminol-propan-2-ol Cf A + ` I F NH3 ----^-- Hd ~f / ~
~!/C{ CI~~,N~ \
O CI CI
To a solution of 2,6-dichlorobenzaldehyde (18.9 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated.
The organics layer is dried on MgSOa (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to give the title compound as oil. 'H NMR (400 MHz, CDC13) S 3.74 (m, 4 H), 3.85 (s, 6 H), 4.11 (m, 1. H), 6.44 (s, 1 H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J = 8 Hz, 1 H), 8.68 (s, 1 H); 13C NMR
(CDC13) S 47.11, 55.44, 55.46, 63.39; "C NMR (CDC13) 8 71.07, 97.94, 105.32, 117.40, 128.45, 159.13, 160.20, 163.35.
Example 9 Preparation of (S)-5-{[4-bromo-benzylidene)-aminoj-methyl}-3-(3-fluoro-4-morphol in-4-yl-phenyl)-oxazol idin-2-one ~ 6r ~.N OH
~/ II + CI~~N~ ~~ F
F NJ~
I
Br H
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.51 g, 22.7 mmol,' 1 eq) is added lithium t-butoxide (4.64 g, 57.9 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)- 1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-ol (8.55 g, 30.9 mmol, 1..36 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 21. h. The resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.29 eq) in methanol (46 g) and rinsed in with methanol (24 g). The resultant slurry is concentrated via atmospheric distillation to a total volume of 100 ml. The resultant slurry is cooled to 3 C
and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. 1H NMR
(CD.CII) S 3.05 (t, J = 5 Hz, 4 H), 3.87 (t, J= 5 Hz, 4 H), 3.90 (dd, J = 5, 14 Hz, 1 H), 3.96 (dd, J= 5, 13 Hz, 1 H), 4.04 (dd, J= 6, 9 Hz, 1 H), 4.12 (t, J- 9 Hz, I H), 4.95 (p, J= 5 Hz, I
H), 6.92 (t, J= 9 Hz, I H), 7.13 (dd, J= 10, 2 Hz, H), 7.43 (dd, J= 14, 3 Hz, 1 H), 7.52 (d, J=
9 Hz, 2 H), 7.56 (d, J = 9 Hz, 2 H), 8.33 (s, 1 H);13C NMR (CDC13) S 48.05, 50.84 (JC-F =
4 Hz), 63.03, 66.77, 71.49, 107.25 (Jc.F = 26 Hz), 113.70 (JC.r = 4 Hz), 118.60, 125.56, 129.54, 131.72, 133.18 (Jc_F = 10 Hz), 134.20, 136,09 (Jc.F = 6 Hz), 154.30, 155.32 (Jc_r =
245 Hz), 163.41.
Example 10 Preparation of (S)-1-chloro-3-[(2,4-dichloro-benzylidene)-amino}-propan-2-ol , CI
CI HO
A + + NH3 ----~- ~
."'CI CI"Y' N~
0 Cf ci To a solution of 2,4-dichlorobenzaldehyde (112 g, 639 mmol) in MTBE (267 g) is added ammonia (28 wt%, 63,0 ml, 943 mmol, 1.48 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 50.0 mL, 639 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSOd (2 g) clarified with an MTBE
rinse (50 ml) and the solution concentrated to 200 ml. Heptane (300 ml) is added and the resultant precipitate collected by vacuum filtration at room temperature and washed with heptane.
Drying in a nitrogen stream to provide the title compound as crystalline in solid. 'H NMR
(CDC13) S 3.66 (dd, J= 6, 1 1 Hz, 1 H), 3.70 (dd, J= 5, 1 1 Hz, 1 H), 3.80 (ddd, J= i, 6, i 3 Hz, 1 H), 3.86 (ddd, J= 2, 5, 13 Hz, 1 H), 4.14 (p, J= 6 Hz, 1 H), 7.28 (dd, J= 2, 8 Hz, 1 H), 5 7.40 (d, J = 2 Hz, I H), 7.96 (d, J = 8 Hz, 1 H), 8.71 (s, 1 H); 13C NMR
(CDCl3) S 46.98, 63.21, 70.66, 127.37, 128.95, 129.49, 131.06, 135.64, 137.22, 159.13.
Example 11 Preparation of (S)-5-{ (2,4-dichloro-benzylidene)-arnino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one N
N ~ O OH Ci I\ J'~
~{~, N i' O + CI~/N~ p ~ N O
H~ ci =l 10 ci To (3-fluoro-4=morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.59 g, 23.0 mmol, 1 eq) is added lithium t-butoxide (4.69 g, 58.5 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-15 chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol (8.24 g, 30.9 mmol, 1.35 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 21 h.
The resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.27 eq) in methanol (46 g) and rinsed in.with methanol (24 g). The resultant mixture is concentrated via atmospheric distillation to 51 g net weight. The resultant slurry is cooled to 0 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. 'H NMR (CDC13) 8 3.05 (t, J = 4 Hz, 4 H), 3.87 (t, J= 4 Hz, 4 H), 3.98 (t, J= 4 Hz, 1 H), 4.04 (dd, J= 6,9 9 Hz, 1 H), 4.13 (t, J= 9 Hz, 1 H), 4.97 (p, J= 5 Hz, 1 H), 6.92 (t, J= 9 Hz, I H), 7.14 (dd, J= 2, 9 Hz, 1 H), 7.22 (dd, J= 2, 9 Hz, 1 H), 7.39 (d, J= 2 Hz, I H), 7.44 (dd, J= 3, 14 Hz, 1 H), 7.87 (d, J= 2 Hz, 1 H), 8.75 (s, 1 H); 13C NMR (CDCl3) $ 48.03, 50.83, 63.16, 66.78, 71.44, 107.20 (Jc_F = 26 Hz), 113.62, 118.59, 1.27.37, 129.05, 129.46, 130.93, 133.16 (JC.F = 11 Hz), 135.71, 136.09 (Jc_r = 9 Hz), 137.38, 154.26, 155.32 (3C.F = 245 Hz), 160.24.
(enantiomer of title compound) = 4.1 min.
Example 5 Preparation of (S)-1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-ol Br A + + NH3 ,= HO =~ ~
Cl To a solution of 4-bromobenzaldehyde (20,8 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated.
The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 m.l) is added to the filtrate. The solution is concentrated- in vacuo to 75 ml total volume and the resultant precipitate collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream afforded the title compound as crystalline in solid. 'H NMR (400 MHz, CDC13) S 3.69 (m, 2 H), 3.77 (dd, J =
6,13 Hz, I H), 3.84 (dd, J = 13, 5 Hz, 1 H), 4.15 (m, 1 H), 7.57 (d, J= 8 Hz, 2 H), 7.62 (d, J= 8 Hz, 2 H), 8.31 (s, I H);13C NMR (CDC13) 5 47.05, 63.11, 70.80, 129.60, 131.89, 134.49, 137.36, 162.41.
Example 6 Preparation of (S)-I-chloro-3-[(4-nitro-benzylidene)-amino]-propan-2-ol / I
~ + NO* NH3 ~-~- WO NO2 CI~_,N
O
To a mixture of 4-nitrobenzaldehyde (2.69 g, 17.8 mmol), THF (10 ml), and aqueous ammonia (28%, 1.80 ml, 26.7 mmol, 1.5 eq) at 18 C is added (S)-(+)-epichlorohydrin (> 99 % ee, 1.39 mL, 17.8 mmol, 1.0 eq.). The mixture is stirred at 40 C for 18 h then concentrated to in vacuo to provide the title compound as oil. GC (column - 30 meter HP-1, 0.25mm ID and 0.25 micron film and 15 psi head pressure, I.0 1 injection size;
Tir,; = 70 C, ramp of 20 C/min) Ta (title compound) =11.16 min, 64 area%.
Example 7 Preparation of (S)-1-chloro-3-[(2,4-dimethoxy-benzylidene)-aminol-propan-2-ol / OMe OMe HO / I
0 + \ ~ + NH3 30 CI~,N ~ \
I
0 OMe OMe To a solution of 2,4-dimethoxybenzaldehyde (18.0 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSO4(2 g) clarified with an MTBE
rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to 75 ml total volume. The resultant biphasal mixture is allowed to stand at room temperature for 24 hours. The resultant waxy solid is collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream to provide the title compound 1H NMR (400 MHz, CDC13) 8 3.74 (rn, 4 H), 3.85 (s, 6 H), 4.11 (m, 1 H), 6.44 (s, I H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J= 8 Hz, 1 H), 8.68 (s, 1 H); "C NMR (CDC13) S
47.11, 55.44, 55.46, 63.39; 13C NMR (CDC13) 8 71.07, 97.94, 105.32, 117.40, 128.45, 159.1.3, 1.60.20, 163.35.
Example 8 Preparation of (S)-1-chloro-3-[(2,6-dichloro-benzylidene)-aminol-propan-2-ol Cf A + ` I F NH3 ----^-- Hd ~f / ~
~!/C{ CI~~,N~ \
O CI CI
To a solution of 2,6-dichlorobenzaldehyde (18.9 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated.
The organics layer is dried on MgSOa (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to give the title compound as oil. 'H NMR (400 MHz, CDC13) S 3.74 (m, 4 H), 3.85 (s, 6 H), 4.11 (m, 1. H), 6.44 (s, 1 H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J = 8 Hz, 1 H), 8.68 (s, 1 H); 13C NMR
(CDC13) S 47.11, 55.44, 55.46, 63.39; "C NMR (CDC13) 8 71.07, 97.94, 105.32, 117.40, 128.45, 159.13, 160.20, 163.35.
Example 9 Preparation of (S)-5-{[4-bromo-benzylidene)-aminoj-methyl}-3-(3-fluoro-4-morphol in-4-yl-phenyl)-oxazol idin-2-one ~ 6r ~.N OH
~/ II + CI~~N~ ~~ F
F NJ~
I
Br H
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.51 g, 22.7 mmol,' 1 eq) is added lithium t-butoxide (4.64 g, 57.9 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)- 1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-ol (8.55 g, 30.9 mmol, 1..36 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 21. h. The resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.29 eq) in methanol (46 g) and rinsed in with methanol (24 g). The resultant slurry is concentrated via atmospheric distillation to a total volume of 100 ml. The resultant slurry is cooled to 3 C
and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. 1H NMR
(CD.CII) S 3.05 (t, J = 5 Hz, 4 H), 3.87 (t, J= 5 Hz, 4 H), 3.90 (dd, J = 5, 14 Hz, 1 H), 3.96 (dd, J= 5, 13 Hz, 1 H), 4.04 (dd, J= 6, 9 Hz, 1 H), 4.12 (t, J- 9 Hz, I H), 4.95 (p, J= 5 Hz, I
H), 6.92 (t, J= 9 Hz, I H), 7.13 (dd, J= 10, 2 Hz, H), 7.43 (dd, J= 14, 3 Hz, 1 H), 7.52 (d, J=
9 Hz, 2 H), 7.56 (d, J = 9 Hz, 2 H), 8.33 (s, 1 H);13C NMR (CDC13) S 48.05, 50.84 (JC-F =
4 Hz), 63.03, 66.77, 71.49, 107.25 (Jc.F = 26 Hz), 113.70 (JC.r = 4 Hz), 118.60, 125.56, 129.54, 131.72, 133.18 (Jc_F = 10 Hz), 134.20, 136,09 (Jc.F = 6 Hz), 154.30, 155.32 (Jc_r =
245 Hz), 163.41.
Example 10 Preparation of (S)-1-chloro-3-[(2,4-dichloro-benzylidene)-amino}-propan-2-ol , CI
CI HO
A + + NH3 ----~- ~
."'CI CI"Y' N~
0 Cf ci To a solution of 2,4-dichlorobenzaldehyde (112 g, 639 mmol) in MTBE (267 g) is added ammonia (28 wt%, 63,0 ml, 943 mmol, 1.48 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 50.0 mL, 639 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSOd (2 g) clarified with an MTBE
rinse (50 ml) and the solution concentrated to 200 ml. Heptane (300 ml) is added and the resultant precipitate collected by vacuum filtration at room temperature and washed with heptane.
Drying in a nitrogen stream to provide the title compound as crystalline in solid. 'H NMR
(CDC13) S 3.66 (dd, J= 6, 1 1 Hz, 1 H), 3.70 (dd, J= 5, 1 1 Hz, 1 H), 3.80 (ddd, J= i, 6, i 3 Hz, 1 H), 3.86 (ddd, J= 2, 5, 13 Hz, 1 H), 4.14 (p, J= 6 Hz, 1 H), 7.28 (dd, J= 2, 8 Hz, 1 H), 5 7.40 (d, J = 2 Hz, I H), 7.96 (d, J = 8 Hz, 1 H), 8.71 (s, 1 H); 13C NMR
(CDCl3) S 46.98, 63.21, 70.66, 127.37, 128.95, 129.49, 131.06, 135.64, 137.22, 159.13.
Example 11 Preparation of (S)-5-{ (2,4-dichloro-benzylidene)-arnino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one N
N ~ O OH Ci I\ J'~
~{~, N i' O + CI~/N~ p ~ N O
H~ ci =l 10 ci To (3-fluoro-4=morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.59 g, 23.0 mmol, 1 eq) is added lithium t-butoxide (4.69 g, 58.5 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)-1-15 chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol (8.24 g, 30.9 mmol, 1.35 eq) in one portion. The resulting thin suspension is heated to reflux (41 C) for 21 h.
The resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.27 eq) in methanol (46 g) and rinsed in.with methanol (24 g). The resultant mixture is concentrated via atmospheric distillation to 51 g net weight. The resultant slurry is cooled to 0 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. 'H NMR (CDC13) 8 3.05 (t, J = 4 Hz, 4 H), 3.87 (t, J= 4 Hz, 4 H), 3.98 (t, J= 4 Hz, 1 H), 4.04 (dd, J= 6,9 9 Hz, 1 H), 4.13 (t, J= 9 Hz, 1 H), 4.97 (p, J= 5 Hz, 1 H), 6.92 (t, J= 9 Hz, I H), 7.14 (dd, J= 2, 9 Hz, 1 H), 7.22 (dd, J= 2, 9 Hz, 1 H), 7.39 (d, J= 2 Hz, I H), 7.44 (dd, J= 3, 14 Hz, 1 H), 7.87 (d, J= 2 Hz, 1 H), 8.75 (s, 1 H); 13C NMR (CDCl3) $ 48.03, 50.83, 63.16, 66.78, 71.44, 107.20 (Jc_F = 26 Hz), 113.62, 118.59, 1.27.37, 129.05, 129.46, 130.93, 133.16 (JC.F = 11 Hz), 135.71, 136.09 (Jc_r = 9 Hz), 137.38, 154.26, 155.32 (3C.F = 245 Hz), 160.24.
Claims (26)
1. A process to prepare linezolid Linezolid which comprises:
a) reacting a compound of structure (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) at a temperature in a range from ambient temperature to about 65°C, wherein R is benzyl or C1-8alkyl to provide a compound of structure (3);
wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
b) hydrolyzing the compound of structure (3) and subsequently acylation to provide linezolid.
a) reacting a compound of structure (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) at a temperature in a range from ambient temperature to about 65°C, wherein R is benzyl or C1-8alkyl to provide a compound of structure (3);
wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
b) hydrolyzing the compound of structure (3) and subsequently acylation to provide linezolid.
2. A compound of structure (1) in claim 1 which is (S)-1-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol.
3. A compound of structure (1) in claim 1 which is (S)-1-chloro-3-[(4-bromo-E-benzylidene)-amino]-propan-2-ol.
4. A compound of structure (1) in claim 1 which is (S)-1-chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol.
5. A compound of structure (3) in claim 1 which is (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.
6. A compound of structure (3)(S)-5-{[4-bromo-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one
7. A compound of structure (3) in claim 1 which is (S)-5-{[2,4-dichloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.
8. The temperature of claim 1 which is in a range from about 30-65 °C.
9. A compound of structure (2) in claim 1 where R is benzyl.
10. A compound of structure (2) in claim 1 where R is tert-butyl.
11. A process to prepare a compound of structure (3) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
which comprises a) reacting a compound of structure (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) at a temperature in a range from ambient temperature to about 65°C, wherein R is benzyl or C1-8alkyl.
which comprises a) reacting a compound of structure (1) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2) at a temperature in a range from ambient temperature to about 65°C, wherein R is benzyl or C1-8alkyl.
12. The temperature of claim 8 which is in a range from about 30-65 °C.
13. A compound of structure (1) Wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl.
14. A compound of claim 12 which is (S)-1-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol.
15. A compound of claim 12 which is (S)-1-chloro-3-[(4-bromo-E-benzylidene)-amino]-propan-2-ol.
16 A compound of claim 12 which is (S)-1-chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol.
17. (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.
18. A method of crystallization a compound of structure (1) which comprises a) liquefying a compound of structure (1) in the presence of a non-polar aprotic hydrocarbon solvent at a temperature in a range from ambient temperature to about 55 °C, optionally in the presence of an aprotic polar solvent; and b) Slowly cooling the temperature to ambient temperature or lower.
19 19. The method of claim 18 wherein the hydrocarbon solvent is an alkane or mixtures of alkanes.
20. The method of claim 18 wherein the hydrocarbon solvent is hexane, heptane, octane, isooctane, or mixtures thereof.
21. The method of claim 18 wherein the aprotic polar solvent is an ethereal solvent, a chlorinated solvent, an aromatic solvent, or mixtures thereof.
22. The method of claim 18 wherein the aprotic plar solvent is MTBE.
23. The method of claim 18 wherein the aprotic plar solvent is toluene.
24. The method of claim 18 wherein the aprotic plar solvent is methylene chloride.
25. The method of claim 18 wherein the temperature is in a range from about 30 to 50 °C.
26. The method of claim 18 wherein the temperature is in a range from about 38 to 45 °C.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79036006P | 2006-04-07 | 2006-04-07 | |
US60/790,360 | 2006-04-07 | ||
US81698306P | 2006-06-28 | 2006-06-28 | |
US60/816,983 | 2006-06-28 | ||
PCT/IB2007/000882 WO2007116284A1 (en) | 2006-04-07 | 2007-03-26 | Process for preparing linezolid |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2648178A1 true CA2648178A1 (en) | 2007-10-18 |
Family
ID=38308763
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002648178A Abandoned CA2648178A1 (en) | 2006-04-07 | 2007-03-26 | Process for preparing linezolid |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP2007740A1 (en) |
JP (1) | JP2007277243A (en) |
KR (1) | KR20080104178A (en) |
AR (1) | AR060299A1 (en) |
AU (1) | AU2007235635A1 (en) |
BR (1) | BRPI0710312A2 (en) |
CA (1) | CA2648178A1 (en) |
MX (1) | MX2008012941A (en) |
RU (1) | RU2008139612A (en) |
TW (1) | TW200808782A (en) |
WO (1) | WO2007116284A1 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010084514A2 (en) * | 2009-01-02 | 2010-07-29 | Neuland Laboratories Ltd. | A process for the preparation of (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide |
CN101774978B (en) * | 2009-01-13 | 2011-09-21 | 联化科技股份有限公司 | Preparation method of linezolid and intermediate thereof |
EP2563781B1 (en) | 2010-04-30 | 2016-10-26 | Indiana University Research and Technology Corporation | Processes for preparing linezolid |
EP2603506A1 (en) | 2010-08-11 | 2013-06-19 | Synthon BV | Process for making linezolid |
WO2012019632A1 (en) | 2010-08-11 | 2012-02-16 | Synthon B.V. | Process for making linezolid |
ES2395304B1 (en) * | 2011-05-20 | 2014-01-16 | Interquim, S.A. | PROCEDURE FOR OBTAINING A THIOPHEN-2-CARBOXAMIDE. |
CN102827154B (en) * | 2011-06-14 | 2015-04-22 | 上海科胜药物研发有限公司 | New method for synthesizing rivaroxaban intermediate 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-ketone |
WO2013072923A1 (en) | 2011-09-19 | 2013-05-23 | Cadila Healthcare Limited | Process for the preparation of crystalline linezolid |
CN103254148B (en) | 2012-02-15 | 2016-04-13 | 浙江海正药业股份有限公司 | The preparation method of linezolid intermediate |
CZ2012111A3 (en) | 2012-02-16 | 2013-08-28 | Zentiva, K.S. | Process for preparing rivaroxaban based on the use of (S)-epichlorohydrin |
WO2014071990A1 (en) | 2012-11-09 | 2014-05-15 | Synthon Bv | Process for making linezolid |
US9643939B1 (en) | 2016-04-18 | 2017-05-09 | Optimus Drugs Private Limited | Process for the preparation of linezolid |
USRE47606E1 (en) | 2016-04-21 | 2019-09-17 | Optimus Drugs Private Limited | Process for the preparation of linezolid |
CN110579556A (en) * | 2018-06-08 | 2019-12-17 | 天津科伦药物研究有限公司 | Detection method of linezolid product |
CN115236236A (en) * | 2022-07-26 | 2022-10-25 | 上海市食品药品检验研究院 | Linezolid and separation and analysis method of enantiomers in preparation thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5688792A (en) * | 1994-08-16 | 1997-11-18 | Pharmacia & Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
CZ200788A3 (en) * | 1996-04-11 | 2017-01-25 | Pfizer Inc. | A method of preparation of 5-aminomethyl substituted oxazolidinone amines |
JP2001522828A (en) * | 1997-11-07 | 2001-11-20 | ファルマシア・アンド・アップジョン・カンパニー | Oxazolidinone production |
-
2007
- 2007-03-26 BR BRPI0710312-3A patent/BRPI0710312A2/en not_active IP Right Cessation
- 2007-03-26 RU RU2008139612/04A patent/RU2008139612A/en not_active Application Discontinuation
- 2007-03-26 MX MX2008012941A patent/MX2008012941A/en unknown
- 2007-03-26 AU AU2007235635A patent/AU2007235635A1/en not_active Abandoned
- 2007-03-26 KR KR1020087024348A patent/KR20080104178A/en not_active Application Discontinuation
- 2007-03-26 CA CA002648178A patent/CA2648178A1/en not_active Abandoned
- 2007-03-26 EP EP07734203A patent/EP2007740A1/en not_active Withdrawn
- 2007-03-26 WO PCT/IB2007/000882 patent/WO2007116284A1/en active Application Filing
- 2007-04-04 AR ARP070101433A patent/AR060299A1/en not_active Application Discontinuation
- 2007-04-04 TW TW096112188A patent/TW200808782A/en unknown
- 2007-04-06 JP JP2007099953A patent/JP2007277243A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
BRPI0710312A2 (en) | 2011-08-09 |
AU2007235635A1 (en) | 2007-10-18 |
AR060299A1 (en) | 2008-06-04 |
EP2007740A1 (en) | 2008-12-31 |
RU2008139612A (en) | 2010-04-20 |
WO2007116284A1 (en) | 2007-10-18 |
JP2007277243A (en) | 2007-10-25 |
MX2008012941A (en) | 2008-10-15 |
KR20080104178A (en) | 2008-12-01 |
TW200808782A (en) | 2008-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2648178A1 (en) | Process for preparing linezolid | |
KR100580408B1 (en) | Process to Produce Oxazolidinones | |
EP1768967B1 (en) | Novel intermediates for linezolid and related compounds | |
US6998420B2 (en) | Oxazolidinone compounds | |
US9376407B2 (en) | Process for preparation of Linezolid and its novel intermediates | |
US9126990B2 (en) | Method for synthesizing rivaroxaban intermediate, 4-(4-[(5S)-(aminomethyl)-2-oxo-1,3-oxazoligdin-3-YL]phenyl)morpholin-3-one | |
CN101415694A (en) | Process for preparing linezolid | |
US20050070526A1 (en) | Novel antibacterial agents | |
US8841306B2 (en) | Antimicrobials | |
US8962827B2 (en) | Linezolid intermediate and method for synthesizing linezolid | |
CA2521685A1 (en) | Antimicrobial [3.1.0] bicyclohexylphenyl-oxazolidinone derivatives and analogues | |
US20160039803A1 (en) | Process for the preparation of oxazolidinone derivatives | |
US20040224939A1 (en) | Antibacterial agents | |
US9586913B2 (en) | Processes for the preparation of linezolid using novel intermediates | |
RU2766082C9 (en) | Improved process of obtaining linezolid | |
USRE47606E1 (en) | Process for the preparation of linezolid | |
EP1615917A1 (en) | N-aryl-2-oxazolidinone-5-carboxamides derivatives with antibacterial activity | |
US9643939B1 (en) | Process for the preparation of linezolid | |
WO2013111048A1 (en) | Improved process for the preparation of stable crystalline form-i of linezolid, substantially free of residual solvent | |
WO2018055499A1 (en) | One pot synthesis for the preparation of substituted phthalimido oxazolidinone antibacterials and oxazolidinone antiharombotics compounds by using recyclable heterogeneous catalyst |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |