CN103420933B - A kind of preparation method of Linezolid - Google Patents
A kind of preparation method of Linezolid Download PDFInfo
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- CN103420933B CN103420933B CN201210167668.6A CN201210167668A CN103420933B CN 103420933 B CN103420933 B CN 103420933B CN 201210167668 A CN201210167668 A CN 201210167668A CN 103420933 B CN103420933 B CN 103420933B
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- morpholinyl
- carbobenzoxy
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- 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 37
- 229960003907 linezolid Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 38
- GPBVDKFJJAYKCR-UHFFFAOYSA-N N-fluoro-2-morpholin-4-ylaniline Chemical compound FNC1=C(C=CC=C1)N1CCOCC1 GPBVDKFJJAYKCR-UHFFFAOYSA-N 0.000 claims abstract description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 59
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 9
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- -1 fluoro-4-morpholinyl phenyl Chemical group 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 229940086542 triethylamine Drugs 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001207 fluorophenyl group Chemical group 0.000 description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- DCNHLVVHLYKXCC-UHFFFAOYSA-N C(=O)(OCC1=CC=CC=C1)N(C1=C(C(=CC=C1)F)N1CCOCC1)C(=O)OCC1=CC=CC=C1 Chemical compound C(=O)(OCC1=CC=CC=C1)N(C1=C(C(=CC=C1)F)N1CCOCC1)C(=O)OCC1=CC=CC=C1 DCNHLVVHLYKXCC-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 231100000004 severe toxicity Toxicity 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 238000005642 Gabriel synthesis reaction Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- LRWZZZWJMFNZIK-NFJMKROFSA-N (2R)-2-chloro-3-methyloxirane Chemical compound CC1O[C@@H]1Cl LRWZZZWJMFNZIK-NFJMKROFSA-N 0.000 description 1
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical class NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N C1CC=CCC1 Chemical compound C1CC=CCC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- RNDTYJSNEQPOGF-UHFFFAOYSA-N CC(C)[ClH]C([I](C)C(C1)=CCC1(CN1CC[ClH]CC1)I)=[TlH] Chemical compound CC(C)[ClH]C([I](C)C(C1)=CCC1(CN1CC[ClH]CC1)I)=[TlH] RNDTYJSNEQPOGF-UHFFFAOYSA-N 0.000 description 1
- YSQNMHIWPZAPKN-TXNCSXONSA-N CCC(C)[IH]C([IH]C(I)[I](C=C1C)[IH]C[C@H](C)C1N1CCNCC1)=C Chemical compound CCC(C)[IH]C([IH]C(I)[I](C=C1C)[IH]C[C@H](C)C1N1CCNCC1)=C YSQNMHIWPZAPKN-TXNCSXONSA-N 0.000 description 1
- XAZKFISIRYLAEE-KNVOCYPGSA-N C[C@H]1C[C@@H](C)CC1 Chemical compound C[C@H]1C[C@@H](C)CC1 XAZKFISIRYLAEE-KNVOCYPGSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to the preparation method of a kind of Linezolid (1); the method is with 3; 4-difluoro nitrobenzene is raw material; first react with morpholine; by reduction, be obtained by reacting the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-with chloroformic acid benzyl ester; and then with (S)-N-(2,3-epoxypropyl) phthalic imidine cyclization, then obtain Linezolid (1) through ammonia solution, acetylize.
Description
Technical field
The present invention relates to a kind of novel method of oxazolidinones class antiseptic-germicide processed.Especially the present invention relates to a kind of novel method preparing Linezolid.
Background technology
Linezolid, English name is Linezolid, and chemical name is (S)-N-{ [3-(the fluoro-4-of 3-(4-morpholinyl) phenyl)-2-oxo-5-azoles quinoline base] methyl } ethanamide.The molecular formula of Linezolid is C
16h
20fN
3o
4, molecular weight is 337.35, and it is white solid, and fusing point is 181.0 ~ 183.0 DEG C, and its structural formula is as follows:
Linezolid is the oxazolidinones microbiotic of first man work synthesis, is to be researched and developed by Pharmacia & Upjhon company of the U.S., and on April 18th, 2000, commodity were called ZYVOX by U.S. FDA approval listing.This medicine can treat the diseases such as Nosocomial Pneumonia, skin and soft tissue infection, community sensitivity metachromia pneumonia, and its curative effect obtains clinical research confirmation.In addition, the clinical efficacy of Linezolid is better than or is equal to conventional antimicrobial medicine, and the infection caused methicillin-resistant Staphylococci (MRSA), glycopeptide class resistance faecalis, Penicillin-resistant streptococcus pneumoniae (PRSP) etc. is also effective, and toxicity is very little, use safety is easy.Linezolid is Bacterioprotein biosynthesis inhibitor, different from other drug, Linezolid does not affect peptidyl transferase activity, but selective binding is in 50S subunit rrna, due to site of action and the mode uniqueness of Linezolid, therefore the antimicrobial drug generation crossing drug resistant not easily synthesized with other anti-bacteria albumen, also not easily induction produces resistance in vitro.
At present, the synthetic method of Linezolid mainly contains following several:
1. first US Patent No. 5688792 discloses the purposes of compound Linezolid and treatment bacteriological infection thereof.This patent also discloses the preparation method of this compound simultaneously, with 3,4-difluoro nitrobenzene for raw material, is substituted, reduces, cyclisation, and functional group changes, and acetylize etc. obtain Linezolid:
The cyclization of this route needs to use n-Butyl Lithium under-78 DEG C of ultra-low temperature surroundings and protection of inert gas, is unfavorable for suitability for industrialized production, and uses sodiumazide, Hydrogenation, requires higher and have certain potential safety hazard to synthesis device.
JMedChem.1996,39 (3): 673-679 improve aforesaid method, and adopt the reactions such as Gabriel reaction, ammonia solution to avoid the use of sodiumazide, reaction formula is as follows:
But, still use n-Butyl Lithium in this reaction, higher to the requirement of air and moisture, and want control temperature at-78 DEG C, this adds difficulty to experimental implementation undoubtedly.Meanwhile, when carrying out Gabriel reaction, because the sylvite alkalescence of phthalic imidine is comparatively strong, is easy to the open loop of Shi oxazolidone and produces impurity.
BioorgMedChemLett, 2001,12 (6): 857 pairs of aforesaid methods improve again, replace methylsulfonyl chloride to become ester with hydroxyl, then through ammonia ammonia solution, acetylize obtain Linezolid, and reaction formula is as follows with the 4-Nitrobenzenesulfonyl chloride that leaving away property is stronger:
This approach avoid and use the sylvite of phthalic imidine and produce impurity, operationally feasibility is comparatively strong, but yield is on the low side, and technique needs to optimize further.
2. US Patent No. 20060247435 discloses with 3; 4-difluoro nitrobenzene is raw material; be substituted, reduce and generate 3-fluoro-4-morpholine aniline; with (R)-epichlorohydrin reaction; then react with the sylvite of phthalic imidine, the chlorine atom in substitution compound, then react cyclization with carbonyl dimidazoles; last ammonia solution, acetylize obtain Linezolid, and reaction formula is as follows:
Find that this method is immature through research, the reaction yield of epoxy chloropropane and arylamine is difficult to reappear, and in method, the sylvite of chloro thing and phthalic imidine reacts difficult, and yield is not high, and whole technique is still needed optimization.
JMedChem, 2005,48 (19): 5900 improve this method, with (S)-N-(2,3-epoxypropyl) phthalic imidine replacement (R)-epoxy chloropropane, successfully synthesize Linezolid, reaction formula is as follows:
This method agents useful for same toxicity is little, and aftertreatment is simple, but the first step reaction times is longer, and reaction is very not thorough, and technique still needs to optimize.
3.OrgLett; 2003; 5 (7): 963 report a kind of catalysis coupling process synthesis Linezolid, with 3-fluoro-4-morpholine aniline for raw material, through nitrosification; cuprous bromide replaces; amino is made to be converted into bromine, the oxazolidone coupling then protected with THP or phthalic imidine, last deprotection; acetylize obtains Linezolid, and reaction formula is as follows:
the linked reaction yield of this route is not high, and chiral raw material synthesis is loaded down with trivial details, uses the metal reagents such as cuprous bromide, is not suitable for suitability for industrialized production.
4. world patent WO2007116284 discloses with 4-chloro-benzaldehyde is the method for raw material, and reaction formula is as follows:
This route total recovery is on the low side, and production cost is higher, is not suitable for suitability for industrialized production equally.
5. Chinese patent CN1772750 discloses following synthetic method:
Need in this method to use the phosgene of severe toxicity and explosive sodiumazide, route is longer, and cost is higher, is not suitable for suitability for industrialized production.
In sum, above-described synthetic route, ubiquity use explosive sodiumazide or under the ultra-low temperature surroundings of anhydrous and oxygen-free user's n-Butyl Lithium or Hydrogenation or use the phosgene of severe toxicity or total recovery on the low side, the problem that cost is higher, brings certain difficulty to the suitability for industrialized production of Linezolid.
Summary of the invention
The present invention relates to a kind of new Linezolid synthetic method.Contriver conducts in-depth research the synthetic method of Linezolid on the basis of bibliographical information; invent a brand-new synthetic route; namely 3; 4-difluoro nitrobenzene is raw material; first react with morpholine, by reduction, with chloroformic acid benzyl ester be obtained by reacting the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-, and then with (S)-N-(2; 3-epoxypropyl) phthalic imidine cyclization, then obtain Linezolid through ammonia solution, acetylize.This route does not need to use n-Butyl Lithium under anhydrous and oxygen-free condition of ultralow temperature, do not need to use the phosgene of severe toxicity and explosive sodiumazide yet, low in raw material price is easy to get, technological process is simple, product yield is higher, overcome traditional technology Problems existing in the industrial production, the suitability for industrialized production for Linezolid provides an outstanding operational path, is expected to become the industrial main method of Linezolid.
Synthetic route of the present invention is as follows:
The method mainly comprises following reaction:
Under the effect of organic bases, 3,4-difluoro nitrobenzene and morpholine generation nucleophilic substitution reaction, generate 3-fluoro-4-morpholine oil of mirbane:
This reacts organic weak base used is triethylamine, diisopropylethylamine, pyridine and DMAP, preferred triethylamine; Reaction solvent for use is ethyl acetate, acetone, acetonitrile, one or more mixed solvents in DMF, ethyl acetate; Temperature of reaction is 0 ~ 50 DEG C, preferably 20 ~ 30 DEG C.
Take Pd/C as catalyzer, reduction 3-fluoro-4-morpholine oil of mirbane is 3-fluoro-4-morpholine aniline:
Reaction solvent for use is acetone, reductive agent is hydrogen or ammonium formiate, experiment finds, hydrogen reducing 3-fluoro-4-morpholine oil of mirbane is used to need High Temperature High Pressure, there is certain potentially dangerous, and reaction yield and be reductive agent with ammonium formiate time yield close, take ammonium formiate as the gentle easily control of reductive agent reaction conditions, yield is higher, so reductive agent preferable formic acid ammonium.The 3-fluoro-4-morpholine aniline that reaction generates is unstable, easily oxidized and cause darkening, and impurity increases, so product is not purified be directly used in next step reaction.
Fluoro-for not purified 3-4-morpholine aniline and chloroformic acid benzyl ester are reacted and generate the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-, reaction solvent is the mixture of acetone and water, and acid binding agent is sodium bicarbonate, and temperature of reaction is 0 ~ 30 DEG C.
The fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-and (S)-N-(2,3-epoxypropyl) phthalic imidine reaction cyclization Sheng Cheng oxazolidinone compounds 2-({ (5S)-2-oxo-3-[4-(4-morpholinyl-3-fluorophenyl)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-diketone:
Reaction selects trimethyl carbinol lithium and n-Butyl Lithium to be reaction promotor respectively, and the required condition of reaction and reaction yield are listed in the table below:
N-Butyl Lithium needs to use in the anhydrous and oxygen-free environment of-78 DEG C, and the reaction times is longer, and yield is 63%, and trimethyl carbinol lithium can at room temperature use, and the reaction times is short, and yield can reach 84%, so preferred tertiary butanols lithium.
Ratio 1:1 ~ the 4:1 of trimethyl carbinol lithium and the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-in reaction, find in experiment, increase the consumption of trimethyl carbinol lithium, can fast reaction speed, but the amount of trimethyl carbinol lithium is too many, easily cause the solution alkaline of post-reaction treatment too strong and decompose oxazolidone generation impurity, considering reaction times, yield and cost factor, the preferred 2:1 of ratio of first-selected trimethyl carbinol lithium and N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl phenylamine.
This reaction adopts the solvent of the strong polarity of aprotic, as one or more the mixture in methyl-sulphoxide (DMSO), acetonitrile, acetone, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA) and tetrahydrofuran (THF) (THF), the mixed solvent of preferred THF and DMF.
Find in experiment; this reaction optimum temps be 0 ~ 50 DEG C; temperature is lower than 0 DEG C, and slowly, after 48h is carried out in reaction, feed stock conversion is less than 50% for speed of response; temperature is higher than 50 DEG C; speed of response is very fast, but temperature raises the open loop easily causing oxazolidone; so preferable reaction temperature is 20 ~ 30 DEG C.
Take methyl alcohol as solvent, with hydrazine hydrate back hydrolysis 2-({ (5S)-2-oxo-3-[4-(4-morpholinyl-3-fluorophenyl)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-bis-ketogenesis (S)-5-aminomethyl-3-(the fluoro-4-morpholinyl phenyl of 3-) oxazolidine-2-ketone, in reaction, the consumption of hydrazine hydrate is 2-({ (5S)-2-oxo-3-[4-(4-morpholinyl-3-fluorophenyl)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,10 times of 3-diketone, reaction formula is as follows:
Hydrolysis gained mixture is concentrated into dry; steam except methyl alcohol; then dissolve with methylene dichloride; water washing; dry; use acetic anhydride acylation (S)-5-aminomethyl-3-(3-fluoro-4-morpholinyl phenyl) oxazolidine-2-ketone in the presence of triethyl amine; obtain Linezolid; wherein 2-({ (5S)-2-oxo-3-[4-(the fluoro-phenyl of 4-morpholinyl-3-)]-1; 3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-diketone and triethylamine, diacetyl oxide ratio be classified as 1:2:1.2.
Technique effect of the present invention is, with 3,4-difluoro nitrobenzene and morpholine for raw material, generates 3-fluoro-4-morpholine oil of mirbane under the effect of triethylamine, and reaction room temperature is carried out, mild condition, and cheaper starting materials is easy to get, be that in the reaction of catalyst reduction 3-fluoro-4-morpholine oil of mirbane, formic acid ammonium is reductive agent, abandons hydrogen with Pd/C, avoid the severe condition of High Temperature High Pressure, decrease the potentially dangerous in reaction, the 3-fluoro-4-morpholine aniline that reduction obtains, without purification process, directly obtains the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-by chloroformic acid benzyl ester acidylate, decreases the treating process of reaction product, simplify operation, improve reaction yield, the fluoro-4-morpholinyl phenylamine of creationary employing N-carbobenzoxy-(Cbz)-3-and (S)-N-(2, 3-epoxypropyl) phthalic imidine reaction directly synthesize Oxazolidinone compound, trimethyl carbinol lithium is selected in reaction, abandon n-Butyl Lithium, avoid the harsh reaction conditions of anhydrous and oxygen-free and very low temperature, products therefrom is extracted with ethyl acetate, crystallization, obtain the very high 2-of purity ({ (5S)-2-oxo-3-[4-(the fluoro-phenyl of 4-morpholinyl-3-)]-1, 3-oxazolidine-5-base } methyl)-1H-isoindole-1, 3-diketone, avoid loaded down with trivial details column separation process, react with hydrazine hydrate further, ammonia products, without the need to purifying, directly obtains Linezolid with acetic anhydride acylation.Whole technique breaches the limitation of traditional technology, the gentle easily control of reaction conditions, and cheaper starting materials is easy to get, simple to operate, and product yield is higher, be conducive to product suitability for industrialized production.
Embodiment
Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiments only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
The preparation of embodiment 13-fluoro-4-morpholine oil of mirbane
In 3L there-necked flask, install mechanical stirring and thermometer respectively additional, add morpholine 150g (1.72mol), triethylamine 175g (1.73mol) and ethyl acetate 800mL, stirring at room temperature is even, slow dropping 3,4-difluoro nitrobenzene 250g (1.57mol), dropwises in 40min, stirring at room temperature 24h, has a large amount of yellow solid to generate.Completely, by reaction mixture impouring 2.8L ethyl acetate, abundant stirring and dissolving, solution uses water and saturated common salt water washing respectively, separatory, dry, and filter, filtrate concentrates crystallization, obtains bright yellow solid 351.3g, yield 99.0% in TLC display reaction.
The preparation of embodiment 23-fluoro-4-morpholine aniline
In 3L there-necked flask, install mechanical stirring and thermometer respectively additional, add 3-fluoro-4-morpholine oil of mirbane 100g (0.44mol), acetone 1L, 10%Pd/C3.0g and ammonium formiate 137.5g (2.18mol), abundant stirring, is warming up to 50 DEG C, stirring reaction 8h, TLC display reaction completes, then adds acetone 500mL, stirs, ageing 2h, filter, filtrate is concentrated into dry, obtains off-white color solid 96g, product is not purified, is directly used in next step reaction.
The preparation of the fluoro-4-morpholinyl phenylamine of embodiment 3N-carbobenzoxy-(Cbz)-3-
In 3L there-necked flask, add not purified 3-fluoro-4-morpholine aniline 96g, acetone 1.8L, water 800mL and sodium bicarbonate 73.9g (0.88mol), abundant stirring, ice-water bath is cooled to 0 ~ 5 DEG C, then slowly chloroformic acid benzyl ester 90.0g (0.53mol) is dripped, dropwise, slowly rise to room temperature, stirring reaction spends the night.By in reaction mixture impouring frozen water, separate out solid, leave standstill 2h, filter, solid uses water and washing with alcohol respectively, dry, obtains off-white color solid 132g, yield 91.0%.
The preparation of embodiment 42-({ (5S)-2-oxo-3-[4-(the fluoro-phenyl of 4-morpholinyl-3-)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-diketone
In 2L there-necked flask, add N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl phenylamine 99g (0.3mol), N respectively, dinethylformamide 180mL and tetrahydrofuran (THF) 540mL, less than 5 DEG C are cooled to after stirring and dissolving, add trimethyl carbinol lithium 48g (0.6mol), insulated and stirred 30 minutes in batches, add (S)-N-(2,3-epoxypropyl) phthalic imidine 81.2g (0.4mol), stirring at room temperature reacts 24 hours.TLC(methylene dichloride: ethyl acetate=12:1) show reaction substantially completely, add saturated ammonium chloride solution 600mL, extract with ethyl acetate 2L × 2, organic phase uses water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, filters, concentrated crystallization, obtains off-white color solid 107.1g, yield 84%.
The preparation of embodiment 52-({ (5S)-2-oxo-3-[4-(the fluoro-phenyl of 4-morpholinyl-3-)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-diketone
In 3L there-necked flask, add N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl phenylamine 99g (0.3mol), N respectively, dinethylformamide 180mL and tetrahydrofuran (THF) 540mL, logical nitrogen,-78 DEG C are cooled to after stirring and dissolving, slow instillation 2M n-Butyl Lithium hexane solution 300mL (containing n-Butyl Lithium 0.6mol), insulated and stirred 30 minutes, add (S)-N-(2,3-epoxypropyl) phthalic imidine 81.2g (0.4mol), be incubated-78 DEG C of stirring reactions 2 hours, then naturally rise to room temperature, stirring reaction 34 hours.TLC(methylene dichloride: ethyl acetate=12:1) show reaction and can not carry out completely, add saturated ammonium chloride solution 600mL, extract with ethyl acetate 2L × 2, organic phase uses water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, filters, concentrated crystallization, obtain off-white color solid 80.3g, yield 63%.
Embodiment 6 (S)-N-{ [3-(the fluoro-4-of 3-(4-morpholinyl) phenyl)-2-oxo-5-azoles quinoline base] methyl } preparation of-ethanamide (Linezolid)
In 3L there-necked flask, add 2-({ (5S)-2-oxo-3-[4-(the fluoro-phenyl of 4-morpholinyl-3-)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1, the water of 3-diketone 51g (0.12mol), methyl alcohol 1.5L and 80% and hydrazine 75g (1.2mol), heat 60 DEG C of reactions 1 hour.TLC(methylene dichloride: ethyl acetate=12:1) show reaction substantially completely, reaction solution is evaporated to dry, adds methylene dichloride 1.8L and water 600mL, abundant stirring and dissolving, separatory, organic layer 600mL water washing, anhydrous sodium sulfate drying, filter, filtrate proceeds in 3L there-necked flask, adds triethylamine 24.2g (0.24mol), stirring is cooled to 0 DEG C, slow dropping diacetyl oxide 14.7g (0.144mol), is incubated 0 DEG C of reaction 1 hour, then rises to room temperature reaction 1 hour.TLC(ethyl acetate) show and react substantially complete, add the stirring of 600mL water, separatory, organic layer uses saturated sodium bicarbonate solution, water washing respectively, anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, obtains white solid re-crystallizing in ethyl acetate, obtain white crystal Linezolid 36.1g, yield 89.1%.
Claims (18)
1. prepare a method for Linezolid, comprise the following steps:
1) under the effect of organic bases, 3,4-difluoro nitrobenzene and morpholine generation nucleophilic substitution reaction, generate 3-fluoro-4-morpholine oil of mirbane (2)
2) take Pd/C as catalyzer, reduction 3-fluoro-4-morpholine oil of mirbane is 3-fluoro-4-morpholine aniline (3)
3) 3-fluoro-4-morpholine aniline and chloroformic acid benzyl ester react and generate the fluoro-4-morpholinyl phenylamine (4) of N-carbobenzoxy-(Cbz)-3-
4) the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-and (S)-N-(2,3-epoxypropyl) phthalic imidine reaction cyclization Sheng Cheng oxazolidinone compounds 2-({ (5S)-2-oxo-3-[4-(4-morpholinyl-3-fluorophenyl)]-1,3-oxazolidine-5-base } methyl)-1H-isoindole-1,3-diketone (5)
5) 2-({ (5S)-2-oxo-3-[4-(4-morpholinyl-3-fluorophenyl)]-1; 3-oxazolidine-5-base } methyl)-1H-isoindole-1; 3-bis-ketogenesis (S)-5-aminomethyl-3-(the fluoro-4-morpholinyl phenyl of 3-) oxazolidine-2-ketone hydrazine hydrate back hydrolysis, then acetylize obtains Linezolid (1)
2. method according to claim 1, is characterized in that step 1) in solvent used be ethyl acetate, acetone, acetonitrile, one or more mixed solvents in DMF, temperature of reaction is 20 ~ 30 DEG C.
3. method according to claim 2, is characterized in that step 1) in solvent used be ethyl acetate.
4. method according to claim 1, is characterized in that step 1) in organic bases used be one or more in triethylamine, diisopropylethylamine, pyridine and DMAP.
5. method according to claim 4, is characterized in that step 1) in organic bases used be triethylamine.
6. method according to claim 1, is characterized in that step 2) in reductive agent used be hydrogen and ammonium formiate, reaction solvent is acetone.
7. method according to claim 6, is characterized in that step 2) in reductive agent used be ammonium formiate.
8. method according to claim 1, is characterized in that step 3) in acid binding agent used be sodium bicarbonate, reaction solvent is the mixture of acetone and water, and temperature of reaction is 0 ~ 30 DEG C.
9. method according to claim 1, is characterized in that step 4) in organic alkali used be trimethyl carbinol lithium.
10. method according to claim 1, is characterized in that step 4) in the ratio of trimethyl carbinol lithium and the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-be 1:1 ~ 4:1.
11. methods according to claim 10, is characterized in that step 4) in the ratio of trimethyl carbinol lithium and the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-be 2:1.
12. methods according to claim 1, it is characterized in that step 4) in the solvent of non-proton strong polarity used be methyl-sulphoxide (DMSO), acetonitrile, acetone, N, one or more mixture in dinethylformamide (DMF), N,N-dimethylacetamide (DMA) and tetrahydrofuran (THF) (THF).
13. methods according to claim 12, is characterized in that step 4) in the solvent of non-proton strong polarity used be the mixture of THF and DMF.
14. methods according to claim 1, is characterized in that step 4) in the temperature of reaction of trimethyl carbinol lithium and the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-be 0 ~ 50 DEG C.
15. methods according to claim 14, is characterized in that step 4) in the temperature of reaction of trimethyl carbinol lithium and the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-be 20 ~ 30 DEG C.
16. methods according to claim 1, is characterized in that step 5) in ammonia solution reagent used be hydrazine hydrate, the mol ratio of hydrazine hydrate and compound (5) is 10:1, solvent for use methyl alcohol.
17. methods according to claim 1, is characterized in that step 5) in acylating reagent used be diacetyl oxide, acid binding agent is triethylamine, and the mol ratio of diacetyl oxide, triethylamine and compound (5) is 1.2:2:1.
18. methods according to claim 1, is characterized in that step 5) in reaction solvent used be methylene dichloride.
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