CN104370854A - 3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 - Google Patents
3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 Download PDFInfo
- Publication number
- CN104370854A CN104370854A CN201310348657.2A CN201310348657A CN104370854A CN 104370854 A CN104370854 A CN 104370854A CN 201310348657 A CN201310348657 A CN 201310348657A CN 104370854 A CN104370854 A CN 104370854A
- Authority
- CN
- China
- Prior art keywords
- hydroxypropyl
- halogen
- represent
- morpholinyl
- ammonia
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- -1 3-oxo-4-morpholinyl group Chemical group 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 18
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 230000003287 optical effect Effects 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 9
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 9
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 57
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 229910021529 ammonia Inorganic materials 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 11
- 238000006462 rearrangement reaction Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 150000001448 anilines Chemical class 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000011630 iodine Chemical group 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 150000002191 fatty alcohols Chemical class 0.000 claims description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 230000006340 racemization Effects 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical class O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 abstract description 15
- 229960003907 linezolid Drugs 0.000 abstract description 14
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical class S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 abstract description 6
- 229960001148 rivaroxaban Drugs 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 2
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 25
- 150000001412 amines Chemical class 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 13
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 229950010535 razaxaban Drugs 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 0 CCC(*)c1cc(*(CC(C*)OC2C=*C2)C(*(C)C)[U])ccc1*=C Chemical compound CCC(*)c1cc(*(CC(C*)OC2C=*C2)C(*(C)C)[U])ccc1*=C 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 9
- 125000003368 amide group Chemical group 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- GPBVDKFJJAYKCR-UHFFFAOYSA-N N-fluoro-2-morpholin-4-ylaniline Chemical compound FNC1=C(C=CC=C1)N1CCOCC1 GPBVDKFJJAYKCR-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ODLMAHJVESYWTB-UHFFFAOYSA-N ethylmethylbenzene Natural products CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 3
- CSFAYIHXWKUTHH-UHFFFAOYSA-N n-phenylmorpholin-4-amine Chemical compound C1COCCN1NC1=CC=CC=C1 CSFAYIHXWKUTHH-UHFFFAOYSA-N 0.000 description 3
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical class NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- FTQBIKFTBHLHMF-UHFFFAOYSA-N 1-(2-aminophenyl)propan-2-ol Chemical class CC(O)CC1=CC=CC=C1N FTQBIKFTBHLHMF-UHFFFAOYSA-N 0.000 description 2
- VWIIJDNADIEEDB-UHFFFAOYSA-N 3-methyl-1,3-oxazolidin-2-one Chemical class CN1CCOC1=O VWIIJDNADIEEDB-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000005826 halohydrocarbons Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 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 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N CCC1CCCCC1 Chemical compound CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 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
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- AZHSSKPUVBVXLK-UHFFFAOYSA-N ethane-1,1-diol Chemical compound CC(O)O AZHSSKPUVBVXLK-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- LVCPZGHKQJLTEV-UHFFFAOYSA-N isoindole-1,3-dione 3-methyl-1,3-oxazolidin-2-one Chemical class C1(C=2C(C(N1)=O)=CC=CC2)=O.CN2C(OCC2)=O LVCPZGHKQJLTEV-UHFFFAOYSA-N 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 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
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明公开了一类3-卤-2-羟基丙基-1-酰基苯胺类化合物（ I ），还公开了该类化合物的制备方法，及其在制备噁唑烷酮类治疗药物，包括但不限于利奈唑胺和利伐沙班消旋体或光学异构体中的应用，式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、 (S) -光学异构体、或 (R) -光学异构体。
Description
技术领域
本发明属药物化学领域，涉及3-卤-2-羟基丙基-1-酰基苯胺类化合物（I），其制备方法和在制备噁唑烷酮类治疗药物消旋体或光学异构体中的应用，
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体。
背景技术
利奈唑胺（linezolid），化学名为(S)-5-(乙酰胺甲基)-3-[(3-氟-4-吗啉基)苯基]-1,3-噁唑烷-2-酮，是Pharmacia & Upjohn公司研制的新型噁唑烷酮类抗菌药，2000年4月首次在美国上市，商品名Zyvox，临床用于治疗由耐甲氧西林金葡球菌引起的肺炎和综合性皮肤感染，以及由耐万古霉素肠球菌（VREF）或耐青霉素肺炎链球菌（PRSP）引起的菌血症等。
利伐沙班（Rivaroxaban），化学名为5-氯-N-[[(5S)-2-氧-3-[4-(3-氧-4-吗啉基)苯基]-1,3-噁唑烷-5基]甲基]-2-噻吩甲酰胺，是德国Bayer公司开发的噁唑烷酮类凝血因子Xa直接抑制剂，于2008年9月首次在加拿大上市，商品名Xarelto，临床上主要用于预防髋或膝关节置换术患者静脉血栓栓塞，本品作为新型口服抗凝血药物具有生物利用度高，量效关系稳定，出血风险低特点，已成为预防血栓栓塞性疾病的首选药物。
目前，已有文献分别对利奈唑胺【（1）陈炜, 胡建良, 张兴贤. 利奈唑胺合成路线图解. 中国医药工业杂志, 2010, 41(1): 62-63；（2）何飚, 张乐. 噁唑烷酮类抗菌药物的合成. 国外医药——抗生素分册, 2009, 30(2): 82-88】和利伐沙班【（3）王海燕, 郭飞, 宫平. 利伐沙班合成路线图解. 中国药物化学杂志, 2012, 22(3): 249-251；（4）高扬, 梁斌, 倪国伟, 王环,等. 利伐沙班合成路线图解. 中国新药杂志, 2012, 21(4): 371-374；（4）符利梅, 蒋翔锐, 沈敬山. 利伐沙班合成路线图解. 中国医药导报, 2012, 9(13): 112-113；（5）Rivaroxaban. Drugs of the Future 2006, 31(6): 484-493】的合成方法进行了综述。其中，以苯胺类化合物（1）与环氧氯丙烷反应，生成3-氯-2-羟基丙基苯胺类化合物（2），然后再经多步反应转化为利奈唑胺或利伐沙班的合成策略具有原料价廉易得，反应条件温和，不需低温和无水操作等特点，因而具有较好的应用潜力，采用该策略来制备噁唑烷酮类治疗药物的文献方法总结如下：
式中R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基。
上述合成策略均是围绕着将3-氯-2-羟基丙基苯胺类化合物（2）中的氯原子转化为氨基进行的，具体制备方法如下：将化合物（2）与碳酰二咪唑（CDI）环合，得氯甲基噁唑烷酮类化合物（6），经与叠氮钠反应后再经还原和酰化，即可制得噁唑烷酮类治疗药物；也可将化合物（6）与邻苯二甲酰亚胺钾（8）反应，得相应的邻苯二甲酰亚胺甲基噁唑烷酮类化合物（9），再经进一步肼解和酰化，得到噁唑烷酮类治疗药物；或者先将化合物（2）与邻苯二甲酰亚胺钾（8）反应，得相应的邻苯二甲酰亚胺2-羟基丙基苯胺类化合物（11），经CDI环合后得化合物（9）；也可先将化合物（2）与氢氧化钠作用，转化为相应环氧化合物（10），再与邻苯二甲酰亚胺钾（8）反应，得相应的邻苯二甲酰亚胺2-羟基丙基苯胺类化合物（11）。但上述方法存在反应步骤较多、反应条件苛刻，需使用易爆的叠氮化钠和水合肼，叠氮基还原需使用氢气以及贵金属钯，且总收率低、中间体需柱层析纯化等问题。为克服上述问题，我们对上述各路线反应条件进行了研究，经多次试验发现将3-氯-2-羟基丙基苯胺类化合物（2）与大大过量的各种氨反应时，虽可将氯原子转化为氨基，但同时生成较多仲胺和叔胺副产物，导致所需氨解产物收率低于30%；且我们还发现，氯甲基噁唑烷酮类化合物（6）与大大过量的各种氨反应时，反应几乎不能发生，且无预期的胺基物生成。
综上所述，目前文献公开的利奈唑胺和利伐沙班合成技术存在反应条件苛刻（低温和无水操作）、反应步骤多、总收率低，制备过程中“三废”排放严重，反应操作及后处理过程繁琐等不足，使利奈唑胺和利伐沙班的制备成本较高，大量制备受到限制。因此，本领域仍需开发原料价廉易得、反应条件温和、操作简便、化学收率和光学纯度高、“绿色环保”的利奈唑胺和利伐沙班合成新方法。
发明内容
本发明的目的在于公开一类3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）；
本发明的另一目的在于公开该类3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的制备方法；
本发明的又一目的在于公开该类3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）在制备噁唑烷酮类治疗药物——包括但不限于利奈唑胺（Linezolid）和利伐沙班（Rivaroxaban）消旋体或光学异构体中的应用。
本发明所公开的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的化学结构通式为：
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体。
本发明所公开的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）可通过下述方法制备得到，其化学反应式如下；
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体。
其具体制备方法如下：以消旋或光学活性的3-卤-2-羟基丙基苯胺类化合物（2）为起始原料，与适当溶剂或无溶剂、以及碱性条件下与相应的酰化试剂反应，得相应的3-卤-2-羟基丙基-1-酰基苯胺类化合物（(I)-1）、3-卤-2-羟基丙基-1,2-二酰基苯胺类化合物（(I)-2）、或(I)-1与(I)-2的任意比例混合物；其中反应所用溶剂为：C3-8脂肪酮、C5-10脂肪烷烃或环烷烃（如：正己烷、正庚烷等）、N,N-二甲基甲酰胺、醚类（如：乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚等）、C1-6脂肪酸与C1-6脂肪醇所形成酯、卤代烃（如：二氯甲烷、氯仿、1,2-二氯乙烷、邻二氯苯等）、苯、甲苯、或乙腈，反应可在上述单一溶剂中进行，也可在上述混合溶剂中进行，混合溶剂体积比为1：0.1~10，优选溶剂为：四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、氯仿、丙酮、乙酸乙酯、乙腈或甲苯；反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、哌啶、四氢吡咯、三乙胺、三丁胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺、或上述各种碱的组合，优选碱为：碳酸氢钠、碳酸钾、三乙胺、吡啶、或N-甲基吗啉；所用酰化试剂为：C1-12酰氯或C1-12酰溴、C1-12羧酸所形成的相应酸酐、5-氯噻吩-2-甲酰氯、C1-12羧酸与氯甲酸乙酯形成的混合酸酐、或5-氯噻吩-2-甲酸与氯甲酸乙酯形成的混合酸酐；3-卤-2-羟基丙基苯胺类化合物（2）：酰化试剂：碱的摩尔投料比为1.0：1.0~10.0：1.0~10.0，优选为1.0：1.0~5.0：1.0~5.0；反应温度为-20℃~120℃，优选为0℃~80℃；反应时间为20分钟~24小时，优选为1~12小时。
利用上述方法制得的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）（包括：(I)-1、(I)-2、或(I)-1与(I)-2的任意比例混合物）可用以下方法将其转化为噁唑烷酮类治疗药物（II），这些噁唑烷酮类治疗药物包括但不限于利奈唑胺（Linezolid）和利伐沙班（Rivaroxaban）消旋体或光学异构体，其合成路线如下：
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体。
其合成方法具体描述如下：
3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）在合适溶剂中与氨经氨解重排反应，得2-羟基-1,3-丙二胺类化合物（3）；所得化合物（3）再利用现有技术，在合适溶剂中与酰化试剂进行环合反应，得噁唑烷酮类治疗药物（II）；其中，氨解重排反应所用氨为：氨气、氨水溶液、氨的C1-8脂肪醇溶液、液氨、或遇热分解可释放出氨的化合物（如：碳酸铵、碳酸氢铵、醋酸铵等）或六次甲基四胺；氨解重排反应所用溶剂为：水、C1-8脂肪醇、C3-8脂肪酮、C5-10脂肪烷烃或环烷烃（如：正己烷、正庚烷等）、N,N-二甲基甲酰胺、醚类（如：乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、1,4-二氧六环等）、C1-6脂肪酸与C1-6脂肪醇所形成酯、乙二醇单甲醚、乙二醇、卤代烃（如：二氯甲烷、氯仿、1,2-二氯乙烷、邻二氯苯等）、苯、甲苯、或乙腈，反应可在上述单一溶剂中进行，也可在上述混合溶剂中进行，混合溶剂体积比为1：0.1~10，优选溶剂为：水、甲醇、乙醇、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、氯仿、乙腈、乙二醇单甲醚、丙酮或1,4-二氧六环；3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）：氨的摩尔投料比为1.0：1.0~1000，优选为1.0：5.0~100；氨解重排反应温度为-40℃~100℃，优选为0℃~60℃；氨解重排反应时间为20分钟~24小时，优选为2小时~12小时；酰化环合反应步骤中所用酰化试剂为：碳酰二咪唑（CDI）、光气、氯甲酸三氯甲酯、双(三氯甲基)碳酸酯、氯甲酸C1-8脂肪醇酯类化合物（如：氯甲酸乙酯、氯甲酸叔丁酯、氯甲酸苄酯等）、碳酸的C1-8脂肪醇酯类化合物（如：碳酸二甲酯、碳酸二乙酯等）、或二琥珀酰亚胺碳酸酯（DSC）。
本发明所用3-卤-2-羟基丙基苯胺类化合物（2）可用苯胺类化合物与相应环氧卤丙烷按照现有技术制备得到，收率95%-98%。本发明的优点在于：与现有技术相比，该方法具有原料价廉易得，反应条件温和、反应步骤少，操作简便，不使用危险试剂，且收率高、成本低，产品光学纯度高，适合较大规模制备噁唑烷酮类治疗药物等特点。
具体实施方式
通过下面的实施例可对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。
IA6304型熔点仪，温度计未经校正；Varian INOVA-400核磁共振仪（溶剂为CDCl3或DMSO-d 6 ，内标TMS）；Agilent-6210 TOF LC/MS高分辨质谱仪；Perkin-Elmer model 341自动旋光仪。薄层层析用硅胶板为山东烟台化工研究所生产，用紫外灯或碘显色；HPLC手性柱：Chiralcel OD-H (250mm×4.6mm)，流动相：正己烷-异丙醇-三氟乙酸。
实施例1
(R)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(R)-Ia）和(R)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(R)-Ib）的制备
在反应瓶中依次加入(R)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺（0.01 mol）、二氯甲烷100 ml、三乙胺（0.02 mol），室温搅拌均匀后，加入乙酰氯（0.015 mol），继续于室温搅拌反应，反应进程用TLC监测（展开剂：石油醚/乙酸乙酯=1/30 v/v），反应毕，反应液依次用去离子水、饱和NaHCO3水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后过滤，滤液减压蒸去溶剂，得(R)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(R)-Ia）和(R)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(R)-Ib）的混合物，可不经纯化直接用于下步反应，收率定量；取少量混合物经硅胶柱色谱[洗脱剂：石油醚/乙酸乙酯=1/30 v/v]纯化，分别得(R)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺纯品，收率75.2%；1H NMR(CDCl3, 400 MHz) d: 6.97-6.90(m, 3H, Ar-H), 4.09-4.05(m, 1H, CHOH), 4.03(dd, J 1=1.6 Hz, J 2=12.0 Hz, 1H, CH2NAc), 3.86(t, J=4.8 Hz, 4H, 2×OCH2), 3.60(dd, J 1=4.0 Hz, J 2=12.0 Hz, 1H, CH2NAc), 3.51(d, J=5.6 Hz, 2H, CH2Cl), 3.10(t, J=4.8 Hz, 4H, 2×NCH2), 2.10(brs, 1H, OH), 1.89(s, 3H, CH3CO); HR-TOF-MS (+Q) m/z:353.1049 ([C15H20ClFN2O3+Na]+计算值：353.1044)；以及(R)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯纯品，收率15.7%；1H NMR(CDCl3, 400 MHz) d: 6.94-6.90(m, 3H, Ar-H), 5.28-5.25(m, 1H, CHO), 3.94(d, J=6.0 Hz, 2H, CH2Cl), 3.88(t, J=4.8 Hz, 4H, 2×OCH2), 3.71(dd, J 1=4.0 Hz, J 2=12.0 Hz, 1H, CH2NAc), 3.62(dd, J 1=2.0 Hz, J 2=12.0 Hz, 1H, CH2NAc), 3.12(t, J=4.8 Hz, 4H, 2×NCH2), 2.00(s, 3H, CH3CO), 1.86(s, 3H, CH3CO); 13C NMR(CDCl3, 100 MHz) d: 171.0, 170.1, 155.0(d, J = 247.7Hz), 139.7(d, J = 7.6Hz), 137.1(d, J = 9.1Hz), 123.9, 118.7(d, J = 3.8Hz), 115.8(d, J = 21. Hz), 71.3, 66.7, 50.5, 50.3, 44.0, 22.4, 20.7；HR-TOF-MS (+Q) m/z:373.1328 ([C17H22ClFN2O4+H]+计算值：373.1330)。
实施例2
(S)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(S)-Ia）的制备
在反应瓶中依次加入(S)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺（0.01 mol）、乙酸乙酯80 ml、吡啶（0.018 mol），室温搅拌均匀后，加入乙酸酐（0.015 mol），继续于室温搅拌反应4小时，反应毕，反应液依次用去离子水、饱和NaHCO3水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后过滤，滤液减压蒸去溶剂，得(S)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺，无需纯化直接用于下步反应，收率定量；HR-TOF-MS (+Q) m/z:353.1040 ([C15H20ClFN2O3+Na]+计算值：353.1044)。
实施例3
(S)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(S)-Ib）的制备
在反应瓶中依次加入(S)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺（0.01 mol）、甲苯120 ml、碳酸钾（0.035 mol），室温搅拌均匀后，加入乙酰氯（0.03 mol），于室温搅拌反应2小时后升温至50-60℃继续反应3小时，反应毕，反应液依次用去离子水、饱和NaHCO3水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后过滤，滤液减压蒸去溶剂，得(S)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯，无需纯化直接用于下步反应，收率定量；HR-TOF-MS (+Q) m/z:373.1326 ([C17H22ClFN2O4+H]+计算值：373.1330)。
实施例4
(dl)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(dl)-Ia）和(dl)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(dl)-Ib）的制备
操作方法同实施例1，只是将(R)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺用(dl)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺替代，即可得到相应的目标物。
实施例5
(R)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(R)-Ic）和(R)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(R)-Id）的制备
操作过程同实施例1，只是将(R)-N-(3-氯-2-羟基丙基)-3-氟-4-吗啉基苯胺用(R)-4-[4-[(3-氯-2-羟基丙基)氨基]苯基]-3-吗啉酮替代，乙酰氯用5-氯-2-噻吩甲酰氯替代，即可制备得到(R)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(R)-Ic）和少量(R)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(R)-Id）混合物，可不经纯化直接用于下步反应，收率定量；也可将此混合物用常规方法纯化，得(R)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(R)-Ic），收率90.0%；1H NMR(CDCl3, 400 MHz) d: 7.49(d, J=8.8 Hz, 2H, Ph-H), 7.37(d, J=8.8 Hz, 2H, Ph-H), 6.72(d, J=4.0 Hz, 1H, Thiophene-H), 6.67(d, J=4.0 Hz, 1H, Thiophene-H), 4.37(s, 2H, OCH2CO), 4.26(dd, J 1=8.4 Hz, J 2=14.0 Hz, 1H, CH2NCOAr), 4.14-4.10(m, 1H, CHOH), 4.08(t, J=5.2 Hz, 2H, CH2N), 3.84(t, J=5.2 Hz, 2H, CH2O), 3.81(dd, J 1=2.8 Hz, J 2=14.0 Hz, 1H, CH2NCOAr), 3.60-3.58(m, 2H, CH2Cl); 13C NMR(CDCl3, 100 MHz) d: 166.6, 163.3, 141.6, 140.1, 136.8, 135.1, 132.9, 129.3, 126.3, 126.2, 69.8, 68.4, 63.9, 55.6, 49.1, 47.0; HR-TOF-MS (+Q) m/z: 429.0437 ([C18H18Cl2N2O4S+H]+计算值：429.0443)。
实施例6
(S)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(S)-Ic）的制备
在反应瓶中依次加入(S)-4-[4-[(3-氯-2-羟基丙基)氨基]苯基]-3-吗啉酮（0.01 mol）、乙酸乙酯120 ml、吡啶（0.02 mol），室温搅拌均匀后，加入5-氯-2-噻吩甲酰氯（0.012 mol），继续于室温搅拌反应5小时，反应毕，反应液依次用去离子水、饱和NaHCO3水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后过滤，滤液减压蒸去溶剂，得(S)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺，无需纯化直接用于下步反应，收率定量；HR-TOF-MS (+Q) m/z: 429.0446 ([C18H18Cl2N2O4S+H]+计算值：429.0443)。
实施例7
(S)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(S)-Ic）和(S)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(S)-Id）的制备
在反应瓶中加入5-氯-2-噻吩甲酸（0.02 mol）、甲苯120 ml和4-甲基吗啉（0.04 mol）搅拌均匀后，冷却至0-5℃，加入氯甲酸乙酯（0.03 mol），继续搅拌反应30分钟后，加入(S)-4-[4-[(3-氯-2-羟基丙基)氨基]苯基]-3-吗啉酮（0.01 mol），于室温搅拌反应2小时后升温至50-60℃继续反应3小时，反应毕，反应液依次用去离子水、饱和NaHCO3水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后过滤，滤液减压蒸去溶剂，得(S)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺和(S)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯混合物，可不经纯化直接用于下步反应，收率定量。
实施例8
(dl)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(dl)-Ic）和(dl)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(dl)-Id）的制备
操作方法同实施例5，只是将(R)-4-[4-[(3-氯-2-羟基丙基)氨基]苯基]-3-吗啉酮用(dl)-4-[4-[(3-氯-2-羟基丙基)氨基]苯基]-3-吗啉酮替代，即可得到相应的目标物。
实施例9-17
采用实施例1-8类似方法，即得到相应的3-卤-2-羟基丙基-1-酰基苯胺类化合物和3-卤-2-羟基丙基-1,2-二酰基苯胺类化合物，其代表性实验的结果如下：
（续上表）
注：实施例9-17各反应粗品收率定量，可不经纯化直接用于下步反应。
实施例18
N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺（R-3a）的制备
在反应瓶中加入如实施例1所制备得到的(R)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(R)-Ia）和(R)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(R)-Ib）的混合物（0.01 mol）、甲醇30 ml、市售25%-28%氨水20 ml，室温搅拌反应8小时，反应结束后，减压蒸除甲醇，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺，收率86.0%，化学纯度99.7%，光学纯度99.8%ee；m.p. 124.2-125.7℃，[a]= -0.9 (c 1.0, CH3OH），HRMS-ESI(m/z): 312.1716[M+H]+；1H-NMR(DMSO-d 6 , 400MHz) δ: 7.86(t, J = 4.8Hz, 1H, NHCO), 6.82(t, J = 9.6Hz, 1H, Ar-H), 6.41(dd, J = 2.4, 15.2Hz, 1H, Ar-H), 6.33(dd, J = 2.4, 8.4Hz, 1H, Ar-H), 5.47(t, J = 5.6Hz, 1H, Ar-NH), 4.97(d, J = 5.2Hz, 1H, OH), 3.69(t, J = 4.8Hz, 4H, 2×-CH2O), 3.62(m, 1H, CHOH), 3.15(m, 1H, CH2NHCO), 3.04(m, 1H, CH2NHCO), 2.98(m, 1H, CH2NHAr), 2.87(m, 1H, CH2NHAr), 2.82(t, J = 4.8Hz, 4H, 2×CH2N), 1.82(s, 3H, CH3)。
实施例19
N-[(2S)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺（S-3a）的制备
在反应瓶中加入如实施例3所制备得到的(S)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（0.01 mol）、四氢呋喃30 ml、氨的甲醇饱和溶液30 ml、室温搅拌反应8小时，反应结束后，减压蒸除溶剂，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色固体，收率89.0%，其结构经HRMS-ESI、1H-NMR确证。
实施例20
(dl)-N-[-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺（dl-3a）的制备
在反应瓶中加入如实施例4所制备得到的(dl)-N-(3-氯-2-羟基丙基)-N-(3-氟-4-吗啉苯基)乙酰胺（(dl)-Ia）和(dl)-1-氯-3-[N-(3-氟-4-吗啉苯基)乙酰胺基]-2-丙醇乙酸酯（(dl)-Ib）混合物（0.01 mol）、甲醇50 ml和碳酸铵（0.1 mol），升温回流搅拌反应3小时，反应结束后，趁热过滤，滤液减压蒸除溶剂，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色固体，收率78.0%，其结构经HRMS-ESI、1H-NMR确证。
实施例21
(R)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺（R-3b）的制备
在反应瓶中加入如实施例5所制备得到的(R)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(R)-Ic）和(R)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(R)-Id）混合物（0.01 mol）、乙腈30 ml、市售25%-28%氨水20 ml，室温搅拌反应8小时，反应结束后，减压蒸除溶剂，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色固体，收率95.0%，化学纯度99.6%，光学纯度大于99.8%ee; m.p. 195.5-196.5℃, [a]= +5.5o(c 0.5, DMSO), HRMS-ESI(m/z): 410.0945 [M+H]+; 1H-NMR(DMSO-d 6 , 400MHz) δ: 8.61(t, J = 5.6Hz, 1H, NHCO), 7.68(d, J=4.0 Hz, 1H, Thiophene-H), 7.18(d, J=4.0 Hz, 1H, Thiophene-H), 7.01(d, J=8.4 Hz, 2H, Ph-H), 6.59(d, J=8.4 Hz, 2H, Ph-H), 5.65(t, J = 5.6Hz, 1H, Ar-NH), 5.08(d, J = 4.8Hz, 1H, OH), 4.13(s, 2H, OCH2CO), 3.92(t, J=4.8 Hz, 2H, CH2N), 3.81-3.78(m, 1H, CHOH), 3.60(t, J=4.8 Hz, 2H, CH2O), 3.39-3.30(m, 1H, CH2N), 3.28-3.21(m, 1H, CH2N), 3.14-3.08(m, 1H, CH2N), 3.00-2.94(m, 1H, CH2N)。
实施例22
(S)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺（S-3b）的制备
在反应瓶中加入如实施例6所制备得到的(S)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（0.01 mol）、1,4-二氧六环30 ml、市售25%-28%氨水30 ml，室温搅拌反应8小时，反应结束后，减压蒸除溶剂，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色固体，收率90.6%，其结构经HRMS-ESI、1H-NMR确证。
实施例23
(dl)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺（dl-3b）的制备
在反应瓶中加入如实施例8所制备得到的(dl)-5-氯-N-(3-氯-2-羟基丙基)-N-[4-(3-吗啉酮基)苯基)]-2-噻吩甲酰胺（(dl)-Ic）和(dl)-1-氯-3-[N-[4-(3-吗啉酮基)苯基)]-5-氯-2-噻吩甲酰胺基]-2-丙醇-(5-氯-2-噻吩基)甲酸酯（(dl)-Id）混合物（0.01 mol）、去离子水20 ml、氨的乙醇醇饱和溶液30 ml、室温搅拌反应8小时，反应结束后，减压蒸除溶剂，残余物用100毫升二氯甲烷溶解，依次用去离子水50毫升，饱和NaCl水溶液50毫升洗涤，有机层经无水Na2SO4干燥，减压蒸除溶剂，残余物经常规方法纯化，得白色固体，收率93.0%，其结构经HRMS-ESI、1H-NMR确证。
实施例24-32
采用实施例18-23类似方法，只是将底物替换为相应的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I），然后在溶剂中与氨经氨解重排反应，得相应的2-羟基-1,3-丙二胺类化合物（3），其代表性实验的结果如下：
（续上表）
。
实施例33
(S)-N-((3-(3-氟-4-(4-吗琳基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺（利奈唑胺）的制备
在反应瓶中加入按照实施例18所制备得到的N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺（0.01 mol）、二氯甲烷100 ml和三乙胺（0.015 mol），搅拌均匀后，置冰浴中冷却至0-5℃，加入双(三氯甲基)碳酸酯（0.004 mol），自然升温至室温反应2小时，反应液依次用5%NaOH水溶液、饱和NaCl水溶液洗涤，有机层经无水硫酸钠干燥，过滤，减压除去溶剂，残余物用乙酸乙酯重结晶得白色针状晶体，收率95.0%，mp:178～179℃；[a]= -9.2o (c 1.0, CHCl3)，化学纯度99.90%，光学纯度99.8%ee；1H NMR(CDCl3, 400 MHz) d: 7.43(dd, J 1=2.8 Hz, J 2=14.4 Hz, 1H, Ar-H), 7.06(dd, J 1=1.6 Hz, J 2=8.8 Hz, 1H, Ar-H), 6.94(t, J=9.2 Hz, 1H, Ar-H), 6.17(t, J=6.0 Hz, 1H, NH), 4.80～4.74(m, 1H, CHO), 4.02(t, J=8.8 Hz, 1H, CH2CHO), 3.86(t, J=4.8 Hz, 4H, 2×OCH2), 3.75(dd, J 1=6.8 Hz, J 2=8.8 Hz, 1H, CH2CHO), 3.71～3.58(m, 2H, CH2NH), 3.06(t, J=4.8 Hz, 4H, 2×NCH2), 2.02(s, 3H, CH3CO)；13C NMR(CDCl3, 100 MHz) : 171.4, 155.7(d, J=245 Hz), 154.5, 136.4(d, J=8.8 Hz), 132.8(d, J=10.4 Hz), 118.6(d, J=3.9 Hz), 113.8(d, J=3.0 Hz), 107.4(d, J=26.1 Hz), 72.0, 66.8, 50.8, 47.5, 41.7, 22.8；HR-TOF-MS (+Q) m/z:338.1510([C16H20FN3O4+H]+计算值：338.1516)。
实施例34
(R)-N-((3-(3-氟-4-(4-吗琳基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺的制备
操作同实施例33，只是将N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺用N-[(2S)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺替代，二氯甲烷用四氢呋喃替代，双(三氯甲基)碳酸酯用碳酰二咪唑替代，得(R)-N-((3-(3-氟-4-(4-吗琳基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺，收率92.0%，mp:178～179℃；其结构经HRMS-ESI、1H-NMR确证。
实施例35
(dl)-N-((3-(3-氟-4-(4-吗琳基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺的制备
操作过程同实施例33，只是将N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺用(dl)-N-[-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺替代，二氯甲烷用乙酸乙酯替代，双(三氯甲基)碳酸酯用氯甲酸甲酯替代，得(dl)-N-((3-(3-氟-4-(4-吗琳基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺，收率90.0%；其结构经HRMS-ESI、1H-NMR确证。
实施例36
(S)-5-氯-N-[[(5S)-2-氧-3-[4-(3-氧-4-吗啉基)苯基]-1,3-噁唑烷-5基]甲基]-2-噻吩甲酰胺（利伐沙班）的制备
操作过程同实施例33，只是将N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺用(R)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺替代，得(S)-5-氯-N-[2-氧代-3-[4-(3-羰基吗啉-4-基)苯基]-1,3-噁唑烷-5-基]甲基]噻吩-2-甲酰胺，收率95.3%，mp:232～233℃；[a]= -41.0o(c 0.5, DMSO)，化学纯度99.85%，光学纯度99.8% ee；其结构经HRMS-ESI、1H-NMR确证。
实施例37
(R)-5-氯-N-[[(5S)-2-氧-3-[4-(3-氧-4-吗啉基)苯基]-1,3-噁唑烷-5基]甲基]-2-噻吩甲酰胺的制备
操作过程同实施例33，只是将N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺用(S)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺替代，二氯甲烷用四氢呋喃替代，双(三氯甲基)碳酸酯用碳酰二咪唑替代，得(R)-5-氯-N-[2-氧代-3-[4-(3-羰基吗啉-4-基)苯基]-1,3-噁唑烷-5-基]甲基]噻吩-2-甲酰胺，收率90.0%，mp:232～233℃；其结构经HRMS-ESI、1H-NMR确证。
实施例38
(dl)-5-氯-N-[[(5S)-2-氧-3-[4-(3-氧-4-吗啉基)苯基]-1,3-噁唑烷-5基]甲基]-2-噻吩甲酰胺的制备
操作过程同实施例33，只是将N-[(2R)-3-[[3-氟-4-(4-吗啉基)苯基]氨基]-2-羟基丙基]-乙酰胺用(dl)-5-氯-N-[2-羟基-3-[[4-(3-氧-4-吗啉基)苯基]氨基]丙基]-2-噻吩甲酰胺替代，二氯甲烷用乙酸乙酯替代，双(三氯甲基)碳酸酯用氯甲酸甲酯替代，得(dl)-5-氯-N-[2-氧代-3-[4-(3-羰基吗啉-4-基)苯基]-1,3-噁唑烷-5-基]甲基]噻吩-2-甲酰胺，收率87.8%；其结构经HRMS-ESI、1H-NMR确证。
Claims (8)
1.一类3-卤-2-羟基丙基-1-酰基苯胺类化合物（I），其特征在于，它是具有化学结构通式（I）所示的化合物：
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体。
2.如权利要求1所述3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的制备方法，其特征在于可通过下述方法制备得到：
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体；
以消旋或光学活性的3-卤-2-羟基丙基苯胺类化合物2为起始原料，与适当溶剂或无溶剂、以及碱性条件下与相应的酰化试剂反应，得相应的3-卤-2-羟基丙基-1-酰基苯胺类化合物（(I)-1）、3-卤-2-羟基丙基-1,2-二酰基苯胺类化合物（(I)-2）、或(I)-1与(I)-2的任意比例混合物。
3.如权利要求2所述的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的制备方法，其特征在于，反应所用溶剂为：C3-8脂肪酮、正己烷、正庚烷、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、邻二氯苯、苯、甲苯、或乙腈，反应可在单一溶剂中进行，也可在混合溶剂中进行，混合溶剂体积比为1：0.1~10。
4.如权利要求2所述的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的制备方法，其特征在于，反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、哌啶、四氢吡咯、三乙胺、三丁胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺。
5.如权利要求2所述的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）的制备方法，其特征在于，所用酰化试剂为：C1-12酰氯或C1-12酰溴、C1-12羧酸所形成的相应酸酐、5-氯噻吩-2-甲酰氯、C1-12羧酸与氯甲酸乙酯形成的混合酸酐、或5-氯噻吩-2-甲酸与氯甲酸乙酯形成的混合酸酐。
6.一种噁唑烷酮类治疗药物（II）的制备方法，其特征在于，以权利要求1所述的3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）为原料，通过下述方法制备得到：
式中：R1表示吗啉基或3-氧-4-吗啉基；R2表示H或F；R3表示C1-12烷基或5-氯噻吩-2-基；R4表示H、C2-13酰基、或5-氯噻吩-2-甲酰基；X表示氯、溴或碘；所述化合物为消旋体、(S)-光学异构体、或(R)-光学异构体；
3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）在溶剂中与氨经氨解重排反应，得2-羟基-1,3-丙二胺类化合物（3）；所得化合物（3）再利用现有技术，在溶剂中与酰化试剂进行环合反应，得噁唑烷酮类治疗药物（II）。
7.如权利要求6所述的噁唑烷酮类治疗药物（II）的制备方法，其特征在于，氨解重排反应所用氨为：氨气、氨水溶液、氨的C1-8脂肪醇溶液、液氨、碳酸铵、碳酸氢铵、醋酸铵、或六次甲基四胺；氨解重排反应所用溶剂为：水、C1-8脂肪醇、C3-8脂肪酮、正己烷、正庚烷等）、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、1,4-二氧六环、C1-6脂肪酸与C1-6脂肪醇所形成酯、乙二醇单甲醚、乙二醇、二氯甲烷、氯仿、1,2-二氯乙烷、邻二氯苯、苯、甲苯、或乙腈，反应可在上述单一溶剂中进行，也可在上述混合溶剂中进行，混合溶剂体积比为1：0.1~10；3-卤-2-羟基丙基-1-酰基苯胺类化合物（I）：氨的摩尔投料比为1.0：1.0~1000；氨解重排反应温度为-40℃~100℃；氨解重排反应时间为20分钟~24小时。
8.如权利要求1所述化合物在制备噁唑烷酮类治疗药物的消旋体或光学异构体中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310348657.2A CN104370854B (zh) | 2013-08-12 | 2013-08-12 | 3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310348657.2A CN104370854B (zh) | 2013-08-12 | 2013-08-12 | 3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104370854A true CN104370854A (zh) | 2015-02-25 |
| CN104370854B CN104370854B (zh) | 2016-07-06 |
Family
ID=52550089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310348657.2A Expired - Fee Related CN104370854B (zh) | 2013-08-12 | 2013-08-12 | 3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104370854B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316988B (zh) * | 2015-06-16 | 2018-07-24 | 重庆常捷医药有限公司 | 利奈唑胺注射液降解杂质的制备方法 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220001A (zh) * | 2008-01-25 | 2008-07-16 | 浙江博泰化工有限公司 | 一种利奈唑酮的合成方法 |
| CN102267956A (zh) * | 2011-06-15 | 2011-12-07 | 亚邦医药股份有限公司 | 1,3-噁唑烷-2-酮类化合物、其制备方法和用途 |
| CN102351807A (zh) * | 2011-09-03 | 2012-02-15 | 四川大学 | 二苄基-1,3-噁唑烷-2-酮类化合物、其制备方法和用途 |
| CN102516191A (zh) * | 2011-12-21 | 2012-06-27 | 吉林省博大伟业制药有限公司 | 一种利奈唑胺的制备方法 |
| CN102844309A (zh) * | 2009-04-28 | 2012-12-26 | 阿普泰克斯药物化学公司 | 利伐沙班及其中间体的制备方法 |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
-
2013
- 2013-08-12 CN CN201310348657.2A patent/CN104370854B/zh not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220001A (zh) * | 2008-01-25 | 2008-07-16 | 浙江博泰化工有限公司 | 一种利奈唑酮的合成方法 |
| CN102844309A (zh) * | 2009-04-28 | 2012-12-26 | 阿普泰克斯药物化学公司 | 利伐沙班及其中间体的制备方法 |
| CN102267956A (zh) * | 2011-06-15 | 2011-12-07 | 亚邦医药股份有限公司 | 1,3-噁唑烷-2-酮类化合物、其制备方法和用途 |
| CN102351807A (zh) * | 2011-09-03 | 2012-02-15 | 四川大学 | 二苄基-1,3-噁唑烷-2-酮类化合物、其制备方法和用途 |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
| CN102516191A (zh) * | 2011-12-21 | 2012-06-27 | 吉林省博大伟业制药有限公司 | 一种利奈唑胺的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| 张慧等: "利奈唑胺的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316988B (zh) * | 2015-06-16 | 2018-07-24 | 重庆常捷医药有限公司 | 利奈唑胺注射液降解杂质的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104370854B (zh) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2709207C2 (ru) | 1,3,4-оксадиазольные производные соединения в качестве ингибитора гистондеацетилазы 6 и фармацевтическая композиция, содержащая их | |
| CA2553237C (en) | Production method | |
| CA2724508C (en) | Phenyl and benzodioxinyl substituted indazoles derivatives | |
| WO2013098833A2 (en) | Processes and intermediates for preparing rivaroxaban | |
| WO2007109456A2 (en) | Substituted biphenyl isoxazole sulfonamides as dual angiotensin endothelin receptor antagonists | |
| CA2135861A1 (en) | Oxazolidin-2-one derivatives | |
| WO2011080341A1 (en) | Process for the preparation of rivaroxaban and intermediates thereof | |
| NZ525923A (en) | Methods of producing oxazolidinone compounds | |
| AU2011245302A1 (en) | Processes for preparing linezolid | |
| BR112020018562A2 (pt) | Processo preparativo | |
| CA2771601A1 (en) | Morpholinone compounds as factor ixa inhibitors | |
| KR20190025990A (ko) | 4-알콕시-3-(아실 또는 알킬)옥시피콜린아미드의 제조 방법 | |
| CA3208103A1 (en) | Anti-viral compounds | |
| CA2743557A1 (en) | Spiro azepane-oxazolidinones as kv1.3 potassium channel blockers | |
| CA2926754C (en) | Piperazine derivatives and the use thereof as medicament | |
| ES2647607T3 (es) | Procedimiento para la preparación de rivaroxabán | |
| AU2019376282A1 (en) | Process for preparation of optically enriched isoxazolines | |
| CN104592143B (zh) | 一种噁唑烷酮类化合物的制备方法 | |
| WO2009027395A1 (en) | A new class of histone deacetylase inhibitors | |
| CN104370854A (zh) | 3-卤-2-羟基丙基-1-酰基苯胺类化合物其制备方法和用途 | |
| KR20150065190A (ko) | 피라진 유도체 | |
| CN103804315B (zh) | 一种5-氨甲基噁唑烷酮类化合物的制备方法 | |
| JP5858917B2 (ja) | イソキノリン誘導体又はその塩の新規製造方法 | |
| CN104860904B (zh) | N-环氧丙基-n-酰基苯胺类化合物其制备方法和用途 | |
| WO2012157504A1 (ja) | β－ラクタム化合物およびその製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160706 |