CN104327119A - Preparation method of tedizolid phosphate - Google Patents
Preparation method of tedizolid phosphate Download PDFInfo
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- CN104327119A CN104327119A CN201410553205.2A CN201410553205A CN104327119A CN 104327119 A CN104327119 A CN 104327119A CN 201410553205 A CN201410553205 A CN 201410553205A CN 104327119 A CN104327119 A CN 104327119A
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- Prior art keywords
- phosphoric acid
- preparation
- pyridine
- base
- methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title abstract description 8
- 229960003947 tedizolid phosphate Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 39
- -1 azoles amine Chemical class 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 25
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 21
- 239000004327 boric acid Substances 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004799 bromophenyl group Chemical group 0.000 claims description 6
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000006303 iodophenyl group Chemical group 0.000 claims description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 5
- 229940093916 potassium phosphate Drugs 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 3
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940056137 sivextro Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- GOOVAYJIVMBWPP-UHFFFAOYSA-N 1-bromo-2-isocyanatobenzene Chemical compound BrC1=CC=CC=C1N=C=O GOOVAYJIVMBWPP-UHFFFAOYSA-N 0.000 description 1
- VVNMGFXOVZRKQF-UHFFFAOYSA-N 1-iodo-2-isocyanatobenzene Chemical compound IC1=CC=CC=C1N=C=O VVNMGFXOVZRKQF-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VGAPXKNCPZQJIR-UHFFFAOYSA-N CC1(C)OB(c2ccc(/C(/N)=N/[N](C)(C[BrH]c(cc3)cnc3-c3n[n](C)nn3)N)nc2)OC1(C)C Chemical compound CC1(C)OB(c2ccc(/C(/N)=N/[N](C)(C[BrH]c(cc3)cnc3-c3n[n](C)nn3)N)nc2)OC1(C)C VGAPXKNCPZQJIR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of tedizolid phosphate (I). According to the preparation method, a compound as shown in the formula II and a compound as shown in the formula III have a coupling reaction to generate tedizolid phosphate (I). The preparation method adopts easily available raw materials and a simple process, is economical and environmentally friendly and is suitable for industrial production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly the preparation method of a kind of new oxazolidone antibiotics phosphoric acid safe ground azoles amine.
Background technology
Tedizolid phosphate is the oxazolidinone microbiotic developed by Ka Bisite (Cubist) drugmaker.Tedizolid phosphate obtains U.S. FDA approval in U.S.'s listing in June, 2014, and commodity are called Sivextro.This medicine is first Er Dai oxazolidinone microbiotic obtaining FDA approval, compares with generation product Linezolid, and the vitro inhibition activity of Sivextro to some bacteriums wants high 2-8 doubly, and security also increases to a certain extent.Because compound Tedizolid does not also have the Chinese translation of standard, therefore its transliteration is " safe ground azoles amine " at this by the applicant.
The chemistry of phosphoric acid safe ground azoles amine (Tedizolid phosphate) is called: { (5R)-3-[the fluoro-4-of 3-[6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl] phenyl]-2-azolactone-5 base } methyl alcohol phosphoric acid ester (I), and its structural formula is:
The preparation method of phosphoric acid safe ground azoles amine studies have reported that, and No. WO2005058886th, PCT patent, No. WO2010042887 and " European Journal of Medicinal Chemistry " the 46th phase 1027th ~ 1039 pages in 2011 all report the synthetic method of phosphoric acid safe ground azoles amine and analogue and relevant intermediate.These methods are summed up in contrast, and its synthetic route is all realized by aryl linked reaction by intermediate A and intermediate B (or intermediate B ').
Wherein 2-(2-methyl tetrazolium-5-base)-5-bromopyridine (intermediate A) generates tetrazole radical derivative by the azido reaction of 2-cyano group-5-bromopyridine, methylating reagent such as recycling methyl iodide or methyl-sulfate etc., methylation reaction is carried out to tetrazole ring, the mixture of obtained 2-(2-methyl tetrazolium-5-base)-5-bromopyridine (intermediate A) and 2-(1-methyl tetrazolium-5-base)-5-bromopyridine (by product), is separated through column chromatography or recrystallization and obtains intermediate A.
Intermediate B or B ' are the organotin reagent or organoboron reagent made by R-3-(the fluoro-4-iodophenyl of 3-)-2-oxo-5-oxazolidinyl methyl alcohol, and this reagent, by Stille or Suzuki linked reaction, realizes the coupling with intermediate A.
Find out thus, existing preparation method exists that preparation process is long, raw material is difficult to obtain and the more high weakness of cost; The preparation of organotin reagent and use to equipment and environmental requirement all higher, there is environmental pollution hidden danger.In addition, exist while the fluorine of halogen and iodine in intermediate B or B ' structure, reduce selectivity when organometallic reagent is formed, side reaction is increased, and quality product is difficult to be effectively controlled.
Summary of the invention
The object of the invention is to for defect of the prior art, provide a kind of and have that raw material is easy to get, concise in technology, economic environmental protection and be applicable to the preparation method of industrialized phosphoric acid safe ground azoles amine.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of phosphoric acid safe ground azoles amine (I),
Its preparation process comprises: through type II compound and formula III compound carry out linked reaction and generate phosphoric acid safe ground azoles amine (I).
In addition, the present invention also proposes following attached technical scheme:
In described formula II compound, R is hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl or pinacolyl, corresponding formula II compound is followed successively by 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid, 2-(2-methyl tetrazolium-5-base) pyridine-5-trimethyl borate, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diethyl ester, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid dipropyl, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diisopropyl ester, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diphenyl ester or 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid any ester frequently.
Halogen X in described formula III compound is bromine or iodine, and corresponding formula III compound is followed successively by R-3-(the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester or R-3-(the iodo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester.
The starting materials of formulae II compound of described linked reaction and the molar ratio of formula III compound are 1: 0.5-1.5, preferably 1: 0.9-1.1.
The catalyzer of described linked reaction is Palladous chloride, palladium, two (dibenzalacetone) palladium, tetrakis triphenylphosphine palladium, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride, two (tricyclohexyl phosphine) palladium chloride or two (triphenylphosphine) palladium chloride, preferred tetrakis triphenylphosphine palladium or [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride.
The alkali promotor of described linked reaction is salt of wormwood, sodium carbonate, cesium carbonate, cesium fluoride, Potassium ethanoate or potassiumphosphate, preferred cesium carbonate or potassiumphosphate.
The solvent of described linked reaction is acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene, DMF, N,N-dimethylacetamide or methyl-sulphoxide, preferred Isosorbide-5-Nitrae-dioxane or toluene.
The temperature of described linked reaction is 50-150 DEG C, preferred 80-130 DEG C.
Compared to prior art, the preparation method of phosphoric acid involved in the present invention safe ground azoles amine (I), has that raw material is easy to get, a feature such as concise in technology and environmental protection and economy, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
Under nitrogen atmosphere, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid (II) (2.15g is added in three neck reaction flasks, 10.5mmol), R-3-(the iodo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester (III) (4.17g, 10mmol), tetrakis triphenylphosphine palladium (0.23g, 0.2mmol), 1M potassium phosphate solution 15mL and toluene 30mL, be warming up to backflow, back flow reaction 10-12 hour, TLC detection reaction is kept to complete.Add ethyl acetate 30mL, use water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter normal hexane and ethyl acetate (1: 1, V/V) recrystallization, vacuum-drying obtains white solid phosphoric acid safe ground azoles amine (I) 3.82g, yield 84.9%
1h NMR (DMSO-d6): d 8.92 (s, 1H), 8.20 (m, 2H), 7.74 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (m, 1H), FAB-MS m/z:451 [M+H]
+.
Embodiment two:
Under nitrogen atmosphere, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid any ester (II) (3.01g is frequently added in three neck reaction flasks, 10.5mmol), R-3-(the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester (III) (3.69g, 10mmol), [1, 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride/chloride dichloromethane complex (0.15g, 0.2mmol), Potassium ethanoate (1.17g, 12mmol) He 1, 4-dioxane 50mL, be warming up to 110 DEG C, stirring reaction 4-5 hour, TLC detection reaction completes.Add ethyl acetate 50mL, use water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter normal hexane and ethyl acetate (1: 1, V/V) recrystallization, vacuum-drying obtains white solid phosphoric acid safe ground azoles amine (I) 4.02g, yield 89.3%.
Embodiment three:
Under nitrogen atmosphere, 2-(2-methyl tetrazolium-5-base) the bromo-pyridine of-5-(IV) (2.4g is added in three neck reaction flasks, 10mmol), double frequency any alcohol radical diboron hexahydride (1.27g, 5mmol), 1,1 '-bis-(diphenyl phosphine) ferrocene palladium chloride (0.82g, 1mmol), Potassium ethanoate (1.17g, 12mmol) He 1,4-dioxane 30mL, is warming up to 110 DEG C, stirring reaction 4 hours.Be down to room temperature, still under nitrogen atmosphere, R-3-(the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester (III) (3.69g is added in system, 10mmol), 1,4-dioxane 20mL and 5M potassiumphosphate 0.5mL, again be warming up to 100 DEG C, stirring reaction 4 hours, TLC detection reaction completes.Add ethyl acetate 50mL, filter, filtrate uses water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter normal hexane and ethyl acetate (1: 1, V/V) recrystallization, vacuum-drying obtains white solid phosphoric acid safe ground azoles amine (I) 3.34g, yield 74.2%.
Embodiment four (preparation of intermediate II):
By 2-(2-methyl tetrazolium-5-base) the bromo-pyridine of-5-(IV) (2.4g in three neck reaction flasks, 10mmol) be dissolved in anhydrous tetrahydro furan 25mL, be cooled to-55 DEG C, drip isopropylmagnesium chloride (1M, 15ml), complete rear stirring reaction is dripped 30 minutes.In this reaction system, add trimethyl borate (1.25g, 12mmol), continue stirring reaction 4-5 hour.With saturated ammonium chloride solution cancellation reaction under low temperature, and by reaction solution impouring 1N dilute hydrochloric acid 30mL, room temperature reaction 1 hour.Be extracted with ethyl acetate three times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure, gained solid first uses petroleum ether, then uses water recrystallization, obtains white solid 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid (II) 1.6g, yield 78.0%, FAB-MS m/z:206 [M+H]
+.
Embodiment five (preparation of intermediate II):
2-(2-methyl tetrazolium-5-base) the bromo-pyridine of-5-(IV) (2.4g is added in three neck reaction flasks, 10mmol), double frequency any alcohol radical diboron hexahydride (1.27g, 5mmol), 1,1 '-bis-(diphenyl phosphine) ferrocene palladium chloride (0.82g, 1mmol), Potassium ethanoate (1.17g, 12mmol) and 1,4-dioxane 50mL, be warming up to 110 DEG C, stirring reaction 8-10 hour, TLC detection reaction terminates.Be extracted with ethyl acetate three times, merge organic phase, salt water washing, anhydrous sodium sulfate drying.Concentrated, ethyl acetate and normal hexane (1: 4) recrystallization, obtain pale solid 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid which ester (II) 2.48g, yield 86.4%, FAB-MS m/z:288 [M+H] frequently
+.
Embodiment six (preparation of intermediate III):
Under nitrogen protection; R-Racemic glycidol p-toluenesulfonic esters (TG) (2.28g is added in three neck reaction flasks; 10mmol) with DMF 25mL, after stirring and dissolving; add cesium carbonate (0.33g; 1mmol) with the bromo-phenyl isocyanate of the fluoro-4-of 3-(V) (2.15g, 10mmol), be heated to 100 DEG C; react after 1 hour, TLC detection reaction terminates.Decompression and solvent recovery, residue methylene dichloride and water dissolution, separate organic phase, aqueous phase dichloromethane extraction 2 times, concentrating under reduced pressure, the oily matter R-3-obtained (the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol p-toluenesulfonic esters (VI), without the need to being further purified process, directly add 1N hydrochloric acid to react 5 hours at 50 DEG C, with dichloromethane extraction 3 times, merge organic phase, use saturated aqueous common salt and water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.Enriched material is dissolved in triethyl phosphate 30mL, under room temperature, adds phosphorus oxychloride (2.2mL, 24mmol), stir 2-3 hour.Add 30mL ethyl acetate, after stirring half an hour, in impouring 50g frozen water, and at 0 DEG C, continue stirring 2 hours, adularescent solid is separated out, filter, filter cake washing with acetone, dry, obtain off-white color solid R-3-(the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester (III) 2.45g, yield 66.4%, FAB-MS m/z:369 [M+H]
+.
Embodiment six (preparation of intermediate III):
Under nitrogen protection; R-Racemic glycidol p-toluenesulfonic esters (TG) (2.28g is added in three neck reaction flasks; 10mmol) with tetrahydrofuran (THF) 50mL; after stirring and dissolving, add lithium iodide (0.14g, 1mmol) and the iodo-phenyl isocyanate of the fluoro-4-of 3-(V) (2.63g; 10mmol); be heated to backflow, react after 2 hours, TLC detection reaction terminates.Decompression and solvent recovery, residue methylene dichloride and water dissolution, separate organic phase, aqueous phase dichloromethane extraction 2 times, concentrating under reduced pressure, the oily matter R-3-obtained (the iodo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol p-toluenesulfonic esters (VI), without the need to being further purified process, directly add 1N hydrochloric acid to react 5 hours at 50 DEG C, with dichloromethane extraction 3 times, merge organic phase, use saturated aqueous common salt and water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure.Enriched material is dissolved in triethyl phosphate 30mL, under room temperature, adds phosphorus oxychloride (2.2mL, 24mmol), stir 2-3 hour.Add 30mL ethyl acetate, after stirring half an hour, in impouring 50g frozen water, and at 0 DEG C, continue stirring 2 hours, adularescent solid is separated out, filter, filter cake washing with acetone, dry, obtain off-white color solid R-3-(the iodo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester (III) 2.65g, yield 63.7%, FAB-MS m/z:417 [M+H]
+.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (8)
1. a preparation method for phosphoric acid safe ground azoles amine (I),
Its preparation process comprises: through type II compound and formula III compound carry out linked reaction and generate phosphoric acid safe ground azoles amine (I),
2. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, it is characterized in that: in described formula II compound, R is hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl or pinacolyl, corresponding formula II compound is followed successively by 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid, 2-(2-methyl tetrazolium-5-base) pyridine-5-trimethyl borate, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diethyl ester, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid dipropyl, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diisopropyl ester, 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid diphenyl ester or 2-(2-methyl tetrazolium-5-base) pyridine-5-boric acid any ester frequently.
3. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, it is characterized in that: the halogen X in described formula III compound is bromine or iodine, corresponding formula III compound is followed successively by R-3-(the bromo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester or R-3-(the iodo-phenyl of the fluoro-4-of 3-)-2-oxo-5-oxazolidinyl methyl alcohol phosphoric acid ester.
4. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, is characterized in that: the starting materials of formulae II compound of described linked reaction and the molar ratio of formula III compound are 1: 0.5-1.5.
5. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, it is characterized in that: the catalyzer of described linked reaction is Palladous chloride, palladium, two (dibenzalacetone) palladium, tetrakis triphenylphosphine palladium, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride, two (tricyclohexyl phosphine) palladium chloride or two (triphenylphosphine) palladium chloride.
6. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, is characterized in that: the alkali promotor of described linked reaction is salt of wormwood, sodium carbonate, cesium carbonate, cesium fluoride, Potassium ethanoate or potassiumphosphate.
7. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, is characterized in that: the solvent of described linked reaction is acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene, DMF, N,N-dimethylacetamide or methyl-sulphoxide.
8. the preparation method of phosphoric acid safe ground azoles amine as claimed in claim 1, is characterized in that: the temperature of described linked reaction is 50-150 DEG C.
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Application publication date: 20150204 |