CN106397516A - Kengreal intermediates as well as preparation methods and application thereof - Google Patents
Kengreal intermediates as well as preparation methods and application thereof Download PDFInfo
- Publication number
- CN106397516A CN106397516A CN201610780484.5A CN201610780484A CN106397516A CN 106397516 A CN106397516 A CN 106397516A CN 201610780484 A CN201610780484 A CN 201610780484A CN 106397516 A CN106397516 A CN 106397516A
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- China
- Prior art keywords
- reaction
- compound
- formula
- alkali
- cangrelor
- Prior art date
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- PAEBIVWUMLRPSK-IDTAVKCVSA-N cangrelor Chemical compound C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)C(Cl)(Cl)P(O)(O)=O)[C@@H](O)[C@H]1O PAEBIVWUMLRPSK-IDTAVKCVSA-N 0.000 title claims abstract 5
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 239000000543 intermediate Substances 0.000 title abstract description 18
- 229940101712 kengreal Drugs 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 83
- 150000001875 compounds Chemical class 0.000 claims description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 229960001080 cangrelor Drugs 0.000 claims description 21
- ZGVUPMJCZYBIDI-IDTAVKCVSA-N (2r,3s,4r,5r)-2-(hydroxymethyl)-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolane-3,4-diol Chemical compound C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ZGVUPMJCZYBIDI-IDTAVKCVSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 15
- -1 methyl mercapto Chemical class 0.000 claims description 14
- 239000000376 reactant Substances 0.000 claims description 14
- 150000007529 inorganic bases Chemical class 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000005660 chlorination reaction Methods 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- XCDTWHHINWNFHY-UHFFFAOYSA-N 3,3,3-trifluoropropane-1-thiol Chemical compound FC(F)(F)CCS XCDTWHHINWNFHY-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 26
- COWWROCHWNGJHQ-OPKBHZIBSA-J cangrelor tetrasodium Chemical compound [Na+].[Na+].[Na+].[Na+].C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)C(Cl)(Cl)P([O-])([O-])=O)[C@@H](O)[C@H]1O COWWROCHWNGJHQ-OPKBHZIBSA-J 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 230000000269 nucleophilic effect Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 0 CC1N=CN([C@@]([C@@]2*)O[C@](C*)[C@@]2OC(C)=O)C1=NC(Cl)=NC(NCCSC)=C Chemical compound CC1N=CN([C@@]([C@@]2*)O[C@](C*)[C@@]2OC(C)=O)C1=NC(Cl)=NC(NCCSC)=C 0.000 description 5
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 5
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 229940029575 guanosine Drugs 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-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
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- GCVZNVTXNUTBFB-XNIJJKJLSA-N [(2r,3r,4r,5r)-3,4-diacetyloxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methyl acetate Chemical group CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 GCVZNVTXNUTBFB-XNIJJKJLSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 229960003116 amyl nitrite Drugs 0.000 description 2
- 229940017687 beta-d-ribose Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- ULIYQAUQKZDZOX-UHFFFAOYSA-N 1,1,1-trifluoro-3-iodopropane Chemical compound FC(F)(F)CCI ULIYQAUQKZDZOX-UHFFFAOYSA-N 0.000 description 1
- VORLTHPZWVELIX-UHFFFAOYSA-N 1-methyl-2h-quinoline Chemical compound C1=CC=C2N(C)CC=CC2=C1 VORLTHPZWVELIX-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- LDWZFTYBPDQMDL-ZMVZMBOQSA-N CSCCNc1c2nc[n](C3OC[C@H](CO)C[C@H]3O)c2nc([ClH]C)n1 Chemical compound CSCCNc1c2nc[n](C3OC[C@H](CO)C[C@H]3O)c2nc([ClH]C)n1 LDWZFTYBPDQMDL-ZMVZMBOQSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- YGZSVWMBUCGDCV-UHFFFAOYSA-N chloro(methyl)silane Chemical compound C[SiH2]Cl YGZSVWMBUCGDCV-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005732 thioetherification reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses Kengreal intermediates as well as preparation methods and an application thereof. The intermediates respectively comprise chemical structures as shown in formula VI and formula VII. The intermediates can be applied to synthesis of a known key intermediate TEPAD of Kengreal, and the method has advantages of high total molar yield, simple operation without special requirements for equipment, safety without pollution, low cost, and the like; the method has extremely high practical value for industrialization of Kengreal, and compared with the prior art, the method has significant progress.
Description
Technical field
The present invention relates to cangrelor intermediate and its preparation method and application, belong to chemicalses synthesis technical field.
Background technology
Cangrelor is to be developed by AstraZeneca, authorizes reversibility P2Y12 of The Medicines Company exploitation to be subject to
Body antagonist, the features such as have rapid-action, half-life short, is a kind of preferable vein antiplatelet drug, prevention heart coronaries are moved
In arteries and veins, harmful blood clot is formed, for acute thrombus such as percutaneous coronary intervention (pci) and acute coronary syndromes
Potentiality is prevented.On June 22nd, 2015 cangrelor ratifies listing through FDA, and preparation specification is 50mg lyophilized injectable powder, trade name
Kengreal.The molecular formula of cangrelor is：C17H21Cl2F3N5Na4O12P3S2, molecular weight is：864.286, No. CAS is：
163706-36-3, chemical structural formula is：
TEPAD, Chinese is：N- [2- (first mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) sulfydryl] -5 '-adenosine,
No. CAS is：163706-58-9, molecular formula is：C16H22F3N5O4S2, molecular weight is：469.11, chemical structural formula is：
This compound is the key intermediate of synthesis cangrelor, current cangrelor
Preparation is generally all first to synthesize TEPAD using certain process route, is then subsequently synthesized TEPAD, and bank is finally obtained
The cangrelor synthetic route of report in Gray Lip river, such as document (J.Med.Chem.1999,42,213-220)：
At present with regard to the synthesis report of TEPAD, mainly there is following several synthetic route：
1) development company The Medicines Company disclose TEPAD synthetic route (J.Med.Chem.1999,
42,213-220), the wherein synthesized reference of compound 3 document (Chem.Pharm.Bull.25 (8) 1959-1969 (1977))
Preparation method：
This route with adenosine as raw material, through peroxidating, hydrolysis, cyclization and reduction reaction, obtain compound 3 (adenosine-
2- thioketone), then compound 3, through nucleophilic displacement of fluorine, acetylation, replacement and hydrolysis, obtains TEPAD.Step in this route
Rapid 1 and 2, when prepare compound 1 and 2, have substantial amounts of water in reaction system, during post processing removing water has certain operation easier；
Step 3 needs to generate in autoclave high temperature reaction under high pressure, and uses hypertoxic solvent carbon disulfide, can produce a large amount of waste liquids with
And H2S gas, pollutes environment；And this route needs 7 step reactions altogether, route is longer, and operation is complex, and from step 4 to step
Rapid 7, the total recovery of this several step is relatively low, and only 15～20%；Therefore, in general, this route is not suitable for industrialized production.
2) document (fine-chemical intermediate 2013.30 (7), P 835-840) and document (Journal of Medicinal
Chemistry；vol.42；2；(1999)；P.213-220 disclose the synthetic route of TEPAD in)：
This route with guanosine as raw material, through acetylation, chlorination, diazonium, nucleophilic and deprotection reaction, totally 5 steps reaction
Prepare TEPAD although process route is shorter, but in the diazo-reaction of step 3, use substantial amounts of thioetherification of crossing and close
Thing, it is more difficult that this crosses sulfide compound synthesis, relatively costly, and this process route yield is relatively low, total recovery only 15～20%；Cause
This, in general, this route is not suitable for industrialized production.
3) Chinese patent CN105061431 discloses the synthetic route of TEPAD：
This route is with 2- thiobarbituricacidα- as raw material, anti-through nucleophilic, nitrification, replacement, reduction, nucleophilic, cyclization etc. 9 step
TEPAD should be prepared, route is longer, and overall yield is relatively low；The raw material 2- thiobarbituricacidα- adopting in this route belongs to pipe
Class article processed are it is impossible to large-scale use；Nitration reaction that route is related to, the substitution reaction of ammonia, hydrogenation reduction are dangerous
Larger；And multistep reaction is reacted in crude product mode in this route, it is unfavorable for the quality control of final products；Therefore, always
For body, this route is also not suitable for industrialized production.
4) Chinese patent CN201510881033 discloses the synthetic route of TEPAD：
This route with compound II as starting material, through ammonification, nucleophilic, reduction, cyclization, nucleophilic and replacement etc. 6 step
Reaction prepares TEPAD, although this route is 45% according to its total recovery described in patent, its multistep reaction is oily
Compound, is unfavorable for that the quality control of intermediate produces with amplifying；The big production of the non-commercialization of starting material compound II, is not easy to obtain,
Relatively costly；And it is related to ammonolysis and be sealing system reaction under high pressure with nitro-reduction reaction, dangerous larger；Therefore, always
For body, this route is still not suitable for industrialized production.
Content of the invention
The problems referred to above existing for prior art, it is an object of the invention to provide for the intermediate preparing cangrelor
And preparation method thereof and described intermediate cangrelor preparation in application, to meet the industrialized production need of cangrelor
Ask.
For achieving the above object, the technical solution used in the present invention is as follows：
A kind of cangrelor intermediate, has chemical constitution shown in formula VI：
A kind of method of the cangrelor intermediate shown in formula VI, reacts including following：
A) formula II compound (i.e. guanosine) is left to be reacted with acetylizing agent in alkali and is obtained formula III compound；
B) formula III compound is reacted with chlorination reagent in the presence of acid binding agent, catalyst and obtains formula IV compound；
C) formula IV compound carries out diazo-reaction and obtains formula V compound；
D) formula V compound is left to be reacted with 2- (methyl mercapto) ethamine in alkali and is obtained formula VI compound；
Its concrete reaction scheme is as follows：
Alkali in a reaction is preferably organic base, and described organic base is selected from N-methylmorpholine, triethylamine or diisopropyl second
Base amine.
Acetylizing agent in a reaction is preferably acetic anhydride.
Reaction dissolvent in a reaction is preferably dichloromethane, chloroform, acetonitrile, at least one in DMF, THF.
Acetylizing agent in a reaction and the mol ratio of formula II compound are preferably 1:1～5:1.
The reaction temperature of a reaction is preferably 0～30 DEG C, more preferably 20～30 DEG C, and the response time is preferably 1～5
Hour.
Add the acylation catalyst of catalytic amount, the preferred DMAP of described acylation catalyst in a reaction.
Acid binding agent in b reaction is preferably triethylamine, diisopropyl ethyl amine, N, accelerine or N- methyl
Quinoline.
Catalyst in b reaction is preferably tetra-alkyl ammonium chloride, for example：Tetramethyl ammonium chloride, tetraethyl ammonia chloride, four fourths
Ammonium chloride.
Chlorination reagent in b reaction is preferably phosphorus oxychloride.
At least one in reaction dissolvent in b reaction preferably DMF, acetonitrile, dichloromethane, chloroform, toluene.
Chlorination reagent in b reaction and the mol ratio of formula III compound are preferably 1:1～5:1.
The reaction temperature of b reaction is preferably 55～85 DEG C, more preferably 75～85 DEG C, and the response time is preferably 1～5
Hour.
Mixing of the crude product good solvent obtaining and poor solvent is reacted with chlorination reagent to the formula III compound in b reaction
Bonding solvent system can get the sterling of formula IV compound, described good solvent ethyl acetate, dichloromethane, second after purification
Nitrile, methanol or ethanol, the preferred normal heptane of described poor solvent, isobutyltrimethylmethane. or petroleum ether.
In c reaction, the reaction system of diazo-reaction is preferably nitrite-hydrochloric acid-Cu-lyt. or nitrites-three
Methylchlorosilane, the preferred sodium nitrite of described nitrite, the preferred amyl nitrite of described nitrites or the tertiary fourth of nitrous acid
Ester.
The reaction temperature of c reaction is preferably -15～55 DEG C, more preferably 0～5 DEG C, and the response time is preferably 1～5
Hour.
The mixed solvent system that diazo-reaction in c reaction is terminated with the crude product good solvent and poor solvent obtaining is pure
The sterling of formula V compound, described good solvent ethyl acetate, dichloromethane, methyl tertiary butyl ether(MTBE) or first is can get after change
Benzene, the preferred normal heptane of described poor solvent, isobutyltrimethylmethane. or petroleum ether.
Alkali in d reaction is preferably organic base or inorganic base, the preferred triethylamine of described organic base or diisopropyl ethyl amine,
The preferred carbonate of described inorganic base, such as potassium carbonate, sodium carbonate etc..
Reaction dissolvent in d reaction is preferably acetonitrile, DMF, DMSO, toluene, at least one in THF.
2- (methyl mercapto) ethamine in d reaction and the mol ratio of formula V compound are preferably 1:1～2:1.
D reaction reaction temperature be preferably 60～100 DEG C, more preferably 70～80 DEG C, the response time be preferably 1～
5 hours.
Another kind of cangrelor intermediate, has chemical constitution shown in formula VII：
A kind of method of the cangrelor intermediate shown in formula VII, alkaline hydrolysis obtains formula VI compound in the basic conditions
Formula VII compound, reaction equation is as follows：
Alkalescence condition in reaction is preferably formed by inorganic base, and described inorganic base can be selected for sodium hydroxide or potassium hydroxide.
Alkaline hydrolysis solvent for use in reaction is preferably methanol, at least one in oxolane.
Reaction temperature is preferably 20～30 DEG C.
A kind of application of the cangrelor intermediate shown in formula VII, is to leave and 3,3,3- trifluoros formula VII compound in alkali
Propyl group thiol reactant, the known formula I intermediate of prepared cangrelor, reaction equation is as follows：
Alkali in reaction be preferably organic base or inorganic base, described organic base be preferably Feldalat NM, Feldalat KM, Sodium ethylate,
Potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide, further preferred Feldalat NM or sodium tert-butoxide, the preferred sodium hydroxide of described inorganic base,
Potassium hydroxide or sodium hydrogen, further preferred sodium hydroxide or sodium hydrogen.
At least one in reaction dissolvent in reaction preferably DMF, DMSO, toluene, NMP.
In reaction, 3,3,3- trifluoro propyl mercaptan and the mol ratio of formula VII compound are preferably 1:1～2:1.
The reaction temperature of reaction is preferably 60～100 DEG C, more preferably 70～80 DEG C, and the response time is preferably 1～5
Hour.
The known formula I intermediate (i.e. TEPAD) of prepared cangrelor, can be used for follow-up bank lattice according to prior art
The preparation of Lei Luo.
Compared with prior art, the present invention has following significance beneficial effect：
1) apply intermediate formula VI provided by the present invention, formula VII compound, the known key of synthesis cangrelor can be made
The preparation process is simple of intermediate TEPAD (i.e. type I compound), cost reduces, and quality is easily controlled, and high income is (from formula II
, to type I compound, the total moles yield of whole synthetic route is more than 35% for compound), be conducive to the preparation of cangrelor；
2) the intermediate formula VI that provided, the preparation of formula VII compound, simple to operate, intermediate product is easy to purification, quality
Controllability is strong, and products obtained therefrom purity is high, and agents useful for same is cheap and easy to get, simultaneously not using poisonous or hazardous agents, safety non-pollution,
Also not using the reagent that severe corrosive reagent etc. is higher to equipment requirements, the reaction of whole route simultaneously is all entered under normal conditions
OK, without High Temperature High Pressure operation (reaction temperature is integrally less than 100 DEG C), there is no any particular/special requirement, production cost to equipment
Low.
In a word, the present invention utilizes raw material (formula II compound, i.e. guanosine) cheap and easy to get, synthesizes cangrelor intermediate formula
VIth, formula VII and type I compound (TEPAD), have total moles high income, simple to operate, safety non-pollution, no special to equipment will
Ask, low production cost the advantages of, to the industrialization realizing cangrelor, there is extremely strong practical value, with respect to prior art tool
There is significance progress.
Specific embodiment
With reference to embodiment and comparative example, technical solution of the present invention is described in further detail and completely.
Embodiment 1：
The preparation of compound III (2', 3', 5'- triacetyl guanosine)：
Acetic anhydride (150g, 1.45mol) is dropped to containing compound ii (i.e. guanosine, 100g, 0.35mol), N- methyl
In morpholine (180g, 1.8mol), acetonitrile (800mL) solution of DMAP (4.3g, 0.035mol), after completion of dropping, reactant liquor exists
React 2 hours at 20～30 DEG C, terminate reaction, reactant liquor is evaporated to no solution and distillates, in residual solution, add ethanol
(200mL) recrystallization, sucking filtration are carried out, filter cake is dried in 45～55 DEG C, obtains final product compound III (2', 3', 5'- triacetyl guanosine)：
125g, molar yield is 86.8%.
After tested：ESI-MS：[M+H]+=410.1.
Embodiment 2：
The system of compounds Ⅳ (9- [2,3,5- tri--o- acetyl group-beta-d- ribofuranose] -2- amido-6-chloropurine)
Standby：
Phosphorus oxychloride (180g, 1.12mol) is dropped to containing compound III (100g, 0.234mol), tetraethyl chlorination
In ammonium (80g, 0.48mol), toluene (800mL) solution of triethylamine (24g, 0.244mol), after completion of dropping, reactant liquor heats up
React two hours to 75～85 DEG C of insulated and stirred, terminate reaction, add water and reaction is quenched, be subsequently adding ethyl acetate (800mL) extraction
Take, twice, then washed with 10wt% sodium bicarbonate aqueous solution to system is in alkalescence to the organic phases washed with water isolated, chlorination
Sodium water solution is washed once, and uses anhydrous sodium sulfate drying, sucking filtration, is evaporated to no solution and distillates, and adds dichloro in residual solution
Methane (100mL) and normal heptane (400mL) carry out recrystallization, sucking filtration, obtain khaki solid matter, that is, compounds Ⅳ (9- [2,3,
5- tri--o- acetyl group-beta-d- ribofuranose] -2- amido-6-chloropurine)：87g, molar yield is 82%.
After tested：ESI-MS：[M+H]+=428.2.
Embodiment 3：
The preparation of compound V (the chloro- 9- of 2,6- bis- (2', 3', 5'- tri--O- acetyl group-β-D-RIBOSE base) purine)：
Amyl nitrite (165g, 1.41mol) is dissolved in dichloromethane (500mL) solution, then in 0～5 DEG C of bar
Under part, add trim,ethylchlorosilane (76g, 0.70mol), be subsequently added into the DCM of compounds Ⅳ (100g, 0.234mol)
(500mL) solution drops in above-mentioned mother solution, after charging finishes, continues at stirring reaction 1 hour under this temperature conditions, terminates anti-
Should, add the sodium sulfite solution of saturation, point liquid, the organic faciess isolated use sodium bicarbonate aqueous solution, saturated aqueous common salt successively
Washing, and use anhydrous sodium sulfate drying, sucking filtration, it is evaporated to no solution and distillates, in residual solution, add dichloromethane (100mL)
Carry out recrystallization, sucking filtration with normal heptane (350mL), obtain yellow solid matter, that is, compound V (2,6- bis- chloro- 9- (2', 3',
5'- tri--O- acetyl group-β-D-RIBOSE base) purine)：86g, molar yield is 82%.
After tested：ESI-MS：[M+H]+=447.0.
Embodiment 4：
The preparation of compound 2- (methyl mercapto) ethamine：
Mercaptamine (113g, 1.0mol) is dissolved in ethanol (1.5L) solution, then under the conditions of -10～0 DEG C,
Add sodium hydroxide (120g, 3.0mol), then Deca iodomethane (170g, 1.2mol), after completion of dropping, continue at this temperature
Under the conditions of stirring reaction 3 hours, terminate reaction, low temperature backspin is evaporated off partial solvent, filter, filtrate is reduced pressure under -0.09MPa
Distillation -0.09MPa, collects 110～120 DEG C of fraction, obtains colourless oily mater, i.e. compound 2- (methyl mercapto) ethamine：
81g, molar yield is 89%.
Embodiment 5：
The preparation of cangrelor midbody compound VI：
Compound V (80g, 0.18mol) is dissolved in acetonitrile (500mL) solution, is subsequently adding the change of embodiment 4 preparation
Compound 2- (methyl mercapto) ethamine (32.5g, 0.36mol) and triethylamine (45.3g, 0.45mol), after charging finishes, reactant liquor liter
Temperature is reacted 3 hours to 70～80 DEG C of insulated and stirred, terminates reaction, and reactant liquor is evaporated to no solution and distillates, and adds in residual solution
Enter ethyl acetate (300mL) and water (200mL), point liquid, the organic faciess isolated are washed with sodium-chloride water solution, anhydrous sodium sulfate
It is dried, sucking filtration, be evaporated to no solution and distillate, obtain tan solid matter, be i.e. cangrelor intermediate of the present invention
Compound VI：75g, molar yield is 83%, HPLC purity is 99.5%, by compound ii to cangrelor midbody compound VI
Four step total moles yields be 52.5%.
After tested：1HNMR(300MHz,CDCl3) δ 2.07 (s, 3H), 2.10～2.22 (m, 9H), 2.80 (t, J=
6.5Hz, 2H), 3.84 (s, 2H), 4.41 (dq, J=6.3,4.1,2.9Hz, 3H), 5.59 (dd, J=5.6,3.8Hz, 1H),
5.77 (t, J=5.5Hz, 1H), 6.16 (d, J=5.6Hz, 1H), 6.47 (s, 1H), 7.90 (s, 1H)；
ESI-MS：[M+H]+=502.05, [M+Na]+=524.00.
Embodiment 6：
The preparation of compound 3,3,3- trifluoro propanethiol：
Trifluoro iodopropane (110g, 0.49mol) is added (30mL second in the ethanol water of thiourea (38g, 0.52mol)
Alcohol+1.5mL water), after charging finishes, reactant liquor is warming up to 90 DEG C of insulated and stirred and reacts 5 hours, terminates reaction, and reactant liquor is lowered the temperature
To 0～5 DEG C, stirring, reactant liquor solidifies, sucking filtration, and filter cake obtains white solid 90g in 45 DEG C of drying；
White solid is dissolved in water (150mL), add 20wt% sodium hydrate aqueous solution, adjust solution pH be 12～
13, reactant liquor back flow reaction 3 hours, terminates reaction, reactant liquor is cooled to room temperature, adjusting pH to solution is in acidity, distillation is collected
55～58 DEG C of fraction, obtains final product compound 3,3,3- trifluoro propanethiol：44g, two step total moles yields are 65%.
Embodiment 7：
The preparation of cangrelor midbody compound VII：
Compound VI (15g, 0.03mol) is dissolved in methanol (50mL) solution, then under the conditions of 20～30 DEG C, adds
Water (100mL) solution of sodium hydroxide (4g, 0.1mol), after charging finishes, continues at stirring reaction 1 under this temperature conditions little
When, terminate reaction, add ethyl acetate (250mL) extraction, be spin-dried for after the organic faciess anhydrous sodium sulfate drying isolated, obtain final product
Compound VII, without purification, is directly used in next step reaction.
After tested：1HNMR(400MHz,DMSO-d6):2.09 (s, 3H), 2.48～2.69 (m, 2H), 3.43～3.70 (m,
4H), 3.93 (q, J=3.8Hz, 1H), 4.02 (dd, J=13.1,6.9Hz, 1H), 4.12 (t, J=4.0Hz, 1H), 4.50 (t,
J=5.5Hz, 1H), 5.01～5.09 (m, 1H), 5.19 (s, 1H), 5.47 (s, 1H), 5.81 (d, J=5.9Hz, 1H), 8.40
(s,1H)；
ESI-MS：[M+H]+=375.95, [M+Na]+=398.00.
Embodiment 8：
The known key intermediate TEPAD of cangrelor is the preparation of compounds I：
Sodium hydrogen (4.2g, 0.105mol) is added in DMF (30mL) solution, then under the conditions of 0～5 DEG C, adds and implement
Compound 3,3, the 3- trifluoro propanethiol (8g, 0.06mol) of example 6 preparation, keeping temperature stirring reaction half an hour, adds embodiment
DMF (20mL) solution of 7 gained compounds VII, after charging finishes, it is little that reactant liquor is warming up to 70～80 DEG C of insulated and stirred reactions 2.5
When, terminate reaction, reactant liquor is cooled to room temperature, add water (100mL), have yellow solid to separate out, sucking filtration, filter cake ethanol
(40mL) carry out recrystallization, sucking filtration with the mixed solution of water (30mL), obtain final product the known key intermediate TEPAD of cangrelor,
I.e. compounds I：9g, HPLC purity is 99.9%, by six steps of the known key intermediate TEPAD of compound ii to cangrelor
Total moles yield is 36.7%.
After tested：
TEPAD：1HNMRδ(500MHz,CD3OD):8.27 (1H, s), 5.91 (1H, d, J=5.0Hz), 4.71～4.68
(1H, t, J=10.0Hz), 4.31～4.29 (1H, m), 4.13～4.11 (1H, m), 3.88～3.71 (4H, m), 3.31
(2H, m), 2.79～2.61 (4H, m), 2.14 (3H, s)；
ESI-MS：[M+H]+=470.05.
In sum, the present invention passes through the preparation of midbody compound VI, VII thus synthesizing TEPAD, with document
(Journal of Medicinal Chemistry；vol.42；2；(1999)；P.213-220) compare, initial using identical
TEPAD prepared by raw material (guanosine), and total moles yield is 36.7% hence it is evident that being higher than document (Journal of Medicinal
Chemistry；vol.42；2；(1999)；P.213-220 15～20% in), and the present invention by compound ii to compound
VIth, VII again in the preparation process of TEPAD, and the intermediate product of preparation can get high-purity through simple solvent recrystallization and produces
Product, purification is simple, quality controllable, it is to avoid brings unnecessary impurity in subsequent operation, is compound VI, VII and TEPAD
High-purity lays a solid foundation；And, whole route is simple to operate, to equipment no particular/special requirement, safety and environmental protection, produces into
This low, suitable large-scale production.
Finally need it is pointed out here that be：The part preferred embodiment that the above is only the present invention is it is impossible to be interpreted as to this
The restriction of bright protection domain, those skilled in the art made according to the above of the present invention some nonessential improve and
Adjustment belongs to protection scope of the present invention.
Claims (10)
1. a kind of cangrelor intermediate is it is characterised in that have chemical constitution shown in formula VI：
2. a kind of method of the cangrelor intermediate prepared described in claim 1 is it is characterised in that include following reaction：
A) formula II compound is left to be reacted with acetylizing agent in alkali and is obtained formula III compound；
B) formula III compound is reacted with chlorination reagent in the presence of acid binding agent, catalyst and obtains formula IV compound；
C) formula IV compound carries out diazo-reaction and obtains formula V compound；
D) formula V compound is left to be reacted with 2- (methyl mercapto) ethamine in alkali and is obtained formula VI compound；
Its concrete reaction scheme is as follows：
3. method according to claim 2 it is characterised in that：Alkali in a reaction selects organic base, and described organic base is selected
N-methylmorpholine, triethylamine or diisopropyl ethyl amine；Acetic anhydride selected by acetylizing agent in a reaction.
4. method according to claim 2 it is characterised in that：Acid binding agent in b reaction selects triethylamine, diisopropyl second
Base amine, N, accelerine or N-methylmorpholine；Tetra-alkyl ammonium chloride selected by catalyst in b reaction；Chlorination in b reaction
Phosphorus oxychloride selected by reagent.
5. method according to claim 2 it is characterised in that：The reaction system of the diazo-reaction in c reaction is nitrous
Hydrochlorate-hydrochloric acid-Cu-lyt. or nitrites-trim,ethylchlorosilane.
6. method according to claim 2 it is characterised in that：Alkali in d reaction selects organic base or inorganic base, and described have
Machine alkali selects triethylamine or diisopropyl ethyl amine, and carbonate selected by described inorganic base.
7. a kind of cangrelor intermediate is it is characterised in that have chemical constitution shown in formula VII：
8. a kind of method of the cangrelor intermediate prepared described in claim 7 it is characterised in that：By formula VI compound in alkali
Under the conditions of property, alkaline hydrolysis obtains formula VII compound, and reaction equation is as follows：
9. the cangrelor intermediate described in a kind of claim 7 application it is characterised in that：Formula VII compound is left in alkali
With 3,3,3- trifluoro propyl thiol reactants, the known formula I intermediate of prepared cangrelor, reaction equation is as follows：
10. according to claim 9 application it is characterised in that：Alkali in reaction selects organic base or inorganic base, and described have
Machine alkali selects Feldalat NM, Feldalat KM, Sodium ethylate, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and hydroxide selected by described inorganic base
Sodium, potassium hydroxide or sodium hydrogen.
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| Publication number | Priority date | Publication date | Assignee | Title |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109781920A (en) * | 2017-11-15 | 2019-05-21 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of HPLC detection method of the cangrelor in relation to substance |
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| CN109912673A (en) * | 2017-12-12 | 2019-06-21 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
| CN109912673B (en) * | 2017-12-12 | 2022-01-25 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
| CN109467523A (en) * | 2018-12-17 | 2019-03-15 | 苏州华道生物药业股份有限公司 | A kind of green synthesis method of the third sulfonic acid chloride of 3- chlorine |
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| CN106397516B (en) | 2019-09-27 |
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