CN102675321B - Preparation method of ticagrelor - Google Patents
Preparation method of ticagrelor Download PDFInfo
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- CN102675321B CN102675321B CN201210146500.7A CN201210146500A CN102675321B CN 102675321 B CN102675321 B CN 102675321B CN 201210146500 A CN201210146500 A CN 201210146500A CN 102675321 B CN102675321 B CN 102675321B
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- compound
- silica
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- preparation
- alkali
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- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title abstract description 5
- 229960002528 ticagrelor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 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 claims abstract description 14
- QVUBIQNXHRPJKK-IMTBSYHQSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- -1 alkali-metal nitrite Chemical class 0.000 claims description 18
- 239000000377 silicon dioxide Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000004305 biphenyl Substances 0.000 claims description 8
- 235000010290 biphenyl Nutrition 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 239000002253 acid Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910001385 heavy metal Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000004304 potassium nitrite Substances 0.000 claims description 4
- 235000010289 potassium nitrite Nutrition 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 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 abstract 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 229940008075 allyl sulfide Drugs 0.000 abstract 1
- 229960000623 carbamazepine Drugs 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- 0 CCCSc(nc1NC(C2)[C@]2c(cc2F)ccc2F)nc2c1nn[n]2[C@@](CC1)C[C@]1OCCO* Chemical compound CCCSc(nc1NC(C2)[C@]2c(cc2F)ccc2F)nc2c1nn[n]2[C@@](CC1)C[C@]1OCCO* 0.000 description 5
- 230000001603 reducing effect Effects 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 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 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OEKWJQXRCDYSHL-RZMMCLRCSA-N CCCSc(nc1NC(C2)[C@@H]2c(cc2F)ccc2F)nc2c1nn[n]2[C@H](C[C@@H]([C@H]1O)OCCO)[C@@H]1O Chemical compound CCCSc(nc1NC(C2)[C@@H]2c(cc2F)ccc2F)nc2c1nn[n]2[C@H](C[C@@H]([C@H]1O)OCCO)[C@@H]1O OEKWJQXRCDYSHL-RZMMCLRCSA-N 0.000 description 1
- AWERSJICSFIJML-ZFRVQZCJSA-N CCCSc(nc1N[C@H](C2)[C@@H]2c(cc2F)ccc2F)nc2c1nn[n]2[C@H](C[C@@H](C1C)OCCO)C1=C Chemical compound CCCSc(nc1N[C@H](C2)[C@@H]2c(cc2F)ccc2F)nc2c1nn[n]2[C@H](C[C@@H](C1C)OCCO)C1=C AWERSJICSFIJML-ZFRVQZCJSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- QVUBIQNXHRPJKK-RCOVLWMOSA-N N[C@@H](C1)[C@@H]1c(cc1)cc(F)c1F Chemical compound N[C@@H](C1)[C@@H]1c(cc1)cc(F)c1F QVUBIQNXHRPJKK-RCOVLWMOSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000013176 antiplatelet therapy Methods 0.000 description 1
- 229940086777 brilinta Drugs 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- DFJDZTPFNSXNAX-UHFFFAOYSA-N ethoxy(triethyl)silane Chemical compound CCO[Si](CC)(CC)CC DFJDZTPFNSXNAX-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002440 industrial waste Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of ticagrelor, belonging to the technical field of medicine manufacturing. According to the method, a compound VII is taken as a raw material, and the method comprises the steps of: carrying out a nucleophilic substitution reaction on the raw material to obtain a compound VI; hydrogenating the VI, removing carbamazepine (Cbz) protection to obtain a compound V; carrying out a reaction on the V and 4, 6-dichloro-2-(allyl sulfide)-5-amio-pyrimidine to obtain a compound IV; carrying out a reaction on the IV and nitrite of alkali metal to obtain a compound III; carrying out a reaction on the III and (1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine to obtain a compound II; and finally, removing protecting group of the II to obtain a compound I.
Description
Technical field
The present invention relates to medical manufacturing technology field, specifically a kind of preparation method of ADZ6140.
Background technology
ADZ6140, chemical name (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluoro phenyl) cyclopropylamino]-5-(propylsulfanyl)-3H-[1,2,3] triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol, U.S. chemical abstract registration number CAS NO:274693-27-5, has the structural formula of formula I:
I ADZ6140 is a kind of novel, there is optionally anticoagulant, also be first reversible mating type P2Y12 adenosine diphosphate (ADP) acceptor (ADP) antagonist, the reversibly purine 2 receptor subtype P2Y12 on vasoactive smooth muscle cell (VSMC), the platelet aggregation that ADP is caused has obvious restraining effect, can effectively improve acute coronary patient's symptom.This product is produced by Astrazeneca AB's research and development, and commodity are called Brilinta, and tablet was in European Initial Public Offering in 2010, and in the whole world, tens countries sell at present, after this medicine listing, in process of clinical application, has shown good therapeutic action.Studies show that, ADZ6140 is compared with clopidogrel, can obviously reduce the primary terminal event such as patient's heart stalk, palsy or cardiovascular death, and severe haemorrhage complication does not increase, this medicine is similar to clopidogrel side effect simultaneously, do not increase, this is the much progress to Antiplatelet therapy beyond doubt.
The existing report for the preparation of Compound I mainly contains (1) WO9905143 (2) WO0192263 etc.
In the patent WO9905143 of Astrazeneca AB of Yuan Yan producer, relate to the syntheti c route (Scheme 1) of a Compound I
This route steps is long, and wherein relates to osmic acid oxidation, DIBAL-H reduction, iron powder reducings etc. have severe toxicity or easily cause the reaction of a large amount of three industrial wastes, this route total recovery is low simultaneously, and production cost is high, therefore can not serve as the first-selected route of synthetic compound I.
Astrazeneca AB has related to the syntheti c route (Scheme 2) of an other Compound I in patent WO0192263.
This route exists route longer equally, and therefore the shortcoming that total recovery is on the low side is also not suitable for the optimal route as large-scale industrial production.
Summary of the invention
The invention provides a kind of preparation method of the ADZ6140 that can overcome above-mentioned deficiency; its syntheti c route is as shown in Scheme 3; the method shortens in step to some extent compared with existing route; after in to existing route, exposed hydroxyl carries out suitable protection simultaneously; the productive rate of reaction is significantly promoted; greatly reduce production cost, realized suitability for industrialized production cheaply for ADZ6140 a kind of method is provided.The synthetic method of the ADZ6140 as shown in Scheme 3 provided by the present invention was not all carried out description in published document.
Its detailed process is:
The preparation of compound VI: compound VI I is in solvent, under alkali effect, with compound L CH
2cH
2oR reaction preparation compound VI.Described solvent is one or several in tetrahydrofuran (THF) or DMF or diethyl ether or diisopropyl ether or methyl tertiary butyl ether or benzene or toluene or dimethylbenzene, preferably tetrahydrofuran (THF); Highly basic is potassium tert.-butoxide or sodium hydride or sodium tert-amyl alcohol; L is chlorine or bromine or iodine.
The preparation of compound V: compound VI, in solvent, adds heavy metal catalyst, the de-Cbz protection of pressure hydration obtains compound V.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF), preferred alcohol; Heavy metal catalyst is palladium carbon or palladium hydroxide, preferably palladium carbon.
The preparation of compound IV: compound V, in solvent, adds alkali obtains compound IV with the reaction of the chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine under hot conditions; Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF), preferred alcohol; Alkali is sodium hydroxide or potassium hydroxide or lithium hydroxide or three (C
1-6) alkyl amine, preferably triethylamine; Hot conditions is 100 DEG C-180 DEG C, preferably 100 DEG C-125 DEG C.
The preparation of compound III: compound IV, in water, adds acid, reacts and obtains compound III with alkali-metal nitrite.Described acid is one or several in formic acid or acetic acid or dilute hydrochloric acid or dilute sulphuric acid, preferably acetic acid; Alkali-metal nitrite is Sodium Nitrite or potassium nitrite, preferably Sodium Nitrite.
The preparation of Compound I I: compound III, in solvent, adds alkali, obtains Compound I I with the reaction of (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or acetonitrile, preferred alcohol; Alkali is three (C
1-6) alkyl amine, preferably triethylamine.
The preparation of Compound I: Compound I I, in solvent, adds deprotecting regent, and Deprotection obtains Compound I.Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF), preferred alcohol; Deprotecting regent is trifluoroacetic acid or hydrochloric acid, preferably hydrochloric acid.
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
Embodiment
Specific embodiments of the invention are below provided, to show possible implementation process, but do not limit the present invention.
Embodiment 1
The preparation of compound VI a
Compound VI Ia (615g, 2mol) is joined in 3.5L tetrahydrofuran (THF), add potassium tert.-butoxide solid (269.5g, 2.4mol) in batches.Mixture stirs 10 minutes, under zero degree, drip 2-bromine oxethyl tertiary butyl dimethylsilane (573.5g, 1L tetrahydrofuran solution 2.4mol), reaction solution stirs 1.5 hours, and TLC demonstration reacts completely, reaction solution adds water 2L, ethyl acetate 2L, separates organic phase, dry, concentrate to obtain compound VI a857.3g, yield is 92%.
The preparation of compound Va
By compound VI a (838.2g, 1.8mol) join in 5L ethanol, add 10% palladium carbon (40g), reaction solution hydrogen exchange is removed air, pressurization 1.5 handkerchiefs, and 50 DEG C are reacted 10 hours, TLC demonstration reacts completely, reacting liquid filtering is removed palladium carbon, and filtrate concentrates to obtain compound Va572.9g, and yield is 96%.
The preparation of compound IV a
Va (563.6g, 1.7mol) is joined in 5L ethanol, add 4, the chloro-2-of 6-bis-(rosickyite alkyl)-5-PYRIMITHAMINE (445g, 1.87mol) and triethylamine (189g, 1.87mol), reaction sealing, is warming up between 100-125 DEG C stirring reaction 20 hours, cooling, pressure reducing and steaming solvent, adds ethyl acetate 3L and water 3L, regulate mixed solution PH to 5 with dilute hydrochloric acid, separate organic phase, dry concentrating obtains compound IV a806.8g, and yield is 89%.
The preparation of compound III a
Va (761.9g, 1.4mol) is dissolved in acetic acid 5L and water 1L, and reaction solution is cooled to below 0 DEG C, drip Sodium Nitrite (96.6g, aqueous solution 500ml 1.4mol), complete, TLC demonstration reacts completely, reaction solution is warming up to room temperature, add ethyl acetate 5L, unsaturated carbonate aqueous solutions of potassium is washed, and separates organic phase, dry concentrating obtains compound IV a 668.7g, and yield is 86%.
The preparation of Compound I Ia
By (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (223.3g, 1.32mol) add compound III a (653g, in 3L ethanolic soln 1.2mol), in room temperature downhill reaction liquid, add triethylamine (133.6g, 1.32mol), complete, stirring reaction 15 hours under room temperature, TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of ethanol, add ethyl acetate 5L, water 3L, regulates PH to 4.5 with dilute hydrochloric acid, separates organic layer, dry concentrating obtains Compound I Ia 714.8g, and yield is 88%.
The preparation of Compound I
IIa (676.9g, 1mol) is dissolved in ethanol 5L, under stirring at room temperature, adds aqueous hydrochloric acid (3M, 3.34L), complete, stirring at room temperature 24 hours, TLC demonstration reacts completely, and reaction solution regulates PH to 7.2 with diluted sodium hydroxide solution, and ethanol is removed in decompression, add ethyl acetate 5L, separate organic phase, saturated common salt washing, dry, concentrating under reduced pressure obtains Compound I 486g, and yield is 93%.
Embodiment 2
The preparation of compound VI b
Compound VI Ib (615g, 2mol) is joined in 3L DMF, add 40% sodium hydride solid (144g, 2.4mol) in batches.Mixture stirs 10 minutes, under zero degree, drip the 1L DMF solution of 2-iodine ethoxy triethyl silane (687g, 2.4mol), reaction solution stirs 1 hour, TLC demonstration reacts completely, and reaction solution adds water 2L, ethyl acetate 2L, separate organic phase, dry, concentrate to obtain compound VI b847.5g, yield is 91%.
The preparation of compound Vb
By compound VI b (838.2g, 1.8mol) join in 5L methyl alcohol, add 15% palladium hydroxide (40g), reaction solution hydrogen exchange is removed air, pressurization 2 handkerchiefs, and 50 DEG C are reacted 12 hours, TLC demonstration reacts completely, reacting liquid filtering is removed palladium hydroxide, and filtrate concentrates to obtain compound Vb578.8g, and yield is 97%.
The preparation of compound IV b
By Vb (563.6g, 1.7mol) join in 5L methyl alcohol, add 4, the chloro-2-of 6-bis-(rosickyite alkyl)-5-PYRIMITHAMINE (445g, 1.87mol) and sodium hydroxide (74.8g, 1.87mol), reaction sealing, is warming up between 100-125 DEG C, stirring reaction 24 hours, cooling, pressure reducing and steaming solvent, adds ethyl acetate 3L and water 3L, regulate mixed solution PH to 5 with dilute hydrochloric acid, separate organic phase, dry concentrating obtains compound IV b770.5g, and yield is 85%.
The preparation of compound III b
V b (761.9g, 1.4mol) is dissolved in formic acid 5L and water 1L, and reaction solution is cooled to below 0 DEG C, drip potassium nitrite (119.1g, aqueous solution 500ml 1.4mol), complete, TLC demonstration reacts completely, reaction solution is warming up to room temperature, add ethyl acetate 5L, unsaturated carbonate aqueous solutions of potassium is washed, and separates organic phase, dry concentrating obtains compound IV b 632.3g, and yield is 83%.
The preparation of Compound I Ib
By (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (204.7g, 1.21mol) add compound III b (598.6g, in 3L methanol solution 1.1mol), in room temperature downhill reaction liquid, add tripropyl amine (173.3g, 1.21mol), complete, stirring reaction 15 hours under room temperature, TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of methyl alcohol, add ethyl acetate 5L, water 3L, regulates PH to 4.5 with dilute hydrochloric acid, separates organic layer, dry concentrating obtains Compound I Ib 670.1g, and yield is 90%.
The preparation of Compound I
IIb (643g, 0.95mol) is dissolved in methyl alcohol 5L, under stirring at room temperature, adds trifluoroacetic acid (1140g, 10mol), complete, stirring at room temperature 24 hours, TLC demonstration reacts completely, and reaction solution regulates PH to 7.2 with diluted sodium hydroxide solution, and methyl alcohol is removed in decompression, add ethyl acetate 5L, separate organic phase, saturated common salt washing, dry, concentrating under reduced pressure obtains Compound I 476.6g, and yield is 96%.
Embodiment 3
The preparation of compound VI c
Compound VI Ic (615g, 2mol) is joined to 5L methyl tertiary butyl ether, add sodium tert-amyl alcohol solid (264g, 2.4mol).Mixture stirs 10 minutes, under zero degree, drip the chloro-2-methoxyl methyl of 1-ethane (299g, 1L methyl tertbutyl ethereal solution 2.4mol), reaction solution stirs 1 hour, and TLC demonstration reacts completely, reaction solution adds water 2L, ethyl acetate 2L, separates organic phase, dry, concentrate to obtain compound VI c704.9g, yield is 89%.
The preparation of compound Vc
By compound VI c (672.3g, 1.7mol) join in 4L Virahol, add 10% palladium carbon (30g), reaction solution hydrogen exchange is removed air, pressurization 1.5 handkerchiefs, and 50 DEG C are reacted 12 hours, TLC demonstration reacts completely, reacting liquid filtering is removed palladium carbon, and filtrate concentrates to obtain compound Vc421.8g, and yield is 95%.
The preparation of compound IV c
By Vc (418.1g, 1.6mol) join in 4L Virahol, add 4, the chloro-2-of 6-bis-(rosickyite alkyl)-5-PYRIMITHAMINE (419.1g, 1.76mol) and potassium hydroxide (98.6g, 1.76mol), reaction sealing, is warming up between 100-125 DEG C, stirring reaction 15 hours, cooling, pressure reducing and steaming solvent, adds ethyl acetate 3L and water 3L, regulate mixed solution PH to 5 with dilute hydrochloric acid, separate organic phase, dry concentrating obtains compound IV c644.5g, and yield is 87%.
The preparation of compound III c
Vc (625g, 1.35mol) is dissolved in hydrochloric acid (3mol/L, 5L), reaction solution is cooled to below 0 DEG C, drips the aqueous solution 500ml of potassium nitrite (114.9g, 1.35mol), complete, TLC demonstration reacts completely, and reaction solution is warming up to room temperature, adds ethyl acetate 5L, unsaturated carbonate aqueous solutions of potassium is washed, separate organic phase, dry concentrating obtains compound IV c 557.7g, and yield is 87%.
The preparation of Compound I Ic
By (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (204.7g, 1.21mol) add compound III c (521.4g, in 3L aqueous isopropanol 1.1mol), in room temperature downhill reaction liquid, add Tributylamine (224.3g, 1.21mol), complete, stirring reaction 15 hours under room temperature, TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of Virahol, add ethyl acetate 5L, water 3L, regulates PH to 4.5 with dilute hydrochloric acid, separates organic layer, dry concentrating obtains Compound I Ic 631.3g, and yield is 86%.
The preparation of Compound I
IIc (606.7g, 1mol) is dissolved in Virahol 5L, under stirring at room temperature, adds trifluoroacetic acid (1140g, 10mol), complete, stirring at room temperature 24 hours, TLC demonstration reacts completely, and reaction solution regulates PH to 7.2 with diluted sodium hydroxide solution, and methyl alcohol is removed in decompression, add ethyl acetate 5L, separate organic phase, saturated common salt washing, dry, concentrating under reduced pressure obtains Compound I 491.2g, and yield is 94%.
Embodiment 4
The preparation of compound VI d
Compound VI Id (615g, 2mol) is joined in 4L toluene, add potassium tert.-butoxide solid (269.5g, 2.4mol).Mixture stirs 10 minutes, under zero degree, drip 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (501.8g, 1L toluene solution 2.4mol), reaction solution stirs 2 hours, and TLC demonstration reacts completely, reaction solution adds water 2L, ethyl acetate 2L, separates organic phase, dry, concentrate to obtain compound VI a775.2g, yield is 89%.
The preparation of compound Vd
By compound VI d (740.4g, 1.7mol) join in the 5L trimethyl carbinol, add 15% palladium hydroxide (40g), reaction solution hydrogen exchange is removed air, pressurization 2 handkerchiefs, and 50 DEG C are reacted 10 hours, TLC demonstration reacts completely, reacting liquid filtering is removed palladium hydroxide, and filtrate concentrates to obtain compound V d476.5g, and yield is 93%.
The preparation of compound IV d
By V d (476.5g, 1.5mol) join in the 5L trimethyl carbinol, add 4, the chloro-2-of 6-bis-(rosickyite alkyl)-5-PYRIMITHAMINE (392.9g, 1.65mol) and lithium hydroxide (39.5g, 1.65mol), reaction sealing, is warming up between 100-125 DEG C, stirring reaction 20 hours, cooling, pressure reducing and steaming solvent, adds ethyl acetate 3L and water 3L, regulate mixed solution PH to 5 with dilute hydrochloric acid, separate organic phase, dry concentrating obtains compound IV d 656.8g, and yield is 87%.
The preparation of compound III d
Vd (654g, 1.3mol) is dissolved in sulfuric acid (3mol/L, 5L), reaction solution is cooled to below 0 DEG C, drips the aqueous solution 500ml of Sodium Nitrite (89.7g, 1.3mol), complete, TLC demonstration reacts completely, and reaction solution is warming up to room temperature, adds ethyl acetate 5L, unsaturated carbonate aqueous solutions of potassium is washed, separate organic phase, dry concentrating obtains compound IV d 588.0g, and yield is 88%.
The preparation of Compound I Id
By (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (204.7g, 1.21mol) add compound III a (598.6g, in 3L t-butanol solution 1.1mol), in room temperature downhill reaction liquid, add triethylamine (122.2g, 1.21mol), complete, stirring reaction 20 hours under room temperature, TLC demonstration reacts completely, and concentrating under reduced pressure boils off most of trimethyl carbinol, add ethyl acetate 5L, water 3L, regulates PH to 4.5 with dilute hydrochloric acid, separates organic layer, dry concentrating obtains Compound I Id 647.4g, and yield is 91%.
The preparation of Compound I
IId (646.8g, 1mol) is dissolved in trimethyl carbinol 5L, under stirring at room temperature, adds aqueous hydrochloric acid (3M, 3.34L), complete, stirring at room temperature 24 hours, TLC demonstration reacts completely, and reaction solution regulates PH to 7.2 with diluted sodium hydroxide solution, and the trimethyl carbinol is removed in decompression, add ethyl acetate 5L, separate organic phase, saturated common salt washing, dry, concentrating under reduced pressure obtains Compound I 475.5g, and yield is 91%.
The recrystallization of Compound I
100g Compound I is joined in 500ml ethyl acetate, be heated to 50 DEG C and stir 30 minutes, remove by filter insolubles.Within ten minutes, be added dropwise to normal hexane 500ml, be completely naturally cooled to 20 DEG C, stir 1 hour at this temperature, filter, filter cake is washed with normal hexane.By vacuum-drying at 40 DEG C of the products of gained 10 hours to pure product I 73g, HPLC detects purity and is greater than 98%.
Claims (7)
1. a preparation method for ADZ6140, is characterized in that experiencing reaction process as follows:
(1) compound VI I is in solvent, under alkali effect, with compound L CH
2cH
2there is nucleophilic substitution reaction and prepare compound VI in OR;
Described solvent is one or several in tetrahydrofuran (THF) or DMF or diethyl ether or diisopropyl ether or methyl tertiary butyl ether or benzene or toluene or dimethylbenzene; L is chlorine or bromine or iodine;
(2) compound VI, in solvent, adds heavy metal catalyst, and the de-Cbz protection of pressure hydration obtains compound V:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF); Heavy metal catalyst is palladium carbon or palladium hydroxide;
(3) compound V, in solvent, adds suitable alkali, under hot conditions, obtains compound IV with the reaction of the chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF); Alkali is sodium hydroxide or potassium hydroxide or lithium hydroxide or three (C
1-6) alkyl amine; Hot conditions is 100 DEG C-180 DEG C;
(4) compound IV, in water, adds acid, reacts and obtains compound III with alkali-metal nitrite:
Described acid is one or several in formic acid or acetic acid or dilute hydrochloric acid or dilute sulphuric acid; Alkali-metal nitrite is Sodium Nitrite or potassium nitrite;
(5) compound III, in solvent, adds alkali, obtains Compound I I with the reaction of (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or acetonitrile; Alkali is three (C
1-6) alkyl amine;
(6) Compound I I, in solvent, adds deprotecting regent, and Deprotection obtains Compound I:
Described solvent is one or several in methyl alcohol or ethanol or Virahol or propyl carbinol or the trimethyl carbinol or tetrahydrofuran (THF); Deprotecting regent is trifluoroacetic acid or hydrochloric acid;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
2. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (1), described solvent is selected from tetrahydrofuran (THF); Described alkali is selected from potassium tert.-butoxide;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
3. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (2), described solvent is selected from ethanol; Described heavy metal catalyst is selected from palladium carbon;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
4. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (3), described solvent is selected from ethanol; Described alkali is selected from triethylamine; Described hot conditions is selected from 100 DEG C-125 DEG C;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
5. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (4), described acid is selected from acetic acid; Described alkali-metal nitrite is selected from Sodium Nitrite;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
6. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (5), described solvent is selected from ethanol; Described alkali is selected from triethylamine;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
7. the preparation method of a kind of ADZ6140 as claimed in claim 1, is characterized in that, in described step (6), described solvent is selected from ethanol; Described deprotecting regent is selected from hydrochloric acid;
Wherein, R is the silica-based or t-Butyldimethylsilyl of triethyl or tert-butyl diphenyl is silica-based or methoxyl methyl or THP trtrahydropyranyl or tetrahydrofuran base.
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