CN104892509A - Preparation method of Roxadustat - Google Patents
Preparation method of Roxadustat Download PDFInfo
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- CN104892509A CN104892509A CN201510299804.0A CN201510299804A CN104892509A CN 104892509 A CN104892509 A CN 104892509A CN 201510299804 A CN201510299804 A CN 201510299804A CN 104892509 A CN104892509 A CN 104892509A
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- Prior art keywords
- preparation
- methyl
- nuo
- reaction
- phenoxy group
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 title abstract description 8
- 229950008113 roxadustat Drugs 0.000 title abstract description 6
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 11
- 238000006266 etherification reaction Methods 0.000 claims abstract description 10
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000005886 esterification reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 8
- -1 tyrosine ester Chemical class 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004643 cupric oxide Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical group OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000006462 rearrangement reaction Methods 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 230000008707 rearrangement Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 0 C*(Cc1cc(*)ccc11)C1=O Chemical compound C*(Cc1cc(*)ccc11)C1=O 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 6
- MWZPENIJLUWBSY-VIFPVBQESA-N methyl L-tyrosinate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-VIFPVBQESA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229960004441 tyrosine Drugs 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MODJGXDBICEJRC-UHFFFAOYSA-N CC(CNC(C(C1O)N=C(C)C(C2)C1=CC=C2OP=C)=O)=O Chemical compound CC(CNC(C(C1O)N=C(C)C(C2)C1=CC=C2OP=C)=O)=O MODJGXDBICEJRC-UHFFFAOYSA-N 0.000 description 1
- FBWXXQSSUUAZCM-UHFFFAOYSA-N Cc1ccc(C(Cl)=O)c(CCl)c1 Chemical compound Cc1ccc(C(Cl)=O)c(CCl)c1 FBWXXQSSUUAZCM-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of Roxadustat. The preparation steps are as follows: the Roxadustat is prepared from tyrosine through esterification, etherification, cyclization, dehydrogenation, oxidative rearrangement and acylation reaction. The preparation method has the advantages that the raw materials are easily obtained; the process is simple; and the preparation method is economic and environmental-friendly, and is suitable for industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of preparation method that may be used for the treatment of the medicine Nuo get Si Ta of chronic anaemia.
Background technology
Nuo get Si Ta (Roxadustat) is researched and developed by Fibrogen Inc of the U.S. (FibroGen), the micromolecular inhibitor of a kind of hypoxia inducible factor (HIF) prolyl hydroxylase that Astellas and AstraZeneca are obtained the arthorization, code name is FG-4592.Initiate brand-new oral pharmaceutical as one, FG-4592 is in the III phase clinical trial stage at present, is used for the treatment of the anemia that chronic nephropathy is relevant with end stagerenaldisease.Because this medicine does not also have the Chinese translation of standard, therefore its transliteration is " Nuo get Si Ta " at this by the applicant.
The chemistry of Nuo get Si Ta (Roxadustat, I) is called: N-[(4-hydroxyl-1-methyl-7-phenoxy group-3-isoquinoline 99.9) carbonyl] glycine, and its structural formula is:
The international monopoly WO2004108681 of Yuan Yan company provides a kind of Nuo get Si Ta intermediate and the synthetic route by this Intermediate Preparation Nuo get Si Ta thereof:
The international monopoly WO2013013609 of Zhejiang Bei Da company has carried out further optimization to the preparation method of core intermediate and acylation reaction, and its synthetic route is:
The international monopoly WO2014014834 of Yuan Yan company and WO2014014835 additionally provides synthetic route prepared by another kind of Nuo get Si Ta:
Analyze said synthesis route, although constantly improve the synthesis of Nuo get Si Ta and optimize, the cyclization mode of its essence, namely the formation of isoquinoline 99.9 female ring is substantially identical.Especially isoquinoline 99.9 change methyl incorporation way otherwise by the suzuki reaction under the plain catalysis of your gold, or to be realized by the reduction of amine.And the enlightenment raw material of above-mentioned reaction scheme all not easily obtains, repeatedly need in reaction process to carry out protecting and deprotection reaction.Obviously, this preparation process is relatively loaded down with trivial details, high expensive, brings certain difficulty to suitability for industrialized production.
For existing defective workmanship, develop concise in technology, economic environmental protection and the technology of preparing had good quality, especially seek the Technology that can adapt to suitability for industrialized production, improving the economic and social benefit of this medicine has important realistic meaning.
Summary of the invention
The object of the present invention is to provide that a kind of raw material is easy to get, concise in technology, economic environmental protection and be applicable to the preparation method of the Nuo get Si Ta (Roxadustat) of suitability for industrialized production.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of Nuo get Si Ta (I),
It is characterized in that its preparation comprises the steps: tyrosine and methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, esterification is there is and obtains corresponding tyrosine ester (II) in isopropylcarbinol or the trimethyl carbinol under the sulphuric acid catalysis of weight percent 65-98%, described tyrosine ester (II) carries out etherification reaction with chlorobenzene or bromobenzene and obtains 2-amino-3-(4-Phenoxyphenyl) propionic ester (III) under catalyst action, described 2-amino-3-(4-Phenoxyphenyl) propionic ester (III) and acetaldehyde carry out cyclization in acid condition and obtain 1-methyl-3-manthanoate-7-phenoxy group-1, 2, 3, 4-tetrahydroisoquinoline (IV), described 1-methyl-3-manthanoate-7-phenoxy group-1, 2, 3, dehydrogenation reaction is there is and obtains 1-methyl-3-manthanoate-7-phenoxy group isoquinoline 99.9 (V) in 4-tetrahydroisoquinoline (IV) under the effect of alkali promotor, Oxido-rearrangement is there is and obtains 1-methyl-3-manthanoate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 (VI) in described 1-methyl-3-manthanoate-7-phenoxy group isoquinoline 99.9 (V) under oxygenant and Tosyl chloride participate in, acylation reaction is there is and obtains Nuo get Si Ta (I) in described 1-methyl-3-manthanoate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 (VI) and glycine under acid binding agent effect.
In addition, the present invention also proposes following attached technical scheme:
Alcohol used during described esterification is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol or benzylalcohol, particular methanol or ethanol.
The molar ratio of described etherification reaction raw material tyrosine ester (II) and chlorobenzene or bromobenzene is 1: 0.5-1.5, preferably 1: 1.
The alkali promotor of described etherification reaction is sodium methylate, sodium ethylate or sodium hydroxide, particular methanol sodium.
The catalyzer of described etherification reaction is copper powder, cupric oxide, Red copper oxide, cuprous chloride, cuprous bromide or cuprous iodide, preferred copper powder or cuprous bromide.
The solvent of described etherification reaction is methyl-sulphoxide.
The temperature of described etherification reaction is 130-180 DEG C, preferred 170-175 DEG C.
Described cyclization carries out under strongly acidic conditions, and the concentrated hydrochloric acid thus by adding weight percent 33-36% realizes its acidic conditions.
The temperature of described cyclization is 90-120 DEG C, preferred 100-105 DEG C.
Described dehydrogenation reaction is realized by the elimination reaction of p-toluenesulfonyl (Ts) as leavings group; so 1-methyl-3-methyl-formiate-7-phenoxy group-1; 2; 3; 4-tetrahydroisoquinoline (IV) first forms intermediate state N-p-toluenesulfonyl-1-methyl-3-methyl-formiate-7-phenoxy group-1,2,3 with Tosyl chloride under salt of wormwood effect; 4-tetrahydroisoquinoline, then this intermediate state again alkali promotor exist under cancellation tosic acid realize dehydrogenation reaction.
The alkali promotor of described dehydrogenation reaction is pyridine, N-methylmorpholine, diisopropylethylamine, DMAP, salt of wormwood, Quilonum Retard, potassium tert.-butoxide, sodium hydroxide or potassium hydroxide.
The temperature of described dehydrogenation reaction is 100-160 DEG C, preferred 120-130 DEG C.
The solvent of described dehydrogenation reaction is dioxane, toluene, dimethylbenzene, DMF or methyl-sulphoxide, preferred methyl-sulphoxide.
Described Oxido-rearrangement is oxidized by the nitrogen of isoquinoline 99.9 ring, then under the catalysis of p-toluenesulfonyl, rearrangement reaction occurs, realize 4-position hydroxylating.
The oxygenant of described Oxido-rearrangement is benzoyl hydroperoxide, metachloroperbenzoic acid, clorox, ozone or hydrogen peroxide, preferred hydrogen peroxide.
The solvent of described Oxido-rearrangement is Glacial acetic acid.
The temperature of described Oxido-rearrangement is 25-60 DEG C, preferred 35-45 DEG C.
The acid binding agent of described acylation reaction is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium carbonate, salt of wormwood or cesium carbonate, particular methanol sodium.
Compared to prior art, the preparation method of Nuo get Si Ta (I) involved in the present invention, has that raw material is easy to get, the feature such as concise in technology and economic environmental protection, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
In dry reaction bottle, add tyrosine (18.1g, 0.1mmol) and methyl alcohol 250mL, ice bath is cooled to 0-5 DEG C, drips the vitriol oil 10g of weight percent 98% in 1 hour.Drip and finish, be warming up to backflow.Stirring reaction 16-20 hour, TLC detection reaction is complete.Normal pressure concentrates, pure water 100mL is added in resistates, pH to 6.5-7.0 is regulated with weight percent 10% sodium hydroxide, solid is had to separate out, filter, first alcohol and water (1: the 1) washing of chlorine cake, vacuum-drying obtains white solid L-Tyrosine methyl ester (II) 15.3g, yield 78.5%; EI-MS m/z:196 [M+H]
+.
Embodiment two:
In nitrogen atmosphere and ice bath, in reaction flask, add L-Tyrosine methyl ester (II) (9.8g, 50mmol), potassium methylate (3.5g, 50mmol) and methyl alcohol 50mL, after not having gas to produce, be heated to backflow, stirring reaction 2 hours.Normal pressure is concentrated removes solvent, copper powder (the 0.2g of methyl-sulphoxide 25mL, brand-new is added in residue, 3.1mmol), slowly be warming up to 150-155 DEG C under stirring, about after half an hour, drip bromobenzene (7.9g, 50mmol), continue to be warming up to 170-175 DEG C, stirring reaction 3 hours, TLC detection reaction terminates.Be cooled to 60 DEG C, add methyl alcohol and keep micro-and boil, filtered while hot, filter cake reusable heat washing with alcohol three times, merge organic phase, be cooled to 0 DEG C, filter, vacuum-drying obtains white solid 2-amino-3-(4-Phenoxyphenyl) methyl propionate (III) 11.5g, yield 84.9%; EI-MS m/z:272 [M+H]
+.
Embodiment three:
2-amino-3-(4-Phenoxyphenyl) methyl propionate (III) (10.8g is added in reaction flask, 40mmol), weight percent 40% acetaldehyde (20g, 0.2mol) and weight percent be 35% concentrated hydrochloric acid 50mL, back flow reaction 1 hour.Continue to add the concentrated hydrochloric acid 25mL that weight percent 40% acetaldehyde (10g, 0.1mol) and weight percent are 35%, then back flow reaction 3-5 hour.Be cooled to 4-7 DEG C, add ethyl acetate, extracting and demixing.Water layer sodium hydroxide solution regulates pH to 11-12, is extracted with ethyl acetate three times, merges organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains white solid 1-methyl-3-methyl-formiate-7-phenoxy group-1,2,3,4-tetrahydroisoquinoline (IV) 8.4g, yield 70.7%; Mass spectrum (EI): EI-MS m/z:298 [M+H]
+.
Embodiment four:
Under ice bath, 1-methyl-3-methyl-formiate-7-phenoxy group-1,2,3 is added in reaction flask, 4-tetrahydroisoquinoline (IV) (5.9g, 20mmol) and methylene dichloride 100mL, 0 DEG C and add salt of wormwood (13.8g, 0.1mol), Tosyl chloride (11.4g under stirring, 60mmol), finish, remove ice bath, stirring at room temperature 3 hours.Add water 30mL, stratification after stirring, organic phase uses dilute hydrochloric acid, water and saturated common salt water washing successively, concentrated, add weight percent 30% sodium hydroxide solution (8.0g, 60mmol) and methyl-sulphoxide 60mL in products therefrom, be progressively warming up to 120-130 DEG C, stirring reaction 2-4 hour, TLC detection reaction terminates.Be down to room temperature, add water 100mL, be extracted with ethyl acetate 3 times, merge organic phase, use water and saturated common salt water washing successively, anhydrous magnesium sulfate drying, concentrated, gained oily matter ethyl acetate and normal hexane (1: 3) recrystallization, vacuum-drying obtains off-white color solid 1-methyl-3-methyl-formiate-7-phenoxy group isoquinoline 99.9 (V) 5.25g, yield 89.6%; EI-MS m/z:294 [M+H]
+,
1h NMR (DMSO-d
6) δ 2.85 (s, 3H), 3.97 (s, 3H), 7.16-7.24 (m, 3H), 7.49-7.60 (m, 4H), 8.35 (d, J=9.0,1H), 8.94 (s, 1H).
Embodiment five:
1-methyl-3-methyl-formiate-7-phenoxy group isoquinoline 99.9 (V) (2.93g is added in reaction flask, 10mmol) with Glacial acetic acid 50mL, stir the lower hydrogen peroxide 5mL dripping weight percent 30%, be warming up to 60-70 DEG C, the mixed solution of weight percent 30% hydrogen peroxide 2mL and Glacial acetic acid 12mL is slowly dripped in 10 hours, drip and finish, continue reaction 20-24 hour.Concentrating under reduced pressure, adds ethanol, continues distillation to eliminate remaining Glacial acetic acid.Residuum methylene dichloride dissolves, and the sodium bicarbonate washing of weight percent 5%, separates organic phase, anhydrous sodium sulfate drying.Filter, add Tosyl chloride (3.8g, 20mmol) in gained solution, be warming up to backflow, stirring reaction 3-4 hour, TLC detection reaction terminates.Decompression steams solvent, is down to room temperature, adds methyl alcohol, have solid to separate out, be cooled to 0 DEG C, hold over night.Filter, filter cake cold methanol washes twice, and vacuum-drying obtains off-white color solid 1-methyl-3-methyl-formiate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 (VI) 1.86g, yield 60.2%; EI-MS m/z:310 [M+H]
+,
1h NMR (DMSO-d
6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7.17-7.26 (m, 3H), 7.49-7.61 (m, 4H), 8.38 (d, J=9.0,1H), 11.7 (s, 1H).
Embodiment six:
1-methyl-3-methyl-formiate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 (VI) (1.55g is added in magnetic agitation and withstand voltage reaction flask, 5mmol), glycine (1.13g, 15mmol) and the methanol solution (30mL) of sodium methylate (3.25g, 6mmol).Sealing, be slowly heated to 120 DEG C, stirring reaction 8-10 hour, TLC detection reaction terminates.Be cooled to room temperature, have solid to separate out.Suction filtration, gained solids with methanol recrystallization, then pull an oar with acetone, gained solid obtains white solid Nuo get Si Ta 1.40g through vacuum-drying, yield 79.5%; EI-MS m/z:353 [M+H]
+,
1h NMR (DMSO-d
6) δ 2.72 (s, 3H), 3.99 (d, J=6.0,2H), 7.18-7.28 (m, 3H), 7.49-7.63 (m, 4H), 8.31 (d, J=8.8,1H), 9.08 (s, 1H), 13.41 (brs, 1H).
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (9)
1. the preparation method of Yi Zhong Nuo get Si Ta (I),
It is characterized in that its preparation comprises the steps: tyrosine and methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, esterification is there is and obtains corresponding tyrosine ester in isopropylcarbinol or the trimethyl carbinol under the sulphuric acid catalysis of weight percent 65-98%, described tyrosine ester and chlorobenzene or bromobenzene carry out etherification reaction and obtain 2-amino-3-(4-Phenoxyphenyl) propionic ester under catalyst action, described 2-amino-3-(4-Phenoxyphenyl) propionic ester and acetaldehyde carry out cyclization in acid condition and obtain 1-methyl-3-manthanoate-7-phenoxy group-1, 2, 3, 4-tetrahydroisoquinoline, described 1-methyl-3-manthanoate-7-phenoxy group-1, 2, 3, dehydrogenation reaction is there is and obtains 1-methyl-3-manthanoate-7-phenoxy group isoquinoline 99.9 in 4-tetrahydroisoquinoline under the effect of alkali promotor, Oxido-rearrangement is there is and obtains 1-methyl-3-manthanoate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 in described 1-methyl-3-manthanoate-7-phenoxy group isoquinoline 99.9 under oxygenant and Tosyl chloride participate in, acylation reaction is there is and obtains Nuo get Si Ta (I) in described 1-methyl-3-manthanoate-4-hydroxyl-7-phenoxy group isoquinoline 99.9 and glycine under acid binding agent effect.
2. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the catalyzer of described etherification reaction is copper powder, cupric oxide, Red copper oxide, cuprous chloride, cuprous bromide or cuprous iodide.
3. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the temperature of described etherification reaction is 130-180 DEG C.
4. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the temperature of described cyclization is 90-120 DEG C.
5. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the alkali promotor of described dehydrogenation reaction is pyridine, N-methylmorpholine, diisopropylethylamine, DMAP, salt of wormwood, Quilonum Retard, potassium tert.-butoxide, sodium hydroxide or potassium hydroxide.
6. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the temperature of described dehydrogenation reaction is 100-160 DEG C.
7. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the solvent of described dehydrogenation reaction is dioxane, toluene, dimethylbenzene, DMF or methyl-sulphoxide.
8. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the oxygenant of described Oxido-rearrangement is benzoyl hydroperoxide, metachloroperbenzoic acid, clorox, ozone or hydrogen peroxide.
9. the preparation method of Nuo get Si Ta as claimed in claim 1, is characterized in that the acid binding agent of described acylation reaction is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium carbonate, salt of wormwood or cesium carbonate.
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| CN112679428A (en) * | 2019-10-17 | 2021-04-20 | 罗欣药业(上海)有限公司 | New crystal form of roxasistat and preparation method thereof |
| WO2021214785A1 (en) | 2020-04-21 | 2021-10-28 | Mylan Laboratories Limited | Improved process for the preparation of roxadustat |
| CN115867537A (en) * | 2020-04-21 | 2023-03-28 | 迈兰实验室有限公司 | Improved process for the preparation of a rasagiline base |
| CN113801060A (en) * | 2020-06-13 | 2021-12-17 | 苏州鹏旭医药科技有限公司 | Preparation method of polysubstituted isoquinoline compound |
| WO2021252295A1 (en) | 2020-06-13 | 2021-12-16 | Suzhou Pengxu Pharmatech Co., Ltd. | Process of making roxadustat |
| CN111592490B (en) * | 2020-07-02 | 2022-04-22 | 浙江工业大学 | Preparation method of key intermediate of roxasistat |
| CN111592490A (en) * | 2020-07-02 | 2020-08-28 | 浙江工业大学 | Preparation method of key intermediate of roxasistat |
| CN112194624A (en) * | 2020-11-18 | 2021-01-08 | 江苏豪森药业集团有限公司 | Crystal form of isoquinoline compound and preparation method thereof |
| CN112500344B (en) * | 2020-11-18 | 2022-07-01 | 江苏豪森药业集团有限公司 | Crystalline form of roxasistat and preparation method thereof |
| CN112500344A (en) * | 2020-11-18 | 2021-03-16 | 江苏豪森药业集团有限公司 | Crystalline form of roxasistat and preparation method thereof |
| CN113248432A (en) * | 2021-04-25 | 2021-08-13 | 南京正济医药研究有限公司 | Novel method for preparing intermediate of roxasistat in high yield |
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