CN113336761A - Preparation method of JAK inhibitor key intermediate - Google Patents
Preparation method of JAK inhibitor key intermediate Download PDFInfo
- Publication number
- CN113336761A CN113336761A CN202110627757.3A CN202110627757A CN113336761A CN 113336761 A CN113336761 A CN 113336761A CN 202110627757 A CN202110627757 A CN 202110627757A CN 113336761 A CN113336761 A CN 113336761A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- chloride
- key intermediate
- jak inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940122245 Janus kinase inhibitor Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 239000012022 methylating agents Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 99
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 39
- 239000003054 catalyst Substances 0.000 claims description 31
- 238000001914 filtration Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- -1 methyl Grignard reagent Chemical class 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 238000001816 cooling Methods 0.000 claims description 18
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 239000003223 protective agent Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 14
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 claims description 9
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 8
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 claims description 8
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical compound [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 239000012445 acidic reagent Substances 0.000 claims description 4
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 claims description 4
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- SRDMJILINNZFLI-UHFFFAOYSA-L CC.Cl[Ni]Cl Chemical compound CC.Cl[Ni]Cl SRDMJILINNZFLI-UHFFFAOYSA-L 0.000 claims 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002699 waste material Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- XGGUTWYJGILAOA-UHFFFAOYSA-N tert-butyl 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylate Chemical compound N1=CN=C2N(C(=O)OC(C)(C)C)C=CC2=C1Cl XGGUTWYJGILAOA-UHFFFAOYSA-N 0.000 description 4
- XSWVYGMWDQITHQ-UHFFFAOYSA-N 2-diphenylphosphanylethyl(diphenyl)phosphane;nickel Chemical compound [Ni].C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XSWVYGMWDQITHQ-UHFFFAOYSA-N 0.000 description 3
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 description 3
- QWIAHMVNMONKCU-UHFFFAOYSA-N 4-methyl-7h-pyrrolo[2,3-d]pyrimidine Chemical compound CC1=NC=NC2=C1C=CN2 QWIAHMVNMONKCU-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000004012 Tofacitinib Substances 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229960001350 tofacitinib Drugs 0.000 description 3
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 3
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 2
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 2
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- 229960002539 ruxolitinib phosphate Drugs 0.000 description 2
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- IDIQAVWEIFSEBU-UHFFFAOYSA-L 1-diphenylphosphanylpropan-2-yl(diphenyl)phosphane;nickel(2+);dichloride Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)CP(C=1C=CC=CC=1)C1=CC=CC=C1 IDIQAVWEIFSEBU-UHFFFAOYSA-L 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- STPWDLTUEZDYPD-UHFFFAOYSA-N CC1=NC=NC2=C1C=CN2C(=O)OC(C)(C)C Chemical compound CC1=NC=NC2=C1C=CN2C(=O)OC(C)(C)C STPWDLTUEZDYPD-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 101150111783 NTRK1 gene Proteins 0.000 description 1
- 101150117329 NTRK3 gene Proteins 0.000 description 1
- 101150056950 Ntrk2 gene Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- COLJYBDTTGVCKH-UHFFFAOYSA-L dichloronickel;diphenylphosphane;propane Chemical compound CCC.Cl[Ni]Cl.C=1C=CC=CC=1PC1=CC=CC=C1 COLJYBDTTGVCKH-UHFFFAOYSA-L 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a JAK inhibitor key intermediate, which comprises the following steps: step a, protecting amino of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine serving as a raw material to synthesize 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine; step b, reacting 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine with a methylating agent to synthesize 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine; and c, deprotecting the 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine to synthesize 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine. According to the preparation method of the JAK inhibitor key intermediate, the raw materials are low in price and easy to obtain in the market, the production cost is low, each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, the operation is simple, the dosage of a format reagent is reduced and the generation of C-N bimolecular coupling impurities is avoided due to protection, the product purity is improved, and the aftertreatment is easier.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a preparation method of a JAK inhibitor key intermediate.
Background
4-methyl-7H-pyrrolo [2,3-d ] pyrimidine is an important medical intermediate, and is mainly used for synthesis of JAK1/JAK2 tyrosine kinase inhibitor (CN108699063), Fms kinase small molecule inhibitor and Kit, Flt3, TrkA/TrkB/TrkC enzyme inhibitor (Joc,2019), wherein the ruxolitinib phosphate (other name: ruxolitinib phosphate) is a JAK1/JAK2 tyrosine kinase inhibitor, and is mainly used for treating high-risk bone fibrosis (PMF) in (1), including primary myelofibrosis (2) myelofibrosis (PPV-MF) secondary to polycythemia vera, approved by the European Union in 8 months in 2012, approved in Japan in 7 months in 2014, and approved as the first therapeutic "true red" by FDA in U.S. 12 months in 2014. 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine is used as a key intermediate, few synthesis routes are reported at present, and the following methods are mainly adopted.
The method comprises the following steps: US2019/23712/WO2020/142557/CN108699063 respectively discloses a synthesis method of the intermediate, 4-chloro-7H-pyrrolo [2,3-d ]]Pyrimidine as a starting material, Pd (dppf) Cl2The catalyst reacts with the methyl-formatted reagent to generate a product, the process uses expensive palladium metal, and the catalyst has large consumption, so that the cost is high and the industrial production amplification is not facilitated; the second method comprises the following steps: in the synthesis method disclosed in US2007/191293, iron acetylacetonate is used to replace palladium catalysts, although the cost is reduced, the reaction time is long, the yield is low, the post-treatment is difficult, column purification is required, and the method is not suitable for industrial amplification; the third method comprises the following steps: WO2018/55097/Bioorganic and Medicinal Chemistry Letters,2012, vol.22, #24p.7742-7747 discloses another synthesis method, uses combustible trimethylaluminum in the air as a methylating agent, has harsh reaction conditions and higher operation requirements, and in addition, a large amount of commercial products of the trimethylaluminum are not provided with stable manufacturers at home and need to be imported, and the amplification production has greater difficulty. At present, the three synthetic methods also have the defects of large solvent consumption and more dangerous wastes.
Because the starting material 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine has imino in the raw material, if the protection is not carried out, the Buchwald-Hartwig C-N coupling reaction can be carried out simultaneously when the Kumada C-C coupling reaction is carried out by a one-step method; in addition, a typical side reaction of the coupling reaction is dechlorination reaction, so that 3 impurities are generated together, the properties of the 3 impurities are very close to those of the product, TLC is only a very regular round dot, the impurities are separated by HPLC after a large amount of experiments, and the product quality is difficult to meet the requirement of API production due to the fact that refining and removing are extremely difficult. Moreover, multiple refinements lead to a considerable reduction in the yield and to an increase in the cost.
Based on the above, in order to solve the disadvantages in the above synthesis process, the present application aims to provide a preparation method of a key intermediate 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which has the advantages of low cost, safety, environmental protection, easy operation and industrial production prospect.
Disclosure of Invention
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps: protecting amino group of the compound of formula (IV) to convert into compound of formula (III), reacting compound of formula (III) with methylating agent to convert into compound of formula (II), and deprotecting compound of formula (II) to convert into compound of formula (I). The preparation method of the intermediate compound of the invention comprises the following steps:
in some embodiments of the present application, the specific steps are as follows:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reacting for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III);
b, dissolving the compound shown in the formula (III) in an ether solvent, adding a catalyst, dropwise adding a methyl Grignard reagent at a controlled temperature, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain a compound shown in the formula (II);
and c, suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by hydrochloric acid, extracting by ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I).
According to the preparation method of the JAK inhibitor key intermediate provided by the embodiment of the invention, the used starting material, tofacitinib hydrochloride and rukutinib phosphate are the same intermediate, and the intermediate is cheap and easy to obtain in the market; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, the three wastes are reduced, and the treatment cost of the three wastes is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
According to some embodiments of the invention, in step a, the amino protecting agent is selected from the group consisting of 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc-Cl)2O) one or more of; the alkaline reagent is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen.
According to some embodiments of the invention, in the step a, the amino protecting agent is p-methyl benzenesulfonyl chloride (Tos-Cl) or di-tert-butyl dicarbonate (Boc)2O); the alkaline reagent is sodium hydroxide.
According to some embodiments of the present invention, in the step b, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; the catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl2) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl2) 1, 2-bis (diphenyl)Phosphine propane nickel chloride (Ni (dppp) Cl2) One or more of iron acetylacetonate and nickel acetylacetonate; the methyl Grignard reagent is selected from one or more of 3.0M methyl magnesium bromide/2-methyl tetrahydrofuran solution, 3.0M methyl magnesium chloride/tetrahydrofuran solution and 1.0M methyl magnesium bromide/tetrahydrofuran solution; the molar ratio of the compound of formula (III), the catalyst and the methyl Grignard reagent is 1: 0.01-0.1: 1.2-3.
According to some embodiments of the invention, in step b, the catalyst is selected from the group consisting of 1, 2-bis (diphenylphosphino) propanenickel chloride (ni (dppp) Cl2) One or more of iron acetylacetonate; the molar ratio of the compound of formula (III), the catalyst and the methylating agent is 1: 0.05-0.07: 1.5-2.5.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is subjected to deprotection on amino group under basic condition by a solvent and a catalyst to obtain the compound of formula (i), wherein the solvent is one or more selected from methanol, tetrahydrofuran and acetonitrile, and the basic agent is one or more selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide and potassium carbonate.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is deprotected on amino group under acidic condition by a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and water and a catalyst to obtain the compound of formula (i), and the acidic reagent is one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid and boron trifluoride diethyl etherate.
According to some embodiments of the present invention, in step c, the purification process includes dissolving the compound of formula (i) in tetrahydrofuran under heating, filtering, evaporating the solvent, adding acetonitrile, heating, refluxing, and pulping, wherein the mass ratio of formula (i) to tetrahydrofuran and acetonitrile is 1: 5-10: 1-5.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.5; in the step b, the reaction temperature is 35-80 ℃; in the step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.0-5.0.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.2; in the step b, the reaction temperature is 60-70 ℃; in step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.5-2.5.
Drawings
In order to more clearly illustrate the embodiments of the present invention, we will briefly introduce the drawings that need to be used in the embodiments, and the drawings described below are only exemplary illustrations of the present application.
Figure 1 is a process scheme of a method for the preparation of key intermediates of JAK inhibitors according to an embodiment of the invention.
Detailed Description
Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar chemical structures represent like or similar compounds throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
The preparation of key intermediates of JAK inhibitors according to the embodiments of the present invention is described below with reference to fig. 1.
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps: protecting amino group of the compound of formula (IV) to convert into compound of formula (III), reacting compound of formula (III) with methylating agent to convert into compound of formula (II), and deprotecting compound of formula (II) to convert into compound of formula (I). The preparation method of the intermediate compound of the invention comprises the following steps:
in some embodiments of the present application, the specific steps are as follows:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reacting for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III);
b, dissolving the compound shown in the formula (III) in an ether solvent, adding a catalyst, dropwise adding a methyl Grignard reagent at a controlled temperature, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain a compound shown in the formula (II);
and c, suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by hydrochloric acid, extracting by ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I).
According to the preparation method of the JAK inhibitor key intermediate provided by the embodiment of the invention, the used starting material, tofacitinib hydrochloride and rukutinib phosphate are the same intermediate, and the intermediate is cheap and easy to obtain in the market; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, the three wastes are reduced, and the treatment cost of the three wastes is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
According to some embodiments of the invention, in step a, the amino protecting agent is selected from the group consisting of 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc-Cl)2O) one or more of; the alkaline reagent is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen.
Some according to the inventionSpecifically, in the step a, the amino protecting agent is p-methyl benzenesulfonyl chloride (Tos-Cl) or di-tert-butyl dicarbonate (Boc)2O); the alkaline reagent is sodium hydroxide.
According to some embodiments of the present invention, in the step b, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; the catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl2) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl2) 1, 2-bis (diphenylphosphino) propanenickel (Ni) (dppp) Cl2) One or more of iron acetylacetonate and nickel acetylacetonate; the methyl Grignard reagent is selected from one or more of 3.0M methyl magnesium bromide/2-methyl tetrahydrofuran solution, 3.0M methyl magnesium chloride/tetrahydrofuran solution and 1.0M methyl magnesium bromide/tetrahydrofuran solution; the molar ratio of the compound of formula (III), the catalyst and the methyl Grignard reagent is 1: 0.01-0.1: 1.2-3.
According to some embodiments of the invention, in step b, the catalyst is selected from the group consisting of 1, 2-bis (diphenylphosphino) propanenickel chloride (ni (dppp) Cl2) One or more of iron acetylacetonate; the molar ratio of the compound of formula (III), the catalyst and the methylating agent is 1: 0.05-0.07: 1.5-2.5.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is subjected to deprotection on amino group under basic condition by a solvent and a catalyst to obtain the compound of formula (i), wherein the solvent is one or more selected from methanol, tetrahydrofuran and acetonitrile, and the basic agent is one or more selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide and potassium carbonate.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is deprotected on amino group under acidic condition by a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and water and a catalyst to obtain the compound of formula (i), and the acidic reagent is one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid and boron trifluoride diethyl etherate.
According to some embodiments of the present invention, in step c, the purification process includes dissolving the compound of formula (i) in tetrahydrofuran under heating, filtering, evaporating the solvent, adding acetonitrile, heating, refluxing, and pulping, wherein the mass ratio of formula (i) to tetrahydrofuran and acetonitrile is 1: 5-10: 1-5.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.5; in the step b, the reaction temperature is 35-80 ℃; in the step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.0-5.0.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.2; in the step b, the reaction temperature is 60-70 ℃; in step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.5-2.5.
The preparation of key intermediates of JAK inhibitors according to embodiments of the present invention is described below with reference to specific examples, and solvents, reagents, starting materials, etc. used in the present invention are all commercially available chemically pure or analytically pure products.
Example 1:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 300mL of 2.5N aqueous NaOH was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (190g, 94.81%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 30g of compound (III), dissolving 1.7g of ferric acetylacetonate in 300mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be less than 5 ℃ under the protection of nitrogen, slowly dropwise adding 65mL of 3.0M methyl magnesium bromide, heating to 65 ℃ after the completion of dropwise addition, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding 200mL of saturated ammonium chloride aqueous solution for quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by 100mL of EA, combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain compound (II) (23.6g, 84.26%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 23.6g of the compound (II) and suspending the compound (II) in 120mL of methanol, adding 9.22g of potassium hydroxide, stirring to dissolve the mixture, reacting at room temperature for 1 hour, monitoring by TLC (PE: EA 1:1), adding 200mL of purified water after the reaction is finished, dropwise adding 2MHCl to adjust the pH value to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a crude compound (I) (10.7g, 97.8%). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (8.86g, 80.99% of two-step yield)
Example 2:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 300mL of 2.5N aqueous NaOH was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (190g, 94.81%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
30g of Compound (III), 2.63g of 1, 2-bis (diphenylphosphino) ethanenickel (Ni) (dppe) Cl2) Dissolving in 300mL tetrahydrofuran, cooling the reaction solution to-5-0 deg.C, controlling temperature under nitrogen protection<Slowly adding 65mL of 3.0M methyl magnesium bromide dropwise at 5 ℃, heating to 65 ℃ after dropping, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, and controlling the temperature<And (3) dropwise adding 200mL of saturated ammonium chloride aqueous solution at 10 ℃ for extraction, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by using 100mL of EA, combining the organic phases, drying by using anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a compound (II) (21.1g, 75.33%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
21.1g of the compound (II) is weighed, suspended in 110mL of methanol, added with 8.24g of potassium hydroxide, stirred to dissolve and clear, reacted at room temperature for 1 hour, monitored by TLC (PE: EA 1:1), after the reaction is finished, added with 200mL of purified water, dropwise added with 2MHCl to adjust the pH to 6-7, extracted 3 times with 100mL of EA, combined with the organic phases, dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain a crude compound (I) (9.2g, 94.09%). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (8.0g, the two-step yield is 81.80%)
Example 3:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 320mL of a 2.5N KOH aqueous solution was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (195.5g, 97.55%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
Weighing 30g of compound (III), dissolving 1.7g of ferric acetylacetonate in 300mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be less than 5 ℃ under the protection of nitrogen, slowly dropwise adding 65mL of 3.0M methyl magnesium bromide, heating to 65 ℃ after the completion of dropwise addition, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding 200mL of saturated ammonium chloride aqueous solution for quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by 100mL of EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain compound (II) (23.6g, 84.26%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 23.6g of compound (II) and dissolving in 100mL of dichloromethane, adding 29.45g of trifluoroacetic acid in an ice-water bath, reacting at room temperature for 6 hours after the addition is finished, monitoring by TLC (PE: EA ═ 1:1), concentrating and pouring into ice water after the reaction is finished, dropwise adding 2N NaOH aqueous solution to adjust the pH to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a crude product (8.4g, 76.81%) of compound (I). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (7.4g, the two-step yield is 67.64%)
Example 4:
step a: synthesis of tert-butyl 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylate
Weighing 18.8g of sodium hydride, dissolving in 240mL of tetrahydrofuran, cooling the reaction liquid to-5-0 ℃, adding 60g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine in batches, stirring for 1 hour under heat preservation, adding 93.8g of di-tert-butyl dicarbonate, stirring for reaction for 2 hours at room temperature after the addition is finished, monitoring by TLC (DCM: MeOH 10:1), cooling after the reaction is finished, controlling the temperature to be less than 15 ℃, dropwise adding 150mL of water for quenching, stirring for 30 minutes, adding 100mL of EA for extraction, combining organic phases, adding 200mL of saturated sodium chloride aqueous solution for washing once, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester (89.3g, 90.1%).
Step b: synthesis of tert-butyl 4-methylpyrrolo [2,3-d ] pyrimidine-7-carboxylate
Weighing 20g of 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester and 1.39g of iron acetylacetonate in 200mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be below 5 ℃ under the protection of nitrogen, slowly adding 52.5mL of 3.0M methyl magnesium bromide dropwise, heating to 65 ℃ after dropping, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be below 10 ℃, adding 200mL of saturated ammonium chloride aqueous solution dropwise, quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase by 100mL of EA, combining the organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to obtain a compound (II) (15.1g, 82.10%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 15.1g of 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester, suspending the mixture in 80mL of methanol, adding 7.25g of potassium hydroxide, stirring to dissolve, reacting at room temperature for 1 hour, monitoring by TLC (PE: EA ═ 1:1), adding 150mL of purified water after the reaction is finished, dropwise adding 2M HCl to adjust the pH to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to obtain a crude compound (I) (9.1g, 86.69%). Heating, refluxing and dissolving the crude product in 45mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 18mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain the compound (I) (7.8g, the two-step yield is 74.29%).
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, keeping the temperature for reaction for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III), wherein the used amino protective agent is selected from 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc)2O), preferably p-methylbenzenesulfonyl chloride (Tos-Cl), di-tert-butyl dicarbonate (Boc)2O); the alkaline agent used is selected from sodium hydroxide, potassium carbonate, sodium hydrogen, preferably sodium hydroxide, potassium hydroxide, sodium hydrogen, more preferably sodium hydroxide.
Step b, dissolving the compound shown in the formula (III) in tetrahydrofuran, adding a catalyst, controlling the temperature, dropwise adding a methyl Grignard reagent, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain the compound shown in the formula (II), wherein the used solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether, preferably tetrahydrofuran, and the used catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl)2) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl2) 1, 2-bis (diphenylphosphino) propaneNickel chloride (Ni (dppp) Cl2) Iron acetylacetonate, nickel acetylacetonate, preferably nickel 1, 2-bis (diphenylphosphino) propane chloride (Ni (dppp) Cl)2) Ferric acetylacetonate, the methylating agent used being selected from the group consisting of 3.0M methylmagnesium bromide/2-methyltetrahydrofuran solution, 3.0M methylmagnesium chloride/tetrahydrofuran solution, 1.0M methylmagnesium bromide/tetrahydrofuran solution, preferably 3.0M methylmagnesium bromide/2-methyltetrahydrofuran solution; the molar ratio of the compound of formula (iii) to the catalyst and methylating agent is 1: 0.01-0.1: 1.2-3, preferably 1: 0.05-0.07: 1.5-2.5.
Suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by using dilute hydrochloric acid, extracting by using ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I), wherein the compound shown in the formula (II) can be obtained by removing a protecting group on an amino group by selecting a proper solvent and a proper catalyst under an alkaline or acidic condition. In alkaline conditions, the solvent used is selected from methanol, tetrahydrofuran, acetonitrile, preferably methanol, and the alkaline agent used is selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, preferably potassium hydroxide. In acidic conditions, the solvent used is selected from dichloromethane, tetrahydrofuran, acetonitrile, water, preferably dichloromethane, and the acidic reagent used is selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid, boron trifluoride diethyl etherate, preferably trifluoroacetic acid. And the agricultural purification process in the step c comprises the steps of mixing, heating and dissolving the compound shown in the formula (I) and tetrahydrofuran, carrying out heat filtration, evaporating the solvent to dryness, adding acetonitrile, heating, refluxing and pulping, wherein the mass ratio of the compound shown in the formula (I) to the tetrahydrofuran to the acetonitrile is 1: 5-10: 1-5, preferably 1: 5-7: 2.
according to the preparation method of the JAK inhibitor key intermediate provided by the embodiment of the invention, the used starting material, tofacitinib hydrochloride and rukutinib phosphate are the same intermediate, and the market price is low and is easy to obtain; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, three wastes are reduced, and the treatment cost of intermediate waste is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, a specific operation, a chemical name, a process control parameter, etc., described in connection with the embodiment or example, is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, particular operations, chemical names, or process control parameters described, etc. may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (10)
1. A preparation method of a JAK inhibitor key intermediate is characterized by comprising the following steps:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reacting for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III);
b, dissolving the compound shown in the formula (III) in an ether solvent, adding a catalyst, dropwise adding a methyl Grignard reagent at a controlled temperature, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain a compound shown in the formula (II);
suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 with hydrochloric acid, extracting with ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I);
the synthesis process is as follows:
2. the method of preparing a key intermediate of a JAK inhibitor according to claim 1, wherein in step a, the amino protecting agent is selected from the group consisting of 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc-Cl)2O) one or more of;
the alkaline reagent is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen.
3. The process for preparing a key intermediate of a JAK inhibitor according to claim 2, wherein in step a, the amino protecting agent is p-toluenesulfonyl chloride (Tos-Cl) or di-tert-butyl dicarbonate (Boc)2O)；
The alkaline reagent is sodium hydroxide.
4. The method for preparing a key intermediate of a JAK inhibitor according to claim 1, wherein in the step b, the etheric solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether;
the catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl2) 1, 2-bis (diphenyl)Phosphine based) ethane Nickel chloride (Ni (dppe) Cl2) 1, 2-bis (diphenylphosphino) propanenickel (Ni) (dppp) Cl2) One or more of iron acetylacetonate and nickel acetylacetonate;
the methyl Grignard reagent is selected from one or more of 3.0M methyl magnesium bromide/2-methyl tetrahydrofuran solution, 3.0M methyl magnesium chloride/tetrahydrofuran solution and 1.0M methyl magnesium bromide/tetrahydrofuran solution;
the molar ratio of the compound of formula (III), the catalyst and the methyl Grignard reagent is 1: 0.01-0.1: 1.2-3.
5. The process for the preparation of a key intermediate of a JAK inhibitor according to claim 4, wherein in step b, the catalyst is selected from the group consisting of 1, 2-bis (diphenylphosphino) propanenickel chloride (ni (dppp) Cl2) One or more of iron acetylacetonate;
the molar ratio of the compound of formula (III), the catalyst and the methylating agent is 1: 0.05-0.07: 1.5-2.5.
6. The method for preparing a key intermediate of a JAK inhibitor according to claim 1, wherein in the step c, the compound of formula (II) is subjected to amino protecting group removal by a solvent and a catalyst under a basic condition to obtain the compound of formula (I), wherein the solvent is selected from one or more of methanol, tetrahydrofuran and acetonitrile, and the basic reagent is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide and potassium carbonate.
7. A process for the preparation of a key intermediate of a JAK inhibitor according to claim 1, wherein in step c, the compound of formula (ii) is deprotected at the amino group by a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and water and a catalyst under acidic conditions to obtain the compound of formula (i), and the acidic reagent is one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid and boron trifluoride etherate.
8. The preparation method of a key intermediate of a JAK inhibitor according to claim 1, wherein in the step c, the purification process comprises mixing the compound of formula (I) with tetrahydrofuran, heating to dissolve, performing heat filtration, evaporating the solvent, adding acetonitrile, heating, refluxing and pulping, wherein the mass ratio of the compound of formula (I) to the tetrahydrofuran and the acetonitrile is 1: 5-10: 1-5.
9. The method for preparing a key intermediate of a JAK inhibitor according to claim 1, wherein in the step a, the molar ratio of the compound represented by formula (iv) to the protective agent is 1: 1.0-1.5;
in the step b, the reaction temperature is 35-80 ℃;
in the step c, the molar ratio of the compound shown in the formula (II) to the potassium hydroxide is 1: 1.0-5.0.
10. The method for preparing a key intermediate of a JAK inhibitor according to claim 9, wherein in the step a, the molar ratio of the compound represented by formula (iv) to the protecting agent is 1: 1.0-1.2;
in the step b, the reaction temperature is 60-70 ℃;
in step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.5-2.5.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110627757.3A CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
| PCT/CN2022/084233 WO2022252789A1 (en) | 2021-06-05 | 2022-03-31 | Method for preparing jak inhibitor key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110627757.3A CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113336761A true CN113336761A (en) | 2021-09-03 |
| CN113336761B CN113336761B (en) | 2022-07-29 |
Family
ID=77474212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110627757.3A Active CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113336761B (en) |
| WO (1) | WO2022252789A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022252789A1 (en) * | 2021-06-05 | 2022-12-08 | 山东莱福科技发展有限公司 | Method for preparing jak inhibitor key intermediate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116789588B (en) * | 2023-06-25 | 2025-06-13 | 上海予君生物科技发展有限公司 | A preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160152624A1 (en) * | 2013-08-09 | 2016-06-02 | Grünenthal GmbH | Novel substituted condensed pyrimidine compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111763209B (en) * | 2015-12-31 | 2021-12-03 | 正大天晴药业集团股份有限公司 | Synthesis process of luccotinib |
| WO2020142557A1 (en) * | 2018-12-31 | 2020-07-09 | Biomea Fusion, Llc | Irreversible inhibitors of menin-mll interaction |
| CN113336761B (en) * | 2021-06-05 | 2022-07-29 | 山东莱福科技发展有限公司 | Preparation method of JAK inhibitor key intermediate |
-
2021
- 2021-06-05 CN CN202110627757.3A patent/CN113336761B/en active Active
-
2022
- 2022-03-31 WO PCT/CN2022/084233 patent/WO2022252789A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160152624A1 (en) * | 2013-08-09 | 2016-06-02 | Grünenthal GmbH | Novel substituted condensed pyrimidine compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022252789A1 (en) * | 2021-06-05 | 2022-12-08 | 山东莱福科技发展有限公司 | Method for preparing jak inhibitor key intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113336761B (en) | 2022-07-29 |
| WO2022252789A1 (en) | 2022-12-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111333656B (en) | Process for preparing BTK inhibitors | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| JP6719527B2 (en) | Method for preparing azoxystrobin intermediate | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN114989103B (en) | Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline | |
| CN109608468B (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
| CN113980024B (en) | Preparation method of adefovir intermediate compound | |
| CN107056681B (en) | A kind of support method replaces the preparation method of cloth intermediate | |
| CN115477653B (en) | Preparation method of trehalfline key intermediate and trehalfline | |
| CN117105931A (en) | Method for preparing pyridopyrimidine compounds and intermediate thereof | |
| CN112920053B (en) | Preparation method of chiral alpha-methyl aromatic ethylamine | |
| CN115947675A (en) | Rasagiline intermediate and preparation method and application thereof | |
| CN110668951A (en) | Synthesis process of selegiline hydrochloride | |
| CN108164423A (en) | A kind of preparation method of naftifine hydrochloride | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN106543050A (en) | Synthetic process of apremilast intermediate | |
| CN107353250B (en) | A kind of synthetic method of lorcaserin | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN103288742A (en) | Preparation method for high-purity ingavirin raw material | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| CN117946013B (en) | Method for synthesizing 5, 6-dihalogen-3-aminopyrazine-2-methyl formate by one-pot method | |
| CN115572262B (en) | Isoquinoline derivative and preparation method thereof | |
| CN107089928A (en) | The synthetic method of N Boc L propargylglycines | |
| CN103130729B (en) | Preparation method of 4-chloro-7-methoxyl quinazoline-6-alchol acetate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhao Hongshuang Inventor after: Zhao Weijian Inventor after: Song Sujun Inventor after: Sang Yunfu Inventor before: Zhao Hongshuang Inventor before: Zhao Weijian Inventor before: Song Sujun Inventor before: Sang Yunfu |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |