CN117903138A - Preparation method and application of larotinib - Google Patents
Preparation method and application of larotinib Download PDFInfo
- Publication number
- CN117903138A CN117903138A CN202211232027.4A CN202211232027A CN117903138A CN 117903138 A CN117903138 A CN 117903138A CN 202211232027 A CN202211232027 A CN 202211232027A CN 117903138 A CN117903138 A CN 117903138A
- Authority
- CN
- China
- Prior art keywords
- compound
- hydroxide
- present
- preferred
- preparation
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229940126214 compound 3 Drugs 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- CWQSNJSRIUPVNR-UHFFFAOYSA-M [OH-].[Fr+] Chemical compound [OH-].[Fr+] CWQSNJSRIUPVNR-UHFFFAOYSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000011698 potassium fluoride Substances 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-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
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- RTRODVUDEWDGEQ-UHFFFAOYSA-N bis(trichloromethyl) carbonate;trichloromethyl hydrogen carbonate Chemical compound OC(=O)OC(Cl)(Cl)Cl.ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl RTRODVUDEWDGEQ-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000007864 suspending Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000037843 metastatic solid tumor Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- -1 p-nitrophenoxy Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of drug synthesis, in particular to a preparation method and application of larotinib. The preparation method of the larotinib or the pharmaceutically acceptable salt thereof provided by the invention is characterized in that the compound 3 and the compound 4 react under the action of alkali. The preparation method of the larrotib has the advantages of high yield, controllable reaction time, mild reaction conditions, no pollution, reduced production cost, improved production efficiency, more friendly environment and operators, simple and convenient operation, stable and controllable process, suitability for large-scale industrial production and the like.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method and application of larotinib.
Background
Larotinib was approved by the FDA in 2018 for use in the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors of NTRK gene fusion.
CN107987082a discloses a preparation method of larotinib, the specific route is as follows:
In the route, p-nitrophenoxy in the compound 5 is a genotoxic warning structure, and the genotoxic impurities possibly existing in subsequent products need to be controlled.
CN113307812a discloses a preparation method of larotinib, the route is as follows:
in the last step of the route, pyrrolidone is reduced into chiral hydroxyl through chiral reduction, a chiral reducing agent or a chiral inducer is needed, and the chiral purity of the prepared product is not easy to meet the medicinal requirement.
In view of the above, the invention provides a preparation method of larotinib, which improves the preparation efficiency of the larotinib, improves the yield, improves the product quality and is more environment-friendly.
Disclosure of Invention
The invention aims to provide a preparation method of larotinib, which comprises the following steps:
In a preferred embodiment of the present invention, in step four, the molar ratio of compound 3 to compound 2 is 1:1-5.
In a preferred embodiment of the present invention, in step four, the molar ratio of compound 3 to compound 2 is 1:1-2.
In a preferred embodiment of the present invention, a base is added in the third step, and the base is selected from an organic base or an inorganic base.
In a preferred embodiment of the present invention, the organic base is selected from any one or a combination of triethylamine, pyridine, N-lutidine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N-Diisopropylethylamine (DIPEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
In a preferred embodiment of the present invention, the inorganic base is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, sodium phosphate, or a combination thereof.
In a preferred embodiment of the present invention, in step four, the molar ratio of compound 3 to organic base is 1:0.5-3, preferably 1:0.8-1.5.
In a preferred embodiment of the present invention, the solvent in the fourth step is selected from any one of acetonitrile, tetrahydrofuran, 1, 4-dioxane, acetone, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), n.n-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, isopropanol, or a combination thereof.
In a preferred embodiment of the present invention, the reaction temperature in step four is 20-100 ℃.
In a preferred embodiment of the present invention, the reaction temperature in step four is 30-80 ℃.
In a preferred embodiment of the present invention, the larotinib produced in step four may be isolated or not isolated.
In the preferred technical scheme of the invention, the larrotide prepared in the step four is further refined after being separated.
In a preferred embodiment of the present invention, the refining is selected from any one of washing, suspending, beating, and recrystallization, or a combination thereof.
In a preferred embodiment of the present invention, the prepared larotinib is dried.
In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.
In a preferred embodiment of the present invention, the drying temperature is 20 to 80 ℃, preferably 30 to 70 ℃, more preferably 40 to 60 ℃.
In a preferred technical scheme of the invention, the larotinib prepared in the step four can be further prepared into pharmaceutically acceptable salts thereof.
In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from any one of sulfate, tosylate, mesylate, sulfonate, benzoate, hydrochloride, hydrobromide, phosphate, nitrate, tartrate, fumarate, maleate, citrate, formate, acetate, succinate, malonate, malate, cinnamate, or a combination thereof.
It is another object of the present invention to provide a high purity larotinib or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the high purity larrotib or a pharmaceutically acceptable salt thereof has a purity of not less than 95.0%.
In a preferred embodiment of the present invention, the high purity larrotib or a pharmaceutically acceptable salt thereof has a purity of not less than 98.0%.
In a preferred embodiment of the present invention, the high purity larrotib or a pharmaceutically acceptable salt thereof has a purity of not less than 99.0%.
In a preferred embodiment of the present invention, the high purity larrotib or a pharmaceutically acceptable salt thereof has a purity of not less than 99.5%.
In a preferred embodiment of the present invention, the high purity larrotib or a pharmaceutically acceptable salt thereof has a purity of not less than 99.9%.
It is another object of the present invention to provide the use of said high purity lartinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain, cancer, inflammation, neurodegenerative diseases or trypanosoma cruzi infection.
It is another object of the present invention to provide a compound 3, said compound 3 having the structure,
The invention also provides a preparation method of the compound 3, which is to react the compound 4 with N-hydroxysuccinimide.
In a preferred embodiment of the invention, the molar ratio of compound 4 to N-hydroxysuccinimide is 1:1-5.
In a preferred embodiment of the invention, the molar ratio of compound 4 to N-hydroxysuccinimide is 1:1-3.
In a preferred embodiment of the present invention, the condensing agent is added in step three.
In a preferred embodiment of the present invention, the condensing agent is selected from any one of N, N' -disuccinimidyl carbonate (DSC), carbonyl Diimidazole (CDI), isobutyl chloroformate, triphosgene, or a combination thereof.
In a preferred embodiment of the present invention, a base is added in the third step, and the base is selected from an organic base or an inorganic base.
In a preferred embodiment of the present invention, the organic base is selected from any one or a combination of triethylamine, pyridine, N-lutidine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N-Diisopropylethylamine (DIPEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
In a preferred embodiment of the present invention, the inorganic base is selected from any one of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, sodium phosphate, or a combination thereof.
In a preferred embodiment of the present invention, the solvent in the third step is an organic solvent.
In a preferred embodiment of the present invention, the organic solvent is selected from any one of acetonitrile, tetrahydrofuran, 1, 4-dioxane, acetone, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), n.n-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, isopropanol, or a combination thereof.
In a preferred embodiment of the present invention, the molar ratio of the compound 4 to the condensing agent is 1:1-4, preferably 1:1-2.
In a preferred embodiment of the present invention, the molar ratio of the compound 4 to the base is 1:0.5-5.
In a preferred embodiment of the present invention, the molar ratio of the compound 4 to the base is 1:1-3.
In a preferred embodiment of the present invention, the reaction temperature in the third step is 0 to 60 ℃, preferably 20 to 40 ℃.
In a preferred embodiment of the present invention, the compound 3 obtained is purified.
In a preferred embodiment of the present invention, the refining is selected from any one of washing, suspending, beating, and recrystallizing, or a combination thereof.
In a preferred embodiment of the present invention, the compound 3 obtained is dried.
In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.
In a preferred embodiment of the present invention, the drying temperature is 20 to 80 ℃, preferably 30 to 70 ℃, more preferably 40 to 60 ℃.
Another object of the present invention is to provide compound 3 in high purity.
In a preferred embodiment of the present invention, the purity of the high purity compound 3 is not less than 95.0%.
In a preferred embodiment of the present invention, the purity of the high purity compound 3 is not less than 98.0%.
In a preferred embodiment of the present invention, the purity of the high purity compound 3 is not less than 99.0%.
In a preferred embodiment of the present invention, the purity of the high purity compound 3 is not less than 99.5%.
In a preferred embodiment of the present invention, the purity of the high purity compound 3 is not less than 99.9%.
It is another object of the present invention to provide the use of compound 3 for the preparation of larotinib or a pharmaceutically acceptable salt thereof.
It will be appreciated by those skilled in the art that compound 4 may be obtained by methods known in the art.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. The preparation method of the larotinib provided by the invention is simple and convenient, raw materials are easy to obtain, a high-feasibility choice is provided for the preparation of the larotinib, and a guarantee is provided for patients to obtain medicines with high quality and low cost.
2. The preparation method of the larrotib has the advantages of high yield, controllable reaction time, mild reaction conditions, no pollution, reduced production cost, improved production efficiency and more friendly environment and operators.
3. The preparation method has the advantages of simple operation, stable and controllable process, suitability for large-scale industrial production and the like.
Detailed Description
The invention is illustrated by the following examples, which are given solely for the purpose of further illustration and are not intended to limit the scope of the invention. Some insubstantial modifications and adaptations of the invention by others are within the scope of the invention.
Compound 4 of the present invention can be prepared by the method disclosed in CN107428760A, CN109354578A, CN109414442A, CN110049987A, CN102264736A, etc.
EXAMPLE 1 preparation of Larotigotine according to the invention
Compound 3 (1 eq) and compound 2 (1.1 eq) were dissolved in tetrahydrofuran, triethylamine (1.1 eq) was added for reaction at 70 ℃, TLC monitored that compound 3 was completely reacted, solvent was evaporated, ethyl acetate/petroleum ether was recrystallized and dried to give a larotinib concentrate as a pale yellow powder with a yield of 94.4% and an HPLC purity of 99.96%.
EXAMPLE 2 preparation of Larotigotine according to the present invention
Compound 3 (1 eq) and compound 2 (1.05 eq) were dissolved in acetonitrile, N-diisopropylethylamine (1.2 eq) was added for reaction at 60 ℃, TLC monitored until compound 3 was completely reacted, methyl tert-butyl ether was added, stirred for crystallization, filtered and dried to give larotinib as a pale yellow powder in 95.1% yield.
EXAMPLE 3 preparation of Compound 3 of the present invention
(1) Into a three-necked flask, 30mL of tetrahydrofuran, compound 4 (5.Og, 15.9mmol,1.0 eq), N-hydroxysuccinimide (2.2 g,19mmol,1.2 eq) and triethylamine (4.0 g,39.75mmol,2.5 eq) were put into the flask, magnetically stirred, and the ice water bath was cooled to 0-10 ℃;
(2) Trichloromethyl carbonate (triphosgene) (5.0 g,16.7mmol,1.05 eq) was dissolved in tetrahydrofuran (10 mL) and the system was slowly added dropwise with an internal temperature of 0-10 ℃. After the addition is finished, heating to 20-40 ℃, and reacting for 2h in a nitrogen atmosphere;
(3) 40mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2 to 3 hours, whereby crystals were gradually precipitated in the system. Continuously dropwise adding 40mL of purified water into the system, stirring at room temperature for 2-3h, filtering, collecting crystals, washing with a mixed solvent of water (10 mL) and tetrahydrofuran (5 mL), and drying at 45-55 ℃ under reduced pressure (-0.08 to-0.10 MPa) to obtain the compound 3, wherein the yield is 93.7%, and the HPLC purity is 99.95%.
EXAMPLE 4 preparation of Compound 3 of the present invention
(1) 30ML of acetonitrile, compound 4 (5.Og, 15.9mmol,1.0 eq), N-hydroxysuccinimide (2.0 g,17.5mmol,1.1 eq) and sodium carbonate (3.4 g,31.8mmol,2.0 eq) were put into a three-necked flask, magnetically stirred, and the ice water bath was cooled to 0-10 ℃;
(2) Carbonyl diimidazole (2.8 g,17.5mmol,1.1 eq) was dissolved in acetonitrile (10 mL) and the system was slowly added dropwise, maintaining an internal temperature of 0-10 ℃. After the addition is finished, heating to 30 ℃, and reacting for 2 hours in a nitrogen atmosphere;
(3) 30mL of purified water was slowly added dropwise to the system, and the mixture was stirred at room temperature for 2 hours, whereby crystals were gradually precipitated in the system. Continuously dropwise adding 40mL of purified water into the system, stirring at room temperature for 2-3h, filtering, collecting crystals, washing with acetonitrile, and drying at 60 ℃ to obtain the compound 3, wherein the yield is 91.5%, and the HPLC purity is 99.96%.
EXAMPLE 5 preparation of Larotigotine sulfate salt of the present invention
At room temperature, larotigotine (5.0 g) is dissolved in tetrahydrofuran (100 ml), tetrahydrofuran solution (10 ml) of sulfuric acid (0.63 ml) is added dropwise under stirring, stirring is continued for 30min after the dripping is finished, concentration and ethanol/water recrystallization are carried out, thus obtaining Larotigotine sulfate 6.1g, the yield is 98.3%, and the HPLC purity is 99.99%;
EXAMPLE 6 preparation of Larotigotine sulphate
(1) Tetrahydrofuran (30 mL), compound 4 (5.Og, 15.9 mmol), N-hydroxysuccinimide (2.2 g,19 mmol) and triethylamine (5.6 g,55.7 mmol) were put into a three-necked flask, magnetically stirred, and the ice water bath was cooled to 0-10 ℃;
(2) Trichloromethyl carbonate (triphosgene) (5.0 g,17 mmol) was dissolved in tetrahydrofuran (10 mL), and the system was slowly added dropwise, maintaining an internal temperature of 0-10 ℃. After the addition is finished, heating to 20-40 ℃, and reacting in a nitrogen atmosphere, wherein TLC monitors that the compound 4 is completely reacted;
(3) Compound 2 (1.7 g,19 mmol) was dissolved in tetrahydrofuran (10 ml), added dropwise to the reaction system under stirring at room temperature, and after the addition, the temperature was raised to 60 ℃ until TLC monitored that compound 3 was completely reacted, and the temperature was lowered to room temperature;
(4) Adding sulfuric acid (0.9 ml) tetrahydrofuran solution (10 ml) dropwise under stirring, continuing stirring for 30min after the dropwise addition, concentrating, recrystallizing with ethanol/water to obtain Larotigotine sulfate 6.9g, total yield 82.4%, and HPLC purity 99.97%; hydrogen spectrum ：1H NMR(400MHz,D2O)(ppm):2.18-2.33(m,7H),2.68-2.70(m,1H),3.43-3.74(m,2H),3.94-4.25(m,2H),4.64-4.71(m,1H),5.46-5.62(m,1H),6.25-6.80(m,1H),7.03(m,1H),7.17-7.20(m,1H),7.25-7.31(m,1H),7.90-8.10(m,1H),8.40-8.65(m,1H).
Claims (10)
1. A method of preparing larotinib, the method comprising the steps of:
2. the process according to claim 1, wherein in step four the molar ratio of compound 3 to compound 2 is from 1:1 to 5, preferably from 1:1 to 2.
3. The method of claim 1, wherein a base is added in step three, wherein the base is selected from an organic base or an inorganic base.
4. The method of claim 3, wherein the organic base is selected from any one of triethylamine, pyridine, N-lutidine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine, N-methylpiperidine, trimethylamine, tripropylamine, N-Diisopropylethylamine (DIPEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), or a combination thereof.
5. The method of claim 3, wherein the inorganic base is selected from any one or a combination of potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium methoxide, sodium ethoxide, potassium fluoride/aluminum oxide, potassium phosphate, sodium phosphate.
6. A process according to claim 3, in step four, the molar ratio of compound 3 to organic base is from 1:0.5 to 3, preferably from 1:0.8 to 1.5.
7. The method of claim 1, wherein the solvent in step four is selected from any one of acetonitrile, tetrahydrofuran, 1, 4-dioxane, acetone, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), n.n-dimethylacetamide (DMAc), N-methylpyrrolidone, benzene, toluene, xylene, methanol, ethanol, isopropanol, or a combination thereof.
8. The process according to claim 1, wherein the reaction temperature in step four is 20-100 ℃, preferably 30-80 ℃.
9. A compound 3, said compound 3 having the structure,
10. The preparation method of the compound 3 comprises the step of reacting the compound 4 with N-hydroxysuccinimide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211232027.4A CN117903138A (en) | 2022-10-10 | 2022-10-10 | Preparation method and application of larotinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211232027.4A CN117903138A (en) | 2022-10-10 | 2022-10-10 | Preparation method and application of larotinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117903138A true CN117903138A (en) | 2024-04-19 |
Family
ID=90682468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211232027.4A Pending CN117903138A (en) | 2022-10-10 | 2022-10-10 | Preparation method and application of larotinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117903138A (en) |
-
2022
- 2022-10-10 CN CN202211232027.4A patent/CN117903138A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2208265T3 (en) | TELMISARTAN POLYMORPHES, PROCEDURE FOR PREPARATION AND USE FOR THE PREPARATION OF A MEDICINAL PRODUCT. | |
| US20220024967A1 (en) | Salts and crystal forms of gaba-a positive allosteric modulator | |
| EP3248983A1 (en) | Crystal form a of obeticholic acid and preparation method therefor | |
| CN112898220B (en) | Preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and intermediate thereof | |
| CN111630049B (en) | Process for preparing 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole and bisulphates thereof | |
| EP2033960A2 (en) | Linezolid crystalline hydrate form and linezolid salts | |
| CN108912109A (en) | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof | |
| CN111606827B (en) | Method for preparing chiral amine intermediate of edoxaban | |
| US11702393B2 (en) | Synthesis of a monoacylglycerol lipase inhibitor | |
| SK14672001A3 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| EP3527556B1 (en) | Method for preparing deuterated imidazole diketone compound | |
| US7776852B2 (en) | Process for producing highly pure midazolam and salts thereof | |
| CN117903138A (en) | Preparation method and application of larotinib | |
| CN114394957B (en) | Preparation method of MET inhibitor terpotinib hydrochloride | |
| CN111732586B (en) | Crystal form of alkynyl-containing compound salt, preparation method and application | |
| WO2022153187A1 (en) | Methods for producing of lipids | |
| US11434226B2 (en) | Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof | |
| WO2000029383A1 (en) | Crystalline forms of 3-(2,4-dichlorobenzyl)-2-methyl-n-(pentylsulfonyl)-3h-benzimidazole-5-carboxamide | |
| CN108586450A (en) | A kind of recrystallization purifying method of choline m receptor anticaking agent | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN115557892B (en) | Synthesis method of bupivacaine impurity serving as local anesthetic | |
| CN111196782B (en) | Dihydronaphthyridine compounds, preparation method and application thereof | |
| CN115716817B (en) | Preparation method of 6, 8-cyclotristhioctic acid | |
| CN113307810B (en) | Synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile | |
| CN113754643A (en) | Refining method of benzopyran derivative, crystal form thereof and preparation method of crystal form |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |