CN108997340B - 一种5-溴-7-氮杂吲哚的合成方法 - Google Patents
一种5-溴-7-氮杂吲哚的合成方法 Download PDFInfo
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- CN108997340B CN108997340B CN201811150335.6A CN201811150335A CN108997340B CN 108997340 B CN108997340 B CN 108997340B CN 201811150335 A CN201811150335 A CN 201811150335A CN 108997340 B CN108997340 B CN 108997340B
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- bromo
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- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- -1 (3, 5-dibromopyridine-2-yl) imino Chemical group 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 14
- PLUBDQHYMHSVEI-UHFFFAOYSA-N methyl 2h-pyrimidine-1-carboxylate Chemical compound COC(=O)N1CN=CC=C1 PLUBDQHYMHSVEI-UHFFFAOYSA-N 0.000 claims abstract description 13
- SAQAERNKMHATDZ-UHFFFAOYSA-N 2-bromo-1h-pyrrole Chemical compound BrC1=CC=CN1 SAQAERNKMHATDZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- WVTGRZKTVZZBRK-UHFFFAOYSA-N 2,5-dibromo-1H-pyridin-2-amine Chemical compound BrC1(NC=C(C=C1)Br)N WVTGRZKTVZZBRK-UHFFFAOYSA-N 0.000 claims abstract description 9
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims abstract description 7
- OQEAMMGZUTWZOR-UHFFFAOYSA-N methyl 3,3-diethoxypropanoate Chemical compound CCOC(OCC)CC(=O)OC OQEAMMGZUTWZOR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940017219 methyl propionate Drugs 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 20
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 238000001704 evaporation Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 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
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 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
- 230000003197 catalytic effect Effects 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960001183 venetoclax Drugs 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DHPKTHROZFIEJK-UHFFFAOYSA-N 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound BrC1=CN=C2NC(=O)CC2=C1 DHPKTHROZFIEJK-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
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CN201811150335.6A CN108997340B (zh) | 2018-09-29 | 2018-09-29 | 一种5-溴-7-氮杂吲哚的合成方法 |
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CN108997340A CN108997340A (zh) | 2018-12-14 |
CN108997340B true CN108997340B (zh) | 2020-03-20 |
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Family Cites Families (3)
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GB201012686D0 (en) * | 2010-07-28 | 2010-09-15 | Glaxo Group Ltd | Novel compounds |
CN105622605B (zh) * | 2016-03-01 | 2017-10-13 | 苏州艾缇克药物化学有限公司 | 一种5‑溴‑7‑氮杂吲哚的合成方法 |
CN108084076A (zh) * | 2017-12-21 | 2018-05-29 | 苏州艾缇克药物化学有限公司 | 一种5-溴-7-氮杂吲哚的合成方法 |
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Effective date of registration: 20220505 Address after: 250101 411-40, building 17, industrialization base of small and medium-sized enterprises, biomedical park, 1777 Dazheng Road, high tech Zone, Jinan, Shandong Province Patentee after: Shandong xuanshuo Medical Technology Co.,Ltd. Address before: Room 437, a comprehensive building, 271000, west of Taishan Road, north of Mengguan Road, south of Changjiang Road and east of Jinshuihu Lake, Ningyang County Economic Development Zone, Taian City, Shandong Province Patentee before: SHANDONG SHINNING PHARM CO.,LTD. |
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CP03 | Change of name, title or address | ||
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Address after: Yinfeng International Biological City C9, No. 1177 Chunlan Road, High tech Zone, Jinan City, Shandong Province, 250102 Patentee after: Shandong xuanshuo Medical Technology Co.,Ltd. Country or region after: China Address before: 250101 411-40, building 17, industrialization base of small and medium-sized enterprises, biomedical park, 1777 Dazheng Road, high tech Zone, Jinan, Shandong Province Patentee before: Shandong xuanshuo Medical Technology Co.,Ltd. Country or region before: China |