WO2022127327A1 - Impureté dimère de 1,3-propanediéther de bosutinib et son procédé de préparation - Google Patents
Impureté dimère de 1,3-propanediéther de bosutinib et son procédé de préparation Download PDFInfo
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- WO2022127327A1 WO2022127327A1 PCT/CN2021/123807 CN2021123807W WO2022127327A1 WO 2022127327 A1 WO2022127327 A1 WO 2022127327A1 CN 2021123807 W CN2021123807 W CN 2021123807W WO 2022127327 A1 WO2022127327 A1 WO 2022127327A1
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- reaction
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- bosutinib
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- 239000012535 impurity Substances 0.000 title claims abstract description 24
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 239000002145 L01XE14 - Bosutinib Substances 0.000 title claims abstract description 20
- 229960003736 bosutinib Drugs 0.000 title claims abstract description 18
- 239000000539 dimer Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 23
- 238000003786 synthesis reaction Methods 0.000 abstract description 23
- 238000000034 method Methods 0.000 abstract description 12
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000007664 blowing Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 238000005422 blasting Methods 0.000 description 2
- 229940083476 bosulif Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000004214 philadelphia chromosome Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- -1 2,4-Dichloro-5-methoxyphenyl Chemical group 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- 208000004860 Blast Crisis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Definitions
- step 3 Under the catalysis of triethyl orthoformate, the formula IV obtained in step 2) and formula V are added to generate formula VI, and step 3) reaction formula is as follows:
- step 2 the mass ratio of formula III, ammonium formate and Pd/C (mass fraction 10%) is 1:(1.2 ⁇ 2):(0.15 ⁇ 0.4), the solvent is isopropanol and tetrahydrofuran, and the reaction is stirred at room temperature for 16 ⁇ 17h, filtered, the filtrate was concentrated under reduced pressure to obtain compound formula IV.
- the invention discloses a synthesis process of bosutinib 1,3-propanediether dimer impurities.
- the synthesis process is simple, the purity is high, the raw materials are simple and easy to obtain, the purity of the prepared product can reach more than 99%, and the To provide a qualified impurity reference for the quality control of bosutinib.
- Figure 1 is the liquid phase spectrum of the compound of formula I prepared in Example 1.
- Figure 2 is the MS spectrum of the compound of formula I prepared in Example 1.
- Figure 3 is the hydrogen spectrum of the compound of formula I prepared in Example 1.
- Figure 4 is the carbon spectrum of the compound of formula I prepared in Example 1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une impureté dimère de 1,3-propanediéther de bosutinib et un procédé de synthèse de celle-ci. Le procédé de synthèse est simple, la pureté est élevée, des matières premières sont simples et faciles à obtenir, la pureté d'un produit fini préparé peut atteindre 99 % ou plus, et une substance de référence d'impureté qualifiée peut être fournie pour la régulation de qualité du bosutinib.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011484510.2A CN112552236B (zh) | 2020-12-16 | 2020-12-16 | 一种博舒替尼1,3-丙二醚类二聚体杂质及其制备方法 |
| CN202011484510.2 | 2020-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022127327A1 true WO2022127327A1 (fr) | 2022-06-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/123807 WO2022127327A1 (fr) | 2020-12-16 | 2021-10-14 | Impureté dimère de 1,3-propanediéther de bosutinib et son procédé de préparation |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112552236B (fr) |
| WO (1) | WO2022127327A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552236B (zh) * | 2020-12-16 | 2022-02-22 | 南京华威医药科技集团有限公司 | 一种博舒替尼1,3-丙二醚类二聚体杂质及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019186429A1 (fr) * | 2018-03-30 | 2019-10-03 | Sun Pharmaceutical Industries Limited | Procédé de préparation de bosutinib |
| CN112552236A (zh) * | 2020-12-16 | 2021-03-26 | 南京华威医药科技集团有限公司 | 一种博舒替尼1,3-丙二醚类二聚体杂质及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105085398A (zh) * | 2015-09-06 | 2015-11-25 | 合肥华方医药科技有限公司 | 一种博舒替尼异构体杂质的制备方法 |
| CN110372539A (zh) * | 2019-07-15 | 2019-10-25 | 杭州中美华东制药有限公司 | 一种伯舒替尼化合物及其制备方法 |
-
2020
- 2020-12-16 CN CN202011484510.2A patent/CN112552236B/zh active Active
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- 2021-10-14 WO PCT/CN2021/123807 patent/WO2022127327A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019186429A1 (fr) * | 2018-03-30 | 2019-10-03 | Sun Pharmaceutical Industries Limited | Procédé de préparation de bosutinib |
| CN112552236A (zh) * | 2020-12-16 | 2021-03-26 | 南京华威医药科技集团有限公司 | 一种博舒替尼1,3-丙二醚类二聚体杂质及其制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| CHEN HONG , WANG YINGLI , LIU TONGBIN: "Synthesis of Bosutinib", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 44, no. 11, 10 November 2013 (2013-11-10), pages 1086 - 1088, XP055944392, ISSN: 1001-8255, DOI: 10.16522/j.cnki.cjph.2013.11.022 * |
| GREGORY J. WITHBROE, CHRIS SEADEEK, KEVIN P. GIRARD, STEVEN M. GUINNESS, BRIAN C. VANDERPLAS, RAJAPPA VAIDYANATHAN: "A Robust, Streamlined Approach to Bosutinib Monohydrate", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 17, no. 3, 15 March 2013 (2013-03-15), pages 500 - 504, XP055133427, ISSN: 10836160, DOI: 10.1021/op300087r * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112552236B (zh) | 2022-02-22 |
| CN112552236A (zh) | 2021-03-26 |
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