CA2971460C - Synthesis of a bruton's tyrosine kinase inhibitor - Google Patents
Synthesis of a bruton's tyrosine kinase inhibitor Download PDFInfo
- Publication number
- CA2971460C CA2971460C CA2971460A CA2971460A CA2971460C CA 2971460 C CA2971460 C CA 2971460C CA 2971460 A CA2971460 A CA 2971460A CA 2971460 A CA2971460 A CA 2971460A CA 2971460 C CA2971460 C CA 2971460C
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- Canada
- Prior art keywords
- formula
- compound
- ibrutinib
- scheme
- acid
- Prior art date
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 9
- 230000015572 biosynthetic process Effects 0.000 title abstract description 7
- 229940125814 BTK kinase inhibitor Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 330
- 238000000034 method Methods 0.000 claims abstract description 254
- 230000008569 process Effects 0.000 claims abstract description 242
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims abstract description 150
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims abstract description 148
- 229960001507 ibrutinib Drugs 0.000 claims abstract description 148
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 105
- 239000002904 solvent Substances 0.000 claims description 76
- 238000002360 preparation method Methods 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 43
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 238000003379 elimination reaction Methods 0.000 claims description 32
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 29
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- 230000010933 acylation Effects 0.000 claims description 16
- 238000005917 acylation reaction Methods 0.000 claims description 16
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- 230000000996 additive effect Effects 0.000 claims description 9
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
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- 125000004432 carbon atom Chemical group C* 0.000 description 8
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 8
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
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|---|---|---|---|
| CA3210320A CA3210320A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| US201562103507P | 2015-01-14 | 2015-01-14 | |
| US62/103,507 | 2015-01-14 | ||
| PCT/US2016/013424 WO2016115356A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA3210320A Division CA3210320A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA2971460A1 CA2971460A1 (en) | 2016-07-21 |
| CA2971460C true CA2971460C (en) | 2023-10-10 |
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| CA3210320A Pending CA3210320A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| CA3210320A Pending CA3210320A1 (en) | 2015-01-14 | 2016-01-14 | Synthesis of a bruton's tyrosine kinase inhibitor |
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| EP (1) | EP3245208A4 (enExample) |
| JP (2) | JP2018502077A (enExample) |
| KR (1) | KR20170102887A (enExample) |
| CN (2) | CN107108640A (enExample) |
| AU (2) | AU2016206693A1 (enExample) |
| BR (1) | BR112017015206B1 (enExample) |
| CA (2) | CA2971460C (enExample) |
| HK (1) | HK1246293A1 (enExample) |
| IL (4) | IL322449A (enExample) |
| MA (1) | MA41350A (enExample) |
| MX (2) | MX366827B (enExample) |
| RU (1) | RU2017128308A (enExample) |
| SG (2) | SG11201705678YA (enExample) |
| WO (1) | WO2016115356A1 (enExample) |
| ZA (1) | ZA201704338B (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016127915A1 (zh) * | 2015-02-12 | 2016-08-18 | 上海度德医药科技有限公司 | 伊布替尼的制备方法 |
| US11883404B2 (en) | 2016-03-04 | 2024-01-30 | Taiho Pharmaceuticals Co., Ltd. | Preparation and composition for treatment of malignant tumors |
| KR102793563B1 (ko) | 2016-03-04 | 2025-04-11 | 다이호야쿠힌고교 가부시키가이샤 | 악성 종양 치료용 제제 및 조성물 |
| CN109206426B (zh) * | 2017-07-06 | 2021-10-08 | 上海复星星泰医药科技有限公司 | 吡唑并嘧啶类化合物的制备方法 |
| JP7166331B2 (ja) | 2017-08-01 | 2022-11-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 中間体化合物及び方法 |
| CN107814804A (zh) * | 2017-10-27 | 2018-03-20 | 广州科锐特生物科技有限公司 | 依鲁替尼的制备方法 |
| EP4353222A1 (en) | 2018-03-19 | 2024-04-17 | Taiho Pharmaceutical Co., Ltd. | Use of sodium alkyl sulfate |
| EP3787751A1 (en) | 2018-05-03 | 2021-03-10 | Juno Therapeutics, Inc. | Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor |
| JP6944496B2 (ja) | 2018-10-22 | 2021-10-06 | ファイザー・インク | ピロロ［２，３−ｄ］ピリミジントシル酸塩、その結晶形態、ならびにその製造方法および中間体 |
| KR102742083B1 (ko) | 2018-11-09 | 2024-12-16 | 다이호야쿠힌고교 가부시키가이샤 | 디메톡시벤젠 화합물의 제조 방법 |
| CN109988175A (zh) * | 2019-04-28 | 2019-07-09 | 梯尔希（南京）药物研发有限公司 | 一种依鲁替尼-d5的制备方法 |
| EP3972977A1 (en) * | 2019-05-21 | 2022-03-30 | Janssen Pharmaceutica NV | Processes and intermediates for preparing a btk inhibitor |
| US12459948B2 (en) | 2019-05-21 | 2025-11-04 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a Btk inhibitor |
| EP4281454B1 (en) | 2021-01-21 | 2025-03-05 | Synthon B.V. | Process for making ibrutinib |
| CN114853662B (zh) * | 2021-02-05 | 2024-01-12 | 四川青木制药有限公司 | 手性肼基哌啶衍生物的制备方法 |
| US20250302954A1 (en) | 2022-05-11 | 2025-10-02 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
| WO2023242384A1 (en) | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550214A (en) * | 1981-01-05 | 1985-10-29 | Polaroid Corporation | Blocked vinyl biphenyl compounds |
| US4874822A (en) * | 1988-04-07 | 1989-10-17 | Minnesota Mining And Manufacturing Company | Process for the acrylamidoacylation of alcohols |
| MXPA06007326A (es) * | 2003-12-23 | 2007-01-26 | Astex Therapeutics Ltd | Derivados de pirazol como moduladores de proteina cinasa. |
| DK2529622T3 (en) * | 2006-09-22 | 2018-05-07 | Pharmacyclics Llc | INHIBITORS OF BRUTON-TYROSINKINASE |
| NZ579911A (en) * | 2007-03-28 | 2012-05-25 | Pharmacyclics Inc | Inhibitors of bruton's tyrosine kinase |
| US7718662B1 (en) * | 2009-10-12 | 2010-05-18 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of bruton's tyrosine kinase |
| EP2882751B1 (en) * | 2012-07-30 | 2018-06-27 | Concert Pharmaceuticals Inc. | Deuterated ibrutinib |
| CN103121999A (zh) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | 一种酪氨酸激酶抑制剂pci-32765的合成方法 |
| US9156847B2 (en) * | 2013-03-15 | 2015-10-13 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
| US8957080B2 (en) * | 2013-04-09 | 2015-02-17 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
| CN103626774B (zh) * | 2013-11-20 | 2015-11-04 | 苏州明锐医药科技有限公司 | 伊鲁替尼的制备方法 |
| CN105471823B (zh) * | 2014-09-03 | 2018-10-26 | 阿里巴巴集团控股有限公司 | 一种敏感信息处理方法、装置、服务器及安全判定系统 |
| EP3248979B1 (en) * | 2015-01-21 | 2021-04-14 | Hefei Institutes of Physical Science, Chinese Academy of Sciences | Novel inhibitor of flt3 kinase and use thereof |
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