WO2017039425A1 - A method for preparation of ibrutinib precursor - Google Patents
A method for preparation of ibrutinib precursor Download PDFInfo
- Publication number
- WO2017039425A1 WO2017039425A1 PCT/LV2015/000009 LV2015000009W WO2017039425A1 WO 2017039425 A1 WO2017039425 A1 WO 2017039425A1 LV 2015000009 W LV2015000009 W LV 2015000009W WO 2017039425 A1 WO2017039425 A1 WO 2017039425A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- boc
- ibrutinib
- cbz
- arylation
- Prior art date
Links
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Definitions
- the present invention relates to a method for the preparation of pharmaceutically active compounds.
- the present invention relates to a method for the preparation of precursor of anti-cancer drug ibrutinib.
- Ibrutinib is the compound of formula (I) [1] - anti-cancer drug used to treat malignant B-lymphoproliferative disorders.
- Ibrutinib's synthesis scheme involves an intermediate (precursor) of formula (II), that contains main fragments of ibrutinib's structure: pyrazolo[3,4-i ]pyrimidine bicyclic system with 4-phenoxyphenyl group at the position 3, as well as N-unsubstituted piperidin-3-yl substituent at the nitrogen atom N-l of the pyrazolo[3,4- ⁇ pyrimidine heterocycle.
- Conversion of the precursor (II) to ibrutinib (I) is performed by trivial methods, using acylation of the piperidine NH group by acrylic acid in the presence of condensing agents or by acryloyl chloride.
- Precursor (II) is obtained from N(l')-protected intermediate (3) by removal of the protecting group (Pg) by known methods.
- the starting compound (6) is obtained from 4-phenoxybenzoic acid converting it into the corresponding acyl chloride following by condensation with malononitrile and methylation (e. g. by dimethyl sulfate).
- methylation e. g. by dimethyl sulfate.
- synthesis of the optically active (piperidin-3-yl)hydrazine (7) in the patent [4] is not disclosed.
- the known methods of ibrutinib's precursor (II) synthesis are characterized by complicated procedures and by use of some reagents that are not versatile for large-scale synthesis.
- Pg 2 H, Boc, Cbz, Bn, etc.
- the described method allows to obtain the ibrutinib's precursor (II) with good yields by direct C-arylation of protected derivatives (III) of known [6] l-(piperidin-3-yl)pyrazolo[3,4- ⁇ /]pyrimidin-4-amine bearing protecting group at the piperidine nitrogen atom and, preferably, also at the 4-NH 2 group.
- Performing synthesis of the ibrutinib's precursor (II) by the method described in this invention eliminates work with unstable and expensive arylboronic acid derivatives and toxic phosphine ligands.
- the most preferable ligands for direct C-arylation are nitrogen-containing heterocycles, e. g.
- the described method can be performed in different solvents, e. g. toluene, xylene, dimethylacetamide, diglyme, dioxane, 1,2-dimethoxyethane or in a mixture of solvents.
- Different complex-forming compounds can be used as the catalyst, more preferable - nitrogen-containing heterocycles such as 1,10-phenanthroline, derivatives of 2,2'-bipyridine, etc.
- As the base alkali metal carbonates, phosphates, alkoxides can be used, e. g. Cs 2 C0 3 , t- BuOK, etc.
- the reaction temperature depending on the solvent used, may vary from 80 to 180°C; the reaction time is from 4 to 48 h.
- the invented method may be realized in pharmaceutical industry using the corresponding equipment and conditions.
- the method allows to obtain the product, which can be purified to pharmaceutical quality (>99%) by routine procedures.
- the process is characterized by utilizable waste and easily separable impurities in the target product.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2987708A CA2987708C (en) | 2015-08-31 | 2015-11-13 | A method for preparation of ibrutinib precursor |
GB1800657.7A GB2556535B (en) | 2015-08-31 | 2015-11-13 | A method for preparation of ibrutinib precursor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LVP-15-98 | 2015-08-31 | ||
LVP-15-98A LV15201B (en) | 2015-08-31 | 2015-08-31 | The method for the preparation of ibrutinib intermediate |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017039425A1 true WO2017039425A1 (en) | 2017-03-09 |
Family
ID=54754721
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/LV2015/000009 WO2017039425A1 (en) | 2015-08-31 | 2015-11-13 | A method for preparation of ibrutinib precursor |
Country Status (4)
Country | Link |
---|---|
CA (1) | CA2987708C (en) |
GB (1) | GB2556535B (en) |
LV (1) | LV15201B (en) |
WO (1) | WO2017039425A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107674079A (en) * | 2017-09-27 | 2018-02-09 | 黑龙江珍宝岛药业股份有限公司 | Her a kind of cloth replaces the synthetic method of Buddhist nun |
CN113200986A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib intermediate |
WO2023045411A1 (en) * | 2021-09-26 | 2023-03-30 | 上海贵之言医药科技有限公司 | Pyrazolopyrimidine ester compound |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080007621A1 (en) | 2006-07-06 | 2008-01-10 | Sbc Knowledge Ventures, Lp | System and method of controlling access to an entrance |
WO2008121742A2 (en) | 2007-03-28 | 2008-10-09 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2009062118A2 (en) | 2007-11-07 | 2009-05-14 | Foldrx Pharmaceuticals, Inc. | Modulation of protein trafficking |
WO2012058645A1 (en) | 2010-10-29 | 2012-05-03 | Biogen Idec Ma Inc. | Heterocyclic tyrosine kinase inhibitors |
WO2012158795A1 (en) | 2011-05-17 | 2012-11-22 | Principia Biopharma Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
WO2014139970A1 (en) | 2013-03-15 | 2014-09-18 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
-
2015
- 2015-08-31 LV LVP-15-98A patent/LV15201B/en unknown
- 2015-11-13 GB GB1800657.7A patent/GB2556535B/en active Active
- 2015-11-13 WO PCT/LV2015/000009 patent/WO2017039425A1/en active Application Filing
- 2015-11-13 CA CA2987708A patent/CA2987708C/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080007621A1 (en) | 2006-07-06 | 2008-01-10 | Sbc Knowledge Ventures, Lp | System and method of controlling access to an entrance |
WO2008121742A2 (en) | 2007-03-28 | 2008-10-09 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
WO2009062118A2 (en) | 2007-11-07 | 2009-05-14 | Foldrx Pharmaceuticals, Inc. | Modulation of protein trafficking |
WO2012058645A1 (en) | 2010-10-29 | 2012-05-03 | Biogen Idec Ma Inc. | Heterocyclic tyrosine kinase inhibitors |
WO2012158795A1 (en) | 2011-05-17 | 2012-11-22 | Principia Biopharma Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
WO2014139970A1 (en) | 2013-03-15 | 2014-09-18 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
Non-Patent Citations (8)
Title |
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A. BEN-YAHIA; M. NAAS; S. EL KAZZOULI; E. M. ESSASSI; G. GUILLAUMET, EUR. J. ORG. CHEM., 2012, pages 7075 |
A. UNSINN; P. KNOCHEL, CHEM. COMMUN., vol. 48, 2012, pages 2680 |
ALI BEN-YAHIA ET AL: "Direct C-3-Arylations of 1 H -Indazoles", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2012, no. 36, 7 December 2012 (2012-12-07), DE, pages 7075 - 7081, XP055239226, ISSN: 1434-193X, DOI: 10.1002/ejoc.201200860 * |
K. M. ENGLE; J.-Q. YU, J. ORG. CHEM., vol. 78, 2013, pages 8927 |
M. NAAS; S. EL KAZZOULI; E. M. ESSASSI; M. BOUSMINA; G. GUILLAUMET, J. ORG. CHEM., vol. 79, 2014, pages 7286 |
M. YE; A. J. F. EDMUNDS; J. A. MORRIS; D. SALE; Y. ZHANG; J.-Q. YU, CHEM. SCI., vol. 4, 2013, pages 2374 |
M. YE; G.-L. GAO; A. J. F. EDMUNDS; P. A. WORTHINGTON; J. A. MORRIS; J. . YU, J. AM. CHEM. SOC., vol. 133, 2011, pages 19090 |
T. S. KAUFMAN, TETRAHEDRON LETT., vol. 37, 1996, pages 5329 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107674079A (en) * | 2017-09-27 | 2018-02-09 | 黑龙江珍宝岛药业股份有限公司 | Her a kind of cloth replaces the synthetic method of Buddhist nun |
CN107674079B (en) * | 2017-09-27 | 2019-12-13 | 黑龙江珍宝岛药业股份有限公司 | Synthesis method of ibrutinib |
CN113200986A (en) * | 2021-04-29 | 2021-08-03 | 湖南华腾制药有限公司 | Preparation method of ibrutinib intermediate |
WO2023045411A1 (en) * | 2021-09-26 | 2023-03-30 | 上海贵之言医药科技有限公司 | Pyrazolopyrimidine ester compound |
Also Published As
Publication number | Publication date |
---|---|
LV15201A (en) | 2017-03-20 |
CA2987708A1 (en) | 2017-03-09 |
GB201800657D0 (en) | 2018-02-28 |
LV15201B (en) | 2017-07-20 |
GB2556535A (en) | 2018-05-30 |
GB2556535B (en) | 2020-10-14 |
CA2987708C (en) | 2022-08-02 |
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