- Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Congeners
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Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable
- Elleraas, Jeff,Ewanicki, Jason,Johnson, Ted W.,Sach, Neal W.,Collins, Michael R.,Richardson, Paul F.
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Read Online
- Preparation method of lorlatinib
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The invention relates to a preparation method of lorlatinib. Specifically, the invention provides a preparation method of lorlatinib. According to the method, a compound 1-methyl-3-((methyl-t-butyloxycarboryl-amino) methyl)-1H-pyrazole-4-bromine-5-nitrile as shown in a formula VII and a compound 2-(t-butyloxycarboryl-amino)-3-hydroxy-5-bromopyridine as shown in a formula VI are used as raw materials and subjected to a coupling reaction, a Williamson reaction, a hydrolysis reaction, an acidolysis reaction and a condensation reaction, so as to prepare lorlatinib. The preparation method of the lorlatinib has the advantages of being short in synthesis route, simple and convenient to operate, mild in reaction condition, high in yield and the like, and is suitable for industrial production of the lorlatinib.
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- Preparation method of anti-tumor drug Lorlatinib
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The invention relates to a preparation method of an anti-tumor drug Lorlatinib, which comprises the steps of (1) coupling tert-butyl (5-bromo-3-((trimethylsilane) oxy) pyridine-2-yl) carbamate and 1, 3-dimethyl-1H-pyrazole-5-nitrile to obtain a first intermediate; (2) brominating the first intermediate with NBS to obtain a second intermediate; (3) enabling the second intermediate and (R)-1-(5-fluoro-2-N-methylformamide phenyl)-ethanol to be subjected to a one-pot method under the alkaline condition to obtain and a third intermediate; and (4) removing a protecting group from the third intermediate under an acidic condition to obtain the final product Lorlatinib. The method has the advantages of simple and easily available raw materials, short steps, high total yield, relatively convenient operation, low cost, suitability for industrial production and the like.
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- Preparation method of anticancer drug
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The invention provides a preparation method of an anticancer drug lapatinib, which is characterized by comprising the following steps: dissolving a compound of formula A in an organic solvent, addinga condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 DEG C, keeping the temperature to react for 2-3 hours, cooling to room temperature after the reaction is completed through TLC detection, and adding an ammonium chloride solution to quench the reaction, performing extraction and separation to obtain lorlatinib; according to the invention, TBTU is used as a condensing agent, DBU is used as an alkali promoter, and the TBTU and the DBU are combined for use, so compared with the prior art, the use amounts of the condensing agent and the alkali promoter used in the invention are obviously reduced, the reaction time is shorter, but the reaction yield is much higher than that in the prior art, and the method is very suitable for industrial production.
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Paragraph 0028-0047
(2021/03/13)
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- Application of TBTU in preparation of anti-cancer drug
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The invention provides application of TBTU in preparation of an anticancer drug Lorlatinib, which is characterized by comprising the following steps: dissolving a compound of formula A in an organic solvent, adding a condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 DEG C, keeping the temperature to react for 23 hours, cooling to room temperature after the reaction is detected by TLC, and adding an ammonium chloride solution to quench the reaction, and performing extraction and separation to obtain the Lorlatinib. According to the invention, theTBTU is used as the condensing agent, DBU is used as the alkali promoter, and the TBTU and the DBU are combined for use, so compared with the prior art, the use amounts of the condensing agent and thealkali promoter used in the invention are obviously reduced, the reaction time is shorter, but the reaction yield is much higher than that in the prior art, and the method is very suitable for industrial production.
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Paragraph 0028-0048
(2021/03/11)
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- CRYSTALLINE LORLATINIB : FUMARIC ACID AND SOLID STATE FORM THEREOF
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The present disclosure relates to crystalline Lorlatinib : Fumaric acid, solid state forms thereof, processes for preparation thereof, pharmaceutical compositions and methods of use thereof.
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Paragraph 00114
(2021/02/12)
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- Benzoxadiazepine tetradecene derivative and application thereof
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The invention discloses a benzoxadiazepine tetradecene derivative and application thereof, belonging to the field of medicines. The benzoxadiazepine tetradecene derivative with a structure as shown ina general formula (I) has excellent anaplastic lymphoma enzyme (ALK) inhibition activity and excellent pharmacodynamic performance, and can obviously prolong the large metabolic half-life period of adrug; the derivative can be safely and effectively used for treating anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC) and the like, thereby providing a new means for treating cancers, metabolic and immune diseases, cardiovascular diseases, neurological diseases and the like.
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Paragraph 0110-0112; 0119-0122
(2020/07/15)
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- SOLID STATE FORMS OF LORLATINIB AND THEIR PREPARATION
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The present disclosure relates to Lorlatinib solid state forms, Lorlatinib salts and solid states thereof, processes for preparation thereof, pharmaceutical compositions and methods of use thereof.
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- Bromo-midbody for synthesizing Lorlatinib and catalytic synthesis method for Lorlatinib
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The invention discloses a bromo-midbody for synthesizing Lorlatinib. The structure of the bromo-midbody for synthesizing the Lorlatinib is shown as a compound 1 (The formula is defined in the description). The invention also discloses a method for catalyz
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Paragraph 0051; 0054; 0058; 0059
(2019/04/30)
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- Lauratinib intermediate and method for preparing lorazinib
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The invention discloses a labatinib intermediate. The lorazinib intermediate is as shown in a compound 2, a compound 1 is used as a starting material, the compound 2 is prepared according to a synthetic route shown below, according to the labatinib interm
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- Lorazinib bulk drug synthesis intermediate and method for preparing lorazinib by using organometallic palladium catalytic coupling
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The invention discloses a lorazinib bulk drug synthesis intermediate. The structure of the lorazinib bulk drug synthesis intermediate is as shown in a compound 2, the compound 2 is prepared by using the compound 1 as a starting material according to a syn
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- Method for synthesizing lorlatinib
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The invention belongs to the technical field of medicines, and relates to a method for synthesizing lorlatinib (PF-06463922), which is finally synthesized from 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone and 1-methyl-3-((methylamino)methyl)-1H-pyrazol-5-
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- Deprotection of N-Boc Groups under Continuous-Flow High-Temperature Conditions
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The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.
- Li, Bryan,Li, Ruizhi,Dorff, Peter,McWilliams, J. Christopher,Guinn, Robert M.,Guinness, Steven M.,Han, Lu,Wang, Ke,Yu, Shu
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p. 4846 - 4855
(2019/01/30)
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- CRYSTALLINE FORM OF LORLATINIB FREE BASE
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This invention relates to acrystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl- 5-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclo- tetradecine-3-carbonitrile (lorlatinib) free base (Form 7). This invention also relates to pharmaceutical compositions comprising Form 7, and to methods of using Form 7 and such compositions in the treatment of abnormal cell growth, such as cancer, in a mammal.
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Page/Page column 18
(2017/02/28)
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- SOLID FORMS OF A MACROCYCLIC KINASE INHIBITOR
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This invention relates to crystalline solvates of (10R)-7-amino-12-fluoro-2,10,16- trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benz- oxadiazacyclotetradecine-3-carbonitrile, useful in the treatment of abnormal cell growt
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Page/Page column 59-60
(2015/01/16)
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- Discovery of (10 R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17- tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations
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Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
- Johnson, Ted W.,Richardson, Paul F.,Bailey, Simon,Brooun, Alexei,Burke, Benjamin J.,Collins, Michael R.,Cui, J. Jean,Deal, Judith G.,Deng, Ya-Li,Dinh, Dac,Engstrom, Lars D.,He, Mingying,Hoffman, Jacqui,Hoffman, Robert L.,Huang, Qinhua,Kania, Robert S.,Kath, John C.,Lam, Hieu,Lam, Justine L.,Le, Phuong T.,Lingardo, Laura,Liu, Wei,McTigue, Michele,Palmer, Cynthia L.,Sach, Neal W.,Smeal, Tod,Smith, Graham L.,Stewart, Albert E.,Timofeevski, Sergei,Zhu, Huichun,Zhu, Jinjiang,Zou, Helen Y.,Edwards, Martin P.
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p. 4720 - 4744
(2014/07/07)
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- MACROCYCLIC DERIVATIVES FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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The invention relates to compounds of formula (Φ) as further defined herein and to the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds and salts of the present invention inhibit anaplastic lymphoma kinase (ALK) and/or EML4-ALK and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
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