- Unexpected Single Crystal Growth Induced by a Wire and New Crystalline Structures of Lapatinib
-
Single crystal growth of lapatinib free base was induced by immersion of a copper wire into a supersaturated methanolic aqueous solution yielding monoclinic anhydrous plates (space group P21/c, Form 1) and needles of a previously unknown channel hydrate (in P42212). Also, a new method has been developed herein to obtain anhydrous Form 1 via acid-base reaction of lapatinib ditosylate and sodium methoxide, avoiding the usage of an aqueous solution and hydrate formation. Anhydrous Form 2 as well as new solvates were produced via solution mediated transformation experiments, including a dichloromethane solvate with a powder X-ray diffraction pattern similar to that of anhydrous Form 2. Differential scanning calorimetry and solution equilibrium experiments helped to elucidate the interconversion pathways between Form 1, Form 2, and the solvates.
- De Araujo, Gabriel L.B.,Zeller, Matthias,Smith, Daniel,Nie, Haichen,Byrn, Stephen R.
-
-
Read Online
- IMPROVED PROCESS FOR THE PREPARATION OF LAPATINIB BASE AND IT'S ANHYDROUS DITOSYLATE SALT
-
The present invention relates to an improved, high yielding and industrially viable process for the preparation of high pure Lapatinib of formula (1). The present invention involves simple crystallization techniques avoiding column chromatographic techniques and the process conditions can be easily adopted for scale-up studies.
- -
-
Paragraph 11
(2020/07/15)
-
- Preparation method of 6-substituted furanyl-4-substituted aminoquinazoline derivative and key intermediate thereof
-
The invention relates to a preparation method of a 6-substituted furanyl-4-substituted aminoquinazoline derivative and a key intermediate thereof. 2-halo-5-cyanobenzoate and 3-chloro-4-(3-fluorobenzyloxy)aniline are used as raw materials, and 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline is obtain through an amidation reaction, a formamidine salt substitution reaction and a condensation reaction; then 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline or 6-(5-formylfuran-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline are obtained througha Grignard reaction and an acidification reaction; and then lapatinib or selatinib are prepared through a Mannich reaction or imidization and a reductive amination reaction. The preparation method hasthe advantages that the raw materials are cheap and are easily available, selectivity of the reaction is high, purity of the product is high, and industrial production is facilitated.
- -
-
-
- A process for preparing the lapatinib method and intermediate (by machine translation)
-
A through novel intermediate to prepare lapatinib or its pharmaceutically acceptable salt of the method, the method using 5 - bromo furfural and and 2 - nitrobenzene formic acid as the starting material through the Suzuki coupling reaction. This kind of synthetic pulls the handkerchief to raise nepal method can reach 32.2% overall yield. (by machine translation)
- -
-
-
- A preparation method of the lapatinib
-
The invention discloses a lapatinib preparation method. In the synthesis method, the initial raw materials of 2-amino-5-iodobenzoic acid and a cyclization reagent are used for preparing a midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III), quinazoline sulfide (V) is generated through the midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III) under the condition of sulpho-reagent and methine halide, and a target molecule is further synthesized. Due to reaction, the lapatinib yield of a final product is increased, generation of an unstable midbody of 4-chloroquinazoline product is avoided, meanwhile, use of corrosive phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and other chlorinating agents is avoided, and the lapatinib preparation method is suitable for industrial production.
- -
-
-
- Method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib
-
The invention relates to a method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib. The method for synthesizing the intermediate comprises steps as follows: 4-hydroxy-6-nitro quinazoline reacts with hydrazine hydrate in a solvent in the presence of a catalytic amount of catalyst, and 4-hydroxy-6-amino quinazoline is prepared; 4-hydroxy-6-amino quinazoline reacts with furaldehyde in the solvent in presence of acid, sodium nitrite and a catalytic amount of catalyst, and the intermediate is prepared. The invention further relates to a method for synthesizing lapatinib and/or a lapatinib salt, a lapatinib intermediate and/or a pharmaceutically acceptable salt of the intermediate. The method is performed by using the intermediate synthesized with the method. The method has the advantages that steps are simplified, agents are cheap, available and high in utilization rate, heavy metal pollution is avoided, the reaction condition/operation requirement is lower and/or the yield is high and the like.
- -
-
Paragraph 0034; 0051; 0052; 0053
(2017/03/22)
-
- Method for synthesizing lapatinib or intermediate thereof
-
The invention relates to a method for synthesizing lapatinib or an intermediate thereof. The method for synthesizing the intermediate comprises the steps as follows: under the condition that a catalytic quantity of a catalyst exists in a solvent, 4-amino-5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline reacts with furfural for preparation of 5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline-6-yl)furyl-2-carboxaldehyde hydrochloride, and the intermediate is prepared. The invention further relates to a method for synthesizing lapatinib and/or salt of lapatinib, the intermediate of lapatinib and/or pharmaceutically acceptable salt of the intermediate, and the method is performed with the intermediate which is synthesized by the previous method. The method has the advantages that steps are simplified, a reagent is cheap, available and high in use ratio, pollution from heavy metal is avoided, and requirements for reaction conditions/operation are relatively low and/or the yield is high.
- -
-
Paragraph 0052; 0053; 0054
(2017/06/30)
-
- Preparation lapatinib method and intermediate
-
The invention provides a compound as shown in formula (X), and the formula is as shown in the specification, and the compound can be used for preparing lapatinib and a medically acceptable intermidate thereof.
- -
-
-
- Synthesis and in vitro biological evaluation of novel quinazoline derivatives
-
A series of novel 4-arylamino-6-(5-substituted furan-2-yl)quinazoline derivatives were designed, synthesized and evaluated on biological activities in vitro. Compound 2a, 3a and 3c exhibited highly anti-proliferation activities on all tested tumor cell lines including SW480, A549, A431 and NCI-H1975 cells. Especially, compound 2a not only exhibited strong anti-proliferation activities against the tumor cell lines which expressed wild type or mutant EGFRL858R/T790M, but also showed the most potent inhibitory activity toward wild type EGFR (IC50?=?5.06?nM). The result of docking with EGFR suggested the binding mode of 2a was similar to that of lapatinib. While Western-blot analyses showed 2a obviously inhibited the activation of EGFR, Akt and Erk1/2 in lung cancer cells at indicated concentration. It is believed that this work would be very useful for developing a new series of TKIs targeting EGFR.
- Zhang, Yaling,Zhang, Ying,Liu, Juan,Chen, Li,Zhao, Lijun,Li, Baolin,Wang, Wei
-
p. 1584 - 1587
(2017/03/16)
-
- Lapatinib intermediate and its preparation method and application
-
The invention discloses a lapatinib intermediate as well as a preparation method and application thereof. The lapatinib intermediate contains chemical structures respectively shown in a formula IV, a formula V and a formula VIII (described in the specification). The lapatinib intermediate provided by the invention has the advantages of simple preparation technology, available raw materials, mild reaction conditions, high yield, easy control on quality and the like; by applying the lapatinib intermediate, a preparation route of lapatinib can be shortened, operation is simple, reaction conditions are mild, especially adoption of poisonous reagents such as sulfoxide chloride and phosphorus oxychloride can be avoided, the lapatinib intermediate can be stable in each step, post treatment is simple, yield is high, the lapatinib intermediate is applicable to mass production and has practical value, and large-scale industrial production demand of lapatinib can be met.
- -
-
-
- Lapatinib a novel process for the preparation of
-
The present invention provides a preparation method of lapatinib. The method comprises contacting a compound shown as a formula 1 with a compound shown as a formula 2 to produce a compound shown as a formula 3; reducing the compound shown as the formula 3 to produce a compound shown as a formula 4; contacting a compound shown as a formula 5 with N,N-dimethylformamide dimethyl acetal to produce a compound shown as a formula 6; contacting the compound shown as the formula 6 with the compound shown as the formula 4 to produce a compound shown as a formula 7; in the presence of an acid, an alkali and NaNH(OAc)3, contacting a compound shown as a formula 8 with a compound shown as a formula 9 to produce a compound shown as a formula 10; in the presence of a catalyst and an alkali, contacting the compound shown as the formula 10 with a compound shown as a formula 11 to produce a transition intermediate, and contacting the transition intermediate with the compound shown as the formula 7 and p-toluenesulfonic acid to produce a compound shown as a formula I; through use of the method, the lapatinib can be effectively prepared.
- -
-
-
- Preparing method of lapatinib and preparing method of lapatinib ditosylate
-
The invention provides a preparing method of lapatinib. The preparing method includes the steps that under nitrogen protection, a compound in the formula (IV) (please see the specification), 5-formyl-2-furanboronic acid, organic base or inorganic base, tetrahydrofuran and ethanol are mixed, the temperature is increased to 60-70 DEG C, stirring is carried out, a palladium catalyst is added, and a reaction is carried out under the temperature control condition; after the mixture is completely reacted, filtering, filter liquor cooling, water dripping, stirring, filtering and drying are carried out, the obtained product and 2-(methylsulfonyl) ethylamine hydrochloride are further reacted under the condition of existing of glacial acetic acid, then NaBH(OAC)3 is added for a reduction reaction, and lapatinib is obtained. The invention further provides a preparing method of lapatinib ditosylate. The preparing method includes the steps that a tetrahydrofuran solution of p-toluenesulfonic acid-monohydrate is dropwise added into the lapatinib or a solution obtained before concentrating, and the lapatinib ditosylate is obtained. The methods are convenient to operate, small in solvent dosage, low in production cost, small in environment pollution, high in product yield and purity and more suitable for industrial production.
- -
-
-
- CANCER TREATMENT METHOD
-
A method of treating cancer is described including administration of a 4-quinazolineamine and at least one other anti-neoplastic agent as well as a pharmaceutical combination including the 4-quinazolineamines.
- -
-
Paragraph 0153; 0161
(2016/03/12)
-
- Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
-
A pharmaceutical formulation comprising the compound of formula
- -
-
Page/Page column 62; 75
(2015/12/18)
-
- EFFICIENT PROCESS FOR THE PREPARATION OF LAPATINIB AND SALTS THEREOF BY MEANS OF NEW INTERMEDIATES
-
The present invention refers to a new efficient process for the synthesis of the active pharmaceutical ingredient Lapatinib and salts thereof. In particular, the present synthesis is carried out employing new intermediates in which the amine function is protected by a group cleavable in basic milieu that provides a higher overall yield of the synthesis process.
- -
-
-
- Synthesis of Lapatinib via direct regioselective arylation of furfural
-
A new synthesis of Lapatinib, an orally active drug for breast cancer, is described. The synthesis involves a palladium catalyzed regioselective arylation of furfural with 6-bromo-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)quinazolin-4-amine. This key step replaces an atom inefficient Suzuki cross coupling reaction used in a previously disclosed route and significantly shortens the synthesis.
- Erickson, Greg,Guo, Jiasheng,McClure, Mike,Mitchell, Mark,Salaun, Marie-Catherine,Whitehead, Andrew
-
p. 6007 - 6010
(2015/01/08)
-
- A METHOD OF PRODUCING THE KEY INTERMEDIATE OF LAPATINIB SYNTHESIS
-
The present invention relates to a production method of the compound of formula I, consisting in coupling the iodo derivative of formula III with boronic acid derivatives, catalyzed by suitable Pd catalysts in a solvent, wherein the boronic acid derivatives are cyclic boronates of the general formula VII, wherein R1, R2, R3 and R4 is H, or a C1-C4 (un)branched alky and wherein X is either a bond or CR5R6 wherein R5 and R6 is H, or a C1-C4 (un)branched alkyl. Other aspects of the invention are cyclic boronates and use of the compound of formula I.
- -
-
-
- LAPATINIB SALTS
-
Disclosed are new lapatinib salts and polymorphic forms thereof and processes for their preparation. More specifically disclosed are new salts of lapatinib, namely lapatinib salts formed by (1S)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
- -
-
Page/Page column 47-48
(2014/12/12)
-
- A PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS DITOSYLATE SALT
-
There is provided processes for preparing Lapatinib and pharmaceutically acceptable salts thereof by the reductive amination of the aldehyde of Formula II by treatment with 2-methanesulphonylethylamine followed by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst.
- -
-
Page/Page column 14
(2012/07/13)
-
- 4-(Substituted Anilino)-Quinazoline Derivatives Useful as Tyrosine Kinase Inhibitors
-
The present invention relates to 4-(substituted anilino)-quinazoline derivatives as tyrosine kinase inhibitors. Specifically, compounds of formula I, or pharmaceutically acceptable salts or solvates thereof are disclosed, in which each substitutent in formula I is defined in the description. Preparation method of the compounds of formula I, pharmaceutical compositions and pharmaceutical uses thereof are also disclosed. The compounds of formula I are effective tyrosine kinase inhibitors.
- -
-
Page/Page column 16; 17
(2012/08/28)
-
- SALTS OF LAPATINIB
-
The present invention provides novel dioxalate salt of lapatinib, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides novel monobesylate salt of lapatinib, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a process for the preparation of monohydrate form of lapatinib ditosylate. The present invention further provides a process for the preparation of anhydrous form of lapatinib ditosylate.
- -
-
-
- PROCESS AND INTERMEDIATES FOR PREPARING LAPATINIB
-
Provided are a process for preparing lapatinib and its pharmaceutically acceptable salt by use of new intermediates, and a process for obtaining a pharmaceutical form of lapatinib ditosylate monohydrate.
- -
-
Page/Page column 19
(2011/10/13)
-
- NOVEL PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
The present invention relates to an improved and novel process for the preparation of high purity crystalline base of Lapatinib of formula-(1) having chemical name N-{3-chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl]-2-furyl]-4-quin-azolinamine and its pharmaceutically acceptable salts. The present invention further relates to intermediates according to formula (8) and formula (9) used in this process
- -
-
-
- A NEW PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
The present invention relates to an improved and new process for the preparation of high purity crystalline base of Lapatinib of formula (1) having chemical name N-{3-chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesulfonyl) ethyl]amino}methyl]-2-furyl]-4-quin -azolinamine and its pharmaceutically acceptable salts.
- -
-
-
- LAPATINIB INTERMEDIATES
-
The invention provides lapatinib intermediates and improved processes for preparing lapatinib intermediates. The invention also provides processes for preparing lapatinib base and lapatinib ditosylate.
- -
-
Page/Page column 27
(2010/04/03)
-
- A NOVEL PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
The present invention relates to an improved and novel process for the preparation of high purity crystalline base of Lapatinib of formula-(l) having chemical name N-{3-chloro-4-[(3- fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesuIfonyl) ethyl]amino}methyl]-2-furyl]-4-quin - azolinamine and its pharmaceutically acceptable salts. The present invention further relates to intermediates according to formula (8) and formula (9) used in this process
- -
-
Page/Page column 16-17
(2010/06/17)
-
- FORMS OF LAPATINIB COMPOUNDS AND PROCESSES FOR THE PREPARATION THEREOF
-
The present invention provides novel crystalline and amorphous lapatinib compounds and processes for preparing them
- -
-
Page/Page column 7
(2010/04/30)
-
- QUINAZOLINE DITOSYLATE ANHYDRATE FORMS
-
Crystalline forms of anhydrate ditosylate salts of 4-quinazolineamines are described as well as methods of using the same in the treatment of disorders characterized by aberrant erbB family PTK activity.
- -
-
Page/Page column 23
(2009/07/18)
-
- QUINAZOLINE ANHYDRATE FORMS
-
Crystalline forms of 4-quinazolineamines are described as well as methods of using the same in the treatment of disorders characterized by aberrant erbB family PTK activity.
- -
-
Page/Page column 18
(2009/07/18)
-
- CANCER TREATMENT METHOD
-
The present invention relates to a method of treating cancer in a mammal and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering an erb family inhibitor and an IGF-1R inhibitor to a mammal suffering from a cancer.
- -
-
Page/Page column 42; 45
(2008/06/13)
-
- Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series
-
Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
- Petrov, Kimberly G.,Zhang, Yue-Mei,Carter, Malcolm,Cockerill, G. Stuart,Dickerson, Scott,Gauthier, Cassandra A.,Guo, Yu,Mook Jr., Robert A.,Rusnak, David W.,Walker, Ann L.,Wood, Edgar R.,Lackey, Karen E.
-
p. 4686 - 4691
(2007/10/03)
-
- CANCER TREATMENT METHOD
-
A method of treating cancer is described including administration of a pyrimidine derivative and a quinazoline derivative as well as a pharmaceutical composition including the same.
- -
-
Page/Page column 43
(2010/02/14)
-
- CANCER TREATMENT METHOD
-
The present invention relates to a method of treating cancer in a mammal and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering an erb family inhibitor and a PI3K and/or Akt inhibitor to a mammal suffering from a cancer.
- -
-
Page/Page column 69-70
(2010/02/11)
-
- CANCER TREATMENT METHOD
-
The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and at least one additional anti-neoplastic compound. In particular, the method relates to a methods of treating cancers by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof in combination with at least one additional anti-neoplastic compound.
- -
-
Page/Page column 25
(2008/06/13)
-
- CANCER TREATMENT METHOD
-
The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and pharmaceutical compositions containing the same. In particular, the method relates to a methods of treating cancers which are mediated by the tyrosine kinases EGFR and/or erbB2 by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof.
- -
-
Page/Page column 32
(2008/06/13)
-
- Cancer treatment method
-
A method of treating cancer is described including administration of a 4-quinazolineamine and at least one other anti-neoplastic agent as well as a pharmaceutical combination including the 4-quinazolineamines.
- -
-
-
- Heterocyclic compounds
-
The present invention relates to substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. Specifically, the invention relates to quinazoline derivatives useful in treating disorders mediated by protein tyrosine kinase activity, in particular erbB-2 and/or EGFR activity.
- -
-
-