- Synthesis and anticancer activities of ceritinib analogs modified in the terminal piperidine ring
-
A series of new ceritinib analogs by extensive functionalization of the tail piperidine ring with various phosphamides and carbamates have been synthesized. All the ceritinib derivatives were evaluated for their cytotoxic activities against H2228 cell line. From the activity profile obtained, three of the tested compounds (compounds 4, 7 and 9) showed significant cytotoxic effects. Among these derivatives compound 9 was found to possess cytotoxicity that is better than standard drug ceritinib (IC50 Combining double low line 24 nM). Moreover, compound 9 demonstrated robust tumor growth inhibition in vivo model.
- Wang, Peng,Cai, Jin,Chen, Junqing,Ji, Min
-
-
Read Online
- An efficient synthesis of Ceritinib (LDK378) using a sandmeyer reaction
-
A convenient route for the synthesis of Novartis's second-generation anaplastic lymphoma kinase inhibitor Ceritinib (LDK378) involving starting materials that are commercially available has been achieved. The procedure employed mild reaction conditions and avoided the use of expensive reagents compared to the original synthetic route reported by Novartis. More importantly, gram scale synthesis was accomplished and this protocol could be valid in drug discovery synthesis.
- Liu, Haidong,Li, Yuan,Wang, Dongdong,Qin, Yu,Ji, Min
-
-
Read Online
- CHEMICAL PROCESS FOR PREPARING PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
-
PROBLEM TO BE SOLVED: To provide a process for preparing ceritinib and/or intermediates thereof. SOLUTION: There is provided a process for preparing (C2-1), an intermediate of ceritinib synthesis, comprising the step of reacting (A) with (B) in a solvent in the presence of at least one catalyst, wherein P is a protecting group and T and X1 independently denote Cl and the like. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
- -
-
-
- Chemical Process for Preparing Pyrimidine Derivatives and Intermediates Thereof
-
The present disclosure relates to a method of synthesizing 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (ceritinib) and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing ceritinib.
- -
-
-
- Diaminopyrimidine compound and application
-
The present invention provides a diaminopyrimidine compound represented by Formula I, which can be used as a three-mutant-type (sensitive mutation/T790M/C797S) EGFR kinase inhibitor for preventing and/or treating tumors.
- -
-
Paragraph 0085-0089
(2020/03/13)
-
- Preparation method of ceritinib
-
The invention relates to the field of medicinal chemistry, in particular to a preparation method of Ceritinib. According to the method, 2,5-dichloro-N-(2-(isopropylthio)phenyl)pyrimidine-4-amine is used as a raw material, and compared with the prior art, when the cefacitinib is prepared, impurities are reduced, the condition that impurities in a final product cefacitinib bulk drug exceed the standard is avoided, aftertreatment is simple, the refining frequency is small, and the reaction yield is increased.
- -
-
Paragraph 0040-0054
(2020/07/24)
-
- CHEMICAL PROCESS FOR PREPARING PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
-
PROBLEM TO BE SOLVED: To provide a method for producing intermediates for preparing ceritinib. SOLUTION: There is provided a method for preparing (C2-1), comprising reacting (A) with (B) in a solvent in the presence of at least one catalyst, wherein P is a protecting group and T and X1 can be independently C1 and the like. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
- -
-
-
- Ceritinib intermediate and method for preparing ceritinib
-
The invention relates to a ceritinib intermediate and a method for preparing ceritinib. A ceritinib intermediate compound is 4-isopropoxy-5-guanidyl-2-N-substituted piperidine-4-base toluene nitrate (VII). The method includes carrying out substation reaction on 2-nitro-4,5-dimethyl chlorobenzene and isopropyl alcohol in the presence of alkali to generate compounds III; carrying out condensation onthe compounds III and halogenated acetaldehyde di-acetal and carrying out reduction ring formation by ammonia-ammonium chloride-sodium borohydride to obtain compounds IV; carrying out amino protection to obtain compounds V; carrying out catalytic hydrogenation in solvents and carrying out nitro reduction to obtain amino so as to obtain compounds VI; carrying out reaction on the compounds VI and cyanamide to obtain compounds VII. The ceritinib can be prepared from the compounds VII by the aid of the method. The ceritinib intermediate and the method have the advantages of inexpensive and easilyavailable raw materials, simplicity and convenience in operation, high elementary reaction selectivity, low wastewater quantity and green environmental protection.
- -
-
-
- Preparation method and application of ceritinib intermediate
-
The invention relates to a preparation method and application of a ceritinib intermediate, in particular to a preparation process of an intermediate which is 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidine-4-amine, and belongs to the field of medicine synthesis. The preparation method includes the detailed following steps that a compound 1-a, a compound 1-b, palladium acetate, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and alkali are added into a solvent, a reaction is conducted, and then the ceritinib intermediate can be prepared. The route is simple and short, operation is easy,production costs are lowered, and the preparation method is suitable for large-scale industrialized production.
- -
-
-
- Chemical Process for Preparing Pyrimidine Derivatives and Intermediates Thereof
-
The present disclosure relates to a method of synthesizing 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (ceritinib) and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing ceritinib.
- -
-
-
- Preparation method for ceritinib
-
The invention discloses a preparation method for ceritinib, which comprises the following steps: under nitrogen atmosphere, a compound shown as formula (2) and a compound shown as formula (3) are added into organic base, and temperature is increased to 80 DEG C to 120 DEG C for reaction. The organic base is diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecy-7-ene, triethylene diamine or pyridine. The method disclosed by the invention is simple, environmentally friendly and easy to implement. (The reaction formula is shown in the description.).
- -
-
Paragraph 0021-0022; 0024; 0026; 0028; 0030
(2018/11/04)
-
- HYDRATE OF 2-ISOPROPOXY-5-METHYL-4-(PIPERIDIN-4-YL) ANILINE DIHYDROCHLORIDE, PREPARATION METHOD AND USE OF THE SAME
-
The present invention relates to 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate and a preparation method of the same. The 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride monohydrate has a very good crystal form and is well suitable for recrystallization purification; further, the effect of impurity removal effect is very good, and any single impurity can be controlled less than 0.1%.
- -
-
-
- A MODIFIED PROCESS FOR THE PREPARATION OF CERITINIB AND AMORPHOUS FORM OF CERITINIB
-
The present invention is related to an improved process for the preparation of ceritinib with high yield and high purity. The present process is cost effective and feasible in large scale production also. The present invention also related to a stable amorphous form of ceritinib and its preparation. The present invention also relates to a process for the preparation of Crystalline form A of Ceritinib.
- -
-
-
- A method for preparing color Switzerland for Nepal
-
The invention discloses a method for preparing ceritinib, belonging to the field of chemical pharmacy. The method comprises the following steps: by taking 3-bromine-4-methylphenol as an initial raw material, performing phenolic hydroxyl isopropylation, nitration, coupling and reduction reaction, obtaining a midbody 1, by further taking o-nitro fluorobenzene as another initial raw material, performing isosulfhydrylation, oxidation, reduction and pyrimidine, obtaining a midbody 2, performing coupling reduction on the midbody 1 and the midbody 1, obtaining ceritinib which is protected by BOC acid anhydride, and finally removing a t-butyloxycarboryl protecting group, and obtaining ceritinib. The method is simple and feasible to operate, relatively high in yield, small in pollution and applicable to industrial production.
- -
-
-
- Preparation color Switzerland for Nepal new intermediate and its preparation method
-
The invention relates to intermediates, namely a compound 1 of a formula (1) as shown in the specification and a compound 2 of a formula (2) as shown in the specification, for preparing ceritinib, or a chemically acceptable salt of the compound 2, wherein R represents the benzylic group of saturated or unsaturated aromatic ring methylene or heteroaromatic ring methylene, and X represents a halogen. The invention relates to a method for preparing a compound 4 by use of the new intermediates, namely the compound 1 and the compound 2, wherein the step of reduction from the compound 1 to the compound 2 is performed by use of a hydroboron or a composition thereof and an alcohol solvent; the compound 2 is reduced by use of a catalytic hydrogenation or transfer hydrogenation method to generate the compound 4. The route of preparing the compound 4 by use of the compound 1 and the compound 2 has the advantages that the chemical reduction step is combined with a catalytic hydrogenation, the use of expensive platinum dioxide is avoided and the cost of synthesizing the intermediate 4 of the ceritinib is effectively reduced.
- -
-
-
- Preparation method for ceritinib and intermediate thereof
-
The invention provides a preparation method for ceritinib and an intermediate thereof. The method comprises the following steps: (1) coupling the compound 1-dihydrochloride with the compound 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (a compound 3) so as to produce 5-chloro-N2-(2-isopropanolato-5-methyl-4-(piperid-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (a compound 4, i.e., ceritinib dihydrochloride); and (2) subjecting the compound 4 to dissociation so as to produce ceritinib. The preparation method provided by the invention is low in cost and high in yield, and the purity of the intermediate in each step is 99.5% or above, so high purity of ceritinib is guaranteed. The method is few in steps, simple to operate and suitable for industrial production and has great application value.
- -
-
Paragraph 0078; 0079; 0080; 0081; 0082; 0083; 0084
(2017/07/22)
-
- Ceritinib intermediate and preparation method and application thereof
-
The present invention discloses a ceritinib intermediate and a preparation method and application thereof. The ceritinib intermediate has a structure shown as a formula I, R and R2 are as defined in the specification and claims. The ceritinib intermediate is prepared from a compound of a formula 1 and a benzyl halide compound by substitution reaction and then reduction. After further reduction of the nitro by catalytic hydrogenation and removal of amino-protection, the compound of the formula I is reacted with a compound of a formula III to obtain ceritinib. According to the method, raw materials are readily available and inexpensive, the method does not require special equipment, production cost is greatly reduced, and the method is suitable for industrial application.
- -
-
-
- PROCESS FOR PREPARATION OF CERITINIB
-
The present application relates to a process for preparation of ceritinib and intermediates thereof. Specifically, the present application relates to a process for preparation of N-(4-(1-benzyl- 1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)acetamide (VC) comprising treating N-(4-(bromomethyl)-2-isopropoxy-5-methylphenyl)acetamide (IIID) with 1- benzylpiperidin-4-one (IVA). The present application also relates to a process for conversion of N-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-acetamide (VC) to ceritinib or an acid-addition salt thereof.
- -
-
-
- Preparation method for ALK inhibitor
-
The invention provides a preparation method for an ALK inhibitor. The preparation method comprises a step of contacting a compound as shown in a formula 4 with a compound as shown in a formula 12. The method can rapidly and efficiently prepare the target ALK inhibitor and is simple in steps, mild in reaction conditions and low in cost.
- -
-
-
- Novel kinase inhibitors
-
The present invention relates to a novel kinase inhibitor useful as a medicine for tumor, nerve disorder and mental illness. The purpose of the present invention is to provide a compound having improved blood-aqueous barrier penetrability to neurodegenerative diseases that cancer spreads to brain or progresses in brain. To this end, provided is a compound represented by chemical formula 1 or a pharmaceutically allowable salt thereof.COPYRIGHT KIPO 2017
- -
-
-
- Ceritinib synthesis intermediate and preparation method thereof
-
The invention provides a synthesis intermediate 8 of an anti-tumor drug ceritinib, a preparation method thereof, and an application of the intermediate 8 in synthesizing ceritinib. The preparation method of the intermediate 8 comprises the following steps: step (1), a compound 1 and an acid HX are subjected to salt formation, such that a compound 7 is obtained; step (2), the compound 7 is reduced through sodium borohydride, such that the compound 8 is obtained. The reaction formula is as the following. With prior arts, expensive platinum oxide is needed as a hydrogenation catalyst for preparing an intermediate 2 in a next step. With the intermediate 8, the above problem is avoided. Therefore, the intermediate 8 is suitable to be used in industrialized production of ceritinib.
- -
-
-
- Ceritinic synthesis intermediate and preparation method thereof
-
The invention provides a synthesis intermediate 7 of an anti-tumor drug ceritinib. The intermediate 7 has a structural general formula as the following image. In the formula, Ar is phenyl or phenyl substituted by C1-C4 alkyl, C1-C4 alkoxyl, cyano, nitro or halogen; and X is Cl or Br. A preparation method of the intermediate 7 comprises the following step: the intermediate 7 is produced through a reaction of a compound 1 and substituted or unsubstituted benzyl halide (or ArCH2X). The invention also provides a novel route for applying an intermediate 7b in synthesizing ceritinib. With the route, a problem of using expensive platinum oxide as a reduction catalyst in an existing route 1 can be avoided. In the synthesis route 2 for synthesizing ceritinib with the compound 7b, the obtained synthesis intermediate 7b is quaternary ammonium salt. The salt can be precipitated from a solvent, and can be obtained by filtration, such that impurities can be retained in filtrate. Also, the conditions for all steps of reactions in the synthesis route 2 are mild, and post-treatment is simple. All the obtained intermediates 8b-10b do not need column chromatography purification. Therefore, the route is suitable for industrialized production.
- -
-
-
- New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof
-
The present invention relates to the field of pharmaceutical chemistry, to a preparation method of a new intermediate of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib). According to the present invention, o-fluoronitrobenzene is adopted as a starting raw material, substitution, reduction and condensation are performed to obtain the new intermediate 2-X-5-chloro-N-(2-(isopropyl sulfide)phenyl)pyrimidine-4-amine (X is halogen, p-methyl benzene sulfonyloxy, methyl sulfonyloxy or trifluoromethylsulfonyloxy), the new intermediate can be oxidized to obtain a sulfonyl derivative, and the sulfonyl derivative and 2-isopropoxy-5-methyl-4-(piperidine-4-yl)aniline are subjected to condensation to finally obtain 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib); and the synthesis method has characteristics of readily available raw materials, high yield, mild reaction, simple operation and low production cost, and is suitable for industrial production.
- -
-
-
- SOLID STATE FORMS OF CERITINIB AND SALTS THEREOF
-
The present disclosure relates to solid state forms of Ceritinib and of Ceritinib salts, in particular of Ceritinib dihydrochloride, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
-
- Method for preparing ALK inhibitor ceritinib
-
Embodiment of present disclosure provides a method for preparing ceritinib of formula I, comprising: (1) contacting a compound of formula 12b with an amino protective group to obtain a compound of formula 3; (2) contacting the compound of formula 3 with a compound of formula 9a to obtain a compound of formula 5; and (3) subjecting the compound of formula 5 to a deprotection reaction to obtain the ceritinib of formula I. Then ceritinib may be effectively prepared.
- -
-
-
- Ceritinib crystal form and preparation method thereof
-
The invention discloses a ceritinib crystal form C, an amorphous substance, preparation methods and an application thereof. Concretely, the invention relates to the ceritinib amorphous substance and the crystal form C, and respective preparation methods of the ceritinib amorphous substance and the crystal form C. The ceritinib amorphous substance provided by the invention has good dissolvability, and the ceritinib crystal form C has good thermostability.
- -
-
Paragraph 0105; 0106; 0107; 0108
(2016/11/02)
-
- CRYSTALLINE FORMS OF 5-CHLORO-N2-(2-ISOPROPOXY-5-METHYL-4-PIPERIDIN-4-YL-PHENYL)-N4[2-(PROPANE-2-SULFONYL)-PHENYL]-PYRIMIDINE-2,4-DIAMINE
-
The present invention describes specific crystalline forms of 5 -chloro-N-(2-isopropoxy- 5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.
- -
-
Page/Page column 11-12
(2012/06/30)
-