863127-77-9

Usage

Uses

Used in Antineoplastic Applications:
Dasatinib monohydrate is used as an antineoplastic agent for its ability to inhibit the activity of SRC-family protein-tyrosine kinases, which play a crucial role in the growth and proliferation of cancer cells. By targeting these kinases, Dasatinib monohydrate can help control tumor growth and potentially lead to the regression of cancerous masses.
Used in COVID-19 Research:
Dasatinib monohydrate is used as a research product in the context of COVID-19, where it may contribute to the understanding of the virus's mechanisms and the development of potential therapeutic interventions. Its role in this research could be multifaceted, including the exploration of its effects on viral replication, immune response modulation, or other pathways relevant to COVID-19 infection and treatment.

Biological Activity

chronic myeloid leukemia (cml) is a disease characterized by the presence of the philadelphia (ph+) chromosome and its oncogenic product, bcr-abl, that is present in >90% of the patients. dasatinib (bms-354825) is a novel, potent, and multitargeted kinase inhibitor that targets abl, src, kit, pdgfr, and other tyrosine kinases.

in vitro

dasatinib is a potent atp-competitive inhibitor in biochemical assays with broad-spectrum antiproliferative activities against hematological and solid tumor cell lines. dasatinib was more potent than imatinib at inhibiting nonmutated bcr-abl kinase activity. in addition, the kinase activity of 14 out of 15 different clinically relevant, imatinib-resistant bcr-abl isoforms was successfully inhibited [1].

in vivo

mice were dosed with dasatinib or vehicle alone by gavage for 2 weeks, beginning 3 days after injection of ba/f3 cells. all vehicle-treated mice developed progressive disease. in contrast, dasatinib–treated mice harboring nonmutant bcr-abl or the clinically common imatinib-resistant mutation m351t appeared healthy with no evidence of weight loss, lethargy, or ruffled fur and showed more than one log lower levels of bioluminescent activity after 2 weeks of therapy [2].

IC 50

0.55 and 3.0 nm for src and bcr-abl tyrosine kinases, respectively

references

[1] shah np, tran c, lee fy, chen p, norris d, sawyers cl. overriding imatinib resistance with a novel abl kinase inhibitor. science. 2004 jul 16;305(5682):399-401.[2] monika conchon, carla maria boquimpani de moura freitas, maria aparecida do carmo rego, and josé wilson ramos braga junior. dasatinib -

InChI:InChI=1/C22H27N7O2S2.H2O/c1-14-4-3-5-16(32)20(14)27-21(31)17-13-23-22(33-17)26-18-12-19(25-15(2)24-18)29-8-6-28(7-9-29)10-11-30;/h3-5,12-13,30,32H,6-11H2,1-2H3,(H,27,31)(H,23,24,25,26);1H2

Synthetic route

dasatanib (302962-49-8) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
With ethanol; water at 80℃; for 2h; Large scale;	96.44%
With water In ethanol at 75 - 80℃;
With water In ethanol at 0 - 80℃; for 5h;
With water In methanol Solvent; Heating;	21 g

N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin 4-yl)amino)thiazole-5-carboxamide (910297-51-7) + 2-bromoethanol (540-51-2) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
With caesium carbonate; potassium iodide In acetonitrile for 6h; Temperature; Solvent; Reagent/catalyst; Reflux;	93%

1-(2-hydroxyethyl)piperazine (103-76-4) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
Stage #1: 1-(2-hydroxyethyl)piperazine; 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide With N-ethyl-N,N-diisopropylamine In butan-1-ol at 118℃; for 4.5h; Stage #2: With water In ethanol	83.2%
Stage #1: 1-(2-hydroxyethyl)piperazine; 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 2.5h; Stage #2: With water In N,N-dimethyl-formamide at 20 - 100℃; for 2h;

2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (302964-24-5) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium t-butanolate / tetrahydrofuran / 10 - 20 °C 1.2: 2 h / 0 - 5 °C / pH 2 - 3 2.1: N-ethyl-N,N-diisopropylamine / pentan-1-ol / 8 h / Reflux 3.1: hydrogenchloride / water / 3 h / 55 - 60 °C 4.1: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: sodium t-butanolate / tetrahydrofuran / 10 - 20 °C 1.2: 2 h / 0 - 5 °C / pH 2 - 3 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 80 - 85 °C 3.1: sulfuric acid / methanol / 5 h / 5 - 65 °C 4.1: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme

[5-(2-chloro-6-methylphenylcarbamoyl)thiazol-2-yl]-carbamic acid tert-butyl ester (302964-06-3) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / 2 h / 25 - 30 °C 2.1: sodium t-butanolate / tetrahydrofuran / 10 - 20 °C 2.2: 2 h / 0 - 5 °C / pH 2 - 3 3.1: N-ethyl-N,N-diisopropylamine / pentan-1-ol / 8 h / Reflux 4.1: hydrogenchloride / water / 3 h / 55 - 60 °C 5.1: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / 2 h / 25 - 30 °C 2.1: sodium t-butanolate / tetrahydrofuran / 10 - 20 °C 2.2: 2 h / 0 - 5 °C / pH 2 - 3 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 80 - 85 °C 4.1: sulfuric acid / methanol / 5 h / 5 - 65 °C 5.1: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme

2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → dasatinib monohydrate (863127-77-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 80 - 85 °C 2: sulfuric acid / methanol / 5 h / 5 - 65 °C 3: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / pentan-1-ol / 8 h / Reflux 2: hydrogenchloride / water / 3 h / 55 - 60 °C 3: potassium iodide; caesium carbonate / acetonitrile / 6 h / Reflux View Scheme

dasatinib monohydrate (863127-77-9) → dasatanib (302962-49-8)

Conditions	Yield
In propan-1-ol; water at 0 - 5℃; for 1h; Product distribution / selectivity; Heating / reflux;
In water; isopropyl alcohol at 0 - 5℃; for 1h; Product distribution / selectivity; Heating / reflux;

Upstream product

• 103-76-4 1-(2-hydroxyethyl)piperazine 
• 302964-08-5 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 
• 302962-49-8 dasatanib 
• 910297-51-7 N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide 
• 540-51-2 2-bromoethanol 
• 302964-24-5 2-amino-N-(2-chloro-6-methylphenyl)-1.3-thiazole-5-carboxamide 
• 302964-06-3 [5-(2-chloro-6-methylphenylcarbamoyl)thiazol-2-yl]-carbamic acid tert-butyl ester 
• 1780-26-3 2,4-dichloro-2-methylpyrimidine 

Downstream Products

• 302962-49-8 dasatanib 

Relevant academic research and scientific papers

Preparation method for dasatinib monohydrate

The invention provides a preparation method for a dasatinib monohydrate. The dasatinib monohydrate is obtained by a reaction of dasatinib in an ethanol aqueous solution. According to a technical scheme of the invention, the high-quality dasatinib monohydrate can be obtained; tedious separation and purification steps are avoided; operation is simple; the waste of raw materials is also avoided; theproduction cost is reduced; and the preparation method is more applicable to industrial production.

[...] a novel crystalline form of water composition and its preparation method and pharmaceutical composition

The invention relates to the technical field of pharmaceuticals, and specifically relates to a novel crystal form of dasatinib monohydrate, and a preparation method and a pharmaceutical composition thereof. The novel crystal form of dasatinib monohydrate is very stable under conditions of illumination, high temperature, high humidity and accelerated experimentation conditions. The pharmaceutical composition has good dissolution rate, and is stable under a condition with a high temperature. Besides, compared with a conventional method, the preparation method provided by the invention has the advantages of simple operation and controllable quality. More importantly, the novel crystal form is relatively stable in a preparation process.

A convenient new and efficient commercial synthetic route for dasatinib (Sprycel)

A new and efficient synthetic route for dual-Src/Abl kinase inhibitor dasatinib (Sprycel), an anticancer drug, is described. This commercially viable process yields dasatinib monohydrate free of potential impurities with consistent yield of 68% in route A and 61% in route B with HPLC purity >99.80% over four stages.

POLYMORPHS OF DASATINIB AND PROCESS FOR PREPARATION THEREOF

Provided is dasatinib, solvates thereof and their crystalline forms, methods for their preparation, and pharmaceutical compositions thereof.

ORAL ADMINISTRATION OF N-(2-CHLORO-6-METHYLPHENYL)-2-[[6-[4-(2-HYDROXYETHYL)-1-PIPERAZINYL]-2-METHYL-4-PYRIMIDINYL]AMINO]-1,3-THIAZOLE-5-CARBOXAMIDE AND SALTS THEREOF

Disclosed are a method of treating cancer and/or other proliferative diseases comprising orally administering N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide or a salt thereof, and pharmaceutical compositions comprising N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide or a salt thereof. Also disclosed are N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide salts, as well as crystalline forms thereof.

PROCESS FOR PREPARING 2-AMINOTHIAZOLE-5-AROMATIC CARBOXAMIDES AS KINASE INHIBITORS

The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.