302964-08-5

Basic information

• Product Name: N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide
• Synonyms: Dasatinib Int N-1;N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-yrimidinyl)amino]-5-thiazolecarboxamide;N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino];CAY10697;N-(2-Chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-pyrimidin-4-yl)amino]thiazole-5-carboxamide;N-(2-CHLORO-6-METHYLPHENYL)-2-[(6-CHLORO-2-METHYL-4-PYRIMIDINYL)AMINO]-5-THIAZOLECARBOXAMIDE;2-(6-Chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide;5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-
• CAS NO: 302964-08-5
• Molecular Formula: C₁₆H₁₃Cl₂N₅OS
• Molecular Weight: 394.28
• EINECS: 1308068-626-2
• Product Categories: Dasatinib;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 302964-08-5.mol
• Article Data: 26

Chemical Properties

• Melting Point: 333-335°C
• Appearance: /
• Density: 1.516 g/cm³
• Refractive Index: 1.716
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly)
• PKA: 10.92±0.70(Predicted)
• CAS DataBase Reference: N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide(302964-08-5)
• EPA Substance Registry System: N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide(302964-08-5)

Safety Data

• Hazardous Substances Data: 302964-08-5(Hazardous Substances Data)

Usage

Chemical Properties

Pale Yellow Solid

Uses

Different sources of media describe the Uses of 302964-08-5 differently. You can refer to the following data:
1. Dasatinib intermediate. A protein tyrosine kinase inhibitor.
2. Dasatinib intermediate. A protein tyrosine kinase inhibitor

InChI:InChI=1/C16H13Cl2N5OS/c1-8-4-3-5-10(17)14(8)23-15(24)11-7-19-16(25-11)22-13-6-12(18)20-9(2)21-13/h3-7H,1-2H3,(H,23,24)(H,19,20,21,22)

Synthetic route

N-(4-methoxybenzyl)-2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (834888-64-1) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With trifluorormethanesulfonic acid; trifluoroacetic acid In dichloromethane at 20℃; for 3h;	99%
With trifluorormethanesulfonic acid; trifluoroacetic acid In dichloromethane at 20℃; for 3h;	99%
With trifluorormethanesulfonic acid; trifluoroacetic acid In dichloromethane at 20℃; for 9h; Inert atmosphere;	97.6%
With trifluorormethanesulfonic acid; trifluoroacetic acid Inert atmosphere;	97%

2,4-dichloro-2-methylpyrimidine (1780-26-3) + 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (302964-24-5) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With potassium hydride In tetrahydrofuran at -25 - -10℃; for 4h; Reagent/catalyst; Temperature;	98.7%
Stage #1: 2,4-dichloro-2-methylpyrimidine; 2-amino-N-(2-chloro-6-methylphenyl)-1.3-thiazole-5-carboxamide In tetrahydrofuran at 5 - 20℃; for 0.75h; Stage #2: With sodium t-butanolate In tetrahydrofuran at 5 - 10℃; for 2.25h;	97%
Stage #1: 2,4-dichloro-2-methylpyrimidine; 2-amino-N-(2-chloro-6-methylphenyl)-1.3-thiazole-5-carboxamide With sodium t-butanolate In tetrahydrofuran at 10 - 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 5℃; for 2h; pH=2 - 3; Temperature; Reagent/catalyst;	94%

N-(2-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)-amino]-5-thiazolecarboxamide → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With N-chloro-succinimide; palladium dichloride In acetonitrile at 100℃; for 12h;	96.8%

N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide + N-(6-chloro-2-methylpyrimidin-4-yl)hydroxylamine (126827-01-8) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With sodium methylate In N,N-dimethyl-formamide at 100℃; for 5h; Temperature;	95%

2-chloro-N-(2-chloro-6-methylphenyl)acetamide (6307-67-1) + C9H12ClN5S → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
In methanol for 24h; Solvent; Reflux;	74%

1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (77296-31-2) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Stage #1: (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide With N-Bromosuccinimide In tetrahydrofuran; water at 0 - 22℃; for 3h; Stage #2: 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea In tetrahydrofuran; water for 2h; Heating / reflux;	71%
Multi-step reaction with 2 steps 1: ethanol / 4 h 2: methanol / 24 h / Reflux View Scheme

4-amino-6-chloro-2-methylpyrimidine (1749-68-4) + 2-bromo-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (302964-07-4) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With sodium hydride

2-chloro-6-methylphenyl isocyanate (40398-01-4) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-BuLi / tetrahydrofuran; hexane / 0.25 h / -78 - -75 °C 1.2: 86 percent / tetrahydrofuran; hexane / 2 h / -78 °C 2.1: NaH / dimethylformamide / 0.5 h 2.2: 95 percent / Bu4NI / dimethylformamide / 16 h / 20 °C 3.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 3.2: 83 percent / tetrahydrofuran / 4 h / Heating 4.1: 99 percent / CF3CO2H; CF3SO3H / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-BuLi / tetrahydrofuran; hexane / 0.25 h / -78 °C 1.2: 86 percent / tetrahydrofuran; hexane / 2 h / -78 °C 2.1: NaH / dimethylformamide / 0.5 h / 20 °C 2.2: 95 percent / tetrabutylammonium iodide / dimethylformamide / 16 h / 20 °C 3.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 3.2: 83 percent / tetrahydrofuran / 4 h / Heating 4.1: 99 percent / TFA; triflic acid / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -78 °C / Inert atmosphere 2.1: caesium carbonate / acetone / 10 h / Reflux; Inert atmosphere 3.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 3.2: 4 h / Reflux; Inert atmosphere 4.1: trifluorormethanesulfonic acid; trifluoroacetic acid / dichloromethane / 9 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: sodium hydride / tetrahydrofuran / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran / Inert atmosphere 4.1: trifluorormethanesulfonic acid; trifluoroacetic acid / Inert atmosphere View Scheme

2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (302964-11-0) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: NaH / dimethylformamide / 0.5 h 1.2: 95 percent / Bu4NI / dimethylformamide / 16 h / 20 °C 2.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 2.2: 83 percent / tetrahydrofuran / 4 h / Heating 3.1: 99 percent / CF3CO2H; CF3SO3H / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: NaH / dimethylformamide / 0.5 h / 20 °C 1.2: 95 percent / tetrabutylammonium iodide / dimethylformamide / 16 h / 20 °C 2.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 2.2: 83 percent / tetrahydrofuran / 4 h / Heating 3.1: 99 percent / TFA; triflic acid / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: caesium carbonate / acetone / 10 h / Reflux; Inert atmosphere 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 2.2: 4 h / Reflux; Inert atmosphere 3.1: trifluorormethanesulfonic acid; trifluoroacetic acid / dichloromethane / 9 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran / Inert atmosphere 2: sodium hydride / tetrahydrofuran / Inert atmosphere 3: trifluorormethanesulfonic acid; trifluoroacetic acid / Inert atmosphere View Scheme

N-(4-methoxybenzyl)-2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (834888-63-0) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 1.2: 83 percent / tetrahydrofuran / 4 h / Heating 2.1: 99 percent / CF3CO2H; CF3SO3H / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: NaH / tetrahydrofuran / 0.5 h / 0 °C 1.2: 83 percent / tetrahydrofuran / 4 h / Heating 2.1: 99 percent / TFA; triflic acid / CH2Cl2 / 3 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 1.2: 4 h / Reflux; Inert atmosphere 2.1: trifluorormethanesulfonic acid; trifluoroacetic acid / dichloromethane / 9 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / Inert atmosphere 2: trifluorormethanesulfonic acid; trifluoroacetic acid / Inert atmosphere View Scheme

2-chloro-6-methylaniline (87-63-8) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: i-Pr2NEt / tetrahydrofuran 2: TFA / CH2Cl2 3: NaH / tetrahydrofuran View Scheme
Multi-step reaction with 4 steps 1: i-Pr2NEt / tetrahydrofuran 2: TFA / CH2Cl2 3: NaNO2; CuBr 4: NaH View Scheme
Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran 2: N-Bromosuccinimide / -10 - 80 °C 3: sodium t-butanolate / tetrahydrofuran / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: N-chloro-succinimide / acetonitrile / 1.5 h 2: iron(III) chloride; tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide / acetonitrile; water / 5 h / 80 °C 3: sodium methylate / N,N-dimethyl-formamide / 5 h / 100 °C View Scheme

2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (302964-24-5) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaNO2; CuBr 2: NaH View Scheme

[5-(2-chloro-6-methylphenylcarbamoyl)thiazol-2-yl]-carbamic acid tert-butyl ester (302964-06-3) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: TFA / CH2Cl2 2: NaH / tetrahydrofuran View Scheme
Multi-step reaction with 3 steps 1: TFA / CH2Cl2 2: NaNO2; CuBr 3: NaH View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane 2: sodium t-butanolate / dichloromethane View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid / 25 - 30 °C 2: sodium t-butanolate / tetrahydrofuran / 10 - 30 °C / Inert atmosphere View Scheme

2,4-dichloro-2-methylpyrimidine (1780-26-3) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane; isopropyl alcohol / 20 h / 20 °C 2.1: triethylamine / tetrahydrofuran; water / 0.17 h / 120 °C / Microwave irradiation 2.2: 0.17 h / 20 °C 3.1: tert.-butylhydroperoxide; sodium iodide / water / 4 h / 80 °C / Inert atmosphere 4.1: N-chloro-succinimide; palladium dichloride / acetonitrile / 12 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; triethylamine / ethanol / 1.5 h / 110 °C 2: sodium methylate / N,N-dimethyl-formamide / 5 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 72 h / 0 - 20 °C / Inert atmosphere 2: sodium hydroxide; water / methanol; water / 16 h / 20 °C 3: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / acetonitrile / 20 °C / Inert atmosphere View Scheme

C13H11ClN4OS → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / methanol; water / 2 h / 60 °C 2: methanol / 4 h 3: methanol / 24 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / methanol; water / 2 h / 60 °C 2: ethanol / 4 h 3: methanol / 24 h / Reflux View Scheme

4-amino-6-chloro-2-methylpyrimidine (1749-68-4) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrahydrofuran / 24 h / Reflux 2: sodium hydroxide / 2 h / 50 °C 3: methanol / 4 h 4: methanol / 24 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: tetrahydrofuran / 24 h / Reflux 2: sodium hydroxide / 2 h / 50 °C 3: ethanol / 4 h 4: methanol / 24 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: tetrahydrofuran / 8 h / Reflux 2: sodium hydroxide / methanol; water / 2 h / 60 °C 3: methanol / 4 h 4: methanol / 24 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: tetrahydrofuran / 8 h / Reflux 2: sodium hydroxide / methanol; water / 2 h / 60 °C 3: ethanol / 4 h 4: methanol / 24 h / Reflux View Scheme

6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (77296-30-1) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / 2 h / 50 °C 2: methanol / 4 h 3: methanol / 24 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / 2 h / 50 °C 2: ethanol / 4 h 3: methanol / 24 h / Reflux View Scheme

(E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide (863127-76-8) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-Bromosuccinimide / water; 1,4-dioxane / 3 h / 25 - 30 °C 1.2: 2 h / 25 - 70 °C 2.1: sodium t-butanolate / tetrahydrofuran / 8 h / 5 - 30 °C View Scheme

N-(2-chloro-6-methylphenyl)-3-ethoxyprop-2-enamide → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / -10 - 80 °C 2: sodium t-butanolate / tetrahydrofuran / 0 - 5 °C View Scheme

(6-chloro-2-methylpyrimidin-4-yl)thiazol-2-yl-amine (1034919-70-4) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran; water / 0.17 h / 120 °C / Microwave irradiation 1.2: 0.17 h / 20 °C 2.1: tert.-butylhydroperoxide; sodium iodide / water / 4 h / 80 °C / Inert atmosphere 3.1: N-chloro-succinimide; palladium dichloride / acetonitrile / 12 h / 100 °C View Scheme

2-(6-chloro-2-methylpyrimidine-4-yl)amino-5-hydroxymethylthiazole → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: tert.-butylhydroperoxide; sodium iodide / water / 4 h / 80 °C / Inert atmosphere 2: N-chloro-succinimide; palladium dichloride / acetonitrile / 12 h / 100 °C View Scheme

C7H7Cl2N → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: iron(III) chloride; tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide / acetonitrile; water / 5 h / 80 °C 2: sodium methylate / N,N-dimethyl-formamide / 5 h / 100 °C View Scheme

ethyl 2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxylate (1202357-66-1) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol; water / 16 h / 20 °C 2: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / acetonitrile / 20 °C / Inert atmosphere View Scheme

2-((6-chloro-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxylic acid + 2-chloro-6-methylaniline (87-63-8) → 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5)

Conditions	Yield
With N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; Inert atmosphere;	480 mg

piperazine (110-85-0) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin 4-yl)amino)thiazole-5-carboxamide (910297-51-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 4h;	98%
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110 - 120℃;	81.2%
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 16h; Inert atmosphere;	80%

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) → dasatanib (302962-49-8)

Conditions	Yield
With tetrabutylammomium bromide In acetonitrile at 30 - 80℃;	97%
In propan-1-ol at 115 - 120℃; Temperature;	93%
With copper(l) chloride In N,N-dimethyl-formamide at 65℃; for 2h; Temperature; Reagent/catalyst;	91.6%

1-(2-hydroxyethyl)piperazine (103-76-4) + thymin (65-71-4) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → dasatinib-thymine

Conditions	Yield
In methanol at 25 - 67℃; Solvent;	91.38%

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 hydrochloride

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 1,4-dioxane for 12h; Reflux; Stage #2: With hydrogenchloride In water	91%

1-t-Butoxycarbonylpiperazine (57260-71-6) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → tbutyl 4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-carboxylate

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 80℃; for 12h;	89%
Stage #1: 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 20℃; for 0.0333333h; Stage #2: 1-t-Butoxycarbonylpiperazine In N,N-dimethyl-formamide at 110℃; for 16h;	89.9%
With N-ethyl-N,N-diisopropylamine In pentan-1-ol for 8h; Reflux;	84%
With triethylamine In N,N-dimethyl-formamide at 80℃;	56.28%

1-(Ethoxycarbonylmethyl)piperazine (40004-08-8) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate (910297-62-0)

Conditions	Yield
In ethanol at 20 - 150℃; for 1.75h; Microwave irradiation;	89%
In ethanol at 150℃; for 0.75h; Irradiation;	89%

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) → N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide ethanolate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 0.416667h;	88.7%

1-t-Butoxycarbonylpiperazine (57260-71-6) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin 4-yl)amino)thiazole-5-carboxamide (910297-51-7)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20 - 80℃; for 1h; Inert atmosphere;	86%

4-(2-Hydroxyethyl)piperidine (622-26-4) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 16h;	84%

methyl piperidine-4-acetate hydrochloride + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → C24H27ClN6O3S

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 16h;	84%

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;

1-(2-hydroxyethyl)piperazine (103-76-4) + i-Amyl alcohol (123-51-3) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide isoamyl alcohol (1613319-06-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 140℃; for 6h; Inert atmosphere;	81%

1-(2-hydroxyethyl)piperazine (103-76-4) + 1-methyl-pyrrolidin-2-one (872-50-4) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide N-methyl-2-pyrrolidone (1613319-05-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 90℃; for 1.16667h; Inert atmosphere;	80%

piperazine-1-carbaldehyde (7755-92-2) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((6-(4-formylpiperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80 - 85℃; for 5h;	79%

ethylenediamine (107-15-3) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → 2-({6-[(2-aminoethyl)amino]-2-methylpyrimidin-4-yl}amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (910297-59-5)

Conditions	Yield
In 1,4-dioxane for 90h; Inert atmosphere;	76.2%
at 120℃; for 6h; Inert atmosphere;	57%

3-amino-1-(t-butoxycarbonyl)pyrrolidine (186550-13-0) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → C25H30ClN7O3S

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; for 12h;	75%

1-(2-hydroxyethyl)piperazine (103-76-4) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide N,N-dimethylformamide (1229345-36-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 90℃; for 3h; Inert atmosphere;	73%

3-chloro-aniline (108-42-9) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → C22H18Cl2N6OS (1587622-91-0)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 110℃; for 12h;	73%

4-chloro-aniline (106-47-8) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((6-((4-chlorophenyl)amino)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (1587623-11-7)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 110℃; for 12h;	73%

3,4-dimethoxyaniline (6315-89-5) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((6-((3,4-dimethoxyphenyl)amino)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (1587622-97-6)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 110℃; for 12h;	69%

3-amino-1-(t-butoxycarbonyl)pyrrolidine (186550-13-0) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → C20H22ClN7OS

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20 - 80℃; for 1h; Inert atmosphere;	68%

1-(2-hydroxyethyl)piperazine (103-76-4) + dimethyl sulfoxide (67-68-5) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide dimethylsulfoxide (1228188-51-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 90℃; for 3h; Inert atmosphere;	67%

4-methoxy-aniline (104-94-9) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → N-(2-chloro-6-methylphenyl)-2-((6-((4-methoxyphenyl)amino)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (1587622-96-5)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 110℃; for 12h;	67%

3-fluoro-4-bromophenylamine (656-65-5) + 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (302964-08-5) → 2-((6-((4-bromo-3-fluorophenyl)amino)-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (1587622-95-4)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 110℃; for 12h;	59%

Upstream product

• 1780-26-3 2,4-dichloro-2-methylpyrimidine 
• 302964-24-5 2-amino-N-(2-chloro-6-methylphenyl)-1.3-thiazole-5-carboxamide 
• 1749-68-4 4-amino-6-chloro-2-methylpyrimidine 
• 302964-07-4 2-bromo-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide 
• 834888-64-1 N-(4-methoxybenzyl)-2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide 
• 40398-01-4 2-chloro-6-methylphenyl isocyanate 
• 302964-11-0 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide 
• 834888-63-0 N-(4-methoxybenzyl)-2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide 
• 87-63-8 2-chloro-6-methylaniline 
• 77296-30-1 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate 
• 6307-67-1 2-chloro-N-(2-chloro-6-methylphenyl)acetamide 
• 1034919-70-4 (6-chloro-2-methylpyrimidin-4-yl)thiazol-2-yl-amine 
• 126827-01-8 N-(6-chloro-2-methylpyrimidin-4-yl)hydroxylamine 
• 1202357-66-1 ethyl 2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxylate 

Downstream Products

• 910297-51-7 N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide 
• 910297-61-9 C₃₆H₃₄Cl₂N₁₂O₂S₂ 
• 910297-62-0 ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate 
• 1092368-05-2 N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(pyridin-3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide 
• 1092367-84-4 N-(2-chloro-6-methylphenyl)-2-(2-methyl-4,5'-bipyrimidin-6-ylamino)thiazole-5-carboxamide 
• 1092367-86-6 N-(2-chloro-6-methylphenyl)-2-(6-(4-methoxypyridin-3-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide 
• 1160297-08-4 N-(2-chloro-6-methylphenyl)-2-(6-(4-(1,1,2,2-d4-2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide 
• 1613319-06-4 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide isoamyl alcohol 
• 1613319-07-5 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide 1,3-propanediol 
• 1613319-05-3 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide N-methyl-2-pyrrolidone 
• 1229345-36-1 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide N,N-dimethylformamide 
• 1228188-51-9 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide dimethylsulfoxide 
• 1587622-91-0 C₂₂H₁₈Cl₂N₆OS 
• 1587623-11-7 N-(2-chloro-6-methylphenyl)-2-((6-((4-chlorophenyl)amino)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide 

Relevant articles and documents

Design and synthesis of novel dasatinib analogues

Design, synthesis, characterization and in vitro biological assay of a series of novel carboxylic acid and amino acid analogs of dasatinib (1) as anticancer agents are reported. Some of the synthesized analogs were identified as potent Src/Abl kinase inhibitors with greater antiproliferative activity against K652 and T315I cancer cell lines. The synthetic process involves condensation of N-(2-chloro-6-methylphenyl)-2-[[6-[4(-1-pipearazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide with carboxylic acids in the presence of dicyclohexylcarbodiimide and oxyma in organic solvent medium. Compounds were characterized and tested for anticancer activity on leukemia cancer cell lines K562 and Baf3/T315. Analogues of lactic acid, mandalic acid, leucine and proline have shown promising antiproliferative activity compared to dasatinib.

HETEROCYCLIC KINASE INHIBITORS AND USES THEREOF

The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the protein-tyrosine kinases LCK, ABL, SRC, KIT, SIK-family and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention can display one or more certain properties distinct to dasatinib. Also, the invention relates to pharmaceutical compositions that comprise one or more of the kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the invention may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. The kinase inhibitors or pharmaceutical compositions may be used in a treatment regimen that corresponds to, is similar to or is distinct from that used with dasatinib for a corresponding disorder, and in particular may be used in a combination treatment regimen together with one or more additional therapeutic agents, such as immune-checkpoint inhibitors.

Scalable and impurity-free process for dasatinib: Src and BCR-Abl inhibitor

An efficient, telescopic, impurity-free and scalable process for Bcr-Abl and Src family tyrosine kinase inhibitor for synthesis of Dasatinib with high yield and purity is described.