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[ CAS No. 1702259-66-2 ] {[proInfo.proName]}

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Chemical Structure| 1702259-66-2
Chemical Structure| 1702259-66-2
Structure of 1702259-66-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1702259-66-2 ]

CAS No. :1702259-66-2 MDL No. :MFCD30377210
Formula : C29H34Cl2N8O4 Boiling Point : -
Linear Structure Formula :- InChI Key :MBWRLLRCTIYXDW-UHFFFAOYSA-N
M.W : 629.54 Pubchem ID :118029202
Synonyms :

Calculated chemistry of [ 1702259-66-2 ]

Physicochemical Properties

Num. heavy atoms : 43
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.31
Num. rotatable bonds : 13
Num. H-bond acceptors : 7.0
Num. H-bond donors : 3.0
Molar Refractivity : 177.92
TPSA : 124.19 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.16
Log Po/w (XLOGP3) : 4.42
Log Po/w (WLOGP) : 4.34
Log Po/w (MLOGP) : 2.77
Log Po/w (SILICOS-IT) : 2.93
Consensus Log Po/w : 3.72

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 1.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -5.98
Solubility : 0.00066 mg/ml ; 0.00000105 mol/l
Class : Moderately soluble
Log S (Ali) : -6.75
Solubility : 0.000113 mg/ml ; 0.00000018 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -8.63
Solubility : 0.00000148 mg/ml ; 0.0000000024 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.58

Safety of [ 1702259-66-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1702259-66-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1702259-66-2 ]

[ 1702259-66-2 ] Synthesis Path-Downstream   1~20

  • 1
  • [ 872511-32-5 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 2 h / 0 - 20 °C 2.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 3.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 2 h / 0 - 20 °C 2.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 3.1: tetrahydrofuran / 1 h / -10 °C
  • 2
  • [ 65766-32-7 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1 h / 100 °C / Enzymatic reaction 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.2: 2 h / 0 - 20 °C 3.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 4.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 4 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.2: 2 h / 0 - 20 °C 3.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 4.1: tetrahydrofuran / 1 h / -10 °C
  • 3
  • [ 1702260-55-6 ]
  • [ 814-68-6 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
20 mg In tetrahydrofuran at -10℃; for 1h; 108.g; 2C g, N~(2-(6~(3~(2,6^ichloro-3,5-dimethoxyphenyl)~l~methylureido)pyrM ethylpiperazin-l-yl)phenyl)acrylamide g, N~(2-(6~(3~(2,6^ichloro-3,5-dimethoxyphenyl)~l~methylureido)pyrM ethylpiperazin-l-yl)phenyl)acrylamide To a solution of l-(6-(2-amino-4-(4-ethylpiperazin-l-yl)phenylamino)pyrimidin-4-yl)-3-(2,6- dichloro-3,5-dimethoxyphenyl)-l-methylurea (280 mg, purity: 90%, 0.44 mmol) in THF (30 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 2 mL, 0.44 mmol) at -10 °C, and the resulting mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-HPLC and prep-TLC to obtain the title compound (20 mg, yield: 7%). 1H NMR (400 MHz, CDC13) δ 1.31 (t, 3H), 2.65 (q, 2H), 2.62-2.68 (m, 4H), 3.27 (s, 3H), 3.36-3.38 (m, 4H), 3.91 (s, 6H), 5.76 (d, 1H), 5.90 (s5 1H), 6.24 (dd, 1H), 6.41 (d, 1H), 6.52 (s, 1H), 6.74 (dd, 1H), 7.07 (br s, 1H), 7.23 (d, 1H), 7.72 (br s, 1H), 7.98 (br s, 1H), 8.37 (s, 1H), 12.52 (s, 1H); MS (ESI): 629 [M+H]+
20 mg In tetrahydrofuran at -10℃; for 1h; 1.g To a solution of l-(6-(2-amino-4-(4-ethylpiperazin-l-yl)phenylamino)pyrimidin-4-yl)-3-(2,6- dichloro-3,5-dimethoxyphenyl)-l-methylurea (280 mg, purity: 90%, 0.44 mmol) in THF (30 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 2 mL, 0.44 mmol) at -10 °C, and the resulting mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-HPLC and prep-TLC to obtain the title compound 108 (20 mg, yield: 7%). NMR (400 MHz, CDC13) δ 1.31 (t, 3H), 2.65 (q, 2H), 2.62-2.68 (m, 4H), 3.27 (s, 3H), 3.36-3.38 (m, 4H), 3.91 (s, 6H), 5.76 (d, 1H), 5.90 (s, 1H), 6.24 (dd, 1H), 6.41 (d, 1H), 6.52 (s, 1H), 6.74 (dd, 1H), 7.07 (br s, 1H), 7.23 (d, 1H), 7.72 (br s, 1H), 7.98 (br s, 1H), 8.37 (s, 1H), 12.52 (s, 1H); MS (ESI): 629 [M+H]+.
  • 4
  • [ 79257-61-7 ]
  • N-{2-[(6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidin-4-yl)amino]-5-(4-ethylpiperazin-1-yl)phenyl}prop-2-enamide [ No CAS ]
  • 5
  • [ 327046-79-7 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 4 h / 100 °C 2.1: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 3.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1 h / 100 °C / Enzymatic reaction 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.2: 2 h / 0 - 20 °C 5.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 6.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 6 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 4 h / 100 °C 2.1: hydrogenchloride / toluene; water / 3 h / 20 - 40 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.2: 2 h / 0 - 20 °C 5.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 6.1: tetrahydrofuran / 1 h / -10 °C
  • 6
  • [ 875-51-4 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / Reflux 2.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 4 h / 100 °C 3.1: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 4.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1 h / 100 °C / Enzymatic reaction 5.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 5.2: 2 h / 0 - 20 °C 6.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 7.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 7 steps 1.1: dmap / tetrahydrofuran / 65 °C 2.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)-palladium(II) / toluene / 95 - 105 °C / Inert atmosphere 3.1: hydrogenchloride / toluene; water / 3 h / 20 - 40 °C / Inert atmosphere 4.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 5.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 5.2: 2 h / 0 - 20 °C 6.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 7.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / Reflux 2.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 4 h / 100 °C 3.1: hydrogenchloride / toluene; water / 3 h / 20 - 40 °C / Inert atmosphere 4.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 5.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 5.2: 2 h / 0 - 20 °C 6.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 7.1: tetrahydrofuran / 1 h / -10 °C
  • 7
  • [ 1702260-51-2 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 2.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1 h / 100 °C / Enzymatic reaction 3.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 3.2: 2 h / 0 - 20 °C 4.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 5.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 5 steps 1.1: hydrogenchloride / toluene; water / 3 h / 20 - 40 °C / Inert atmosphere 2.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 3.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 3.2: 2 h / 0 - 20 °C 4.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 5.1: tetrahydrofuran / 1 h / -10 °C
  • 8
  • [ 1702260-52-3 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1 h / 100 °C / Enzymatic reaction 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.2: 2 h / 0 - 20 °C 3.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 4.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 4 steps 1.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.2: 2 h / 0 - 20 °C 3.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 4.1: tetrahydrofuran / 1 h / -10 °C
  • 9
  • [ 1702260-53-4 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 2 h / 0 - 20 °C 2.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 3.1: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 2 h / 0 - 20 °C 2.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 3.1: tetrahydrofuran / 1 h / -10 °C
  • 10
  • [ 10272-07-8 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: toluene / 15 h / 20 °C / Inert atmosphere 2.1: sulfuryl dichloride / acetonitrile / 0.5 h / 0 °C / Inert atmosphere 3.1: potassium hydroxide / ethanol / 24 h / Reflux 4.1: triethylamine / 1,4-dioxane / 2 h / 130 °C / Microwave irradiation 5.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 5.2: 2 h / 0 - 20 °C 6.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 7.1: tetrahydrofuran / 1 h / -10 °C
  • 11
  • [ 1702260-54-5 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 2: tetrahydrofuran / 1 h / -10 °C
Multi-step reaction with 2 steps 1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 2: tetrahydrofuran / 1 h / -10 °C
  • 12
  • [ 943189-21-7 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium hydroxide / ethanol / 24 h / Reflux 2.1: triethylamine / 1,4-dioxane / 2 h / 130 °C / Microwave irradiation 3.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 3.2: 2 h / 0 - 20 °C 4.1: hydrogen / tetrahydrofuran; methanol; water / 3 h / -10 °C / 760.05 Torr 5.1: tetrahydrofuran / 1 h / -10 °C
  • 13
  • [ 872509-56-3 ]
  • N-{2-[(6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidin-4-yl)amino]-5-(4-ethylpiperazin-1-yl)phenyl}prop-2-enamide [ No CAS ]
  • 14
  • [ 1702259-66-2 ]
  • [ 2025330-86-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In dimethyl sulfoxide; acetone at 20℃; for 168h; Sonication; 8 EXAMPLE 8: Preparation of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methyIureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l-yl)phenyl)acrylamide monohydrochloride crystals EXAMPLE 8: Preparation of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methyIureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l-yl)phenyl)acrylamide monohydrochloride crystals A solution (4 mL) of acetone containing 10% (v/v) DMSO was spiked with hydrochloric acid solution (2.76 μ, leq), added to N-(2((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l-yl)phenyl)acrylamide (20.25 mg), irradiated with ultrasound, and stirred at room temperature for 7 days. Resultant crystals were filtered off and washed with acetone to give N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l-yl)phenyl)acrylamide monohydrochloride crystals.
  • 15
  • [ 1702259-66-2 ]
  • [ 2025330-86-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In acetone at 20℃; for 96h; Sonication; 12 EXAMPLE 12: Preparation of N-(2-((6-(3-(2,6-dichIoro-3,5-dimethoxyphenyl)-l- methyIureido)pyrimidin-4-yl)amino)-5-( 4-ethylpiperazin-l-yl)phenyl)acryIamide dihydrochloride crystals EXAMPLE 12: Preparation of N-(2-((6-(3-(2,6-dichIoro-3,5-dimethoxyphenyl)-l- methyIureido)pyrimidin-4-yl)amino)-5-( 4-ethylpiperazin-l-yl)phenyl)acryIamide dihydrochloride crystals Acetone (3 mL) was spiked with hydrochloric acid solution ( 12.36 L, 3eq), added to N- (2((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)- l-methylureido)pyrimidin-4-yl)amino)-5-(4- ethylpiperazin-l-yl)phenyl)acrylamide (30.19 mg), in-adiated with ultrasound, and stirred at _ room temperature for 4 days. Resultant crystals were filtered off to give N-(2-((6-(3-(2,6- dichloro-3,5-dimethoxyphenyl)- l-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l- yl )phenyl)acrylamide dihydrochloride crystals.
  • 16
  • [ 594-45-6 ]
  • [ 1702259-66-2 ]
  • [ 2025330-88-3 ]
YieldReaction ConditionsOperation in experiment
103.7 mg In acetone at 20℃; for 168h; Sonication; 15 EXAMPLE 15: Preparation of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methylureido)pyrimidin-4-yl)amino)-5-(4-ethyIpiperazin-l-yl)phenyl)acrylamide ethanesulfonate EXAMPLE 15: Preparation of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methylureido)pyrimidin-4-yl)amino)-5-(4-ethyIpiperazin-l-yl)phenyl)acrylamide ethanesulfonate Acetone (5 mL) was spiked with ethanesulfonic acid solution (13.51 iL, l eq), added, to N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-methylurcido)pyrimidin-4-yl)amino) ethylpiperazin-l-yl)phenyl)acrylamide (100.6 mg), irradiated with ultrasound, and stirred at room temperature for 7 days. Resultant crystals were filtered off to give N-(2-((6-(3-(2,6- dichloro-3 ,5-dimethoxyphenyl)- 1 -methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin- 1 - yl)phenyl)acrylamide ethanesulfonate crystals (103.7 mg).
  • 17
  • [ 1228392-59-3 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)-palladium(II) / toluene / 95 - 105 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 3 h / 20 - 40 °C / Inert atmosphere 3.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / toluene / 1 h / 100 °C 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.2: 2 h / 0 - 20 °C 5.1: hydrogen / tetrahydrofuran; water; methanol / 3 h / 20 °C / 760.05 Torr 6.1: tetrahydrofuran / 1 h / -10 °C
  • 18
  • [ CAS Unavailable ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / dichloromethane / 1 h / 0 - 25 °C 1.2: 1 h / 0 - 25 °C 2.1: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 3.1: ammonium hydroxide / water; dichloromethane / 0 - 25 °C
  • 19
  • [ 2025330-85-0 ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C 2: ammonium hydroxide / water; dichloromethane / 0 - 25 °C
  • 20
  • [ CAS Unavailable ]
  • [ 1702259-66-2 ]
YieldReaction ConditionsOperation in experiment
29.56 g With ammonium hydroxide In dichloromethane; water at 0 - 25℃; 3.g g. Synthesis and Crystallization of Free Base Form of Compound 108 Crystalline Free Base Form of Compound 108 A stirred solution of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-methyl-.3-((2- (trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-l- yl)phenyl)acrylamide (1, 51g, 67.12 mol) in dichloromethane (102 mL) was cooled to 0-5 °C. To this solution was added trifluoroacetic acid (102 mL, 1585 mol, 23.6 equiv) at such rate as to maintain the internal temperature < 15 °C. Once addition was complete, the mixture was allowed to warm to room temperature and stirred for 3h, at which point HPLC analysis indicated complete reaction. The mixture was transferred to a second flask containing cold (0-5 °C) saturated ammonium hydroxide solution (550 mL), at such a rate as to maintain internal temperature < 25 °C. The mixture was allowed to stir for 5-10 mins, at which HPLC analysis indicated complete reaction. The mixture was transferred to a separatory funnel and extracted twice with dichloromethane/methanol (5: 1 , 600 mL) and once with dichloromethane/methanol (5: 1, 300 mL). The combined organic phases were concentrated to a minimum stirrable volume and acetonitrile (150 mL) was added. The resulting solid was slurried for 15 mins, then filtered. The solid cake was washed with acetonitrile (4 x 30 mL) and dried on the filter under vacuum with a nitrogen sweep to afford N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l- methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin- 1 -yl)phenyl)acrylamide (108, 29.56g, 70% yield) as a solid. -NMR (d6-DMSO): δ 1.04 (t, 7=7.15 Hz, 3H); 2.37 (m, 2H); 3.13 (m, 4H); 3.22 (m, 4H); 3.31 (s, 3H); 3.93 (s, 6H); 5.72 (dd, 1H, 7=10.27, 1.83 Hz); 6.23 (dd, 1H, 7=17.06, 1.83 Hz; br s, 1H); 6.48 (dd, 1H, 7=16.87, 10.27 Hz); 6.81 (dd, 1H, 7=8.99, 2.75 Hz); 6.89 (s, 1H); 7.29 (br d, 7=9.17 Hz, 2H); 8.32 (s, 1H); 8.71 (s, 1H); 9.58 (s, 1H) (FIGS. 9A-9C). Mass spec: [M+H]+ = 629.2. This was determined on a Varian Inova at 500 MHz.
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