848139-78-6

Basic information

• Product Name: 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile
• Synonyms: 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile;6-AMino-4-((3-chloro-4-(pyridin-2-ylMethoxy)phenyl)aMino)-7-ethoxyquinoline-3-carbonitrile (Hydrochloride);3-Quinolinecarbonitrile, 6-aMino-4-[[3-chloro-4-(2-pyridinylMethoxy)phenyl]aMino]-7-ethoxy-;4-[4-[(2-Pyridyl)methoxy]-3-chloroanilino]-6-amino-3-cyano-7-ethoxyquinoline;6-Amino-4-[3-chloro-4-[(2-pyridinyl)methoxy]anilino]-3-cyano-7-ethoxyquinoline;6-amino-4-[3-chloro-4-(2-pyridylmethoxy)anilino]-7-ethoxy-quinoline-3-carbonitrile;Neratinib Intermediate3;6-amino-4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-ethoxyquinoline-3-carbonitrile
• CAS NO: 848139-78-6
• Molecular Formula: C₂₄H₂₀ClN₅O₂
• Molecular Weight: 446
• EINECS: 1592732-453-0
• Mol File: 848139-78-6.mol

Chemical Properties

• Boiling Point: 649.8±55.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Dichloromethane (Slightly), DMSO (Slightly)
• PKA: 5.09±0.50(Predicted)
• CAS DataBase Reference: 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile(848139-78-6)
• EPA Substance Registry System: 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile(848139-78-6)

Safety Data

• Hazardous Substances Data: 848139-78-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile is used as a pharmaceutical intermediate for the synthesis of various therapeutic agents. Its unique structural features allow it to serve as a building block in the development of new drugs targeting a range of diseases, including infectious diseases, cancer, and neurological disorders.
As a pharmaceutical intermediate, this quinoline derivative can be further modified or used in the synthesis of more complex molecules with specific biological activities. Its potential applications may include the development of antimicrobial agents, anticancer drugs, or central nervous system therapeutics, depending on the specific modifications and the resulting properties of the final compounds.

InChI:InChI=1S/C24H20ClN5O2/c1-2-31-23-11-21-18(10-20(23)27)24(15(12-26)13-29-21)30-16-6-7-22(19(25)9-16)32-14-17-5-3-4-8-28-17/h3-11,13H,2,14,27H2,1H3,(H,29,30)

Synthetic route

4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-nitro-3-cyano quinoline → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
With platinum on carbon; hydrogen In tetrahydrofuran at 25 - 30℃; under 1292.9 Torr; for 6h; Pressure; Temperature; Reagent/catalyst; Solvent;	96%

3-cyano-4-[3-chloro-4-(2-pyridinylmethoxy)]anilino-7-ethoxy-N-phthalimidylquinoline → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
With ammonia In ethanol; water at 62 - 68℃; for 2h;	92%
With ethanolamine In water; acetonitrile at 50℃; for 3h; Temperature;

N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
With hydrogenchloride In water for 5h; Reflux;	78%
With hydrogenchloride; water for 2h; Reflux;	68%
Stage #1: N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide With hydrogenchloride; water Reflux; Stage #2: With potassium carbonate In water
With hydrogenchloride In water at 80 - 85℃; Solvent;

C19H17ClN4O4 + 3-chloro-4-(2-pyridylmethoxy)aniline (524955-09-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + C31H27ClN6O5 + C31H29ClN6O6

Conditions	Yield
With toluene-4-sulfonic acid In acetonitrile at 80℃; for 6h; Reagent/catalyst; Temperature;	A 11.2% B 48% C 16.5%
With trifluoroacetic acid In acetonitrile at 60℃; for 6h;	A 22.6% B 34% C 10.8%

4-[3-chloro-4-(2-pyridylmethoxy)anilino]-3-cyano-7-ethoxy-6-aminoquinoline hydrochloride (915942-01-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
With potassium carbonate In methanol; water for 2.5h; pH=9 - 10;

3-chloro-4-(2-pyridylmethoxy)aniline (524955-09-7) + 7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile (848133-76-6) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Stage #1: 3-chloro-4-(2-pyridylmethoxy)aniline; 7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile With methanesulfonic acid In ethanol for 6h; Reflux; Stage #2: With hydrogenchloride; water In ethanol at 80℃; for 19h; Stage #3: With potassium carbonate In methanol for 3h;

N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (1201080-09-2, 848133-75-5) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: trichlorophosphate / diethylene glycol dimethyl ether / 100 °C 2: pyridine hydrochloride / isopropyl alcohol / Reflux 3: hydrogenchloride / water / 5 h / Reflux View Scheme

2-chloro 4-aminophenol (3964-52-1) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzaldehyde / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: 24 h / 50 °C 2.1: pyridine hydrochloride / isopropyl alcohol / Reflux 3.1: hydrogenchloride / water / 5 h / Reflux View Scheme

N-(2-hydroxy-4-nitrophenyl)acetamide (25351-89-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: potassium carbonate / N,N-dimethyl-formamide / 60 °C 2: palladium on activated charcoal; hydrogen / tetrahydrofuran / 20 °C 3: toluene / 90 °C 4: diphenyl ether-biphenyl eutectic / 250 °C 5: trichlorophosphate / diethylene glycol dimethyl ether / 100 °C 6: pyridine hydrochloride / isopropyl alcohol / Reflux 7: hydrogenchloride / water / 5 h / Reflux View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate / N,N-dimethyl-formamide / 60 °C 2: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 53 h / 28 - 30 °C / 2585.81 Torr 3: toluene / 16 h / 90 °C 4: 20 h / 250 - 255 °C 5: trichlorophosphate / diethylene glycol dimethyl ether / 0.75 h / 100 - 102 °C 6: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 7: hydrogenchloride; water / 2 h / Reflux View Scheme

4-acetamido-3-ethoxynitrobenzene (116496-76-5) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: palladium on activated charcoal; hydrogen / tetrahydrofuran / 20 °C 2: toluene / 90 °C 3: diphenyl ether-biphenyl eutectic / 250 °C 4: trichlorophosphate / diethylene glycol dimethyl ether / 100 °C 5: pyridine hydrochloride / isopropyl alcohol / Reflux 6: hydrogenchloride / water / 5 h / Reflux View Scheme
Multi-step reaction with 6 steps 1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 53 h / 28 - 30 °C / 2585.81 Torr 2: toluene / 16 h / 90 °C 3: 20 h / 250 - 255 °C 4: trichlorophosphate / diethylene glycol dimethyl ether / 0.75 h / 100 - 102 °C 5: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 6: hydrogenchloride; water / 2 h / Reflux View Scheme

2-chloromethylpyridine hydrochloride (6959-47-3) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzaldehyde / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: 24 h / 50 °C 2.1: pyridine hydrochloride / isopropyl alcohol / Reflux 3.1: hydrogenchloride / water / 5 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 50 - 60 °C 2: iron; ammonium chloride / ethanol; water / 1 h / Reflux 3: methanesulfonic acid / ethanol / 2 h / Reflux 4: hydrogenchloride; water / Reflux View Scheme

7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile (848133-76-6) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine hydrochloride / isopropyl alcohol / Reflux 2: hydrogenchloride / water / 5 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: methanesulfonic acid / ethanol / 2 h / Reflux 2: hydrogenchloride; water / Reflux View Scheme
Multi-step reaction with 2 steps 1: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 2: hydrogenchloride; water / 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: methanesulfonic acid / N,N-dimethyl-formamide / 70 - 75 °C 2: hydrogenchloride / water / 80 - 85 °C View Scheme

3-(4-acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester (848133-74-4) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: diphenyl ether-biphenyl eutectic / 250 °C 2: trichlorophosphate / diethylene glycol dimethyl ether / 100 °C 3: pyridine hydrochloride / isopropyl alcohol / Reflux 4: hydrogenchloride / water / 5 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: 20 h / 250 - 255 °C 2: trichlorophosphate / diethylene glycol dimethyl ether / 0.75 h / 100 - 102 °C 3: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 4: hydrogenchloride; water / 2 h / Reflux View Scheme

2-chloro-4-nitrophenol (619-08-9) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 50 - 60 °C 2: iron; ammonium chloride / ethanol; water / 1 h / Reflux 3: methanesulfonic acid / ethanol / 2 h / Reflux 4: hydrogenchloride; water / Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide 2: iron; ammonium chloride / ethanol; water / Reflux 3: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 4: hydrogenchloride; water / 2 h / Reflux View Scheme

2-((2-chloro-4-nitrophenoxy)methyl)pyridine (179687-79-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: iron; ammonium chloride / ethanol; water / 1 h / Reflux 2: methanesulfonic acid / ethanol / 2 h / Reflux 3: hydrogenchloride; water / Reflux View Scheme
Multi-step reaction with 3 steps 1: iron; ammonium chloride / ethanol; water / Reflux 2: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 3: hydrogenchloride; water / 2 h / Reflux View Scheme

1,3-dichloro-4-(pyridin-2-ylmethoxy)benzene (1417558-24-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid / methanol / 4 h / 20 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme

2-(4-trifluoromethane-sulfonyloxy-2-chlorophenoxy)methyl pyridine → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / N,N-dimethyl-formamide / 1 h / 150 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme

3-chloro-4-[(pyridin-2-yl)methoxy]-1-p-toluenesulfonyloxybenzene → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / acetonitrile / 6 h / -20 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme

4-amino-7-ethoxy-3-cyano-6-nitro quinoline → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / N,N-dimethyl-formamide / 1 h / 150 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid / methanol / 4 h / 20 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / acetonitrile / 6 h / -20 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme
Multi-step reaction with 2 steps 1: methanesulfonic acid / ethanol / 2 h / 70 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme

2-((4-bromo-2-chlorophenoxy)methyl)pyridine → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanesulfonic acid / ethanol / 2 h / 70 °C / Inert atmosphere 2: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr View Scheme

3-cyano-4-hydroxyl-6-acetamido-7-ethoxyquinoline (848133-75-5) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: trichlorophosphate / diethylene glycol dimethyl ether / 0.75 h / 100 - 102 °C 2: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 3: hydrogenchloride; water / 2 h / Reflux View Scheme

2-chloromethylpyridine (4377-33-7) → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide 2: iron; ammonium chloride / ethanol; water / Reflux 3: pyridine hydrochloride / isopropyl alcohol / 16 h / Reflux 4: hydrogenchloride; water / 2 h / Reflux View Scheme

C32H24ClN5O5 → 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphoric acid; trichlorophosphate / acetonitrile / 4 h / 60 °C / Reflux 2: ethanolamine / acetonitrile; water / 3 h / 50 °C View Scheme

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 2-chloropropionyl chloride (625-36-5) → 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide (1233953-82-6)

Conditions	Yield
at 50℃; for 16h;	100%
at 50℃;	99%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + diethylphosphonoacetic acid (3095-95-2) → diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate (1269662-79-4)

Conditions	Yield
Stage #1: diethylphosphonoacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 40℃; for 0.5h; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran at 40℃; for 12h;	99.9%
Stage #1: diethylphosphonoacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 40℃; for 0.5h; Inert atmosphere; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran at 40℃; for 12h; Inert atmosphere;	99.9%
Stage #1: diethylphosphonoacetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 40℃; for 0.5h; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran at 40℃; for 12h;	99.9%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 4-N,N-dimethylaminocrotonoylchloride Hydrochloride (501332-27-0) → neratinib (698387-09-6)

Conditions	Yield
With sodium hydroxide In 1-methyl-pyrrolidin-2-one; water at 10 - 40℃; for 15h; Solvent;	98%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (E)-4-(dimethylamino)-2-butenoic acid hydrochloride → neratinib hydrochloride

Conditions	Yield
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With trichlorophosphate In 1-methyl-pyrrolidin-2-one at -15 - 20℃; for 1h; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In 1-methyl-pyrrolidin-2-one at -15 - -10℃; for 1h; Reagent/catalyst; Temperature;	95.16%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride → neratinib (698387-09-6)

Conditions	Yield
Stage #1: (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 5℃; Inert atmosphere; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In 1-methyl-pyrrolidin-2-one; dichloromethane at 10 - 25℃;	95%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + trans-4-dimethylamino crotonic acid chloride hydrochloride salt (1055943-40-2) → neratinib (698387-09-6)

Conditions	Yield
With triethylamine In tetrahydrofuran at 0 - 10℃; for 1h; Reagent/catalyst; Inert atmosphere;	93%
In 1-methyl-pyrrolidin-2-one at -25 - -20℃; for 5h; Temperature;	86.72%
In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 5℃; for 5h; Product distribution / selectivity;	68%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 1-cyclohexenoyl chloride (36278-22-5) → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)cyclohex-1-ene-1-carboxamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	89.9%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + cyclopent-1-enecarbonyl chloride (59253-90-6) → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)cyclopent-1-ene-1-carboxamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	83%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + acryloyl chloride (814-68-6) → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide (1360430-67-6)

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	83%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 4-(pyrrolidin-1-yl)butanoic acid hydrochloride (49637-21-0) → N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(pyrrolidin-1-yl)butanamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	82%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + C8H13NO2 → (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2R)-1-methylpyrrolidin-2-yl]propan-2-enoylamine (1269662-73-8)

Conditions	Yield
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In 1-methyl-pyrrolidin-2-one at 20 - 25℃; Large scale;	80.3%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) → neratinib (698387-09-6)

Conditions	Yield
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 30℃; for 2h; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 5℃; for 3 - 16h;	80%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 2-bromoacetyl chloride (22118-09-8) → 2-bromo-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	72.8%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (E)-4-oxopent-2-enoic chloride (14300-75-5) → (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-oxopent-2-enamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	61%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + acid chloride of 2-pyridineacrylic acid (749838-53-7) → (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(pyridin-2-yl)acrylamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	61%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 3-bromo-5-isoxazolecarboxylic acid chloride (76596-52-6) → C28H20BrClN6O4

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	57.8%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 4-[N-(t-butyloxycarbonyl)methylamino]crotonic acid → (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-[N-(t-butyloxycarbonyl)methylamino]-2-butenamide

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 10℃; for 132h;	56%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (E)-4-(dimethylamino)-2-butenoic acid hydrochloride → neratinib (698387-09-6)

Conditions	Yield
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 30℃; for 2.25h; Stage #2: 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 10℃; for 20.5h;	52%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (E)-2-cyano-3-(pyridin-3-yl)acryloyl chloride → (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-cyano-3-(pyridin-3-yl)acrylamide

Conditions	Yield
With trimethylamine In dichloromethane at 0 - 20℃;	48.9%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + chloroacetyl chloride (79-04-9) → 2-chloro-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	46.1%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + C5H6ClNO3 → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-3-methoxy-4,5-dihydroisoxazole-5-carboxamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	42%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + cyanoacetic acid chloride (16130-58-8) → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-cyanoacetamide

Conditions	Yield
With trimethylamine In dichloromethane at 0 - 20℃;	36.8%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + acrylic acid (79-10-7) → N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide (1360430-67-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 1h;	35%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + (E)-4-oxobut-2-enoyl chloride → (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-oxobut-2-enamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	30.1%

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (848139-78-6) + 3-chloro-4,5-dihydroisoxazole-5-carbonyl chloride → 3-chloro-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4,5-dihydroisoxazole-5-carboxamide

Conditions	Yield
With trimethylamine In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	25.1%

Upstream product

• 1201080-09-2 N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide 
• 915941-95-6 N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide 
• 524955-09-7 3-chloro-4-(2-pyridylmethoxy)aniline 
• 4377-33-7 2-chloromethylpyridine 
• 1417558-24-7 1,3-dichloro-4-(pyridin-2-ylmethoxy)benzene 
• 179687-79-7 2-((2-chloro-4-nitrophenoxy)methyl)pyridine 
• 619-08-9 2-chloro-4-nitrophenol 
• 848133-74-4 3-(4-acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester 
• 848133-76-6 7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile 
• 848655-78-7 4-acetamido-3-ethoxyaniline 
• 121-88-0 5-Nitro-2-aminophenol 
• 6959-47-3 2-chloromethylpyridine hydrochloride 
• 116496-76-5 4-acetamido-3-ethoxynitrobenzene 
• 25351-89-7 N-(2-hydroxy-4-nitrophenyl)acetamide 

Downstream Products

• 698387-09-6 neratinib 
• 1233953-82-6 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide 
• 1259519-18-0 (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)aniline]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethyl-d6-amino)-2-butenamide 
• 1233953-81-5 N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(dimethylamino)propanamide 
• 1233953-83-7 N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)-3-piperidin-1-ylpropanamide 
• 1360430-68-7 N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)-3-morpholinopropanamide 
• 1360430-67-6 N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acrylamide 
• 1269662-69-2 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2S)-1-methylpyrrolidin-2-yl]propan-2-enoylamine 
• 1269662-70-5 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2S)-pyrrolidin-2-yl]propan-2-enoylamide 
• 1269662-80-7 (2S)-2-[(E)-3-[[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]amino]-3-oxopropen-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester 
• 1269662-71-6 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]propan-2-enoylamine 
• 1269662-81-8 (E)-3-[(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methylpyrrolidin-2-yl]-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]prop-2-enoylamine 
• 1269662-73-8 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2R)-1-methylpyrrolidin-2-yl]propan-2-enoylamine 
• 1269662-74-9 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-(1-methyl-2-piperidinyl)prop-2-enoylamine 

Relevant articles and documents

Neratinib intermediate crystal as well as preparation method and application thereof

The invention relates to a neratinib intermediate crystal as well as a preparation method and application thereof. The invention especially relates to a crystal form II of an intermediate A compound 6-amino-4-(3-chloro-4-(pyridine-2-substituted methoxy) aniline)-7-ethoxyquinoline carbonitrile. The crystal form II comprises diffraction peaks with diffraction angles 2 theta of 6.3 degrees, 7.8 degrees, 14.0 degrees, 15.1 degrees, 17.1 degrees, 18.8 degrees, 21.5 degrees, 22.2 degrees, 23.4 degrees and 27.5 degrees in an XRPD spectrum. When the intermediate crystal form II is used for preparing the neratinib, the dosage of a solvent can be remarkably reduced, the reaction time is shortened, the yield is increased, and meanwhile, the residual quantity of the intermediate A in a final product is remarkably reduced.

Synthesis method of pyrrotinib maleate intermediate

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of a pyrrotinib maleate intermediate. The synthesis method comprises the following steps: by taking a formula II as an initial raw material, reacting the formula II with cyanoacetamide under the action of a sulfonic acid compound to obtain a compound shown in a formula III; carrying out heating reflux reaction on the compound as shown in the formula III, 4-nitro-3-ethoxyaniline and triethyl orthoformate, and obtaining a solid intermediate product after the reaction is finished; subjecting the obtained solid intermediate product and Lewis acid to a heating ring closing reaction to obtain a compound shown in a formula IV; and carrying out reduction reaction on the compound as shown in the formula IV, hydrazine hydrate and activated carbon under the action of a catalyst to prepare the compound as shown in the formula I, namely the pyrrotinib maleate intermediate disclosed by the invention. The method is short in reaction route, high in yield, simple and convenient to operate, free of extreme reaction conditions and expensive raw materials, lower in production cost and beneficial to industrial production.

Preparation method of 3-cyano-4-anilino-6-aminoquinoline derivative

The invention discloses a preparation method of a 3-cyano-4-anilino-6-aminoquinoline derivative. According to the preparation method, zinc nitrate is carefully selected as a specific catalyst and is combined with a specific solvent and a specific reaction temperature, so that few byproducts are produced in the preparation process, products of -CN hydrolysis and side chain amide hydrolysis in quinoline rings do not exist in the products basically, and the yield of a target product is high. The method has the advantages of mild reaction process, high safety and no use of specific equipment, andis suitable for industrial production. The preparation method has the advantages of simplicity, cheap and easily available raw materials, mild reaction conditions, no need of large equipment, high final product yield and high purity, and is suitable for industrial popularization.

Preparation Method for Tyrosine Kinase Inhibitor and Intermediate Thereof

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Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro

The discovery and development of a novel HER-2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer are presented in this article. EGFR family has been recognized as a crucial meditator in the cancer progression; HER-2 tyrosine kinase was one of the members among them. In the effort to explore potent HER-2 inhibitors, a novel series of 4-anilino-3-cyanoquinoline derivatives have been designed, synthesized and evaluated. Most compounds possessed modest proliferation inhibition on SK-BR-3 cell line and HER-2 kinase. Compound 16 appeared to be the most potent compound (HER-2 kinase IC50: 19.4?nM, SK-BR-3 IC50: 94?nM). In the experiment of cellular cytotoxicity assay, compound 16 shows a much lower cytotoxicity than neratinib on Beas-2b cell line (Human bronchial epithelial cells). In conclusion, compound 16 would be a promising lead compound for further anti-breast cancer drug discovery.

Preparation method of antineoplastic drug maleic acid neratinib

The invention provides a preparation method of antineoplastic drug maleic acid neratinib. The defects in the prior art are overcome. The preparation method comprises the steps that the formula II and the formula III are coupled to form the formula IV under the effect of a catalyst; a nitro-compound IV is reduced under the effect of a reduction system to form a formula V; an amino compound V and a formula VI are condensed to obtain neratinib VII, and then the neratinib VII and maleic acid form a salt to obtain the maleic acid neratinib I. By the adoption of the technical route, the preparation method has the advantages that the synthetic route is short, reaction conditions are mild, the yield is high, raw materials are wide in source, and environmental protection is achieved.

Quinoline and quinazoline derivatives, preparation method, intermediate, composition and use thereof (by machine translation)

The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.

The Wittig-Horner reaction for the synthesis of neratinib

The Wittig-Horner reaction is a classic method to get alkenes by reaction phosphonates with carbonyl compounds. In this study, it was used for the synthesis of the anticancer drug neratinib. In this method, ethyl diethoxyphosphinylacetate and dimethylaminoacetaldehyde diethylacetal, replacing (E)-4-(dimethylamino)but-2-enoyl acid hydrochloride and oxalyl chloride, were used to synthesize the 6-position side chain of neratinib.

Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

SUBSTITUTED HETEROCYCLIC COMPOUNDS AS KINASES INHIBITORS AND METHOD OF USE THEREOF

The present invention is directed to novel quinolines and quniazolines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof which are useful for the treatment of protein kinases mediated diseases and conditions. The compounds of this invention have a general Formula (I) wherein R1 to R11 and X are defined herein.