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
• Article Data: 13

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

Description

6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile is a quinoline derivative, a class of nitrogen-containing heterocyclic compounds known for their diverse range of biological activities and applications in medicinal chemistry. This specific compound features a chlorinated phenyl ring connected to a pyridine moiety through an ether linkage, and an ethoxy group attached to the quinoline core. The presence of an amino and carbonitrile functional group further contributes to its potential reactivity and use in chemical synthesis.

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

• 524955-09-7 3-chloro-4-(2-pyridylmethoxy)aniline 
• 4377-33-7 2-chloromethylpyridine 
• 848133-75-5 3-cyano-4-hydroxyl-6-acetamido-7-ethoxyquinoline 
• 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 
• 3964-52-1 2-chloro 4-aminophenol 

Downstream Products

• 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 
• 1246089-97-3 pyrotinib 
• 698387-09-6 neratinib 
• 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 
• 1269662-69-2 (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 

Relevant articles and documents

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

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