698387-09-6

Basic information

• Product Name: Neratinib
• Synonyms: (2e)-n-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide;neratinib;(E)-N-[4-[3-Chloro-4-[(2-pyridinyl)methoxy]anilino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide;N-(4-(3-Chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide;Unii-jjh94R3pwb;Neratinib(HKI-272);(2E)-N-[4-[[3-chloro-4-(2-pyridinylMethoxy)phenyl]aMino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(diMethylaMino)-2-butenaMide;(2e)-n-(4-((3-chloro-4-((pyridin-2-yl)Methoxy)phenyl)aMino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(diMethylaMino)but-2-enaMide neratinib
• CAS NO: 698387-09-6
• Molecular Formula: C30H29ClN6O3
• Molecular Weight: 557.04266
• EINECS: 1308068-626-2
• Product Categories: Antineoplastic;Anti-cancer & immunity;Inhibitors;API
• Mol File: 698387-09-6.mol
• Article Data: 15

Chemical Properties

• Boiling Point: 756.97 °C at 760 mmHg
• Flash Point: 411.601 °C
• Appearance: /
• Density: 1.33
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.667
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly, Heated, Sonicated), Methanol (Slightly, Heated)
• PKA: 12.37±0.43(Predicted)
• CAS DataBase Reference: Neratinib(CAS DataBase Reference)
• NIST Chemistry Reference: Neratinib(698387-09-6)
• EPA Substance Registry System: Neratinib(698387-09-6)

Safety Data

• Hazardous Substances Data: 698387-09-6(Hazardous Substances Data)

Usage

New anticancer drug

Neratinib developed by US Wyeth company is an irreversible epidermal growth factor receptor(EGFR) inhibitor. It is a multiple target point of small molecule tyrosine kinase inhibitors to HER 2 and HER1 after Lapatinib, and is an irreversible ErbB receptor tyrosine kinase inhibitor. Neratinib could selectively inhibit HER-1 and HER-2 of EGFR family(IC50 was 92 nmol/L and 59 nmol/L, respectively). Clinical research showed that Neratinib exerted significant therapeutic effect on non-small cell lung cancer, colon cancer, and breast cancer. The phaseⅡclinical trial indicated that Neratinib showed good efficacy and tolerance to HER-2 positive patients with advanced breast cancer who had been received or not Trastuzumab treatment. The phase Ⅲ breast cancer clinical trial was complete in September 2014. The data indicated that the efficacy of Neratinib was better than Roche's Herceptin in treatment of HER-2 positive early breast cancer.

Genotoxicity

Neratinib and its metabolites were not genotoxic. Administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death, and fetal abnormalities at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose. Oral administration of neratinib to pregnant rats from gestation day 7 until lactation day 20 resulted in effects on long-term memory in male offspring at maternal doses less than the maximum recommended clinical dose on a mg/m2 basis. Neratinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice.

Clinical trial

Neratinib was tested in a phase II trial as monotherapy in 2 cohorts of patients with advanced HER2-positive breast cancer those with and those without previous trastuzumab treatment. Sixteen-week progression-free survival (PFS) rates were 59% for patients with previous trastuzumab treatment and 78% for patients with no previous trastuzumab treatment with a median PFS of 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with previous trastuzumab treatment and 56% in the trastuzumab-naive cohort.[4]

Synthesis pathways

3-chloro-4-(pyridin-2-yl-methoxy)-aniline (2) and N-(4-chloro-3-cyano-7-ethoxy-quinolin-6-yl)-acetamide (3) are used as raw material to prepare N-[4-[3-chloro-4-(pyridin-2-yl-methoxy) anilino]-3-cyano-7-ethoxy-quinolin-6-yl] acetamide (4) by nucleophilic substitution. Deprotection of 4 was under the effect of hydrochloric acid, then was precipitated the free base in methanol solution of potassium carbonate to prepare 6-amino-3-cyano-4-[3-chloro-4-(pyridin-2-yl-methoxy) anilino]-7-ethoxy-quinoline (5). Neratinib(1) was obtained by condensation of 5 and acyl chloride which was prepared by trans-4-dimethylamino-crotonic acid hydrochloride (6). Figure 1 Synthesis pathways of Neratinib

Side Effects

Diarrhea, nausea, vomiting, and fatigue.

Description

The receptor tyrosine kinase HER2 (ErbB2) is a key component of epidermal growth factor receptor complexes that are known to have central roles in cell proliferation and cancer. Neratinib is an orally active, irreversible inhibitor of the HER2 kinase (IC50 = 59 nM). It also potently inhibits several mutants of HER2 and shows 10-fold or greater selectivity over a wide variety of other kinases. As an irreversible inhibitor, neratinib may circumvent acquired resistance developed against reversible inhibitors, including gefitinib . Neratinib has been evaluated in clinical trials against cancers characterized by HER2 overexpression or HER2 activating mutations.

Uses

Different sources of media describe the Uses of 698387-09-6 differently. You can refer to the following data:
1. An oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Antitumor agent.
2. Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM, respectively.
3. An oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Antitumor agent

Definition

ChEBI: A quinoline compound having a cyano group at the 3-position, a 3-chloro-4-(2-pyridylmethoxy)anilino group at the 4-position, a 4-dimethylamino-trans-but-2-enamido group at the 6-position, and an ethoxy group at the 7-position.

InChI:InChI=1/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+

Synthetic route

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%

2-(N,N-dimethylamino)ethoxide (52334-92-6) + diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate (1269662-79-4) → neratinib (698387-09-6)

Conditions	Yield
Stage #1: diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate With sodium ethanolate; lithium chloride In ethanol at -5℃; for 0.5h; Stage #2: 2-(N,N-dimethylamino)ethoxide In ethanol for 0.666667h; Temperature; Solvent; Reagent/catalyst;	95.9%

dimethylaminoacetaldehyde diethyl acetal (3616-56-6) + diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate (1269662-79-4) → neratinib (698387-09-6)

Conditions	Yield
Stage #1: dimethylaminoacetaldehyde diethyl acetal With hydrogenchloride; water at 0 - 40℃; Inert atmosphere; Stage #2: diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate With sodium ethanolate; lithium chloride In ethanol; water at -20℃; for 3h;	95.2%

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%

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate (1269662-79-4) + dimethylaminoacetaldehyde-sodium bisulfite adduct → neratinib (698387-09-6)

Conditions	Yield
Stage #1: diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate With sodium ethanolate; lithium chloride In ethanol at 0℃; for 0.5h; Stage #2: dimethylaminoacetaldehyde-sodium bisulfite adduct In ethanol for 3h;	94.1%

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%

neratinib maleate → neratinib (698387-09-6)

Conditions	Yield
With sodium hydroxide In methanol	88.7%
With triethylamine In ethanol; acetonitrile at 73℃;

3-chloro-4-(2-pyridylmethoxy)aniline (524955-09-7) + 4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile (848133-88-0) → neratinib (698387-09-6)

Conditions	Yield
With pyridine hydrochloride In isopropyl alcohol Heating;	85%

2-chloro 4-aminophenol (3964-52-1) + 2-chloromethylpyridine hydrochloride (6959-47-3) + 4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile (848133-88-0) → neratinib (698387-09-6)

Conditions	Yield
Stage #1: 2-chloro 4-aminophenol; 2-chloromethylpyridine hydrochloride; 4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile In tetrahydrofuran at 65℃; for 6h; Inert atmosphere; Stage #2: With potassium carbonate; potassium iodide In tetrahydrofuran at 60℃; for 16h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	82.73%

4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline + (2E)-(N,N-dimethylamino)-2-butenoyl chloride (1056149-69-9) → neratinib (698387-09-6)

Conditions	Yield
Stage #1: 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline; (2E)-(N,N-dimethylamino)-2-butenoyl chloride With 1-methyl-pyrrolidin-2-one In tetrahydrofuran for 3 - 16h; Stage #2: With water In tetrahydrofuran at 40℃; Stage #3: With sodium hydroxide In tetrahydrofuran; water pH=10 - 11;	80%

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) + (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%

(2E)-(N,N-dimethylamino)-2-butenoyl chloride (1056149-69-9) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.97 g / 1-methyl-pyrrolidin-2-one / 2.5 h / 0 - 20 °C 2: 85 percent / pyridine hydrochloride / propan-2-ol / Heating View Scheme

4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile (214476-09-2) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: iron; AcOH; NaOAc / methanol / Heating 2: 7.97 g / 1-methyl-pyrrolidin-2-one / 2.5 h / 0 - 20 °C 3: 85 percent / pyridine hydrochloride / propan-2-ol / Heating View Scheme

4-chloro-6-amino-7-ethoxyquinoline-3-carbonitrile (848133-87-9) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.97 g / 1-methyl-pyrrolidin-2-one / 2.5 h / 0 - 20 °C 2: 85 percent / pyridine hydrochloride / propan-2-ol / Heating View Scheme

(E)-4-(dimethylamino)-2-butenoic acid hydrochloride → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl chloride; DMF / acetonitrile / 0.5 h / 60 °C 2: 7.97 g / 1-methyl-pyrrolidin-2-one / 2.5 h / 0 - 20 °C 3: 85 percent / pyridine hydrochloride / propan-2-ol / Heating View Scheme

N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / Reflux 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 3.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 3.2: 3 h / -20 °C View Scheme

2-chloro-4-nitrophenol (619-08-9) → neratinib (698387-09-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 50 - 60 °C 2.1: iron; ammonium chloride / ethanol; water / 1 h / Reflux 3.1: methanesulfonic acid / ethanol / 2 h / Reflux 4.1: hydrogenchloride; water / Reflux 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 6.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 6.2: 3 h / -20 °C View Scheme

2-chloromethylpyridine hydrochloride (6959-47-3) → neratinib (698387-09-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 50 - 60 °C 2.1: iron; ammonium chloride / ethanol; water / 1 h / Reflux 3.1: methanesulfonic acid / ethanol / 2 h / Reflux 4.1: hydrogenchloride; water / Reflux 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 6.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 6.2: 3 h / -20 °C View Scheme

2-((2-chloro-4-nitrophenoxy)methyl)pyridine (179687-79-7) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: iron; ammonium chloride / ethanol; water / 1 h / Reflux 2.1: methanesulfonic acid / ethanol / 2 h / Reflux 3.1: hydrogenchloride; water / Reflux 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 5.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 5.2: 3 h / -20 °C View Scheme

7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile (848133-76-6) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / ethanol / 2 h / Reflux 2.1: hydrogenchloride; water / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 4.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 4.2: 3 h / -20 °C View Scheme
Multi-step reaction with 3 steps 1: methanesulfonic acid / N,N-dimethyl-formamide / 70 - 75 °C 2: hydrogenchloride / water / 80 - 85 °C 3: sodium hydroxide / water; 1-methyl-pyrrolidin-2-one / 15 h / 10 - 40 °C View Scheme

3-chloro-4-(2-pyridylmethoxy)aniline (524955-09-7) → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / ethanol / 2 h / Reflux 2.1: hydrogenchloride; water / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 40 °C 4.1: hydrogenchloride; water / 0 - 40 °C / Inert atmosphere 4.2: 3 h / -20 °C View Scheme
Multi-step reaction with 3 steps 1: methanesulfonic acid / N,N-dimethyl-formamide / 70 - 75 °C 2: hydrogenchloride / water / 80 - 85 °C 3: sodium hydroxide / water; 1-methyl-pyrrolidin-2-one / 15 h / 10 - 40 °C View Scheme

Conditions	Yield
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

Conditions	Yield
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

3-chloro-4-[(pyridin-2-yl)methoxy]-1-p-toluenesulfonyloxybenzene → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-nitro-3-cyano quinoline → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: platinum on carbon; hydrogen / tetrahydrofuran / 6 h / 25 - 30 °C / 1292.9 Torr 2: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

4-amino-7-ethoxy-3-cyano-6-nitro quinoline → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

2-((4-bromo-2-chlorophenoxy)methyl)pyridine → neratinib (698387-09-6)

Conditions	Yield
Multi-step reaction with 3 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 3: triethylamine / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere View Scheme

maleic acid (110-16-7) + neratinib (698387-09-6) → (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide maleate

Conditions	Yield
In ethanol; water at 20℃; for 1h; Inert atmosphere;	98%
With pyrographite In water; acetone at 20 - 40℃; for 0.666667h; Temperature; Solvent;	87.7%
In water; isopropyl alcohol Product distribution / selectivity;	84%

neratinib (698387-09-6) → (E)-4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-N,N-dimethyl-4-oxobut-2-en-1-amine oxide (1376615-55-2)

Conditions	Yield
Stage #1: neratinib With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	10%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h;	10%

maleic acid (110-16-7) + neratinib (698387-09-6) → neratinib maleate monohydrate (1144516-12-0)

Conditions	Yield
With water In propan-1-ol at 25 - 60℃; Product distribution / selectivity;

Upstream product

• 69838-67-1 2-(4-phenylpiperazin-1-yl)ethyl 2-[(7-chloro-2-methylquinolin-4-yl)amino]benzoate dihydrochloride 
• 69838-66-0 3-(4-phenylpiperazin-1-yl)propyl 2-[(7-chloroquinolin-4-yl)amino]benzoate dihydrochloride 
• 69838-65-9 1-methyl-2-(4-phenylpiperazin-1-yl)ethyl 2-[(7-chloroquinolin-4-yl)amino]benzoate dihydrochloride 
• 69838-64-8 2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl 2-[(3-chloro-2-methylphenyl)amino]pyridine-3-carboxylate dihydrochloride 
• 69838-63-7 2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl 2-({3-[(trifluoromethyl)sulfanyl]phenyl}amino)pyridine-3-carboxylate dihydrochloride 
• 69838-62-6 2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl 2-({3-[(trifluoromethyl)sulfanyl]phenyl}amino)pyridine-3-carboxylate dihydrochloride 
• 69838-61-5 2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl 2-({3-[(trifluoromethyl)sulfanyl]phenyl}amino)benzoate dihydrochloride 
• 69838-60-4 2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl 2-({3-[(trifluoromethyl)sulfanyl]phenyl}amino)benzoate dihydrochloride 
• 69838-57-9 2-(4-phenylpiperazin-1-yl)ethyl 2-{[3-(trifluoromethyl)phenyl]amino}benzoate dihydrochloride 
• 69838-52-4 2-CHLORO-N-[4-(3-METHYLPHENOXY)PHENYL]ACETAMIDE 
• 6983-79-5 BIXIN 
• 698379-36-1 2-Propenal,3-(2-aminophenyl)-,(2E)-(9CI) 
• 69837-92-9 2-(4-METHYLPIPERAZINO)-N-(4-PHENOXYPHENYL)ACETAMIDE 
• 698379-20-3 (1R)-1-(3-CHLOROPHENYL)BUTYLAMINE 

Downstream Products

• 69838-71-7 2-[4-(3-chlorophenyl)piperazin-1-yl]ethyl 2-{[8-(trifluoromethyl)quinolin-4-yl]amino}benzoate dihydrochloride 
• 69838-72-8 2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl 2-{[8-(trifluoromethyl)quinolin-4-yl]amino}benzoate dihydrochloride 
• 698387-41-6 Ethyl Cyanoacetate-13C 
• 698387-65-4 1H-Indole,1-ethyl-2,3-dihydro-5-methoxy-3,3-dimethyl-2-methylene-(9CI) 
• 698387-81-4 (2E,4E)-6-(4-CHLORO-PHENYLSULFANYL)-HEXA-2,4-DIENOIC ACID HYDROXYAMIDE 
• 698388-01-1 POLY(DI(ETHYLENE GLYCOL) PHTHALATE) 
• 698388-27-1 Propanenitrile, 3-[3-(1H-imidazol-5-yl)propoxy]- 
• 69838-86-4 BENZYL-ALPHA-13C BROMIDE 
• 698388-71-5 2,4-Piperidinedione,3,3-diethyl-1-propyl-(9CI) 
• 698388-84-0 2,4-Piperidinedione, 1-(4-methylphenyl)-6-thioxo- 
• 69838-89-7 4-METHOXYBENZOIC ACID-ALPHA-13C 
• 698389-00-3 Rolipoltide 
• 698389-70-7 4-{4-[2-(benzyloxy)ethoxy]-4-methyl-2-hexynyl}morpholine 
• 698389-73-0 1-{4-[2-(benzhydryloxy)ethoxy]-4-methyl-2-pentynyl}piperidine 

Recommend Products

• 524955-09-7  3-chloro-4-(2-pyridylmethoxy)aniline 
• 848133-88-0  4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile 
• 52334-92-6  2-(N,N-dimethylamino)ethoxide 
• 1269662-79-4  diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate 
• 1056149-69-9  (2E)-(N,N-dimethylamino)-2-butenoyl chloride 
• 848133-87-9  6-amino-4-chloro-7-ethoxyquinoline-3-carbonitrile 
• 214476-09-2  4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile 
• 848139-78-6  6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile 
• 501332-27-0  4-N,N-dimethylaminocrotonoylchloride Hydrochloride 
• 110-16-7  maleic acid 
• 1130155-48-4  (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride 
• 3964-52-1  2-chloro 4-aminophenol 
• 6959-47-3  2-chloromethylpyridine hydrochloride