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

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

Uses

Used in Oncology:
Neratinib is used as an antitumor agent for the treatment of breast and non-small cell lung cancer. It functions as a highly selective HER2 and EGFR inhibitor, with IC50 values of 59 nM and 92 nM, respectively. This makes it a valuable drug for targeting cancers with HER2 overexpression or HER2 activating mutations, potentially offering an effective treatment option for patients with these types of cancer.

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. The above information is edited by the lookchem of Liu Yujie.

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.

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

• 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 
• 1056149-69-9 (2E)-(N,N-dimethylamino)-2-butenoyl chloride 
• 214476-09-2 4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile 
• 848133-87-9 6-amino-4-chloro-7-ethoxyquinoline-3-carbonitrile 
• 1130155-48-4 (E)-4-(dimethylamino)-2-butenoic acid hydrochloride 
• 848139-78-6 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile 
• 1055943-40-2 trans-4-dimethylamino crotonic acid chloride hydrochloride salt 
• 915941-95-6 N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide 
• 619-08-9 2-chloro-4-nitrophenol 
• 6959-47-3 2-chloromethylpyridine hydrochloride 
• 179687-79-7 2-((2-chloro-4-nitrophenoxy)methyl)pyridine 
• 3616-56-6 dimethylaminoacetaldehyde diethyl acetal 
• 1269662-79-4 diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate 

Downstream Products

• 1144516-12-0 neratinib maleate monohydrate 
• 1376615-55-2 (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 

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.

Preparation method of neratinib

The invention relates to a preparation method of neratinib. The preparation method specifically comprises the steps: (1) in an organic solvent 1, trans-4-dimethylaminocrotonic acid hydrochloride and achloride agent react, and thus a solution containing (e)-4-(dimethylamino)but-2-enoyl chloride (hydrochloride) is obtained; (2) a solution of an organic solvent 2 containing 6-amino-4-[[3-chloro-4-[(pyridine-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline is added into the solution obtained in the step (1) to react, and then neratinib hydrochloride is obtained; and (3) the neratinib hydrochloride obtained in the step (2) is mixed with water and an organic solvent 3, a reaction is carried out after the pH value is regulated to be 7-10, and then the neratinib is obtained. The synthesis method has the advantages that the yield is high, the product purity is high, the production cost is low, operation is safe, easy and convenient, and large-scale industrial production is easy.

SOLID STATE FORMS OF NERATINIB AND SALTS THEREOF

Solid state forms of Neratinib and salts thereof, processes for preparation thereof and pharmaceutical compositions thereof are disclosed.

Crystal forms and preparation method of neratinib free alkali

The invention relates to crystal forms and a preparation method of neratinib free alkali. Specifically, the invention discloses new crystal forms of a compound shown in a formula (I) or a solvate thereof, namely a crystal form III, a crystal form IV, a crystal form V and a crystal form VI respectively. The new crystal forms disclosed by the invention are beneficial to separation and purification of a compound free alkali shown in the formula (I), and process efficiency and chemical quality of a product are greatly improved. (The formula (I) is as shown in the description.).

A to that of the preparation method of the Buddhist

The invention relates to the field of pharmaceuticals, in particular to a preparation method of neratinib. The preparation method specifically includes: successively condensing 6-[(E)-4-(dimethylamino)-2-butenamido]-7-ethoxy-4-chloro-3-cyanoquinoline (I) with 2-chloro-4-aminophenol (II) and 2-(chloromethyl)pyridine hydrochloride (III) through an intermediate (E)-N-{4-[3-chloro-4-hydroxyanilino]3-cyano-7-ethoxy-6-quinoline}-4-dimethylamino-2-butenamide (IV). The materials in the preparation method are easy to obtain, and the preparation method is simple, green and economical and has greatly worthy of application.

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.

Method for purifying neratinib

The invention relates to a method for purifying neratinib. The method provided by the invention is capable of effectively reducing the content of impurities in neratinib and preparing high-purity neratinib, and moreover is simple in operation, high in yield and very applicable to industrial production.

Method for preparing Neratinib

The invention relates to a preparation method for neratinib. Specifically, N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethyl phosphate-acetamide reacts with 2,2-diethoxy-N,N-dimethylethylamine or 2-(dimethylamino)acetaldehyde in the presence of a lithium salt and an alkali to produce neratinib. The method provided by the invention has the advantages of high yield, mild reaction conditions, usage of common and commercially available reagents, a low price, suitability for industrial production and good economic prospects.

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.

IMPROVED PROCESS FOR PREPARATION OF COUPLED PRODUCTS FROM 4-AMINO-3-CYANOQUINOLINES USING STABILIZED INTERMEDIATES

This invention discloses improved methods for coupling a 4-(amino)-2-butenoyl group to an amino group at the 6- or 7-position of a 4-amino-3-quinolinecarbonitrile by generating a stabilized 4-(amino)-2-butenoyl chloride hydrochloride.