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698387-09-6 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. 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.

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.

Check Digit Verification of cas no

The CAS Registry Mumber 698387-09-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,9,8,3,8 and 7 respectively; the second part has 2 digits, 0 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 698387-09:
(8*6)+(7*9)+(6*8)+(5*3)+(4*8)+(3*7)+(2*0)+(1*9)=236
236 % 10 = 6
So 698387-09-6 is a valid CAS Registry Number.
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+

698387-09-6Synthetic route

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

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile

4-N,N-dimethylaminocrotonoylchloride Hydrochloride
501332-27-0

4-N,N-dimethylaminocrotonoylchloride Hydrochloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

2-(N,N-dimethylamino)ethoxide

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate
1269662-79-4

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

dimethylaminoacetaldehyde diethyl acetal

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate
1269662-79-4

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile

(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride

(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate

dimethylaminoacetaldehyde-sodium bisulfite adduct

dimethylaminoacetaldehyde-sodium bisulfite adduct

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile

trans-4-dimethylamino crotonic acid chloride hydrochloride salt
1055943-40-2

trans-4-dimethylamino crotonic acid chloride hydrochloride salt

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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 maleate

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
With sodium hydroxide In methanol88.7%
With triethylamine In ethanol; acetonitrile at 73℃;
3-chloro-4-(2-pyridylmethoxy)aniline
524955-09-7

3-chloro-4-(2-pyridylmethoxy)aniline

4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile
848133-88-0

4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
With pyridine hydrochloride In isopropyl alcohol Heating;85%
2-chloro 4-aminophenol
3964-52-1

2-chloro 4-aminophenol

2-chloromethylpyridine hydrochloride
6959-47-3

2-chloromethylpyridine hydrochloride

4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile
848133-88-0

4-chloro-6-(5-(dimethylamino)-2-oxopent-3-enyl)-7-ethoxyquinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline

(2E)-(N,N-dimethylamino)-2-butenoyl chloride
1056149-69-9

(2E)-(N,N-dimethylamino)-2-butenoyl chloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile

(E)-4-(dimethylamino)-2-butenoic acid hydrochloride

(E)-4-(dimethylamino)-2-butenoic acid hydrochloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

(2E)-(N,N-dimethylamino)-2-butenoyl chloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

4-chloro-6-amino-7-ethoxyquinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

(E)-4-(dimethylamino)-2-butenoic acid hydrochloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

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

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

2-chloro-4-nitrophenol

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

2-chloromethylpyridine hydrochloride

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

2-((2-chloro-4-nitrophenoxy)methyl)pyridine

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

3-chloro-4-(2-pyridylmethoxy)aniline

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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
ConditionsYield
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
ConditionsYield
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

3-chloro-4-[(pyridin-2-yl)methoxy]-1-p-toluenesulfonyloxybenzene

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

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

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

4-amino-7-ethoxy-3-cyano-6-nitro quinoline

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

2-((4-bromo-2-chlorophenoxy)methyl)pyridine

neratinib
698387-09-6

neratinib

Conditions
ConditionsYield
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

maleic acid

neratinib
698387-09-6

neratinib

(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide maleate

(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
ConditionsYield
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

neratinib

(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

(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

Conditions
ConditionsYield
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

maleic acid

neratinib
698387-09-6

neratinib

neratinib maleate monohydrate
1144516-12-0

neratinib maleate monohydrate

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

698387-09-6Relevant articles and documents

Neratinib intermediate crystal as well as preparation method and application thereof

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Paragraph 0088-0099, (2021/04/21)

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.

Crystal forms and preparation method of neratinib free alkali

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Paragraph 0148; 0149, (2018/09/08)

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

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Paragraph 0033-0057, (2017/10/06)

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.

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