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850140-72-6

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850140-72-6 Usage

General Description

Afatinib is a prescription medicine that can be taken orally for the treatment of non-small cell lung cancer (NSCLC) with atypical Epidermal Growth Factor Receptor (EFGR) agents. Afatinib is also prescribed for the treatment of NSCLC with the potential or radiating to other body tissues other than the lungs (metastatic cancer) as detected through an FDA approved examination. Afatinib is a 4-anilinoquinazoline tyrosine kinase suppressor that is available as a dimaleate salt (brand name: Giltrif). The drug is the first FDA-endorsed oncology product by Boehringer Ingelheim.

Indication

The drug is a kinase agonist that is indicated as monotherapy for EFGR and tyrosine kinase suppressor-naive adult patients whose NSCLC is metastatic or locally advanced and the tumours are resistant to EGFR mutations as approved by an FDA-endorsed examination. In addition, the adult patients should indicate signs of squamous histology progress at the time of platinum-based chemotherapy or after the sessions.

Information on Dosing

The recommended dose of Afatinib is 40mg administered orally once every day 1-2 hours after the consumption of a meal, until the tumours regress or if the patient’s body can no longer tolerate the drug.

Pharmacodynamics

Afatinib is an irreversible ErbB inhibitor that forms covalent bonds with the kinase domains of EGFR, HER4, and human EGFRs (HER) 2, which results in an irreparable obstruction of tyrosine kinase autophosphorylation. Afatinib as a single treatment agent obstructs the ErbB receptor which influences tumour regression and also inhibits further growth of the tumour through deregulation of the ErbB pathway. NSCLC tumours with a characteristic activating EGFR variation (Del 19, L858R) and other uncommon variations in exon 21 (L861Q) and exon 18 (G719X) are responsive to treatment with Afatinib in both clinical and non-clinical setups. Limited clinical and non-clinical activity indicates NSCLC tumours with positioning mutations in exon 20. The accession of a secondary T790M variation is a crucial trait of acquired resistance to the drug and gene dosage of T790M-possessing allele correlates with partial resistance in vitro. The T790M variation is highlighted in about 50% of the patient’s tumour’s whose development on Afatinib may be perceived as a next-line therapeutic option where the T790M aims at EGFR TKIs. Other mechanisms of resistance to the drug have been highlighted MET gene extension clinically and preclinically. The impact of multiple doses of the drug (50 mg once per day) on the QTc interval and the cardiac electrophysiology was examined in a single-arm, open-label study in people with refractory or relapsed solid tumours. The study maintains that there were no developments in the mean QTc interval, >20 ms.

Absorption

An oral administration of Afatinib attains peak plasma concentrations after 2-5 hours. The geometric mean relative bioavailability of 20mg tablets is 92% as opposed to the oral syrup. Systemic exposure to the drug is reduced by 50% and 30%, Cmax and AUC0-∞ respectively, when taken with a high-fat meal as opposed to its administration after a period of fasting. The population pharmacokinetic data obtained from several clinical trials on tumours suggests that there is an average reduction of 26% in AUCss if a patient consumes food about 1-3 hours prior to the administration of Afatinib.

Volume of Distribution

The volume of distribution of the drug in healthy volunteers is 4500 L. The high volume of transmission in plasma indicates that there could be a higher rate of distribution in body tissues.

Metabolism

Different sources of media describe the Metabolism of 850140-72-6 differently. You can refer to the following data:
1. Metabolic reactions that are catalyzed by enzymes play an insignificant role in the synthesis of Afatinib. Covalent bonds to proteins are the fundamental forms of the drug’s metabolites.
2. Enzyme-catalysed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins were the major circulating metabolites of afatinib. Excreted mainly in the faeces.

Interactions

Afatinib may interact with phenobarbital, St. Johns wort, phenytoin, carbamazepine, rifampicin, saquinavir, nelfinavir, tacrolimus, quinidine, itraconazole, amiodarone, verapamil, ketoconazole, cyclosporine A. or erythromycin. This is not an all-inclusive list of all the drugs that may interact with Afatinib hence a patient should always notify their healthcare provider of any herbal supplements, over-the-counter drugs and other medications they are taking prior to the initiation of treatment. Afatinib may also harm a developing fetus hence it is not recommended during pregnancy.

Route of Elimination

The elimination of Afatinib in humans is primarily through the faecal route. The administration of an oral solution of the drug suggests that about 85.4 % of Afatinib is recovered in faeces whereas 4.3% of the drug in urine.

Side Effects

Common side effects associated with the administration of Afatinib include conjunctivitis, fever, runny nose, bloody nose, bladder/urinary tract infection, itching, vomiting, weight loss, loss of appetite nausea, acne, dry skin, skin infections around toenails or fingernails, mouth sores, chapped lips, inflammation of the lips and the mouth, blisters or skin lesions, skin rash, and diarrhoea. Adverse reactions to Afatinib may include Keratitis, hepatic toxicity, Interstitial Lung Disease, Exfoliative and Bullous Skin Disorders, and diarrhoea.

Description

Afatinib (850140-72-6) is a clinically useful kinase inhibitor approved for the treatment of non-small cell lung cancer. It is a potent and highly selective inhibitor of mutant and wild-type EGFR (IC50= 0.5 nM) and HER2 (IC50?= 14 nM).

Uses

An aminocrotonylamino-substituted quinazoline derivative

Definition

ChEBI: A quinazoline compound having a 3-chloro-4-fluoroanilino group at the 4-position, a 4-dimethylamino-trans-but-2-enamido group at the 6-position, and an (S)-tetrahydrofuran-3-yloxy group at the 7-position. Used (as its di aleate salt) for the first-line treatment of patients with metastatic non-small cell lung cancer.

Clinical Use

Protein kinase inhibitor: Treatment of non-small cell lung cancer

Enzyme inhibitor

This oral quinazoline derivative and EGFR/HER2-directed protein kinase inhibitor (FW = 485.94; CASs = 439081-18-2 (free base), 936631-70-8 (maleic acid salt), 1254955-21-9 (HCl salt); Solubility (at 25°C): 197 mg/mL DMSO, 1 mg/mL Water), also known by its code name BIBW2992, its trade names Gilotrif? Tomtovok?, Tovok?, and its systematic name (S,E)-N-(4-(3-chloro-4-fluorophenyl-amino)-7-(tetrahydrofuran- 3-yloxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide, irreversibly inactivates EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2with IC50 values of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively. Mode of Action: The irreversible binding of afatinib to HER2 inactivates its interactions with a preferred partner of EGFR, and blocking the HER2- EGFR heterodimerization reduces their intrinsic tyrosine kinase activities. Irreversible inhibitors (such as afatinib and dacomitinib) that target all ErbB family receptor tyrosine kinases are intended to confer sustained disease control in ErbB-dependent cancers. Because nearly all EGFRmutated patients eventually develop resistance to reversible EGFR-TKIs after a median of 14 months, tafatinib’s irreversible action is thought to be a promising feature of its mode of action. Pharmacokinetics: Afatinib’s PK profile is best described by a two-compartment disposition model, with first-order absorption and linear elimination. There was a slightly more than proportional increase in exposure with increasing dose, most likely due to dose-dependent relative bioavailability. For the therapeutic dose of 40 mg, the estimated apparent total clearance rate at steady state was 734 mL/min.

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine - increased risk of agranulocytosis. Ciclosporin: concentration of afatinib possibly increased, separate administration by 6-12 hours. Tacrolimus: concentration of afatinib possibly increased, separate administration by 6-12 hours.

References

1) Li?et al. (2008),?BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models; Oncogene,?27?4702

Check Digit Verification of cas no

The CAS Registry Mumber 850140-72-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,5,0,1,4 and 0 respectively; the second part has 2 digits, 7 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 850140-72:
(8*8)+(7*5)+(6*0)+(5*1)+(4*4)+(3*0)+(2*7)+(1*2)=136
136 % 10 = 6
So 850140-72-6 is a valid CAS Registry Number.
InChI:InChI=1/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+

850140-72-6SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name afatinib

1.2 Other means of identification

Product number -
Other names Afatinib

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:850140-72-6 SDS

850140-72-6Synthetic route

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

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

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

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With thionyl chloride In 1-methyl-pyrrolidin-2-one at -5 - 0℃; for 0.333333h;
Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline In 1-methyl-pyrrolidin-2-one at -5 - 0℃; for 0.25h;
95%
With Bromoform; triethylamine; triphenylphosphine In dichloromethane at 25℃; for 1h; Reagent/catalyst; Temperature;93%
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With thionyl chloride In 1-methyl-pyrrolidin-2-one; ethyl acetate at 5℃;
Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline In 1-methyl-pyrrolidin-2-one; ethyl acetate at 0℃; Temperature;
87.4%
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With thionyl chloride In N,N-dimethyl acetamide at -20 - -15℃;
Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline In N,N-dimethyl acetamide; water at -25 - -20℃;
48 g
Stage #1: (E)-4-(dimethylamino)-2-butenoic acid hydrochloride With thionyl chloride In N,N-dimethyl acetamide at -20 - -10℃;
Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline In N,N-dimethyl acetamide at -25 - -20℃; for 0.166667h;
Stage #3: In water Alkaline conditions;
dimethylaminoacetaldehyde-hydrogen sulphite adduct
1413945-87-5

dimethylaminoacetaldehyde-hydrogen sulphite adduct

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate With lithium chloride In ethanol at -5℃;
Stage #2: dimethylaminoacetaldehyde-hydrogen sulphite adduct With potassium hydroxide In ethanol; water for 1h;
91%
C36H36ClFN5O5P

C36H36ClFN5O5P

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Temperature; Solvent;87.3%
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

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

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

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With piperidine In tetrahydrofuran at 5 - 40℃; for 9h; Temperature; Reagent/catalyst; Solvent;86.1%
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

(E)-4-(dimethylamino)-2-butenoic acid methyl ester
212776-19-7

(E)-4-(dimethylamino)-2-butenoic acid methyl ester

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline With trimethylaluminum In hexane; dichloromethane at 20℃; for 2h;
Stage #2: (E)-4-(dimethylamino)-2-butenoic acid methyl ester In hexane; dichloromethane at 60℃; for 5h; Solvent;
98%
2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt

2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt

C26H31ClFN4O6P

C26H31ClFN4O6P

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: C26H31ClFN4O6P With lithium chloride; potassium hydroxide In ethanol; water at -5 - 10℃; for 2h; Horner-Wadsworth-Emmons Olefination; Inert atmosphere;
Stage #2: 2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt In ethanol; water at 0 - 18℃; for 7h; Solvent; Reagent/catalyst; Temperature;
91.7%
C20H18ClF2N5O

C20H18ClF2N5O

(S)-3-hydroxytetyrahydrofurane
86087-23-2

(S)-3-hydroxytetyrahydrofurane

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With potassium tert-butylate In tert-butyl alcohol at 50℃; for 1h; Reagent/catalyst; Solvent;89%
dimethylaminoacetaldehyde diethyl acetal
3616-56-6

dimethylaminoacetaldehyde diethyl acetal

diethyl ((4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline-6-ylcarbamoyl)methyl)phosphonate

diethyl ((4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline-6-ylcarbamoyl)methyl)phosphonate

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: dimethylaminoacetaldehyde diethyl acetal With hydrogenchloride In water at 30 - 35℃; for 8.3h; Large scale;
Stage #2: diethyl ((4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline-6-ylcarbamoyl)methyl)phosphonate With lithium chloride; potassium hydroxide In water at -7 - -5℃; for 2h; Large scale;
78%
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

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

trans-4-dimethylamino crotonic acid chloride hydrochloride salt

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
In tetrahydrofuran at 0 - 5℃;97.5%
In 1-methyl-pyrrolidin-2-one; water at -5 - 0℃; for 0.5 - 0.75h;87%
In 1-methyl-pyrrolidin-2-one at -5 - 0℃;14.1 g
(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate
618061-76-0

(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate

2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt

2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With lithium chloride; potassium hydroxide In ethanol; water at -10℃; for 2h;60%
(E)-4-(dimethylamino)but-3-enamide

(E)-4-(dimethylamino)but-3-enamide

C18H14ClFIN3O2

C18H14ClFIN3O2

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With potassium phosphate; copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane In 1,4-dioxane at 110℃; for 48h; Ullmann-Goldberg Substitution; Inert atmosphere;56%
(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate
618061-76-0

(S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate

dimethylaminoacetaldehyde diethyl acetal
3616-56-6

dimethylaminoacetaldehyde diethyl acetal

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: dimethylaminoacetaldehyde diethyl acetal With hydrogenchloride In water at 20 - 30℃; Inert atmosphere;
Stage #2: (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate With lithium chloride; potassium hydroxide In tetrahydrofuran at -15 - 20℃; for 2.5h; Product distribution / selectivity; Inert atmosphere;
97.7%
Stage #1: dimethylaminoacetaldehyde diethyl acetal With hydrogenchloride In water at 30 - 35℃; for 8.33333h;
Stage #2: (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate With potassium hydroxide; lithium chloride In tetrahydrofuran; water at -7 - 30℃; for 2.16667h;
78%
Stage #1: dimethylaminoacetaldehyde diethyl acetal With hydrogenchloride In water at 30 - 35℃; for 8.33333h; Inert atmosphere; Large scale;
Stage #2: With potassium hydroxide In water at -5℃; Large scale;
Stage #3: (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate With lithium chloride In tetrahydrofuran at -7℃; for 1.16667h; Large scale;
C18H14BrClFN3O2

C18H14BrClFN3O2

(E)-4-(dimethylamino)but-3-enamide

(E)-4-(dimethylamino)but-3-enamide

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
With potassium phosphate; dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; palladium diacetate In water; tert-butyl alcohol at 110℃; for 16h; Inert atmosphere; Sealed tube;4%
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

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

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

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride With thionyl chloride In N,N-dimethyl acetamide at -20 - -15℃;
Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline In N,N-dimethyl acetamide at -25 - -20℃;
48 g
4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)quinazoline dihydrochloride

4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)quinazoline dihydrochloride

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

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

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Stage #1: 4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)quinazoline dihydrochloride With hydrogenchloride In ethyl acetate at 25 - 65℃; for 0.25h;
Stage #2: (2E)-(N,N-dimethylamino)-2-butenoyl chloride In 1-methyl-pyrrolidin-2-one at 55 - 60℃; for 3h; Temperature; Solvent;
35 g
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 8 h / 80 °C / 3000.3 Torr
2: piperidine / tetrahydrofuran / 9 h / 5 - 40 °C
View Scheme
Multi-step reaction with 3 steps
1.1: iron; acetic acid / ethyl acetate / 1 h / 70 °C
2.1: tetrahydrofuran / 40 °C
2.2: 2 h / 30 - 40 °C
3.1: lithium chloride; potassium hydroxide / water; ethanol / 2 h / -10 °C
View Scheme
Multi-step reaction with 2 steps
1.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C
1.2: 1.5 h / 0 - 5 °C
2.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C
2.2: 3 h / 55 - 60 °C
View Scheme
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: 1,1'-carbonyldiimidazole / dichloromethane / 30 - 55 °C
1.2: 3 h / 20 - 40 °C
2.1: lithium chloride; potassium hydroxide / ethanol; water / 2 h / -5 - 10 °C / Inert atmosphere
2.2: 7 h / 0 - 18 °C
View Scheme
Multi-step reaction with 2 steps
1.1: tetrahydrofuran / 40 °C
1.2: 2 h / 30 - 40 °C
2.1: lithium chloride; potassium hydroxide / water; ethanol / 2 h / -10 °C
View Scheme
Multi-step reaction with 4 steps
1.1: phosphorus trichloride / dichloromethane / 1.5 h / 0 - 20 °C
1.2: 1.5 h / 20 °C
2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 20 °C
3.1: sodium tetrahydroborate / ethanol / 1 h / Reflux
4.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 20 °C
View Scheme
N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine
162012-67-1

N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: potassium tert-butylate / N,N-dimethyl-d6-formamide / 1 h / 0 °C
1.2: 20 °C
2.1: iron; acetic acid / ethyl acetate / 1 h / 70 °C
3.1: tetrahydrofuran / 40 °C
3.2: 2 h / 30 - 40 °C
4.1: lithium chloride; potassium hydroxide / water; ethanol / 2 h / -10 °C
View Scheme
Multi-step reaction with 4 steps
1.1: iron(III) chloride / tert-butyl alcohol; acetone / 4 h / Inert atmosphere
2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 40 °C
2.2: 1 h
3.1: potassium hydroxide / tetrahydrofuran; water / 0 - 20 °C
4.1: potassium tert-butylate / tert-butyl alcohol / 1 h / 50 °C
View Scheme
Multi-step reaction with 3 steps
1.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere
1.2: 1.5 h / 15 - 20 °C
2.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C
2.2: 1.5 h / 0 - 5 °C
3.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C
3.2: 3 h / 55 - 60 °C
View Scheme
7-fluoro-6-nitro-3H-quinazolin-4-one
162012-69-3

7-fluoro-6-nitro-3H-quinazolin-4-one

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: sodium t-butanolate / acetonitrile / 2 h / 25 °C / Inert atmosphere
1.2: 18 h / 30 - 100 °C
2.1: phosphorus trichloride / acetonitrile / 10 h / 100 °C
3.1: tributyl-amine / propan-1-ol / 24 h / 60 °C
4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 8 h / 80 °C / 3000.3 Torr
5.1: piperidine / tetrahydrofuran / 9 h / 5 - 40 °C
View Scheme
Multi-step reaction with 4 steps
1.1: trichlorophosphate; triethylamine / acetonitrile / 5 h / 0 - 85 °C
1.2: 3 h / 25 - 30 °C
2.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere
2.2: 1.5 h / 15 - 20 °C
3.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C
3.2: 1.5 h / 0 - 5 °C
4.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C
4.2: 3 h / 55 - 60 °C
View Scheme
Multi-step reaction with 5 steps
1.1: trichlorophosphate; triethylamine / acetonitrile
2.1: potassium hydroxide / 1,4-dioxane
3.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere
3.2: 1.5 h / 15 - 20 °C
4.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C
4.2: 1.5 h / 0 - 5 °C
5.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C
5.2: 3 h / 55 - 60 °C
View Scheme
(E)-4-dimethylamino-but-2-enoic acid tert-butyl ester
1421354-12-2

(E)-4-dimethylamino-but-2-enoic acid tert-butyl ester

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: hydrogenchloride / ethyl acetate / 10 - 25 °C / Inert atmosphere
2: thionyl chloride / 1-methyl-pyrrolidin-2-one / 0.42 - 0.5 h / -5 - 0 °C
3: water; 1-methyl-pyrrolidin-2-one / 0.5 - 0.75 h / -5 - 0 °C
View Scheme
Multi-step reaction with 3 steps
1: hydrogenchloride / water; ethyl acetate / 10 - 25 °C / Inert atmosphere
2: thionyl chloride / 1-methyl-pyrrolidin-2-one / -5 - 0 °C
3: 1-methyl-pyrrolidin-2-one / -5 - 0 °C
View Scheme
3-chloro-4-fluorophenylamine
367-21-5

3-chloro-4-fluorophenylamine

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1.1: 3.5 h / 80 °C
2.1: triphenylphosphine; iodine; triethanolamine / dichloromethane / 1 h / 20 °C
3.1: palladium diacetate; oxygen; caesium carbonate / toluene / 4.5 h / Reflux
4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
5.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
6.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
6.2: 5 h / 60 °C
View Scheme
Multi-step reaction with 4 steps
1.1: trichlorophosphate; triethylamine / acetonitrile / 5 h / 0 - 85 °C
1.2: 3 h / 25 - 30 °C
2.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere
2.2: 1.5 h / 15 - 20 °C
3.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C
3.2: 1.5 h / 0 - 5 °C
4.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C
4.2: 3 h / 55 - 60 °C
View Scheme
7-fluoro-3H-quinazolin-4-one
16499-57-3

7-fluoro-3H-quinazolin-4-one

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: sodium hydride / mineral oil / 0.33 h / 0 - 20 °C
1.2: 16 h / 130 °C
2.1: bromine / chloroform / 64 h / 0 - 20 °C / Inert atmosphere
3.1: thionyl chloride / N,N-dimethyl-formamide / 16 h / 90 °C
4.1: isopropyl alcohol / 3 h / 100 °C
5.1: dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; potassium phosphate; palladium diacetate / water; tert-butyl alcohol / 16 h / 110 °C / Inert atmosphere; Sealed tube
View Scheme
Multi-step reaction with 5 steps
1.1: bromine / water / 5 h / 85 °C
2.1: sodium hydride / mineral oil / 0.33 h / 0 - 20 °C
2.2: 2 h / 130 °C
3.1: thionyl chloride / N,N-dimethyl-formamide / 16 h / 90 °C
4.1: isopropyl alcohol / 3 h / 100 °C
5.1: dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; potassium phosphate; palladium diacetate / water; tert-butyl alcohol / 16 h / 110 °C / Inert atmosphere; Sealed tube
View Scheme
6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazoline-4-one
1621182-18-0

6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazoline-4-one

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: phosphorus trichloride / acetonitrile / 10 h / 100 °C
2: tributyl-amine / propan-1-ol / 24 h / 60 °C
3: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 8 h / 80 °C / 3000.3 Torr
4: piperidine / tetrahydrofuran / 9 h / 5 - 40 °C
View Scheme
4-chloro-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

4-chloro-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: tributyl-amine / propan-1-ol / 24 h / 60 °C
2: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran / 8 h / 80 °C / 3000.3 Torr
3: piperidine / tetrahydrofuran / 9 h / 5 - 40 °C
View Scheme
2-chloro-1-fluoro-4-isocyanobenzene

2-chloro-1-fluoro-4-isocyanobenzene

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: palladium diacetate; oxygen; caesium carbonate / toluene / 4.5 h / Reflux
2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
3.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
4.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
4.2: 5 h / 60 °C
View Scheme
7-hydroxy-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine

7-hydroxy-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
2.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
3.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
3.2: 5 h / 60 °C
View Scheme
5-bromo-2-nitrophenol
27684-84-0

5-bromo-2-nitrophenol

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; t-BuBrettPhos / methanol / 2 h / 85 °C
2.1: palladium diacetate; oxygen; caesium carbonate / toluene / 4.5 h / Reflux
3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
4.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
5.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
5.2: 5 h / 60 °C
View Scheme
C7H7N3O3

C7H7N3O3

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: palladium diacetate; oxygen; caesium carbonate / toluene / 4.5 h / Reflux
2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
3.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
4.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
4.2: 5 h / 60 °C
View Scheme
N-(3-chloro-4-fluoro-phenyl)-formamide
770-22-9

N-(3-chloro-4-fluoro-phenyl)-formamide

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1.1: triphenylphosphine; iodine; triethanolamine / dichloromethane / 1 h / 20 °C
2.1: palladium diacetate; oxygen; caesium carbonate / toluene / 4.5 h / Reflux
3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 10 - 20 °C
4.1: iron; hydrogenchloride; sodium hydroxide / water / 10.5 h / 40 - 80 °C / pH 8 - 9
5.1: trimethylaluminum / dichloromethane; hexane / 2 h / 20 °C
5.2: 5 h / 60 °C
View Scheme
N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine

N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine

afatinib
850140-72-6

afatinib

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 40 °C
1.2: 1 h
2.1: potassium hydroxide / tetrahydrofuran; water / 0 - 20 °C
3.1: potassium tert-butylate / tert-butyl alcohol / 1 h / 50 °C
View Scheme
afatinib
850140-72-6

afatinib

L-Aspartic acid
56-84-8

L-Aspartic acid

afatinib di-L-aspartate

afatinib di-L-aspartate

Conditions
ConditionsYield
In tetrahydrofuran; water at 20 - 110℃;97%
afatinib
850140-72-6

afatinib

maleic acid
110-16-7

maleic acid

2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate

2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate

Conditions
ConditionsYield
In tetrahydrofuran at 20℃; Solvent; Temperature; Concentration;96.5%
In ethanol at 70℃;91.5%
In ethanol at 0 - 50℃; for 5.5h; Temperature; Large scale;91%
afatinib
850140-72-6

afatinib

maleic acid
110-16-7

maleic acid

(2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide dimaleate

(2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide dimaleate

Conditions
ConditionsYield
In ethanol at 70℃;94.1%
In ethanol at 0 - 70℃; for 5h; Solvent; Temperature; Large scale;91.5%
In ethyl acetate at 20 - 30℃; Solvent; Temperature;4 g
afatinib
850140-72-6

afatinib

afatinib disulphate

afatinib disulphate

Conditions
ConditionsYield
With sulfuric acid In ethyl acetate at 20℃; Product distribution / selectivity;94%
afatinib
850140-72-6

afatinib

C22H20ClFN4O4

C22H20ClFN4O4

Conditions
ConditionsYield
With water; potassium hydroxide In ethanol at 50℃; for 24h; Solvent; Temperature; Reagent/catalyst;93.3%
afatinib
850140-72-6

afatinib

afatinib diphosphate

afatinib diphosphate

Conditions
ConditionsYield
With phosphoric acid In ethyl acetate at 20℃; for 0.866667h; Product distribution / selectivity;93%
afatinib
850140-72-6

afatinib

methanesulfonic acid
75-75-2

methanesulfonic acid

afatinib dimesylate

afatinib dimesylate

Conditions
ConditionsYield
In ethyl acetate at 20℃; for 0.7h; Product distribution / selectivity;92%
afatinib
850140-72-6

afatinib

(S)-Malic acid
97-67-6

(S)-Malic acid

afatinib di-L-malate

afatinib di-L-malate

Conditions
ConditionsYield
In ethyl acetate at 20℃; for 1.03333h;80.7%
afatinib
850140-72-6

afatinib

dimethyl amine
124-40-3

dimethyl amine

C26H32ClFN6O3

C26H32ClFN6O3

Conditions
ConditionsYield
In water; N,N-dimethyl-formamide at 80℃; for 2h; Temperature; Solvent;80.6%
afatinib
850140-72-6

afatinib

afatinib dihydrochloride

afatinib dihydrochloride

Conditions
ConditionsYield
With hydrogenchloride In isopropyl alcohol at 20℃; for 1.31667h;80%
afatinib
850140-72-6

afatinib

oxalic acid
144-62-7

oxalic acid

afatinib dioxalate

afatinib dioxalate

Conditions
ConditionsYield
In ethanol at 40℃; for 0.833333h; Reflux;78%
afatinib
850140-72-6

afatinib

succinic acid
110-15-6

succinic acid

afatinib disuccinate

afatinib disuccinate

Conditions
ConditionsYield
In ethyl acetate at 20℃; for 6.5h;75.7%
afatinib
850140-72-6

afatinib

(2E)-but-2-enedioic acid
110-17-8

(2E)-but-2-enedioic acid

afatinib fumarate
1398312-22-5

afatinib fumarate

Conditions
ConditionsYield
In ethanol at 20 - 70℃; Product distribution / selectivity;67.7%
afatinib
850140-72-6

afatinib

benzenesulfonic acid
98-11-3

benzenesulfonic acid

afatinib dibenzenesulphonate

afatinib dibenzenesulphonate

Conditions
ConditionsYield
In ethanol at 20 - 70℃;63.6%
afatinib
850140-72-6

afatinib

citric acid
77-92-9

citric acid

afatinib citrate
1398313-22-8

afatinib citrate

Conditions
ConditionsYield
In ethanol at 20℃; for 0.283333h;57%
afatinib
850140-72-6

afatinib

C22H20ClFN4O4

C22H20ClFN4O4

Conditions
ConditionsYield
With sodium hydroxide In methanol; water at 50℃; for 24h; Reagent/catalyst; Temperature; Solvent;43%

850140-72-6Relevant articles and documents

Arab league law for nepal preparation method of the compound

-

Paragraph 0052-0057; 0061, (2019/04/10)

The invention provides a novel preparation method of an afatinib compound. Raw materials and reagents used in the preparation method have the advantages of low cost, stable chemical property and convenience in long-term storage and the content of an impurity cis-isomer in the prepared afatinib compound is very low.

An alternative synthesis of the non-small cell lung carcinoma drug afatinib

Kovacevic, Tatjana,Mesic, Milan,Avdagic, Amir,Zegarac, Miroslav

, p. 4180 - 4182 (2018/10/24)

Afatinib (BIBW2992) is the anticancer drug developed by Boehringer Ingelheim. This work is reporting the synthesis of the afatinib using a new route by Ullmann-Goldberg reaction from corresponding 4-anilinoquinazoline iodide as the last step in the synthesis. This route was not described previously and it could be used for synthesis of afatinib analogues.

A arab league law for nepal and its preparation method and application

-

Paragraph 0051; 0053; 0054; 0055; 0059; 0062; 0065; 0069, (2018/11/03)

The present invention provides afatinib, a preparation method therefor and an application thereof. The method comprises: by taking carbon tetrabromide and an organophosphorus compound as a condensation reagent, taking a dimethyl amino crotonic acid and/or dimethyl amino crotonic acid salt and N4-(3-chlorine-4-fluorine-phenyl)-7-(( S )-tetrahydrofuran-3-yloxy) quinazoline-4, 6-diamine as raw materials, performing a condensation reaction to generate the afatinib. According to the preparation method provided by the present invention, the carbon tetrabromide and the organophosphorus compound are taken as the condensation reagent, and the afatinib can be obtained by virtue of one-step condensation reaction. The process is simple, and during the process of preparing the afatinib, a selection range of the condensation reagent is expanded; and the reaction yield can be higher than 90%, and the product purity is higher than 95%.

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