850140-72-6

Usage

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

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.

Metabolism

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.

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

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+

Synthetic route

6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline + (E)-4-(dimethylamino)-2-butenoic acid hydrochloride → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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 + (2E)-(N,N-dimethylamino)-2-butenoyl chloride (1056149-69-9) → afatinib (850140-72-6)

Conditions	Yield
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 + (E)-4-(dimethylamino)-2-butenoic acid methyl ester (212776-19-7) → afatinib (850140-72-6)

Conditions	Yield
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 + C26H31ClFN4O6P → afatinib (850140-72-6)

Conditions	Yield
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 + (S)-3-hydroxytetyrahydrofurane (86087-23-2) → afatinib (850140-72-6)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol at 50℃; for 1h; Reagent/catalyst; Solvent;	89%

dimethylaminoacetaldehyde diethyl acetal (3616-56-6) + diethyl ((4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline-6-ylcarbamoyl)methyl)phosphonate → afatinib (850140-72-6)

Conditions	Yield
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 + trans-4-dimethylamino crotonic acid chloride hydrochloride salt (1055943-40-2) → afatinib (850140-72-6)

Conditions	Yield
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) + 2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt → afatinib (850140-72-6)

Conditions	Yield
With lithium chloride; potassium hydroxide In ethanol; water at -10℃; for 2h;	60%

(E)-4-(dimethylamino)but-3-enamide + C18H14ClFIN3O2 → afatinib (850140-72-6)

Conditions	Yield
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) + dimethylaminoacetaldehyde diethyl acetal (3616-56-6) → afatinib (850140-72-6)

Conditions	Yield
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 + (E)-4-(dimethylamino)but-3-enamide → afatinib (850140-72-6)

Conditions	Yield
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 + (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride → afatinib (850140-72-6)

Conditions	Yield
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 + (2E)-(N,N-dimethylamino)-2-butenoyl chloride (1056149-69-9) → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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 → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions

Yield

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 → afatinib (850140-72-6)

Conditions	Yield
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) → afatinib (850140-72-6)

Conditions

Yield

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 → afatinib (850140-72-6)

Conditions	Yield
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) + L-Aspartic acid (56-84-8) → afatinib di-L-aspartate

Conditions	Yield
In tetrahydrofuran; water at 20 - 110℃;	97%

afatinib (850140-72-6) + maleic acid (110-16-7) → 2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate

Conditions	Yield
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) + maleic acid (110-16-7) → (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide dimaleate

Conditions	Yield
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 disulphate

Conditions	Yield
With sulfuric acid In ethyl acetate at 20℃; Product distribution / selectivity;	94%

afatinib (850140-72-6) → C22H20ClFN4O4

Conditions	Yield
With water; potassium hydroxide In ethanol at 50℃; for 24h; Solvent; Temperature; Reagent/catalyst;	93.3%

afatinib (850140-72-6) → afatinib diphosphate

Conditions	Yield
With phosphoric acid In ethyl acetate at 20℃; for 0.866667h; Product distribution / selectivity;	93%

afatinib (850140-72-6) + methanesulfonic acid (75-75-2) → afatinib dimesylate

Conditions	Yield
In ethyl acetate at 20℃; for 0.7h; Product distribution / selectivity;	92%

afatinib (850140-72-6) + (S)-Malic acid (97-67-6) → afatinib di-L-malate

Conditions	Yield
In ethyl acetate at 20℃; for 1.03333h;	80.7%

afatinib (850140-72-6) + dimethyl amine (124-40-3) → C26H32ClFN6O3

Conditions	Yield
In water; N,N-dimethyl-formamide at 80℃; for 2h; Temperature; Solvent;	80.6%

afatinib (850140-72-6) → afatinib dihydrochloride

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 20℃; for 1.31667h;	80%

afatinib (850140-72-6) + oxalic acid (144-62-7) → afatinib dioxalate

Conditions	Yield
In ethanol at 40℃; for 0.833333h; Reflux;	78%

afatinib (850140-72-6) + succinic acid (110-15-6) → afatinib disuccinate

Conditions	Yield
In ethyl acetate at 20℃; for 6.5h;	75.7%

afatinib (850140-72-6) + (2E)-but-2-enedioic acid (110-17-8) → afatinib fumarate (1398312-22-5)

Conditions	Yield
In ethanol at 20 - 70℃; Product distribution / selectivity;	67.7%

afatinib (850140-72-6) + benzenesulfonic acid (98-11-3) → afatinib dibenzenesulphonate

Conditions	Yield
In ethanol at 20 - 70℃;	63.6%

afatinib (850140-72-6) + citric acid (77-92-9) → afatinib citrate (1398313-22-8)

Conditions	Yield
In ethanol at 20℃; for 0.283333h;	57%

afatinib (850140-72-6) → C22H20ClFN4O4

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

Upstream product

• 314771-76-1 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline 
• 1130155-48-4 (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride 
• 86087-23-2 (S)-3-hydroxytetyrahydrofurane 
• 16499-57-3 7-fluoro-3H-quinazolin-4-one 
• 162012-70-6 4-chloro-7-fluoro-6-nitroquinazoline 
• 1056149-69-9 (2E)-(N,N-dimethylamino)-2-butenoyl chloride 
• 231278-08-3 2-amino-4-fluoro-5-iodo-benzoic acid 
• 446-32-2 4-fluoroanthranilic acid 
• 367-21-5 3-chloro-4-fluorophenylamine 
• 950577-02-3 6-bromo-7-fluoro-3H-quinazolin-4-one 

Downstream Products

• 1398312-22-5 afatinib fumarate 
• 850140-73-7 (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide dimaleate 
• 1398313-22-8 afatinib citrate 
• 850140-73-7 2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate 

Relevant academic research and scientific papers

Arab league law for nepal preparation method of the compound

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.

PROCESS FOR THE PREPARATION OF N-[4-[(3-CHLORO-4-FLUORO PHENYL) AMINO]-7-[[(3s-TETRAHYDRO-3-FURANYL]OXY]-6-QUINAZOLINYL]-4-(DIMETHYL AMINO)-(2E)-2-BUTENAMIDE (2Z)-2-BUTENEDIOATE (1 :2) AND ITS POLYMORPHS THEREOF

The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:

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

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.

Preparation method of afatinib and maleate thereof

The invention belongs to the technical field of synthesis of compounds, and relates to a preparation method of afatinib and maleate thereof. The preparation method comprises the following steps: in the presence of a first organic solvent, adopting N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-group]oxo}-4,6-quinazoline diamine as a raw material to have the acylation reaction with (E)-4-dimethyl amino crotonate hydrochloride to obtain an acylation reaction solution under the effect of thionyl chloride, water and alkaline water are added into the acylation reaction solution, the water phase is extracted by virtue of butyl acetate, an organic phase is collected, after the organic phase is washed, the organic phase is directly stirred and precipitated to obtain an afatinib crude product, then the afatinib crude product is refined to obtain a competitive product, and the competitive product reacts with maleic acid to obtain maleic acid afatinib. The method has the characteristics of being high in product yield, high in purity, low in impurity content, mild in reaction conditions, simple in operation, suitable for industrialized production and the like.

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

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%.

Medicine solvent compound for treating cancers and preparation method thereof

The invention belongs to the technical field of medicines, and discloses a medicine solvent compound for treating cancers and a preparation method thereof. An afatinib ethanol solvent compound is characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2theta+/-0.2 degree has feature diffraction peaks at 5.54 degrees, 10.47 degrees, 15.54 degrees, 16.37 degrees, 17.95 degrees, 19.71 degrees, 20.40 degrees, 24.13 degrees, 24.28 degrees, 26.05 degrees and 27.22 degrees. The preparation method is different from the prior art. The invention also discloses a preparation method of the afatinib ethanol solvent compound. The preparation method has the advantages that the preparation method is simple, the operation is easy, the yield and purity are high, the reaction conditions are moderate, and the preparation method is suitable for large-scale production.

Preparation method for afatinib

The invention discloses a novel method for preparing afatinib. The method comprises the following steps: reducing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine into N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV; then subjecting N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV and diethylphosphonoacetic acid to a condensation reaction so as to obtain a compound III; then subjecting the compound III and (dimethylamino)acetaldehyde diethyl acetal to a Wittig-Horner-Emmons reaction of so as to obtain a key intermediate II; and subjecting the key intermediate II and (S)-3-hydroxytetrahydrofuran to a substitution reaction so as to obtain a compound I. The method of the invention has high yield and high purity.

Compound, and preparation method and application thereof

The invention relates to a compound, and a preparation method and application thereof. Specifically, the compound is as shown in a formula 1 which is described in the specification. The invention also provides the preparation method for the compound as shown in the formula 1. The preparation method comprises a step of contacting N-[4-[(3-chloro-4-fluorophenyl)amino]-7[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butyleneamide with an alkaline aqueous solution in an organic solvent so as to obtain the compound as shown in the formula 1. The preparation method is simple to operate; a white powder product can be obtained through direct filtering after post-treatment; and the prepared compound has high purity, as high as 99% or above, and can be directly used as an impurity control substance for research on the quality of an afatinib bulk drug.

High-purity afatinib preparation method

The invention discloses a high-purity afatinib preparation method, which comprises: (1) adding a trans-4-dimethylaminocrotonic acid hydrochloride to the mixed solvent of N-methylpyrrolidone and ethyl acetate, cooling, adding thionyl chloride to the system in a dropwise manner, and stirring until the reaction is completely performed; (2) dissolving N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine by using N-methylpyrrolidone, adding the obtained solution to the reaction system obtained in the step (1), and stirring until the reaction is completely performed; and (3) adding purified water to the reaction system obtained in the step (2), quenching the reaction, adjusting the pH value with a sodium hydroxide solution, extracting with ethyl acetate, carrying out pressure reducing concentration, carrying out cooling crystallization, carrying out suction filtration, and drying to obtain the high-purity afatinib product. According to the present invention, the post-treatment of the preparation method is simple and convenient, the high purity product can be obtained without the additional refining, and the preparation method is suitable for industrial large-scale production.

PHARMACEUTICAL COMPOSITIONS COMPRISING AFATINIB

The present invention relates to a tablet comprising Afatinib or a pharmaceutically acceptable salt thereof, wherein the tablet is obtained by direct compression. The present invention further relates to a process for manufacturing a tablet of the invention as well as the use of the tablet of the invention.