1195765-45-7

Basic information

• Product Name: N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
• Synonyms: Dabrafenib;N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;Dabrafenib free base(GSK2118436A);Dabrafenib (GSK2118436);GSK2118436A;Dabrafenib (GSK2118436A);Dabrafenib KB-57246;Debrafenib API
• CAS NO: 1195765-45-7
• Molecular Formula: C₂₃H₂₀F₃N₅O₂S₂
• Molecular Weight: 519.5624096
• EINECS: 1592732-453-0
• Product Categories: Raf B protein kinase inhibitor;inhibitor;MAPK;Inhibitors
• Mol File: 1195765-45-7.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 653.726 °C at 760 mmHg
• Flash Point: 349.161 °C
• Appearance: /
• Density: 1.443
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to 30 mg/ml with warming), or in Ethanol (up to 1 mg/ml with warming).
• PKA: 6.62±0.10(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide(1195765-45-7)
• EPA Substance Registry System: N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide(1195765-45-7)

Safety Data

• Hazardous Substances Data: 1195765-45-7(Hazardous Substances Data)

Usage

Description

N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, commonly known as Dabrafenib, is an organofluorine compound and antineoplastic agent. It is a potent inhibitor of mutated BRAF kinase, playing a crucial role in the regulation of cell growth. Dabrafenib has demonstrated clinical activity with a manageable safety profile in phase 1 and 2 clinical trials for patients with BRAF(V600)-mutated metastatic melanoma. It is also known to act as a Protein Kinase Inhibitor, Cytochrome P450 Inducer, Organic Anion Transporting Polypeptide Inhibitor, and Breast Cancer Resistance Protein Inhibitor. It is commercially available under the brand name Tafinlar.

Uses

Used in Oncology:
Dabrafenib is used as an antineoplastic agent for the treatment of patients with unresectable or metastatic melanoma that possess the BRAFV600E mutation. It is particularly effective against melanoma with the BRAFV600E mutation, as it acts as a potent inhibitor of B-BRAFV600E kinase, showing high selectivity and potency against this specific target.
Used in Clinical Trials:
Dabrafenib is utilized in phase 1 and 2 clinical trials for patients with BRAF(V600)-mutated metastatic melanoma, where it has shown clinical activity with a manageable safety profile. These trials aim to evaluate the drug's efficacy and safety in treating patients with this specific type of cancer.
Used in Drug Synthesis:
Key steps in the synthesis of dabrafenib involve the condensation of an aryl sulfonamide ester with the lithium anion of 2-chloro-4-methylpyrimidine to generate a ketone intermediate, followed by bromination with N-bromosuccinamide and cyclization with tert-butyl thioamide to afford the desired thiazole core. This process is crucial for the production of the drug, making it available for medical use.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Dabrafenib is used as a key component in the development of new cancer treatments targeting the BRAF mutation. Its unique properties and high potency against specific kinases make it a valuable asset in the fight against certain types of cancer.
Used in Research and Development:
Dabrafenib is also used in research and development for the study of BRAF mutations and their role in cancer progression. Understanding the mechanisms of action and potential synergistic effects with other drugs can lead to the development of more effective cancer treatments.

Synthetic Methods

The key step in the synthesis of Dabrafenib is the construction of the 1,3-thiazole ring, which is usually carried out by the closing ring directly of thioamide (as a 1,3-binuclear reagent) and anα-carbonyl halide (as a 1,2-amphiphilic reagent). Sulfonyl chloride 1 and aniline 2 gave sulfonamide 3 under basic conditions. Methyl pyrimidine 4 with non-nucleophilic strong alkali LiHMDS pull out the acid proton on the methyl and react with 3 to obtain 5, and the latter has α-bromination with NBS to obtain 1,2-amphiphilic reagent 6, and then 6 reacts with 1 , 3-parent nucleotides 7 to close the ring to obtain 8, and finally reacts with ammonia to obtain Dabrafenib. Figure 1: synthetic route of Dabrafenib

Biological activity

Dabrafenib (GSK2118436) is a mutant BRAFV600 specific inhibitor with an IC50 of 0.8 nM, and effects for B-Raf (wt) and c-Raf is 4 and 6 fold lower respectively.

How to use

It is usually taken twice a day on an empty stomach, 1 hour before or 2 hours after a meal. Take dabrafenib about 12 hours apart at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Do not stop taking dabrafenib without talking to your doctor. Swallow the capsules whole; do not split, chew, or crush them. Your doctor may adjust your dose of dabrafenib depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Major Side Effects

The following side effects are common (occurring in greater than 30%) for patients taking dabrafenib : Hyperglycemia Hyperkeratosis Hypophosphatemia Headache These side effects are less common side effects (occurring in about 10-29%) of patients receiving dabrafenib: Fever Joint pain Papilloma (warts/growths) Hair loss Hand-foot syndrome (Palmar-planter erythrodyesthesia) Increased Alkaline phosphatase Rash Back pain Cough Muscle aches Constipation Nasopharyngitis

In vitro

Dabrafenib is selective for Raf kinases and is 400 times more active against B-Raf than other tested 91% kinases. Dabrafenib inhibits B-RafV600E kinase, resulting in reduced phosphorylation of ERK and inhibition of cell proliferation. The cells stagnate in the G1 phase in cancer cells that specifically encode mutated B-RafV600E.

In vivo

Dabrafenib (oral) inhibits the growth of B-RafV600E mutated melanoma (A375P). Dabrafenib (oral) also inhibits tumor growth, subcutaneously injecting colon cancer (Colo205) in immunocompromised mice.

References

https://www.caymanchem.com/product/16989 https://en.wikipedia.org/wiki/Dabrafenib https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib Menzies, A. M., and G. V. Long. "Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. " Clinical Cancer Research 20.8(2014): 2035-2043. https://www.hcp.novartis.com/products/tafinlar-mekinist/

References

1) Huang?et al. (2013),?B-Raf and the inhibitors: from bench to bedside; J. Hematol. Oncol.,?6?1 2) Ji?et al. (2016),?Endoplasmic reticulum stress-induced autophagy determines the susceptibility of melanoma cells to dabrafenib; Drugs Des. Dev. Ther.?10?2491 3) Herr?et al.?(2015),?B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells; Cancer Res.,?75?216

Originator

GlaxoSmithKline (United States)

Clinical Use

Selective inhibitor of BRAF-kinase:Treatment of metastatic melanoma and advanced non-small cell lung cancer with a BRAF V600 mutation

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Oestrogens and progestogens: possibly reduced contraceptive effect.

Metabolism

Metabolism is mainly by CYP2C8 and CYP3A4 isoenzymes to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a nonenzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Both hydroxyand desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-darafenib is not likely to be significant.

Synthetic route

N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1195768-23-0) → dabrafenib (1195765-45-7)

Conditions	Yield
With ammonium hydroxide In water at 20 - 103℃; Product distribution / selectivity; sealed tube;	88%
With ammonium hydroxide at 98 - 103℃; for 2h; Sealed tube;	88%
With ammonium hydroxide at 20 - 103℃; Reagent/catalyst; Autoclave;	88%

2,6-difluorobenzene-1-sulfonamide (60230-37-7) + 4-(4-(3-bromo-2-fluorophenyl)-2-(tert-butyl)thiazol-5-yl)pyrimidin-2-amine → dabrafenib (1195765-45-7)

Conditions	Yield
With (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N',N'-tetramethylguanidine In dimethyl sulfoxide at 55℃; for 40h; Inert atmosphere; Glovebox; Irradiation;	57%

2,6-difluorobenzene-1-sulfonyl chloride (60230-36-6) → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 15 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 3.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 3.2: 2.5 h / 10 - 75 °C 4.1: ammonium hydroxide / water / 20 - 103 °C / sealed tube View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 15 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 3.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 3.2: 2.5 h / 10 - 75 °C 4.1: ammonium hydroxide / 2 h / 98 - 103 °C / Sealed tube View Scheme
Multi-step reaction with 5 steps 1: pyridine / dichloromethane / 15 - 25 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 3: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 4: ethyl acetate; N,N-dimethyl acetamide / 10 - 75 °C 5: ammonium hydroxide / 20 - 103 °C / Autoclave View Scheme

methyl 3-amino-2-fluoro-benzoate (1195768-18-3) → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 15 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 3.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 3.2: 2.5 h / 10 - 75 °C 4.1: ammonium hydroxide / water / 20 - 103 °C / sealed tube View Scheme
Multi-step reaction with 6 steps 1: pyridine / dichloromethane / 20 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 °C / Cooling with ice 3: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 4: N,N-dimethyl acetamide / 20 - 60 °C 5: N,N-dimethyl acetamide / 60 - 80 °C 6: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 15 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 3.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 3.2: 2.5 h / 10 - 75 °C 4.1: ammonium hydroxide / 2 h / 98 - 103 °C / Sealed tube View Scheme

3-(2,6-difluorobenzenesulfonamido)-2-fluorobenzoic acid methyl ester (1195768-19-4) → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 2.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 2.2: 2.5 h / 10 - 75 °C 3.1: ammonium hydroxide / water / 20 - 103 °C / sealed tube View Scheme
Multi-step reaction with 5 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 °C / Cooling with ice 2: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 3: N,N-dimethyl acetamide / 20 - 60 °C 4: N,N-dimethyl acetamide / 60 - 80 °C 5: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 3 °C 2.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 2.2: 2.5 h / 10 - 75 °C 3.1: ammonium hydroxide / 2 h / 98 - 103 °C / Sealed tube View Scheme

methyl 3-((tert-butoxycarbonyl)amino)-2-fluorobenzoate (1042055-86-6) → dabrafenib (1195765-45-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2: pyridine / dichloromethane / 20 °C 3: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 °C / Cooling with ice 4: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 5: N,N-dimethyl acetamide / 20 - 60 °C 6: N,N-dimethyl acetamide / 60 - 80 °C 7: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme

N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (1195768-20-7) → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 2: N,N-dimethyl acetamide / 20 - 60 °C 3: N,N-dimethyl acetamide / 60 - 80 °C 4: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1.1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 1.2: 2.5 h / 10 - 75 °C 2.1: ammonium hydroxide / 2 h / 98 - 103 °C / Sealed tube View Scheme
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / dichloromethane / 10 - 20 °C 2: ethyl acetate; N,N-dimethyl acetamide / 10 - 75 °C 3: ammonium hydroxide / 20 - 103 °C / Autoclave View Scheme

N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N-dimethyl acetamide / 20 - 60 °C 2: N,N-dimethyl acetamide / 60 - 80 °C 3: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1: ethyl acetate; N,N-dimethyl acetamide / 10 - 75 °C 2: ammonium hydroxide / 20 - 103 °C / Autoclave View Scheme

2-fluoro-3-bromobenzoic acid methyl ester (206551-41-9) → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 8 steps 1: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; caesium carbonate / 90 °C / Sealed tube; Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: pyridine / dichloromethane / 20 °C 4: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 °C / Cooling with ice 5: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 6: N,N-dimethyl acetamide / 20 - 60 °C 7: N,N-dimethyl acetamide / 60 - 80 °C 8: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 20 °C 2.1: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 2.2: 2 h / 120 °C 3.1: ammonium hydroxide / 1,4-dioxane / 24 h / 90 °C / Sealed tube 4.1: (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N',N'-tetramethylguanidine / dimethyl sulfoxide / 40 h / 55 °C / Inert atmosphere; Glovebox; Irradiation View Scheme

3-bromo-2-fluorobenzoic acid (161957-56-8) → dabrafenib (1195765-45-7)

Conditions

Yield

Multi-step reaction with 9 steps 1: sulfuric acid / 1 h / Reflux 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; caesium carbonate / 90 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: pyridine / dichloromethane / 20 °C 5: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 °C / Cooling with ice 6: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 7: N,N-dimethyl acetamide / 20 - 60 °C 8: N,N-dimethyl acetamide / 60 - 80 °C 9: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme

C23H19BrClF3N4O2S2 → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl acetamide / 60 - 80 °C 2: ammonia / methanol / 24 h / 90 °C / Sealed tube View Scheme

1-(3-bromo-2-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethan-1-one → dabrafenib (1195765-45-7)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 1.2: 2 h / 120 °C 2.1: ammonium hydroxide / 1,4-dioxane / 24 h / 90 °C / Sealed tube 3.1: (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N',N'-tetramethylguanidine / dimethyl sulfoxide / 40 h / 55 °C / Inert atmosphere; Glovebox; Irradiation View Scheme

2-chloro-4-methylpyrimidine (13036-57-2) → dabrafenib (1195765-45-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 20 °C 2.1: N-Bromosuccinimide / N,N-dimethyl acetamide / 0.25 h / 20 °C 2.2: 2 h / 120 °C 3.1: ammonium hydroxide / 1,4-dioxane / 24 h / 90 °C / Sealed tube 4.1: (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N',N'-tetramethylguanidine / dimethyl sulfoxide / 40 h / 55 °C / Inert atmosphere; Glovebox; Irradiation View Scheme

C26H24F3N5O3S2 → dabrafenib (1195765-45-7)

Conditions	Yield
With hydrogenchloride In water for 8h; Reflux; Green chemistry;	31.89 g

C7H10ClNS → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine / 6 h / 43 °C / Green chemistry 2: sodium hydroxide / butan-1-ol / 100 °C / Green chemistry 3: aluminum (III) chloride / Green chemistry 4: sodium hydroxide / 0 - 5 °C / Green chemistry 5: hydrogenchloride / water / 8 h / Reflux; Green chemistry View Scheme

C12H17ClN2OS → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / butan-1-ol / 100 °C / Green chemistry 2: aluminum (III) chloride / Green chemistry 3: sodium hydroxide / 0 - 5 °C / Green chemistry 4: hydrogenchloride / water / 8 h / Reflux; Green chemistry View Scheme

C14H17ClN4OS → dabrafenib (1195765-45-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / Green chemistry 2: sodium hydroxide / 0 - 5 °C / Green chemistry 3: hydrogenchloride / water / 8 h / Reflux; Green chemistry View Scheme

methanesulfonic acid (75-75-2) + dabrafenib (1195765-45-7) → N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonic acid (1195768-06-9)

Conditions	Yield
In isopropyl alcohol at 20℃; for 3h;	87%
In water; acetonitrile at 20 - 60℃; Product distribution / selectivity;	85.1%
In water; acetonitrile at 20 - 60℃; Solvent;	85.1%

methanesulfonic acid (75-75-2) + dabrafenib (1195765-45-7) → N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate

Conditions	Yield
In water; acetonitrile at 50 - 60℃; Solvent; Temperature; Time;	85.1%

dabrafenib (1195765-45-7) → N-(5-amino-2-(tert-butyl)-11-fluorobenzo[f]thiazolo[4,5-h]-quinazolin-10-yl)-2,6-difluorobenzenesulfonamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 0.6h; Solvent; UV-irradiation;	37%

dabrafenib (1195765-45-7) + levulinic acid (123-76-2) → C28H26F3N5O4S2

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 40℃;

dabrafenib (1195765-45-7) → C6H4F2O2S

Conditions	Yield
Multi-step reaction with 2 steps 1: Hexamethylphosphorous triamide / tetrahydrofuran / 0.5 h / 20 °C 2: N,N,N′,N′-tetramethyl-N″-tert-butylguanidine / tetrahydrofuran / 4 h / 65 °C View Scheme

dabrafenib (1195765-45-7) → 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (1195769-01-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: Hexamethylphosphorous triamide / tetrahydrofuran / 0.5 h / 20 °C 2: N,N,N′,N′-tetramethyl-N″-tert-butylguanidine / tetrahydrofuran / 4 h / 65 °C 3: hydroxylamine / tetrahydrofuran; water / 0.5 h / 20 °C View Scheme

dabrafenib (1195765-45-7) → N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: Hexamethylphosphorous triamide / tetrahydrofuran / 0.5 h / 20 °C 2: N,N,N′,N′-tetramethyl-N″-tert-butylguanidine / tetrahydrofuran / 4 h / 65 °C 3: hydroxylamine / tetrahydrofuran; water / 0.5 h / 20 °C 4: pyridine / tetrahydrofuran; water / 1 h / 20 °C View Scheme

phenylglyoxylic acid ethyl ester (1603-79-8) + dabrafenib (1195765-45-7) → C33H30F3N5O4S2

Conditions	Yield
With Hexamethylphosphorous triamide In tetrahydrofuran at 20℃; for 0.5h; chemoselective reaction;

phenylglyoxylic acid ethyl ester (1603-79-8) + dabrafenib (1195765-45-7) → C27H26FN5O2S

Conditions	Yield
Multi-step reaction with 2 steps 1: Hexamethylphosphorous triamide / tetrahydrofuran / 0.5 h / 20 °C 2: N,N,N′,N′-tetramethyl-N″-tert-butylguanidine / tetrahydrofuran / 4 h / 65 °C View Scheme

dabrafenib (1195765-45-7) + saccharin (81-07-2) → C23H20F3N5O2S2*C7H5NO3S

Conditions	Yield
In acetonitrile for 0.166667h; Milling;

dabrafenib (1195765-45-7) + (2E)-but-2-enedioic acid (110-17-8) → C23H20F3N5O2S2*0.5C4H4O4

Conditions	Yield
In acetonitrile for 0.166667h; Milling;

succinic acid (110-15-6) + dabrafenib (1195765-45-7) → C23H20F3N5O2S2*0.5C4H6O4

Conditions	Yield
In acetonitrile for 0.166667h; Milling;

Adipic acid (124-04-9) + dabrafenib (1195765-45-7) → C23H20F3N5O2S2*0.5C6H10O4

Conditions	Yield
In acetonitrile for 0.166667h; Milling;

Upstream product

• 3438-46-8 4-Methylpyrimidine 
• 13036-57-2 2-chloro-4-methylpyrimidine 
• 60230-37-7 2,6-difluorobenzene-1-sulfonamide 
• 161957-56-8 3-bromo-2-fluorobenzoic acid 
• 206551-41-9 2-fluoro-3-bromobenzoic acid methyl ester 
• 1195768-20-7 N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide 
• 1042055-86-6 methyl 3-((tert-butoxycarbonyl)amino)-2-fluorobenzoate 
• 1195768-23-0 N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide 
• 1195768-19-4 3-(2,6-difluorobenzenesulfonamido)-2-fluorobenzoic acid methyl ester 
• 1195768-18-3 3-amino-2-fluorobenzoic acid methyl ester 
• 60230-36-6 2,6-difluorobenzene-1-sulfonyl chloride 

Downstream Products

• 1195768-06-9 N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonic acid 
• 1195768-23-0 N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide 

Relevant articles and documents

C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization

Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in small-molecule discovery. In particular, 2-Aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2-N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C-H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C-H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.

Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis

Herein we report a highly efficient method for nickel-catalyzed C?N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C?N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.

PHARMACEUTICAL COMBINATION COMPRISING THE PI3K INHIBITOR ALPELISIB AND THE B-RAF INHIBITOR DABRAFENIB; THE USE OF SUCH COMBINATION IN THE TREATMENT OR PREVENTION OF CANCER

The present disclosure pertains to a pharmaceutical combination comprising (a) alpha- isoform specific PI3K inhibitor and (b) a B-RAF inhibitor; combined preparations and pharmaceutical compositions thereof; the uses of such combination in the treatment or prevention of cancer; and methods of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of such combination.