Uplarafenib

1425485-87-5

494.5 g/mol

• B-Raf IN 10
• TQU3V7CXC3
• N-[2,4,5-trifluoro-3-(3-morpholin-4-ylquinoxaline-6-carbonyl)phenyl]propane-1-sulfonamide
• B-Raf IN 10; B-Raf IN-10; B-Raf-IN-10

UPLARAFENIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication. Neupharma, Inc.

 There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial

SCHEME

Patent

Compound A [WO2022119905A2]

WO2022119905 69%

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022119905&_cid=P20-M8O7NY-07177-1

Example 1: Preparation of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (Compound A)

[181] Step l : To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HO Ac (1000 mL) was added a solution of Bn (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88%).

[182] Step l : To a suspension of 7-bromoquinoxalin-2(lH)-one (224 g, 1 mol, 1.0 eq.) in POCl₃ (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). The resulting mixture was stirred at 120 °C for 2 h, then cooled to rt and slowly poured into ice-water with vigorous stirring. The precipitate was collected by filtration and dried to afford 7-bromo-2-chloroquinoxaline as brown solid (180 g, 75%).

[183] Step 3 : To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2mol, 1.0 eq.) in CH₃CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K₂CO₃ (85 g, 0.61mol, 3.0 eq). The resulting mixture was stirred at 90 °C for 2 h, then cooled and filtered. The filtrate was concentrated and the residue was re-crystallized from EA to afford 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3%).

[184] Step 4 : To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 0.2 mol, 1.0 eq.) in DMF (500 mL) was added TEA (139 mL, 1.0 mol, 5.0 eq.), EtsSiH (127 mL, 0.8 mol, 4.0 eq) and Pd(dppf)C12.CH2C12 (8.16 g, 0.01 mol, 0.05 eq.). The resulting mixture was stirred at 90 °C for 12h in an autoclave under CO (1 MPa), then cooled and concentrated. The resulting residue was purified by flash column chromatography(EA/PE=l/l) to afford 3-morpholinoquinoxaline-6-carbaldehyde as a yellow solid (40 g, 82.3%).

[185] Step 5 : To a solution of N-(2,4,5-trifluorophenyl)pivalamide (550 mg, 2.4 mmol, E2 eq.) in THF (30 mL) cooled at -78 °C was added LDA (4.1 mL, 4.8mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at -78 °C for 1 h, then a solution of 3-morpholinoquinoxaline-6-carbaldehyde (486 mg, 2.0 mol, 1.0 eq.) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 1 h, then quenched by the addition of NH4CI solution. The mixture was extracted with EA (20 mL X 3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (MeOH/DCM=l/50, v/v) to afford N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 65.2%).

[186] Step 6 : The solution of N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 1.3 mmol, 1.0 eq.) in DCM (10 mL) was added MnCb (358 mg, 6.5 mmol, 5.0 eq.). The resulting mixture was stirred at 50 °C overnight, then cooled and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (PE/EA=l/2,v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg, 90%).

[187] Step 7 : To a solution of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg , 1.2 mmol, 1.0 eq. ) in HO Ac (10 mL) was added cone. HC1 (50 mL). The mixture was stirred at 110 °C for 4h, then poured onto ice. The mixture was adjusted to pH 10 by the addition of IN NaOH solution, then extracted with DCM (100 mL X 3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=l/4,v/v) to afford (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone as brown solid (410 mg, 88 % yield).

[188] Step 8 : To a solution of (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone (40 mg, 0.1 mmol, 1.0 eq.) in DCM (10 mL) was added TEA (101 mg, 1 mol, 10 eq.) and propane- 1 -sulfonyl chloride (0.5 mL, 0.5 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (lOmL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (41 mg, 62.2%).

[189] Step 9 : To a solution of N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l -sulfonamide (41 mg, 0.068 mmol, 1.0 eq.) in MeOH/THF (10 mL /10 mL) was added 1 N NaOH (0.15 mmol, 2.2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=l/l,v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l -sulfonamide (Compound A) (23 mg, 68.9%). LRMS (M+H⁺) m/z calculated 495.1, found 495.1. ^XH NMR (CDCh, 400 MHz) 8 8.67 (s, 1 H), 7.98-8.03 (m, 3 H), 7.66-7.73 (m, 1 H), 6.72 (s, 1 H), 3.78-3.88 (m, 8H), 3.12-3.16 (t, 2 H), 1.87-1.92 (q, 2 H), 1.05-1.09 (t, 3 H).

Example 2. Preparation of Crystalline Form I of Compound A

[190] N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (2.53 kg) and ethyl acetate (EA) (9.1 kg) were added to the reactor. The mixture was stirred under refluxing for 2h. The solution was cooled to room temperature. The resulting precipitate was filtered, washed with EA (1 kg), and dried under vacuum at 45 °C to afford Crystalline Form I of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (1.94 kg, 76.7%).

Example 3. Preparation of Crystalline Form II of Compound A

[191] N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-l-sulfonamide (4.01 kg) was dissolved in EA (60 kg), and water (20 kg) was added. The organic phase was separated and concentrated to 4-6 kg under vacuum at 40-45 °C. The resulting residue was dissolved in EA (6 kg) and stirred for 4 hours at 10-20 oC. The solid was filtered, washed with EA (1.5 kg), and dried under vacuum at 50-55 oC to afford Crystalline Form II of N-(2,4,5-trifluoro-3 -(3 -morpholinoquinoxaline-6-carbonyl)phenyl)propane- 1 -sulfonami de (3.15 kg, 78.6%).

SEE

US20130053384 69%