N-[3-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-4-methoxyphenyl]-N′-(2,4-difluorophenyl)urea

Nelotanserin is a potent 5-HT2A inverse agonist, a moderately potent 5-HT2C partial inverse agonist and a weak 5-HT2B inverse agonist, with IC50s of 1.7, 79, 791 nM in IP accumulation assays, respectively.

Nelotanserin is a member of pyrazoles and a ring assembly.|Nelotanserin has been used in trials studying the treatment of Lewy Body Dementia, Visual Hallucinations, Dementia With Lewy Bodies, and REM Sleep Behavior Disorder. It is a highly selective antagonist at the 5-HT2A serotonin receptor. It increases non-REM sleep, the most restorative phase of the sleep cycle, without sacrificing REM or dream sleep. Nelotanserin works through a mechanism of action that is different from currently marketed drugs.

N-(2, 4-Difluorophenyl)-N-(4-methoxy-3-(4-bromo-I -methyl-lH-pyrazol-5- yl) phenyl)urea (8); Both portions of 5-(2 -methoxy-5 -aminophenyl)-4-bromo-l-methyl-IH-pyrazole (2) from the previous example were combined by dissolution in toluene (15 L) at 27.6° C, suction filtration of the resulting solution, and rotary evaporation of the filtrate at <50° C and 10 mm HgA to a constant weight of 1127.0 g. A solution of 7 (1102.0 g of the 1127.0 g evaporation residue) in toluene (11.02 L) was stirred and refluxed at atmospheric pressure through a Dean-Stark trap under nitrogen. to remove 0.8 mL of water. After the condensate had become completely clear with no further accumulation of water in the Dean-Stark trap, the toluene solution was cooled under nitrogen to 12.9° C. To the resulting solution stirred under nitrogen was added 2, 4- difluorophenyl isocyanate (617.9 g) by addition funnel over 40 minutes at a rate sufficiently slow to enable the reaction mixture to be maintained at 12.9-19° C with reactor jacket cooling. Solid started to precipitate in the reaction mixture about half way through the addition. After the addition had been completed, the reaction slurry continued to be stirred at 16° C under nitrogen. Conversion of 7 to 8 was 90percent, 91.2percent, and 92.6percent five, 60, and. 120 minutes, respectively, after the addition had been completed. Three hours after the addition had been completed, a second portion of 2, 4-difluorophenyl isocyanate (24.4 g) was added, and, after continued stirring of the reaction mixture at 16° C under nitrogen for an additional 30 minutes, conversion of 7 to 8 was 94percent. One hour after the second addition, a third portion of 2, 4-difluorophenyl isocyanate (9.7 g) was added, and, after continued stirring of the reaction mixture at 16° C under nitrogen for an additional 15 minutes, conversion of 7 to 8 was 95percent. The reaction mixture was then stirred at 20° C under nitrogen for anadditional 14.75 hours, after which conversion of 7 to 8 was 100percent. The reaction mixture was suction filtered, and the filtered solid was washed with 2.6° C toluene (2 x 1100 mL) and dried at 100° C and pressures falling to 1 mm HgA to provide 8 (1654.9 g, 96.9 percent yield) of 98.2 percent purity by HPLC with ca. 0.9 mole percent desbromo 8 as the largest impurity.To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (16.7 kg) in acetonitrile (78.6 kg) in a 200 L-glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamme (16.7 kg) in acetonitπle (78.6 kg) m a 200 L glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of < -10 To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (16.7 kg) in acetonitrile (78.6 kg) in a 200 L-glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamme (16.7 kg) in acetonitle (78.6 kg) m a 200 L glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of < -10 0C 2, 4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a 1 micron line filter at a rate substantially slow enough to prevent co-precipitation of the starting material in the product. After continued stirring at < -10 0C for approximately 1 hour post completion of the 2, 4-difluorophenyl-isocyanate addition, the conversion of starting material to product was substantially complete. The product slurry was filtered and washed with cold acetonitle (26.3 kg) at < -5 0C producing the acetomtle solvate of the product. Full house vacuum (~30 in Hg ) was applied to the bottom outlet filter/dryer while nitrogen flowed through from the top enhancing the removal of volatile solvents without application of heat. Samples were removed from the bulk material and LOD was determined using an IR-200 Moisture Analyzer Instrument (Denver Instrument Company). The time course is shown below:Drying of the "wetcake" was maintained at ambient temperature under full house vacuum (-30 in Hg ) for about 19.5 h at which time the LOD was 7.28%. At this point, the temperature was raised to 70 C under full house vacuum (-30 in Hg ) for 11 hrs to afford l-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2, 4-difluoro-phenyl)-urea (24.2 kg, 99.94% EtaPLC purity, form I determined by PXRD, and 92.9% yield).After a stirred mixture of methanol (90 mL), 50 wt % aqueous NaOH (61.60 g, ca. 40.4 mL, 0.7705 mole, 4.993 equivalents), andN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-acetamide (50.0 g, 0.1542 moles, 1.000 equivalent) had been heated under nitrogen with a 9O0C oil bath for 8.5 hr, the conversion of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl] -acetamide to 3 -(4-bromo-2-methyl-2H-pyrazol-3 -yl)-4-methoxy-phenylamine EPO To a mixture of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide (34.7 g, 0.1 mol) in methanol (347 mL) was added acetyl chloride (3 molar equivalents, 23 mL, 0.32 mol) at O0C and the solution was stirred at 450C for 24h. Formation of 3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-methoxy-phenylamine and consumption of N-[3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-acetamide were monitored by LCMS. The volatiles were removed, and the resulting residue was dissolved back in methanol (350 mL). Diisopropylethylamine (DIEA) (3 molar equivalents, 56.1 mL, 0.32 mol) was added at room temperature, and, after 0.5h isocyanate (1.1 molar equivalents, 12.73 mL, 0.101 mol) was then introduced at room temperature. Formation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-3-(2, 4-difluoro-phenyl)-urea and consumption of 3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine were monitored by LCMS, and, after 3 hr, the mixture was heated to 8O0C and diluted using water (70 mL). The white solid product was filtered, washed using water (70 mL), and dried to provide l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-3-(2, 4-difluoro-phenyl)-urea (32.46 g, 74.28 mmol, 69% yield). Preparation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (2, 4-difluoro-phenyl)-urea from N- [4-methoxy-3-(2-methyl-2H-pyrazoI-3-yl)-phenyl] - acetaniide:To a mixture of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (1 g, 4.08 mmol) in methanol (5 mL) was added NuBS (1.2 molar equivalent, 871 mg, 4.9 mmol) and the resulting mixture was stirred at room temperature for 2h. Formation of N-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-rhohenyl]-acetamide and consumption of N-[4-methoxy-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-acetamide were monitored by LCMS. The crude mixture was cooled to O0C, and acetyl chloride (6 molar equivalents, 1.32 mL, 24.28 mmol) was added. The resulting mixture was stirred at 450C for 24h while formation of 3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine and consumption of N-[3-(4-bromo-2-methyl-2H-pyrazol- EPO N-(2, 4-Difluorophenyl)-N-(4-methoxy-3-(4-bromo-I -methyl-lH-pyrazol-5- yl) phenyl)urea (8); Both portions of 5-(2 -methoxy-5 -aminophenyl)-4-bromo-l-methyl-IH-pyrazole (2) from the previous example were combined by dissolution in toluene (15 L) at 27.6 C, suction filtration of the resulting solution, and rotary evaporation of the filtrate at <50 C and 10 mm HgA to a constant weight of 1127.0 g. A solution of 7 (1102.0 g of the 1127.0 g evaporation residue) in toluene (11.02 L) was stirred and refluxed at atmospheric pressure through a Dean-Stark trap under nitrogen. to remove 0.8 mL of water. After the condensate had become completely clear with no further accumulation of water in the Dean-Stark trap, the toluene solution was cooled under nitrogen to 12.9 C. To the resulting solution stirred under nitrogen was added 2, 4- difluorophenyl isocyanate (617.9 g) by addition funnel over 40 minutes at a rate sufficiently slow to enable the reaction mixture to be maintained at 12.9-19 C with reactor jacket cooling. Solid started to precipitate in the reaction mixture about half way through the addition. After the addition had been completed, the reaction slurry continued to be stirred at 16 C under nitrogen. Conversion of 7 to 8 was 90%, 91.2%, and 92.6% five, 60, and. 120 minutes, respectively, after the addition had been completed. Three hours after the addition had been completed, a second portion of 2, 4-difluorophenyl isocyanate (24.4 g) was added, and, after continued stirring of the reaction mixture at 16 C under nitrogen for an additional 30 minutes, conversion of 7 to 8 was 94%. One hour after the second addition, a third portion of 2, 4-difluorophenyl isocyanate (9.7 g) was added, and, after continued stirring of the reaction mixture at 16 C under nitrogen for an additional 15 minutes, conversion of 7 to 8 was 95%. The reaction mixture was then stirred at 20 C under nitrogen for anadditional 14.75 hours, after which conversion of 7 to 8 was 100%. The reaction mixture was suction filtered, and the filtered solid was washed with 2.6 C toluene (2 x 1100 mL) and dried at 100 C and pressures falling to 1 mm HgA to provide 8 (1654.9 g, 96.9 % yield) of 98.2 % purity by HPLC with ca. 0.9 mole % desbromo 8 as the largest impurity. (Compound 8, 1.44 g, 3.30 mmol) was dissolved in anhydrous CH2CI2 (30 ml). The solution was stirred while cooling the temperature to 0C in an ice water bath. After allowing it to stir for another 10 minutes, AlCl3 (1.76 g, 13.20 mmol) was added slowly. This was followed by stirring the reaction for an additional 20 minutes, and subsequently increasing the temperature to 80C. After one hour, the reaction was shown to be complete by TLC and LC/MS. It was worked up with EtOAc (2 x 50 ml) and 10% Potassium Sodium Tartrate (2 x 50 ml). Upon being treated to this work up, the aluminum was removed from the solution. The organic layer was then dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was then purified by HPLC, yielding 1.43 g (100%) of Compound 103 LCMS m/z (%) = 425 (M+H81Br, 100), 423 (M+H79Br, 88). 1H NMR (400 MHz, DMSO-d6) delta 9.74 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.08-8.03 (m, 1H), 7.58 (s, 1H), 7.36 (dd, J1 = 8 Hz, J2 = 4 Hz, 1H), 7.33-7.27 (m, 1H), 7.28 (d, J= 2 Hz, 1H), 7.04-7.01 (m, 1H), 6.95 (d, J= 8 Hz, 1H), 3.67 (s, 3H).

Molecular Weight:437.2
XLogP3:3.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:436.03464
Monoisotopic Mass:436.03464
Topological Polar Surface Area:68.2
Heavy Atom Count:27
Complexity:518
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes