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Resigratinib

Example 78

3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

Step 1: 1-(Tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (8.00 g, 32.62 mmol) and imidazole (4.44 g, 65.23 mmol) in DMF (80.00 mL) was added tert-butyl(chloro)diphenylsilane (13.45 g, 48.93 mmol) at 0° C. over 30 min. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with EA (3×300 mL). The combined organic layers was washed with brine (5×500 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1). The fractions contained desired product were combined and concentrated to afford 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (14.20 g, 90%) as a colorless oil. MS ESI calculated for C ₂₇H ₃₇NO ₅Si [M+H] ⁺, 484.24, found 484.25.

Step 2: Tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (30.00 g, 62.02 mmol) in THF (300.00 mL) was added LiBFi ₄(6.08 g, 0.28 mol) in portions at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was acidified to pH 5 with HCl (1M) at 0° C. and then basified to pH 8 with saturated NaHCO ₃(aq.). The resulting mixture was extracted with EA (4×500 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pynolidine-1-carboxylate (24.00 g, 85%) as a light yellow oil. MS ESI calculated for C ₂₆H ₃₇NO ₄Si [M+H] ⁺, 456.25, found 456.30.

Step 3: Tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a suspension of NaH (0.20 g, 8.33 mmol) in THF (18 mL) was added a solution of tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.50 g, 5.49 mmol) in THF (64.00 mL) slowly at 0° C. under nitrogen atmosphere. After stirred at 0° C. for 1 h, to the above mixture was added CH ₃I (1.17 g, 8.23 mmol) dropwise at 0° C. The reaction mixture was stirred for additional 3 h at room temperature. The resulting mixture was diluted with water (60 mL), and then extracted with EA (3×30 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxyl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (2.30 g, 89%) as a light yellow solid. MS ESI calculated for C ₂₇H ₃₉NO ₄Si [M+H] ⁺, 470.26, found 470.30.

Step 4: Tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-(methoxymethyl)pyrrolidine-1-carboxylate (46.30 g, 98.57 mmol) in THF (375.00 mL) was added tetra-n-butylammonium fluoride (1 M in THF) (146.70 mL, 0.14 mol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (1 L) and extracted with EA (3×500 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (16.60 g, 73%) as a light yellow oil. MS ESI calculated for C ₁₁H ₂₁NO ₄[M+H] ⁺, 232.15, found 232.20.

Step 5: Tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 3.5-dibromo-1H-pyrazole-4-carbonitrile (2.00 g, 7.97 mmol), tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.84 g, 7.97 mmol) and triphenylphosphine (3.14 g, 11.95 mmol) in THF (40.00 mL) was added diisopropyi azodicarboxylate (2.42 g, 11.95 mmol) dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (3.50 g, 94%) as a dark yellow solid. MS ESI calculated for C ₁₅H ₂₀Br ₂N ₄O ₃[M+H−100] ⁺, 361.99, 363.99, 365.99; found 362.10, 364.10, 366.10.

Step 6: Tert-butyl (2S,4R)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrollidine-1-carboxylate

To a stirred solution of tert-butyl (2R)-4-(3,5-dibromo-4-cyanopyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (1.00 g, 2.15 mmol) in NMP (10.00 mL) was added CH ₃NH ₂(2.98 mL, 5.96 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 50° C. under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EA (3×50 mL). The combined organic layers was washed with brine (3×20 mL), dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2S,4R)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.67 g, 35%) as an off-white solid. MS ESI calculated for C ₁₆H ₂₄BrN ₅O ₃[M+H−100] ⁺, 314.11, 316.11, found 314.10, 316.10.

Step 7: (2R,4S)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4S)-4-[3-bromo-4-cyano-5-(methylamino)pyrazol-1-yl]-2-(methoxymethyl)pyrrollidine-1-carboxylate (20.30 g, 49.00 mmol) in DCM (300.00 mL) were added Boc ₂O (20.97 mL, 98.01 mmol), DMAP (0.60 g, 4.90 mmol) and Et ₃N (20.43 mL, 0.14 mol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (3×200 mL) and extracted with DCM (3×200 mL). The combined organic layers was washed with brine (3×100 mL). The organic layer was dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford (2R,4R)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 95%) as an off-white solid. MS ESI calculated for C ₂₁H ₃₂BrN ₅O ₅[M+H] ⁺, 514.16, 516.16, found 514.15, 516.15; ¹H NMR (400 MHz, CDCl ₃) δ 4.94-4.90 (m, 1H), 4.23-4.19 (m, 1H), 3.75-3.66 (m, 3H), 3.44-3.40 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 2.62-2.58 (m, 1H), 2.41-2.19 (m, 1H), 1.48 (s, 18H).

Step 8: Tert-butyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred mixture of (2R,4S)-4-[3-bromo-5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 46.65 mmol), CuI (1.78 g, 9.33 mmol), Pd(PPh ₃) ₂Cl ₂(3,27 g, 4.67 mmol) and trimethylsilylacetylene (19.78 mL, 0.20 mol) in DMF (240.00 mL) was added TEA (19,45 mL, 0.19 inol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with EA (4×500 mL). The combined organic layers was washed with brine (2×500 mL), dried over anhydrous Na ₂SO ₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R, 4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylisilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (2.4.00 g, 96%) as a brown solid. MS ESI calculated for C ₂₆H ₄₁N ₅O ₅Si [M+H]+, 532.29, found 532.40; ¹H NMR (400 MHz, CDCl ₃) δ 4.93-4.89 (m, 1H), 4.23-4.17 (m, 1H), 3.68-3.52 (m, 3H), 3.42-3.37 (m, 1H), 3.35-3.33 (m, 3H), 3.25-3.20 (m, 3H), 2.63-2.58 (m, 1H), 2.33-2.13 (m, 1H), 1.46 (s, 18H), 0.27 (s, 9H).

Step 9: Tert-butyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (2R,4S)-4-[5-[(tert-(butoxycarbonyl)(methyl)amino]-4-cyano-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (24.00 g, 45.14 mmol) in THF (200.00 mL) was added TBAF (67.70 mL, 67.70 mmol, 1 M in THF) at 0° C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×500 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.40 g, 83%) as an off-white solid, MS ESI calculated for C ₂₃H ₃₃N ₅O ₅[M+H] ⁺, 460.25, found 460.40; ¹H NMR (400 MHz, CDCl ₃) δ 4.93-4.89 (m, 1H), 4.22-4.18 (m, 1H), 3.84-3.46 (m, 3H), 3.42-3.37 (m, 1H), 3.37-3.31 (m, 4H), 3.24 (s, 3H), 2.62-2.59 (m, 1H), 2.28-2.24 (m, 1H), 1.46 (s, 18H).

Step 10: Tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of ter tyl (2R,4S)-4-(5-[(tert-butoxycarbonyl)(methyl)amino]-4-cyano-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.40 g, 37.86 mmol) in DMSO (30.00 mL) and EtOH (150.00 mL) were added 0.5 M NaOH (87.09 mL, 43.54 mmol) and H ₂O ₂(10.26 mL, 0.13 mol) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. Then the reaction mixture was warmed up to room temperature and stirred for another 0.5 h at room temperature. The resulting mixture was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×300 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/2). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.20 g, 95%) as an off-white solid. MS ESI calculated for C ₂₃H ₃₅N ₅O ₆[M+H] ⁺, 478.26, found 478.25; ¹H NMR (300 MHz, CDCl ₃) δ 6.80-6.74 (m, 1H), 5.69-5.62 (m, 1H), 5.04-5.00 (m, 1H), 4.23-4.19 (m, 1H), 3.75-3.67 (m, 3H), 3.49-3.42 (m, 1H), 3.39-3.32 (m, 3H), 3.14 (s, 3H), 2.72-2.60 (m, 1H), 2.32-2.21 (m, 1H), 1.62-1.31 (m, 18H).

Step 11: 3-Ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride

To a stirred mixture of tert-butyl (2R,4S)-4-[5-[(tert-butoxycarbonyl)(methyl)amino]-4-carbamoyl-3-ethynylpyrazol-1-yl]-2-(methoxymethyl)pyrrolidine-1-carboxylate (17.20 g, 36.02 minor) in DCM (170,00 mL) was added HCl (180.08 mL, 0.72 mol, 4 M in EA). The reaction mixture was stirred for 1 h at room temperature under argon atmosphere. The resulting mixture was concentrated and dried to afford 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride (12.50 g, crude) as an off-white solid which was used in the next step directly without further purification. MS ESI calculated for C ₁₃H ₂₁Cl ₂N ₅O ₂[M+H−2 HCl] ⁺, 278.15, found 278.05.

Step 12: 3-Ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

To a stirred mixture of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide dihydrochloride (12.50 g, 35.69 mmol) and K ₂CO ₃(172 mL, 0.43 mol, 2.5 M) in THF (250.00 mL) was added acryloyl chloride (2.89 g, 32.15 mmol) dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred for 10 min at 0° C. The resulting mixture was diluted with water (500 mL) and extracted with EA (3×500 mL). The combined organic layers was washed with brine (2×300 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (11.10 g, 84%) as an off-white solid. MS ESI calculated for C ₁₆H ₂₁N ₅O ₃[M+H] ⁺, 332.16, found 332.20; ¹H NMR (400 MHz, CDCl ₃) δ 6.76 (s, 1H), 6.60-6.36 (m, 2H), 5.74-5.68 (m, 1H), 5.50-5.20 (m, 2H), 4.55-4.39 (m, 1H), 4.06-3.83 (m, 3H), 3.53-3.40 (m, 2H), 3.36-3.35 (m, 3H), 3.03-2.99 (m, 3H), 2.68-2.60 (m, 1H), 2.37-2.23 (m, 1H).

Step 13: N-cyclopropyl-3,5-difluoro-2-nitroaniline

To a stirred solution of 1,3,5-trifluoro-2-nitrobenzene (4.50 g, 25.41 mmol) in EtOH (45.00 mL) was added aminocyclopropane (2.90 g, 50.82 mmol) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0° C. The resulting mixture was diluted with water (100 mL) and extracted with EA (3×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford N-cyclopropyl-3,5-difluoro-2-nitroaniline (4.11 g, 85%) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.64 (s, 6.80-6.74 (m, 1H), 6.30-6.27 (m, 1H), 2.59-2.54 (m, 1H), 1.01-0.83 (m, 2H), 0.76-0.61 (m, 2H).

Step 14: N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline

To a stirred mixture of N-cyclopropyl-3,5-difluoro-2-nitroaniline (4.11 g, 19.19 mmol) in methanesulfonic acid (45.00 mL) was added NIS (4.53 g, 20.15 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with ice/water (100 mL) at 0° C. The resulting mixture was basified to pH 8 with sat. NaOH and extracted with EA (3×100 mL). The combined organic layers was washed with brine (3×100 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline (4.50 g, 69%) a yellow solid. ¹H NMR (400 MHz, CDCl ₃) δ 7.53 (s, 1H), 6.90-6.88 (m, 1H), 2.57-2.54 (m, 1H), 1.07-0.85 (m, 2H ), 0.83-0.58 (m, 2H).

Step 15: N1-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine

To a stirred mixture of N-cyclopropyl-3,5-difluoro-4-iodo-2-nitroaniline (4.40 g, 12.94 mmol) and NH ₄Cl (2.77 g, 51.76 mmol) in EtOH (44.00 mL) and H ₂O (8.80 mL) was added Fe (2.89 g, 51.76 mmol). The reaction mixtue was stirred at 70° C. for 6 h. The resulting mixture was diluted with water (150 mL) and extracted with EA×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over anhydrous Na ₂SO ₄and filtered. The filtrate was concentrated under reduced pressure to afford N-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine (3.30 g, crude) as a brown oil which was used in the next step directly without further purification. MS ESI calculated for C ₉H ₉F ₂IN ₂[M+H] ⁺, 310.98, found 311.00; ¹H NMR (300 MHz, CDCl ₃) δ 6.68-6.61 (m, 1H), 2.50-2.41 (m, 1H), 0.89-0.73 (m, 2H), 0.78-0.51 (m, 2H).

Step 16: 1-Cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole

To a stirred solution of N ¹-cyclopropyl-3,5-difluoro-4-iodobenzene-1,2-diamine (3.30 g, 10.64 mmol) in MeOH (33.00 mL) was added trimethyl orthoformate (3.39 g, 31.92 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 70° C. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/2). The fractions contained desired product were combined and concentrated to afford 1-cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole (1.70 g, 50%) as a yellow solid. MS ESI calculated for C ₁₁H ₇F ₂N ₂[M+H] ⁺, 320.96, found 321.00; ¹H NMR (300 MHz, CDCl ₃) δ 7.91 (s, 1H), 7.22-7.18 (m, 1H), 3.41-3.36 (m, 1H), 1.31-1.02 (m, 4H).

Step 17: 3-[2-(1-Cyclopropyl-4,6-difluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide

To a stirred solution of 1-cyclopropyl-4,6-difluoro-5-iodo-1,3-benzodiazole (0.97 g, 3.02 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (1.00 g, 3.02 mmol), Pd(PPh ₃) ₂Cl ₂(0.21 g, 0.30 mmol) and CuI (0.11 g, 0.60 mmol) in DMF (15.00 mL) was added TEA (0.92 g, 9.05 mmol) dropwise at room temperature. The reaction mixture was degassed with argon for three times and stirred for 40 min at 90° C. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. Then the crude product was further purified by reverse phase flash with the following conditions: column: C18 silica gel; mobile phase: ACN in water (10 mmol/L NH ₃HCO ₃), 10% to 50% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(1-cyclopropyl-4,6-difluoro-1,3-b enzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.51 g, 33%) as a white solid. MS ESI calculated for C ₂₆H ₂₇F ₂N ₇O ₃[M+H] ⁺, 524.21, found 524.35; ¹H NMR (300 MHz, CDCl ₃) δ 7.99 (s, 1H), 7.30-7.12 (m, 2H), 6.83 (brs, EH), 6.67-6.32 (m, 2H), 5.84-5.73 (m, 1H), 5.64-5.12 (m, 2H), 4.71-4.38 (m, 1H), 4.25-3.84 (m, 3H), 3.60-3.33 (m, 5H), 3.20-3.08 (m, 3H), 2.86-2.70 (m, 1H), 2.37-2.31 (m, 1H), 1.40-0.89 (m, 4H).

PATENT

WO2021247969 Kinnate Biopharma Inc EG78

WO2023107980 solid state forms, Kinnate Biopharma Inc

WO2023107979 FGFR kinase inhibitor, Kinnate Biopharma Inc

References

Franovic A, Mohan A, Uryu S, Wu Q, Jiang P, Miller N, et al. (February 2022). “Activity of KIN-3248, a next-generation pan-FGFR inhibitor, against acquired FGFR-gatekeeper and molecular-brake drug resistance mutations”. Journal of Clinical Oncology. 40 (4_suppl): 461. doi:10.1200/JCO.2022.40.4_suppl.461.
Harding JJ, Perez CA, Kato S, Sharma M, Garmezy B, Quah CS, et al. (February 2023). “First in human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced cholangiocarcinoma (CCA) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations”. Journal of Clinical Oncology. 41 (4_suppl): TPS637-TPS637. doi:10.1200/JCO.2023.41.4_suppl.TPS637. S2CID 256257314.
Wang Z, Anderson KS (2022). “Therapeutic Targeting of FGFR Signaling in Head and Neck Cancer”. Cancer Journal (Sudbury, Mass.). 28 (5): 354–362. doi:10.1097/PPO.0000000000000615. PMC 9523489. PMID 36165723.

Identifiers

CAS Number	2750709-91-0
PubChem CID	162381323
UNII	W728TB393W
Chemical and physical data
Formula	C₂₆H₂₇F₂N₇O₃
Molar mass	523.545 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

[1]. Tyhonas JS, et al. Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations. J Med Chem. 2024 Feb 8;67(3):1734-1746. [Content Brief][2]. Balasooriya ER, et al. The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations. Clin Cancer Res. 2024 May 15;30(10):2181-2192. [Content Brief]

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By DR ANTHONY MELVIN CRASTO Ph.D in Uncategorized on July 13, 2025.

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Laporolimus
Laporolimus Rapamycin, 42-cyclohexanecarboxylate CAS 1504576-27-5 MF C58H89NO14 MW 1024.3 g/mol [(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] cyclohexanecarboxylate (1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexylcyclohexanecarboxylateimmunosuppressant, CRC-015, CRC 015, F5041W3RVA, Rapamycin, 42-cyclohexanecarboxylate Laporolimus is an experimental immunosuppressant compound that…
Lanoracopan
Lanoracopan CAS 2797066-85-2 MFC27H32N2O4 MW448.6 g/mol 4-[(2S,4S)-4-(cyclopropylmethoxy)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid Benzoic acid, 4-[(2S,4S)-4-(cyclopropylmethoxy)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-piperidinyl]- 4-{(2S,4S)-4-(cyclopropylmethoxy)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoic acidcomplement factor B inhibitor, MY 008211A, Factor B-IN-5, Y5UN7AE8SF Lanoracopan (also known by its…
Lanisidenib
Lanisidenib Cas 2135537-20-9 MF C28H23ClF3N5O4S MW618.03 g/mol (3S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-2-(4-cyano-2-pyridinyl)-N-(3-fluorophenyl)-1,1-dioxo-1,2-thiazolidine-3-carboxamide IUPAC Name: (3S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3, 3-difluorocyclobutyl)amino]-2-oxoethyl}-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-1,1-dioxo-1λ⁶,2-thiazolidine-3-carboxamide 3-Isothiazolidinecarboxamide, N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-2-(4-cyano-2-pyridinyl)-N-(3-fluorophenyl)-, 1,1-dioxide, (3S)- (3S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-1,1-dioxo1λ6,2-thiazolidine-3-carboxamideisocitrate dehydrogenase inhibitor, antineoplastic, G5J396CG5J Lanisidenib is a potent,…
Itareparib
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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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