Under the nitrogen atmosphere, 1-bromo-4-fluorobenzene (100 g, 0.57 mol, 1 equiv.), N-methylpyrrolidone (500 mL), and D-alaninol (51.5 g, 0.69 mol, 1.2 equiv.) were added, and then potassium tert-butoxide (96.1 g, 0.86 mol, 1.5 equiv.) was added thereto at 40° C. or less. The resulting mixture was stirred at an internal temperature of about 65° C. for 3 hours and cooled to 20° C. or less. After that, isopropyl acetate (500 mL) and water (1000 mL) were added thereto, and the resulting mixture was stirred. After standing and separating, the aqueous layer was extracted twice with isopropyl acetate (500 mL), and all the organic layers were combined. The combined organic layer was washed twice with water (500 mL), and the obtained organic layer was concentrated under reduced pressure to 300 mL. The operation of further adding ethanol (1000 mL) thereto and concentrating the obtained mixture under reduced pressure to 300 mL was repeated twice. To this solution, tetrahydrofuran (200 mL) was added, and the resulting mixture was cooled to 5° C. or less. tert-Butyl dicarbonate (162 g, 0.74 mol, 1.3 equiv.) was dissolved in tetrahydrofuran (100 mL), and the resulting solution was added dropwise to the mixture at 6° C. or less over about 2 hours. The resulting mixture was stirred at 5° C. or less for 1 hour, and then raised to about 20° C. and stirred overnight. Ethanol (230 mL) was added thereto, and then water (800 mL) was added dropwise over 1.5 hours. The resulting mixture was stirred at about 50° C. for 1 or more hours, and then gradually cooled to 25° C., and stirred overnight. The precipitated solid was filtered and washed with a mixed solution of ethanol (230 mL) and water (270 mL). The solid was dried under vacuum at an external temperature of 40° C. to obtain the title compound (1) (170 g).
Under the nitrogen atmosphere, benzyltriethylammonium chloride (445 g, 1.95 mol, 1 equiv.) and 6-chloroimidazo[1,2-b]pyridazine (300 g, 1.95 mol, 1 equiv.) (available from Combi-Block or the like) were successively added to dimethyl sulfoxide (1500 mL). Cesium fluoride (534 g, 3.51 mol, 1.8 equiv.) was further added thereto, and then the resulting mixture was stirred at an internal temperature of 79° C. to 81° C. for 4 hours. The mixture was cooled to room temperature, toluene (1500 mL) and sodium bicarbonate (48 g, 0.59 mol, 0.3 equiv.) were added to the mixture, and then water (1500 mL) was added thereto. Acetonitrile (600 mL) was added to the mixture, the resulting mixture was stirred, and then the organic layer and the aqueous layer were separated. Furthermore, the operation of extracting this aqueous layer with a mixed solution of toluene (1500 mL) and acetonitrile (300 mL) was repeated three times, and all the organic layers were combined. The combined organic layer was concentrated under reduced pressure to adjust the liquid volume to 2400 mL. Activated carbon (30 g) moistened with toluene (150 mL) was added thereto. The resulting mixture was stirred around 25° C. for 1 hour, and then filtered and washed with toluene (750 mL). Acetonitrile (900 mL) was added thereto, and then methanesulfonic acid (188 g, 1.95 mol, 1 equiv.) was added dropwise at an internal temperature of 22° C. to 37° C. over 1 hour. The resulting mixture was stirred at 27° C. to 31° C. for 1.5 hours, and then the precipitated solid was filtered and washed with toluene (900 mL). The solid was dried under reduced pressure at an external temperature of 40° C. for 5 hours to obtain the title compound (2) (396.9 g).
Under the nitrogen atmosphere, methyl tert-butyl ether (12 L), water (2.6 L), potassium carbonate (691 g, 5.0 mol, 1.1 equiv.), and the compound of the formula (2) (1.17 kg, 5.0 mol, 1.1 equiv.) were successively added. The resulting mixture was stirred at an internal temperature of 19° C. for 5 minutes and allowed to stand, and then the aqueous layer was discharged. The obtained organic layer was concentrated under reduced pressure to adjust the liquid volume to 7.5 L. Diethylene glycol dimethyl ether (7.5 L) was added thereto, and the resulting mixture was concentrated under reduced pressure again to adjust the liquid volume to 8.25 L. To this solution, the compound of the formula (1) (1.5 kg, 4.54 mol, 1 equiv.), tris(2-methylphenyl)phosphine (27.7 g, 0.09 mol, 0.02 equiv.), potassium carbonate (1.26 kg, 9.12 mol), and palladium acetate (20.4 g, 0.09 mol, 0.02 equiv.) were successively added, followed by washing with diethylene glycol dimethyl ether (0.3 L). The resulting mixture was stirred at an internal temperature of 95° C. to 108° C. for 9 hours and then stirred at an internal temperature of 58° C. to 61° C. for 11 hours. Purified water (7.5 L) was added thereto, and the resulting mixture was warmed to an internal temperature of 71° C., and then the aqueous layer was discharged. To the organic layer, 1-methylimidazole (1.5 L) was added, and the resulting mixture was cooled. The mixture was stirred at 25° C. to 30° C. for 40 minutes, and then water (9 L) was intermittently added thereto at an internal temperature of 25° C. to 29° C. over 1.5 hours. The resulting mixture was stirred around 25° C. for 19 hours, and then crystals were filtered and washed with a mixed solution of diethylene glycol dimethyl ether (3 L) and water (3 L) and then with water (3 L). The obtained solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (3) (1.65 kg, 94.1% (gross weight)).
Under the nitrogen atmosphere, (1R)-1-(3-fluorophenyl)ethanamine (400 g, 2.87 mol, 1 equiv.), trisodium phosphate (471 g, 2.87 mol, 1 equiv.), and the compound of the formula (3) (1.22 kg (net weight: 1.12 kg), 3.16 mol, 1.1 equiv.) were successively added to dimethyl sulfoxide (2.4 L). This mixed solution was warmed, and stirred at an internal temperature of 95° C. to 99° C. for 55 hours. The solution was cooled, and cyclopentyl methyl ether (4 L) and water (8 L) were added thereto at an internal temperature of 24° C. The resulting mixture was warmed to 50° C., and the aqueous layer was discharged. After that, water (4 L) was added to the organic layer remaining, and the aqueous layer was discharged again. The obtained organic layer was concentrated under reduced pressure to adjust the liquid volume to 4 L. The liquid was filtered using cyclopentyl methyl ether (0.4 L).
A portion of the obtained solution in an amount equal to ⅝ times the amount thereof was taken out thereof and used in the subsequent reaction. To the solution, cyclopentyl methyl ether (0.25 L), tetrahydrofuran (3 L), and water (0.05 L) were successively added, and concentrated hydrochloric acid (74.9 g, 1.15 mol, 0.4 equiv.) was added thereto at an internal temperature of 23° C. The resulting mixture was stirred at 25° C. for 1.5 hours, and then a mixed solution of cyclopentyl methyl ether (1.5 L) and tetrahydrofuran (1.5 L) was added thereto. The resulting mixture was further stirred for 1.5 hours, and then concentrated hydrochloric acid (112 g, 1.72 mol, 0.6 equiv.) was added thereto in three portions every hour. The resulting mixture was stirred at an internal temperature of 25° C. for 18 hours. The precipitated solid was filtered and washed with a mixed solution of cyclopentyl methyl ether (1.25 L), tetrahydrofuran (1.25 L), and water (0.025 L). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (4) (808.0 g).
Under the nitrogen atmosphere, the compound of the formula (4) (120.0 g) was dissolved in ethanol (1080 mL), and then activated carbon (12 g) moistened with ethanol (60 mL) was added thereto. The resulting mixture was stirred for 1 hour, and then filtered and washed with ethanol (120 mL). To the obtained solution, concentrated hydrochloric acid (43.3 g) was added, and the resulting mixture was warmed, and stirred at 65° C. to 70° C. for 4 hours. The mixture was cooled to an internal temperature of 20° C. over 2 hours and stirred at that temperature for 1 hour, and then further cooled to 1° C. over 1 hour. The mixture was stirred at an internal temperature of −1° C. to 1° C. for 19.5 hours. After that, the precipitated solid was filtered and washed with a mixed solution of cold ethanol (240 mL) and water (6 mL). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (5) (100.5 g).
The IR data for the crystalline form A of Compound 1 adipate are as follows: IR (cm -1) : 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.
Example 5: Preparation and Characterization of Crystalline Form A of Compound 1 Free Base
[0212]
Compound 1 HCl (75.5 g) (e.g., obtained by using the method described in Example 5 of U.S. Application Publication No. 2020/0062765) was dissolved in ethanol (604 mL) at 50℃. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1℃ in 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the solid thus obtained was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The solid thus obtained was confirmed to be the crystalline form A of Compound 1 free base.
[0213]
The NMR data for the crystalline form A of Compound 1 free base are as follows: 1H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H) , 1.48-1.49 (d, J=5.0 Hz, 3H) , 3.16-3.20 (m, 1H) , 3.75-3.79 (m, 2H) , 4.82-4.86 (m, 1H) , 6.76-6.78 (d, J=10.0 Hz, 1H) , 6.92-6.94 (m, 2H) , 7.01-7.05 (m, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.62-7.63 (d, J=5.0 Hz, 1H) , 7.72-7.75 (m, 4H) .
[0214]
The IR data for the crystalline form A of Compound 1 free base are as follows: IR (cm -1) : 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.
The FDA prescribing information for taletrectinib includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.[1][3]
History
The efficacy of taletrectinib to treat ROS1-positive non-small cell lung cancer was evaluated in participants with locally advanced or metastatic, ROS1-positive non-small cell lung cancer enrolled in two multi-center, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811).[3] The efficacy population included 157 participants (103 in TRUST-I; 54 in TRUST-II) who were naïve to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 participants (66 in TRUST-I; 47 in TRUST-II) who had received one prior ROS1 tyrosine kinase inhibitor.[3] Participants may have received prior chemotherapy for advanced disease.[3] The US Food and Drug Administration (FDA) granted the application for taletrectinib priority review, breakthrough therapy, and orphan drug designations.[3]
Society and culture
Legal status
Taletrectinib was approved for medical use in the United States in June 2025.[3][4]
^ Jump up to:ab Khan I, Sahar A, Numra S, Saha N, Nidhi, Parveen R (April 2025). “Efficacy and safety of taletrectinib for treatment of ROS1 positive non-small cell lung cancer: A systematic review”. Expert Opinion on Pharmacotherapy. 26 (6): 765–772. doi:10.1080/14656566.2025.2487150. PMID40170301.
^World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.
External links
Clinical trial number NCT04395677 for “A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene” at ClinicalTrials.gov
Clinical trial number NCT04919811 for “Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC (TRUST-II)” at ClinicalTrials.gov
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