Deulorlatinib

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Deulorlatinib

CAS 2131126-33-3

MFC21H16²H3FN6O2, MW 409.4 g/mol

(10R)-7-amino-12-fluoro-2-(²H3)methyl-10,16-dimethyl15-oxo-10,15,16,17-tetrahydro-2H-8,4-
(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
tyrosine kinase inhibitor, antineoplastic, 7PW3UT8C9B, TGRX 326, TGRX-326

Deulorlatinib is an orally bioavailable inhibitor of the receptor tyrosine kinases anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), with potential antineoplastic activity. Upon oral administration, deulorlatinib targets, binds to and inhibits the activity of ALK and ROS1, which leads to the disruption of ALK- and ROS1-mediated signaling and the inhibition of cell growth in ALK- and ROS1-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a variety of tumor cell types. ROS1, overexpressed in certain cancer cells, plays a key role in cell growth and survival of cancer cells.

TGRX-326 Chinese Phase III for Advanced Non-small Cell Lung Cancer (NSCLC)CTID: NCT06082635Phase: Phase 3Status: Active, not recruitingDate: 2025-05-18
TGRX-326 Pharmacokinetic Drug InteractionCTID: NCT06294561Phase: Phase 1Status: CompletedDate: 2024-06-27
TGRX-326 Chinese Phase I for Advanced Non-small Cell Lung Cancer (NSCLC)CTID: NCT05441956Phase: Phase 1Status: Active, not recruitingDate: 2025-05-18
TGRX-326 Chinese Phase II for Advanced Non-small Cell Lung Cancer (NSCLC)CTID: NCT05955391Phase: Phase 2Status: Active, not recruitingDate: 2025-05-18

SYN

WO 2017/148325 A1

syn

[US20220024908A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US348430040&_cid=P11-MKG9AH-82468-1

Example 6: Synthesis of (10R)-7-amino-12-fluoro-2-(methyl-d₃)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (the Compound of Formula (A))

To a 250 mL three-necked flask equipped with magnetic stirring were added the compound of formula (J) (7.0 g, 42.2 mmol) and anhydrous dichloromethane (120 mL), and stirred until the solution became clear. The compound of formula (H) (8.77 g, 46.4 mmol) and then triethylamine (4.69 g, 46.4 mmol) were successively added. The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes to give a pale yellow clear solution for further use.

To another 500 mL three-necked flask equipped with magnetic stirring was added anhydrous aluminum chloride (6.17 g, 46.4 mmol), and the system was evacuated with suction and purged with nitrogen gas. Anhydrous dichloromethane (60 mL) was added under nitrogen atmosphere, and the mixture was cooled to 0° C. in an ice-water bath. Triethylamine (6.39 g, 63.3 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at this temperature for 10 minutes. The above-mentioned solution of raw materials in dichloromethane was slowly added dropwise over 30 minutes. The mixture was reacted with stirring at this temperature for another 2 hours. By TLC (PE:EA=1:1) and HPLC monitoring, the reaction was completed. The reaction was quenched by adding water (200 mL). The organic phase was separated, and the aqueous layer was extracted with dichloromethane (100 mL×2). The organic phases were combined, washed successively with water (100 mL) and then saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 12.66 g of a yellow oil in a yield of 94.0% and a purity (HPLC) of >90% (ee>98%). The intermediate is unstable at room temperature, and thus should be directly taken into the next step or stored in a refrigerator at −20° C. LC-MS (APCI): m/z=320.1 (M+1) ⁺. ¹H NMR (300 MHz, CDCl ₃) δ (ppm): 7.92-7.89 (m, 1H), 7.27-7.17 (m, 2H), 7.03-6.97 (m, 1H), 6.84 (s, 1H), 4.92 (q, J=6.3 Hz, 1H), 4.83 (s, 2H), 2.89 (s, 3H), 1.50 (d, J=6.3 Hz, 3H).

Sulfonylation of the Compound of Formula (G) to Form the Compound of Formula (F):

To a 250 mL three-necked flask equipped with magnetic stirring were added the compound of formula (G) (12.6 g, 39.5 mmol) and anhydrous dichloromethane (120 mL), and stirred until the solution became clear. The mixture was cooled in an ice-water bath. Triethylamine (7.98 g, 79.5 mmol) was added, and then methylsulfonyl chloride (5.85 g, 51.4 mmol) was slowly added dropwise. After the addition was completed, the ice bath was removed, and the mixture was reacted with stirring at room temperature under nitrogen atmosphere for 1 hour. TLC (DCM:MeOH=20:1) showed that the reaction was completed. The reaction was quenched by adding ice-water (100 mL). The organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and then saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and then dissolved in anhydrous acetonitrile (50 mL) for further use.

Alkylation of the Compound of Formula (E-a) with the Compound of Formula (F) to Form the Compound of Formula (D-a):

To another 250 mL three-necked flask equipped with magnetic stirring were added the compound of formula (E-a) (11.2 g, 59.3 mmol) and acetonitrile (200 mL), and cesium carbonate (25.7 g, 79.0 mmol) was added with stirring. The mixture was heated to 50° C. under nitrogen atmosphere, and stirred at this temperature for 30 min. The above-mentioned solution of the compound of formula (F) in acetonitrile was slowly added dropwise at 50° C. over 10 minutes. After the dropwise addition was completed, the mixture was reacted with stirring at this temperature for 2 hours. By TLC (DCM:MeOH=20:1) and HPLC monitoring, the reaction was completed. After cooling to room temperature, the reaction was quenched by adding water (200 mL). The reaction solution was diluted with ethyl acetate (300 mL), stirred for 5 minutes, and then filtered through Celite to remove insoluble solids. The filter cake was washed with ethyl acetate (50 mL). The organic layer was separated from the filtrate, and the aqueous phase was extracted with ethyl acetate (60 mL×2). The organic phases were combined, washed with a saturated aqueous solution of sodium carbonate (100 mL×3) and then saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 17.5 g of a brown solid in a yield of 90.1% and a purity (HPLC) of >85% (ee>95%). LC-MS (APCI): m/z=390.1 (M+1) ⁺.

Introduction of Boc Protecting Group into the Compound of Formula (D-a) to Form the Compound of Formula (C):

To a 250 mL single-necked flask equipped with magnetic stirring were added the compound of formula (D-a) (17.5 g, 35.8 mmol) and dichloromethane (200 mL), and stirred until the solution became clear. Triethylamine (14.5 g, 143.2 mmol) and then DMAP (850 mg, 7.2 mmol) were successively added. Boc₂O (23.4 g, 107.4 mmol) was slowly added dropwise, and the mixture was reacted with stirring at room temperature under nitrogen atmosphere overnight. By TLC (DCM:MeOH=20:1) and HPLC monitoring, the reaction was completed. The reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (EA/PE=0-35%) to give 15.4 g of a white solid in a yield of 62.4% and a purity (HPLC) of >95% (ee>95%). LC-MS (APCI): m/z=590.1 (M+1−100) ⁺. ¹H NMR (300 MHz, CDCl ₃) (δ/ppm): 8.06 (d, J=1.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.24-7.20 (m, 2H), 7.04-6.98 (m, 1H), 6.81 (s, 1H), 5.66-5.59 (m, 1H), 4.89-4.69 (m, 2H), 2.97 (s, 3H), 1.58 (d, J=6.0 Hz, 3H), 1.47 (s, 18H).

Cyclization of the Compound of Formula (C) Using Palladium Catalyst to Form the Compound of Formula (B):

To a 500 mL single-necked flask equipped with magnetic stirring were added the compound of formula (C) (15.4 g, 22.3 mmol) and 2-methyl-2-butanol (300 mL), and stirred until the solution became clear. Potassium acetate (6.56 g, 66.9 mmol) was added. The system was evacuated with suction and purged with nitrogen gas three times. Palladium acetate (0.75 g, 3.35 mmol) and n-butylbis(1-adamantyl)phosphine (1.60 g, 4.46 mmol) were quickly added. The system was evacuated with suction and purged with nitrogen gas three times. The reaction solution was heated to 110° C. under nitrogen atmosphere, and reacted with stirring at this temperature overnight. By TLC (PE:EA=1:1) and HPLC monitoring, the reaction was completed. The reaction solution was cooled to room temperature, diluted with dichloromethane (300 mL), and filtered through Celite to remove insoluble solids. The filter cake was washed with dichloromethane (50 mL). The filtrates were combined, and concentrated to dryness under reduced pressure. To the residue was added acetonitrile (150 mL), and the mixture was heated to reflux for 1 hour. The oil bath was removed, and the mixture was allowed to slowly cool to room temperature. A large amount of a white solid precipitated out, and the precipitated solid was filtered. The filter cake was washed with acetonitrile (10 mL), and dried to give 8.2 g of a white solids in a yield of 60.4% and a purity (HPLC) of >99.5% (ee>99.9%). LC-MS (APCI): m/z=510.1 (M+1−100) ⁺. ¹H NMR (300 MHz, CDCl ₃) (δ/ppm): 8.22 (d, J=1.8 Hz, 1H), 7.29-7.25 (m, 1H), 7.22-7.16 (m, 2H), 7.03-6.96 (m, 1H), 5.76-5.70 (m, 1H), 4.42 (q, J=14.1 Hz, 2H), 3.15 (s, 3H), 1.76 (d, J=6.0 Hz, 3H), 1.44 (s, 18H).

Removal of the Boc from the Compound of Formula (B) Using an Acid to Form the Compound of Formula (A):

To a 250 mL single-necked flask equipped with magnetic stirring were added the compound of formula (B) (8.2 g, 13.5 mmol) and dichloromethane (100 mL), and stirred until the solution became clear. The mixture was cooled in an ice-water bath, and trifluoroacetic acid (20 mL) was slowly added dropwise. After the addition was completed, the ice bath was removed, and the mixture was reacted with stirring at room temperature for 2 hours. By TLC (DCM:MeOH=20:1) and HPLC monitoring, the reaction was completed. The reaction solution was evaporated under reduced pressure to remove the organic solvent. Dichloromethane (100 mL) and a saturated aqueous solution of sodium bicarbonate (60 mL) were added under cooling, and the mixture was stirred for 10 minutes. The organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 mL×2). The organic phases were combined, washed successively with water (30 mL) and then saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 5.1 g of an amorphous white solid in a yield of 92.6% and a purity (HPLC) of >99.5% (ee>99.9%). LC-MS (APCI): m/z=410.2 (M+1) ⁺. ¹H NMR (300 MHz, CDCl ₃) (δ) ppm 7.79 (d, J=1.8 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.19 (m, 1H), 7.06-6.97 (m, 1H), 6.87 (d, J=1.8 Hz, 1H), 5.75-5.70 (m, 1H), 5.09 (br s, 2H), 4.40 (q, J=14.1 Hz, 2H), 3.12 (s, 3H), 1.78 (d, J=6.6 Hz, 3H).

PAT

Preparation method for deuterated macrocyclic compound

Publication Number: US-2022024908-A1

Priority Date: 2018-11-28