Investigation into the Formation of Impurities during the Optimization of Brigatinib

Abstract

During the process development of brigatinib, we have made an unusual observation about some impurities. Detailed investigation has led to the conclusion that impurity A is formed via the raw material 2 oxidation, impurity B is formed via the pyrolysis of DMF, impurity C is formed via raw material 4, and impurity D is formed via HCl-catalyzed decomposition of intermediate 3. The present work details a report of the journey toward the development of an efficient process for the commercial production of brigatinib substantially free from all the impurities.

1. Introduction

Brigatinib is a highly potent and selective anaplastic lymphoma kinase inhibitor, the drug active pharmaceutical ingredient (API) of Alunbrig (Figure 1), which was first launched by Ariad Pharmaceuticals in the United States for cancer therapy in the treatment of crizotinib-resistant patients with non-small-cell lung cancer.¹ There are very few processes available for the synthesis of brigatinib revealed in current literature studies. Among them, the synthetic process reported by Ariad Pharmaceuticals is the most commonly used.

Figure 1.

Brigatinib.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines require that all process impurities be controlled either through starting materials, isolated intermediates, or APIs. According to the guidelines for anticancer pharmaceuticals in ICH S9,² the identification threshold of process impurities is <0.1%.³ This article reports the control of all process impurities formed during the optimization of brigatinib (1).

Three main routes have been reported to synthesize brigatinib (1) in recent years. Initially, Ariad Pharmaceuticals reported the synthesis of 1 (Scheme 1).^4,5 The advantage of this route was its short synthesis steps. However, the yield over four steps was only 25.5%, and column chromatography was required in synthesis steps 3 and 1. The major problem with this route was in the synthesis of intermediate 3 that the chlorine at the C(2,4,5) positions of 2 could react competitively with the amino group of 18, which would lead to many byproducts.

Scheme 1. Synthesis of 1 through the Route Proposed by Ariad Pharmaceuticals.

To solve this problem, Suzhou Miracpharma Technology Co., Ltd. reported a new method for the synthesis of 3.⁶ Starting by cyclizing 1-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)guanidine (8) with N,N-dimethylamino acrylate (11), key intermediate 9 was obtained, followed by condensation with 18 and chlorination by N-chlorosuccinimide to obtain 1 (Scheme 2). The exact advantage of this route was that the synthesis of intermediate 9 bearing a pyrimidine ring can avoid the potential competitive substitutions of chlorine at the C(2,4,5) positions of 2. However, unstable cyanamide is heat-sensitive and can produce very toxic gases upon treatment with acids. Another disadvantage of this route was that the last chlorination tended to produce a large amount of 17, which was difficult to be removed by simple crystallization because the structure of 17 is similar to that of 1. Although this route provided an alternative method for the synthesis of intermediate 3, the shortcomings of this route made it unsuitable for industrial production. Later, Anqing Chico Pharmaceutical Co., Ltd. (Scheme 3)⁷ reported an alternative method (Scheme 3) for the synthesis of intermediate 3 by starting with (2-aminophenyl)dimethylphosphine oxide 11 acylated by ethyl 2-chloro-3-oxopropanoate 18 to obtain intermediate state 12. Compound 12 was hydrolyzed to obtain ammonium salts 13 (alkali recovery) and 14, and 14 was condensed and chlorinated to obtain key intermediate 3, which reacted with key intermediate 7 to obtain target compound 1. The advantage of this route was similar to that of the second route in that the synthesis of 16 bearing a pyrimidine ring can avoid the potential competitive substitutions of chlorine at the C(2,4,5) positions of 2. However, similar to the second route, this route also had many shortcomings during the synthesis of 3. The first disadvantage was that the process was not profitable in a highly competitive generic market because of the application of high-cost reagent 11 during manufacturing. The second disadvantage of this route was the condensation between 14 and urea, and the chlorine atom on 14 was easily substituted with the amine group on urea. The third disadvantage of this route was that the reaction required at least seven steps, which led to a lower yield (10.7%).

Scheme 2. Synthesis of Intermediate 3 through the Route Proposed by Suzhou Miracpharma Technology Co., Ltd.

Scheme 3. Synthesis of Intermediate 3 through the Route Proposed by Anqing Chico Pharmaceutical Co., Ltd.

Both routes for the synthesis of intermediate 3 have many shortcomings. Considering the productivity and cost for scale-up, the Ariad Pharmaceuticals-reported route was advantageous. Therefore, it was determined that the Ariad Pharmaceutical route was more suitable for further investigation of scale-up, especially for commercial manufacturing. Moreover, the impurities generated in the process play an important role in researching the quality of a drug substance and evaluating a synthetic route, as well as helping researchers choose the best synthetic route conditions. Therefore, we wish to report the impurities generated within this process, which have not yet been reported to our knowledge.

2. Results and Discussion

The Ariad Pharmaceuticals-reported synthesis route involves the following four steps:⁴ the intermediate (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (3) was obtained by substitution between 2,4,5-trichloropyrimidine (2) and (2-aminophenyl)dimethylphosphine oxide (18). 1-(1-(3-Methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (6) was obtained by amino substitution between 4-fluoro-2-methoxy-1-nitrobenzene (4) and 1-methyl-4-(piperidin-4-yl)piperazine (5); then, 6 was reduced to obtain the intermediate [2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl] phenyl]amine (7). Finally, target compound 1 was obtained by substitution between intermediate 3 and intermediate 7.

2.1. Synthesis of 3

During the route selection period, it was found that the chemical yield of intermediate 3 was less than 75.2% when the reaction was performed as reported by Ariad.⁴ The major byproducts were 1,3-bis(2-(dimethylphosphoryl) phenyl) urea (impurity A) (1.3%), unreacted starting material 2 (approximately 9.5%), and 18 (approximately 7.8%). According to the determined structure of impurity A, the forming mechanism of impurity A may be caused by the oxidation of 18.

The oxidation mechanism was further confirmed by a set of comparative tests (Table 1): The raw materials of 2 (1.0 g) and 18 (1.0 g) were dissolved in 10 mL of anhydrous DMF; the air in the device was exchanged with argon, pure oxygen was slowly ventilated in the device at atmospheric pressure, the mixture was heated at 60 °C in an oil bath, and the process was safe under these oxidizing conditions after repeating many times. The second batch was sealed. The third batch was ventilated with nitrogen. It was shown that the amount of impurity A was significantly decreased with nitrogen sparging; however, there was still a residual of impurity A detected, and the generation of impurity A was related to the oxidizing substance formaldehyde produced by the pyrolysis of DMF. We speculated that impurity A was formed by the condensation of 18 with formaldehyde, followed by oxidation. Therefore, several solvents (CH₃CH₂OH, CH₃CN, DMSO, THF, and pyridine) were screened to replace DMF, and different alkalis (K₂CO₃, Na₂CO₃, KOH, NaOH, K₂HPO₄, K₃PO₄, and triethylamine) were studied in these solvent systems. Reaction conditions free of oxidants helped prevent the formation of impurity A; nitrogen sparging of the reaction mixture prior to heating eliminated impurity formation. As a result, no impurity A was found in these solvent systems. However, the highest yield was 67.5% with CH₃CN as the solvent and K₂CO₃ as the alkali. From these batches, we also found that using organic bases or strong inorganic bases would produce a variety of impurities (such as entries 1, 5, 9, 10, and 11), which may be caused by the competitive substitutions of chlorine at the C(2,4,5) positions of 2. Although we have tested many solvent systems, which were not as good as DMF, it would be better to use DMF as the solvent and replace K₂CO₃ with the proper alkali to avoid the pyrolysis of DMF (entries 1–11, Table 2). As a result, the reaction achieved a high yield with DMF as the solvent and K₂HPO₄ as the alkali. We believe that a suitable alkaline solvent system improves the specificity of the reaction and avoids the decomposition of DMF. The workup procedure was also investigated to avoid column chromatography. Finally, good chemical purity was obtained through petroleum ether/ethyl acetate washing.

Table 1. Cause of Form Impurity A.

entry	condition	temperature (°C)	time (h)	equipment	impurity A content
1	DMF/K2CO3	60 °C	10	oxygen sparging	6.5%
2	DMF/K2CO3	60 °C	10	sealed	1.3%
3	DMF/K2CO3	60 °C	10	nitrogen sparging	trace

Table 2. Further Explored Conditions of Synthesis of 3.

entry	alkali	solvent	temperature (°C)	time (h)	yield (isolated yield)	impurity caused by 2
1	K3PO4	DMF	60	6	32.2%	various impurities
2	K2HPO4	DMF	60	6	91.40%	None
3	K2HPO4	DMF	80	6	82.40%	None
4	KH2PO4	DMF	60	6	trace	None
5	KH2PO4	pyridine	60	6	trace	various impurities
6	K2HPO4	acetone	60	6	40.20%	None
7	KH2PO4	CH3CN	60	6	38.20%	None
8	K2HPO4	CH3CN	60	6	67.30%	None
9	AcONa	acetone	60	6	none	various impurities
10	AcONa	CH3CN	60	6	trace	various impurities
11	DIEA	DMF	60	6	trace	various impurities

2.2. Synthesis of 6

The reaction of 4 with 5 by means of K₂CO₃ in refluxing DMF was performed as the recommended procedure reported by Ariad,⁴ yielding 6 (70%). After washing with water, raw material 5 (approximately 9.5%) was removed. The major byproducts were (2-amino-5-(dimethylamino)phenyl)dimethylphosphine oxide (impurity B) (approximately 4.5%) and starting material 4 (approximately 5.1%). Impurity B was introduced by the pyrolysis of DMF.

Initially, we tried to avoid the pyrolysis of DMF by lowering the reaction temperature (entries 1–4, Table 3). As the temperature dropped to 80 °C, no impurity B appeared, but the low temperature led to a long reaction time and low yield. The temperature played an important role in the yield of 6. To make the reaction more efficient, we believe that low-boiling-point solvents will be very effective. Various low-boiling solvent systems, such as ammonia/ethanol, KHCO₃/MeCN, triethylamine/THF, K₂CO₃/MeCN, and NaOCH₃/CH₃CH₂OH (entries 5–9, Table 3), were investigated. As a result, a better yield and rate of reaction were achieved with K₂CO₃/MeCN, and the content of 4 was approximately 2.5%. To eliminate 4, the crude product was recrystallized with ethanol, as reported in the literature.⁵ In one of six batches, the lowest level of 4 was 0.9%, and recrystallization was not a good workup procedure to control 4. Considering that raw material 5 is cheap and easy to remove, we increased the feed molar amount of 5 to 1.45 times that of 4, and the content of raw material 4 could be limited to 0.12%, which would be acceptable for the next reaction.

Table 3. Conditions of Synthesis of 6.

entry	condition	time (h)	yield (isolated yield)	impurity B content
1	DMF/K2CO3, 120 °C, 12 h	12	74.2%	4.5%
2	DMF/K2CO3, 100 °C, 12 h	12	65.2%	1.5%
3	DMF/K2CO3, 90 °C, 12 h	12	57.0%	trace
4	DMF/K2CO3, 80 °C, 12 h	12	50.7%	not detected
5	ammonia/ethanol, 30 °C, 12 h	18	21.7%	not detected
6	KHCO3/MeCN, 85 °C, 12 h	18	45.0%	not detected
7	triethylamine/THF, 60 °C, 12 h	18	trace	not detected
8	NaOCH3/ethanol, 70 °C, 12 h	18	23.3%	not detected
9	K2CO3/MeCN,85 °C,6h	4	92.5%	not detected

2.3. Synthesis of 7

Reducing the nitro functional group of 6 with Pd/C and ethanol as a solvent to give 7 (approximately 96.7%), the major byproduct was 4-fluoro-2-methoxyaniline (impurity C) (approximately 0.13%), which was formed because of the reduction of raw material 4.

Impurity C cannot be completely avoided because the content of raw material 4 had already been controlled at a minimum level in the previous step, and completely removing impurity C would remove too much product 7. When the reported pressure was 30 psi, the reaction could also proceed smoothly when it decreased to 10 psi, and the purity of 7 did not change. When the pressure dropped to 6.5 psi, the purity of intermediate 6 decreased significantly. The pressure played an important role in the quality of 7.

2.4. Synthesis of 1

Intermediate 3 reacted with 7 by sealing and heating in a solution of 2.5 M HCl in ethanol in 2-methoxyethanol to give target compound 1, yielding 45.6%. Except for the unreacted starting materials 3 (approximately 10.7%) and 7 (approximately 10.4%), the major byproducts were (((5-chloropyrimidine-2,4-diyl)bis(azanediyl))bis(2,1-phenylene)) bis(dimethylphosphine oxide) (impurity D) (approximately 1.2%) and unexpected starting materials 2 (0.54%) and 18 (0.24%). We assumed that impurities D, 2, and 18 were introduced via the acid-catalyzed decomposition of 3. The mechanism of generating impurity D was confirmed by independent synthesis: using commercially available 3 (purity > 99.8%) as the starting material, after dissolving with 2.5 M HCl in ethanol in 2-methoxyethanol, sealed and heated at 120 °C for 4.5 h, giving product impurities D (approximately 45.2%), 2 (approximately 25.4%), and 18 (approximately 12.4%). We postulate that the mechanism of acid-mediated degradation of 3 commences with protonation of the pyridine ring. The resulting electron-deficient pyridine ring is susceptible to electron transfer to form enamine ion 20. Then, 20 can be attacked by chloride ions to form transition state 21, followed by aromatization, forming 2 and 18 (Scheme 4).

Scheme 4. Speculative Mechanism for the Formation of Impurity F, 2, and 18.

The proposed mechanism of chemical degradation suggests that the formation of 2 and 18 may be favored by forming transition state 21. We believe that weak nucleophilic acid ions, such as CF₃COO^–, MeSO₃^–, CH₃COO^–, and H₂PO₄^–, would disfavor the formation of transition state 21. As a result, no impurity was detected in the reaction with trifluoroacetic acid, acetic acid, methanesulfonic acid, or phosphoric acid, and the yield was the highest with trifluoroacetic acid (entries 1–4, Table 4). The influence of the solvent was further investigated (entries 5–7). Finally, 2-methoxyethanol was replaced with 2-butanol, and although the yield was slightly decreased, 2-butanol is considered safer and a solvent commonly used in industry.

Table 4. Conditions of Synthesis of 1.

entry	condition			acid	yield (isolated yield) (%)	impurity content
1	EtOH/2-methoxyethanol	120 °C	6 h	TEA	90.7	none
2	EtOH/2-methoxyethanol	120 °C	6 h	CH3COOH	50.8	none
3	EtOH/2-methoxyethanol	120 °C	6 h	MeSO3H	75.1	none
4	EtOH/2-methoxyethanol	120 °C	6 h	H3PO4	67.3	none
5	EtOH	80 °C	6 h	TEA	trace	none
6	isopropyl alcohol	85 °C	5 h	TEA	33.7	none
7	2-butanol	110 °C	5 h	TEA	86.7	none

The reported workup procedure of the chromatographic purification operation was not suitable for industrial manufacture.¹ Another reported workup procedure involved heating with polyethylene (PE),^4,5 but we failed to obtain a good purified product after repeated beating 15 times.

2.5. Recrystallization of 1

1 is almost insoluble in most organic solvents, making it very difficult to design a feasible recrystallization system. Methanol was identified as a good solvent for product 1. We therefore designed a recrystallization process that involved the dissolution of crude 1 in methanol, and the addition of activated charcoal served as a decolorizing agent. Thus, the purified drug substance was isolated at a 60% yield with a high-performance liquid chromatography (HPLC) purity of 99.9%. However, this process has the following two disadvantages: (1) methanol is a class two solvent;⁸ although the boiling point of methanol is only 65 °C and it is easy to dry, a certain risk remains; (2) the recovery of 1 was not high with methanol.

Eventually, we tested the solubility differences of various class three solvents⁸ with respect to 1 and selected 2-butanone as the recrystallization solvent because 2-butanone was soluble enough in 2-butanone to conduct recrystallization within a practical solvent volume (Table 5). The purified drug substance was isolated at a >80.3% yield with an HPLC purity of over 99.9%.

Table 5. Solubility of 1 to Various Solvents.

solubility of crude 1	acetone	ethyl acetate	methyl isobutyl ketone	EtOH	2-PrOH	methanol	1-propyl alcohol	2-butanone	ether
25 °C (g/L)	5.1	2.7	3.5	3.5	0.8	3.5	0.5	3.9	0.1
reflux (g/L)	13.7			13.5		60.5		30.3

3. Conclusions

Three routes for the synthesis of brigatinib have been investigated and compared, and the Ariad route was chosen for scale-up optimization in a commercial plant. All possible impurities were controlled during the optimization of the Ariad route. In the synthesis of 3, nitrogen sparging of the reaction mixture prior to heating eliminated impurity A. In the synthesis of 6, impurity B was avoided by replacing DMF with the appropriate solvent. In the synthesis of intermediate 7, impurity C was controlled by controlling raw material 4 in the previous step. In the synthesis of 1, impurity D was avoided by replacing HCl with the appropriate acid. We also investigated the recrystallization conditions of brigatinib, and with this improvement, high-quality brigatinib was obtained. In summary, the overall yield of the optimized route was 65.6%, which was 3 times that of the original route (Scheme 1).

4. Experimental Section

4.1. General Methods

All the reagents and solvents were obtained from commercial suppliers and used without further purification. ¹H NMR and ¹³C NMR spectra were recorded using a Bruker 600, 150 MHz spectrometer. Chemical shift data are reported in δ (ppm) from the internal standard tetramethylsilane. High-resolution mass spectra were recorded on a Bruker maXis 4GQ-TOF instrument. Melting points were measured on a WRS-1B apparatus; the isolated intermediates and the final product were analyzed by HPLC (normalized area percentage). The HPLC analysis was performed on a Dionex UltiMate 3000 high-performance liquid chromatograph using standard methods. The chemical purity was analyzed by using an Agilent Eclipse XDB-C18 (5 μm, 46 mm × 250 mm), 30 °C, 0.1 mL/min, 210 nm, and 45 min. Mobile phase A/B: 50/50 v/v solution; A: aqueous monobasic sodium phosphate (0.04% w/w solution) adjusted to pH 4 ± 0.05 with dilute orthophosphoric acid; mobile phase B: methanol.

4.1.1. Preparation of (2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine Oxide (3)

A suspension of 2,4,5-trichloropyrimidine (2) (152 g, 0.83 mol, 1.5 equiv), (2-aminophenyl)dimethy-phosphine oxide (18) (94 g, 0.556 mol, 1 equiv), and K₂HPO₄ (153 g, 1.10 mol, 3 equiv) in DMF (500 mL) was stirred at 65 °C for 4 h. Upon cooling, the reaction mixture was cooled to rt and filtered, the filter cake was washed with ethyl alcohol (EA) (800 mL), and the filtrates were evaporated. The residue was dissolved in EA (1000 mL) and extracted three times with saturated sodium chloride solution (3 × 1000 mL); centration of combined organics yielded a white solid, and the solid was washed three times with a mixture of petroleum ether/ethyl acetate (300 mL/100 mL) to give the desired product 3 as a yellowish white solid; yield: 120.0 g, 90.3%.

4.1.2. Preparation of 1-(1-(3-Methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (6)

A mixture of 5-fluoro-2-nitroanisole (4) (171 g, 1 mol, 1.0 equiv), 1--methyl-4(piperidin-4-yipiperazine (5) (183 g, 1 mol, 1.0 equiv), and potassium carbonate (276.0 g, 2 mol, 2.0 equiv) in MeCN (650 mL) was stirred at reflux for 4.5 h. Upon cooling to rt, the reaction mixture was filtered. The filter cake was washed with DCM (400 mL). The combined filtrates were evaporated. The residue was dissolved in DCM (1000 mL) and extracted three times with 1 mol/L HCl (3 × 300 mL); the water layer was collected and adjusted with potassium carbonate to pH 8.0 and then extracted three times with DCM (3 × 400 mL). The combined organized layer was dried with sodium sulfate, filtered, and concentrated in vacuo to afford the desired product 6 as a bright yellow powder; yield: 290.3 g, 90.8%.

4.1.3. Preparation of [2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amine (7)

The container is a 50 L stainless-steel hydrogenation reactor. Through the pressure cycle replacement method, nitrogen was delivered to the headspace until the pressure was 0.2 MPa and exhausted after mixing for 1.5 h, and the replacement process was repeated seven times. The atmosphere was totally replaced with nitrogen. Material 6 (200.0 g) in EtOH (8000 mL) was pumped into the container. Then, nitrogen was delivered until the pressure was 0.06 MPa. Pd/C (20.0 g, 10% loading, 50% wet) was added in the nitrogen atmosphere; hydrogen was delivered to the headspace until the pressure was 50 psi and exhausted after mixing for 1 h, and the replacement process was repeated five times. The mixture was stirred at a speed of 150–200 rpm under the temperature of 10–15 °C and the hydrogen pressure of 15 psi for 3 h. After the reaction, nitrogen was delivered until the pressure was 50 psi and exhausted after mixing for 1.5 h, and the replacement process was repeated five times to evacuate the gas.

Water (100 mL) was added to the reaction solution and filtered. The filter cloth was filled with 0.5 cm thick Celite, and Celite was rinsed with ice ethanol (100 mL). The solution was filtered (10 °C in air; keeping the filter cake wet, the filter cake was removed by washing with ethanol and then washing with water). Activated carbon (7.0 g) was added to the filtrate, stirred at 70 °C for 2 h, and filtered. The filtrate was combined and concentrated under reduced pressure to give a purple solid; yield: 173.0 g, 95.0%.

4.1.4. Preparation of (2-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Phenyl) Amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine Oxide (Brigatinib)

Intermediates 3 (170.0 g, 540 mmol) and 7 (180.0 g, 590 mmol) were dissolved in 2-butanol (500 mL). The mixture was added into an inner tube of a digestion high-pressure tank, and tetraethylammonium (TEA) (43.1 mL, 580 mmol) was added quickly when a magnetic stirrer was employed at rt. Then, the metal screw cap was sealed immediately, and the mixture was heated to 110 °C and reacted for 5 h under stirring. Upon cooling, volatile components were removed on a Rotavapor, and the resulting semisolid was dissolved in water (500 mL). After washing with EtOAc (500 mL), the aqueous layer was basified with 20% NaOH until the pH value reached 12. Extraction with DCM (3 × 500 mL), followed by concentration of combined organics, furnished a dark residue. Then, washing was done twice with ethyl acetate to give an off-white solid of the crude product (186.6 g, 85.5% yield).

4.2. Recrystallization of 1

The crude product (204 g) was dissolved in 2-butanone (2000 mL) at 80 °C. After thermal filtration, the filtrate was concentrated to one-third of its original value, and after stirring frequently at 0 °C for 8 h, a large amount of the off-white crystal solid precipitated. The isolated crystalline solid was dried in the open air at room temperature overnight at first and then in a vacuum dryer at 60 °C for 2 h to give the product as an off-white powder. Yield: 179.5 g, 88.0%, mp 215–216 °C, HPLC purity > 99.9%. ¹H NMR (600 MHz, DMSO-d₆): δ 10.73 (s, 1H), 8.55 (dd, J = 8.5, 4.4 Hz, 1H), 8.01 (t, J = 4.4 Hz, 2H), 7.47–7.37 (m, 1H), 7.25–7.14 (m, 2H), 7.09–7.00 (m, 1H), 6.51–6.37 (m, 2H), 3.79 (s, 3H), 3.62–3.54 (m, 2H), 2.70–2.53 (m, 6H), 2.42 (s, 5H), 2.23 (s, 3H), 1.88 (d, J = 12.4 Hz, 2H), 1.75 (d, J = 13.2 Hz, 6H), 1.71–1.57 (m, 2H). ¹³C NMR (150 MHz, DMSO-d₆): δ 159.41, 155.65, 155.37, 153.16, 149.58, 143.83 (d, J = 2.2 Hz), 132.28, 131.04 (d, J = 11.1 Hz), 125.88, 122.53 (d, J = 11.9 Hz), 122.09 (d, J = 6.5 Hz), 120.85 (d, J = 92.0 Hz), 120.20, 107.54, 104.32, 100.84, 61.35, 55.85, 55.62, 49.25, 49.01, 46.21, 28.24, 18.96, 18.49. HR-MS: HRMS (ESI) m/z: calcd for C₂₉H₃₉ClN₇O₂P, 583.2591; found, 584.2671 [M + H]⁺.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c03816.

• ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry information for brigatinib and impurities and HPLC information for the final product of brigatinib (PDF)

The authors declare no competing financial interest.