Development of Kilogram-Scale Synthesis of EGFR Inhibitor EAI045

Lü, Hao; Guo, Lijun; Chen, Xiaodong; Mo, Faguang; Tian, Songchuan; Liu, Xuejun

doi:10.1021/acs.oprd.8b00276

Cited by 5 publications

(7 citation statements)

References 26 publications

(23 reference statements)

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“…Preferred additives: HOBt is the preferred additive (0.22–1.4 equiv), , but two examples have also been reported with Oxyma. , …”

Section: Coupling Reagents Used On Large Scale Categorized By Acid Ac...mentioning

confidence: 99%

“… General remarks: Compared with DCC and EDCI, DIC has seen much more limited application in process chemistry, ,,, despite the fact that its urea byproduct (DIU) is more soluble than DCC’s and therefore easier to remove during workup. An application of DIC in SPPS has been reported in the large-scale literature .…”

Section: Coupling Reagents Used On Large Scale Categorized By Acid Ac...mentioning

confidence: 99%

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Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.

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“…Preferred additives: HOBt is the preferred additive (0.22–1.4 equiv), , but two examples have also been reported with Oxyma. , …”

Section: Coupling Reagents Used On Large Scale Categorized By Acid Ac...mentioning

confidence: 99%

Section: Coupling Reagents Used On Large Scale Categorized By Acid Ac...mentioning

confidence: 99%

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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“…1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (s, 1H), 8.49 (s, 1H), 8.24 (dd, J = 6.7, 2.0 Hz, 1H), 7.85 (m, 1H), 7.80 (s, 1H), 7.41 (t, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.00 (s, 3H). 13 4-(3-Chloro-4-fl urophenylamino)-7-methoxy-6-(chloropropoxy)quinazoline (7). To a reactor were charged hydroxyquinazoline 8 (111.95 kg, 350.15 mol, 1.0 equiv), 1bromo-3-chloropropane (115.36 kg, 732.72 mol, 2.0 equiv), and NMP (1152 kg).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSOd 6 ) δ 9.53 (s, 1H), 8.50 (s, 1H), 8.12 (dd, J = 6.8, 2.6 Hz, 1H), 7.81 (m, 1H), 7.78 (s, 1H), 7.43 (t, J = 9.1 Hz, 1H), 7.19 (s, 1H), 4.16 (t, J = 6.3 Hz, 2H), 3.99 (m, 2H), 3.95 (s, 3H), 3.70 (m, 2H), 3.46 (m, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 2.66 (m, 2H), 1.97 (m, 2H). 13 The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.2c00059.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Studies about growth factor signaling pathways controlled by protein kinases, especially epidermal growth factor receptor (EGFR), have focused on novel targeted anticancer drugs in the last decade, as they play an important role in regulating key cellular functions such as cell proliferation, differentiation, metastasis, and survival. − EGFR, a 170 kDa glycoprotein, , is highly expressed in most human tissues and plays a key role in the occurrence and progression of cancer − and is found in more than two-thirds of human cancers, including lung cancer, breast cancer, and esophageal cancer. ,− Till now, several novel EGFR tyrosine kinase inhibitors have been developed, − including gefitinib ( 1 , Iressa), erlotinib ( 2 , Tarceva), and icotinib ( 3 , Conmana) (Figure ) for the treatment of non-small-cell lung cancer (NSCLC).…”

Section: Introductionmentioning

confidence: 99%

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Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC

Zhang

Su²,

Liu³

et al. 2022

Org. Process Res. Dev.

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The development of an efficient synthetic process for a clinical candidate Larotinib (4), which is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of esophageal squamous cell carcinoma (ESCC), is reported for scale-up. The process used 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (12) as the regulatory starting material and provided a stable and industrializable intermediate chloroquinazoline 11 under the process control. Further optimization of the process obviously improved the reaction yield and reduced the impurity level including alkyl halide potential genotoxic impurities (PGIs), at the same time avoiding the use of laborious and time-consuming column chromatography. More than 110 kg of Larotinib (4) in one batch can be finally produced stably for clinical research. Compared to our initial synthetic route in preclinical research, the overall yield of this optimized process increased significantly from 16.2 to 55.6%.

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Bioanalytical assay for the quantification of the tyrosine kinase inhibitor EAI045 and its major metabolite PIA in mouse plasma and tissue homogenates using liquid chromatography–tandem mass spectrometry

Susam

Wang

Schinkel

et al. 2022

Biomedical Chromatography

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EAI045 is a tyrosine kinase inhibitor (TKI) that targets the mutant epidermal growth factor receptor (EGFR). It was developed to control resistance to available EGFR TKIs. In this study, a major metabolite of EAI045, (5-fluoro-2-hydroxyphenyl)(1-oxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid (PIA), was discovered as a hydrolysis product of the parent drug. A validated assay for both analytes in mouse plasma and tissue homogenates from brain, kidney, liver, lung, spleen, and small intestine with content was set up using LC-MS/MS. Samples were prepared by protein precipitation with acetonitrile and with PLX4720 as internal standard. Separation was performed on a bridged ethylene hybrid C 18 column by gradient elution with 0.1% v/v formic acid and methanol. Using positive electrospray, detection was performed in selected reaction monitoring mode. A linear calibration range of 2-2,000 ng/ml was used and validated for both analytes. Precision values ranged between 2.0 and 7.5% for EAI045 and between 2.2 and 12.1% for the metabolite, and accuracy values were between 91.1 and 107.6% for EAI045 and between 87.6 and 100.6% for the metabolite. Both analytes were sufficiently stable under the relevant analytical conditions. Finally, the assay was applied to analyze mouse plasma and tissue levels in a pharmacokinetic study in FVB/NRj wild-type female mice treated with oral EAI045.

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Development of Kilogram-Scale Synthesis of EGFR Inhibitor EAI045

Cited by 5 publications

References 26 publications

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC

Bioanalytical assay for the quantification of the tyrosine kinase inhibitor EAI045 and its major metabolite PIA in mouse plasma and tissue homogenates using liquid chromatography–tandem mass spectrometry

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