Bhoopendra Singh Kushwah, Santosh Gandhi, Devikumar Purandharan, Ashok Kumar Rajendran, Karthik Jayaraman, Venkata Phanikrishna Sharma Mangalampalli, Joel Young and Lakshmikant Bajpai*,
{"title":"低水平估算不稳定遗传毒性硼酸酯杂质的分析策略","authors":"Bhoopendra Singh Kushwah, Santosh Gandhi, Devikumar Purandharan, Ashok Kumar Rajendran, Karthik Jayaraman, Venkata Phanikrishna Sharma Mangalampalli, Joel Young and Lakshmikant Bajpai*, ","doi":"10.1021/acs.oprd.4c00065","DOIUrl":null,"url":null,"abstract":"<p >Boronate esters are commonly used starting materials in the Suzuki–Miyaura coupling reaction for the C–C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO<sub>2</sub> (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [<i>T</i><sub>min</sub>/B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-<i>b</i>]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03–0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. The method was successfully applied for the estimation of 16 structurally different boronate esters with no chemical derivatization or hydrolysis.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities\",\"authors\":\"Bhoopendra Singh Kushwah, Santosh Gandhi, Devikumar Purandharan, Ashok Kumar Rajendran, Karthik Jayaraman, Venkata Phanikrishna Sharma Mangalampalli, Joel Young and Lakshmikant Bajpai*, \",\"doi\":\"10.1021/acs.oprd.4c00065\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Boronate esters are commonly used starting materials in the Suzuki–Miyaura coupling reaction for the C–C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO<sub>2</sub> (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [<i>T</i><sub>min</sub>/B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-<i>b</i>]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03–0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. 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Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities
Boronate esters are commonly used starting materials in the Suzuki–Miyaura coupling reaction for the C–C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO2 (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [Tmin/B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03–0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. The method was successfully applied for the estimation of 16 structurally different boronate esters with no chemical derivatization or hydrolysis.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.