Kinetic studies of bis(chloromethyl)ether hydrolysis by mass spectrometry

Tou, James C.; Westover, L. B.; Sonnabend, L. F.

doi:10.1021/j100604a010

Cited by 24 publications

(8 citation statements)

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“…This leaving group effect can be compared to &rci/&rf = 1 X 106 for tritylhalide solvolysis in 85% acetone at 25 °C and &rciArf = 1 X 105 for tert-butyl halide solvolysis in 80% ethanol at 25 °C. 25 Tou et al 26 have studied the hydrolysis of bis(chloromethyl) ether, which because of the second chlorine hydrolyzes sufficiently slowly to be studied in pure water. The kinetics of the hydrolysis were studied in 1 and 2 M NaOH, 1 and 3 M HC1, and in pure water; in each case the hydrolysis was first order in ether only, and the rate constant for all conditions reasonably constant at about 2 X 10-2 s-1.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of the hydrolysis of fluoromethyl methyl ether in neutral to alkaline solution

Kokesh¹,

Hine²

1976

J. Org. Chem.

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Section: Discussionmentioning

confidence: 99%

Kinetics of the hydrolysis of fluoromethyl methyl ether in neutral to alkaline solution

Kokesh¹,

Hine²

1976

J. Org. Chem.

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“…Tou et al . described the hydrolysis of BCME in water at 20 °C with half-life times, calculated by the authors of this manuscript based on the published value for the rate constant k and assuming an unimolecular reaction for the data provided in the original publication, of 38.5 (neutral), 28.9 (2 N NaOH), and 63.0 s (3 N HCl) …”

Section: Results and Discussionmentioning

confidence: 99%

“…Tou et al described the hydrolysis of BCME in water at 20 °C with half-life times, calculated by the authors of this manuscript based on the published value for the rate constant k and assuming an unimolecular reaction for the data provided in the original publication, of 38.5 (neutral), 28.9 (2 N NaOH), and 63.0 s (3 N HCl). 26 Frankel and co-workers investigated the formation of BCME from formaldehyde and HCl in moist air with a yield of 0.01 mol %. 27 The amount of BCME formed was found to be relatively insensitive to moderate changes in temperature and humidity but strongly dependent on the concentrations of the reactants.…”

Section: ■ Introductionmentioning

confidence: 94%

Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

Hardegger

Mallet

Bianchi

et al. 2020

Org. Process Res. Dev.

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We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet–Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet–Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

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“…The non-cross-linked silicone polymer hollow fiber probe was initially evaluated by sampling air over an Erlenmeyer flask of boiling water. This would test the vacuum attainable as well as the stability of the probe which to date had only been used to sample systems up to 60 °C (12,13). Vacuum system pressures from the non-cross-linked silicone polymer probe were totally unacceptable at temperatures higher than 75 °C.…”

Section: Methodsmentioning

confidence: 99%

Hollow fiber membrane probes for the in situ spectrometric monitoring of nitrogen trichloride formation during wastewater treatment

Savickas¹,

LaPack²,

Tou³

1989

Anal. Chem.

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Kinetic studies of bis(chloromethyl)ether hydrolysis by mass spectrometry

Cited by 24 publications

References 0 publications

Kinetics of the hydrolysis of fluoromethyl methyl ether in neutral to alkaline solution

Kinetics of the hydrolysis of fluoromethyl methyl ether in neutral to alkaline solution

Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

Hollow fiber membrane probes for the in situ spectrometric monitoring of nitrogen trichloride formation during wastewater treatment

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