Academia.eduAcademia.edu

Figure 10 – uploaded by Andrew Teasdale

See full PDFdownloadDownload figure
Table 10. Physicochemical and Other Data on Three Sulfonic Acids Used for Salt Synthesis nucleophiles than sulfonate anion]. An alternative mechanism that might be proposed for the generation of an alkyl sulfonate from reaction with a sulfonic acid salt (protonated amine) with an SCA is proton transfer from the amine to the alcohol, thus producing a C-O*H, moiety. In reality, no such transfer would occur given the much greater basicity of amines compared to alcohols (which are slightly acidic). via a continuous two-step procedure using methanol as starting material, which is first converted to dimethyl disulfide followed by oxidation to MSA.

Table 10 Physicochemical and Other Data on Three Sulfonic Acids Used for Salt Synthesis nucleophiles than sulfonate anion]. An alternative mechanism that might be proposed for the generation of an alkyl sulfonate from reaction with a sulfonic acid salt (protonated amine) with an SCA is proton transfer from the amine to the alcohol, thus producing a C-O*H, moiety. In reality, no such transfer would occur given the much greater basicity of amines compared to alcohols (which are slightly acidic). via a continuous two-step procedure using methanol as starting material, which is first converted to dimethyl disulfide followed by oxidation to MSA.

Related Figures (20)

Table 1. Comments in Published Agency Reviews on Alkyl Sulfonates as Potential Impurities
Table 1. Comments in Published Agency Reviews on Alkyl Sulfonates as Potential Impurities
“+, 22x background revertants; ++, >Sx background revertants. ’Glowienke et al., 2004.” “Hakura et al., 1984.5 “NDF, no data found.
“+, 22x background revertants; ++, >Sx background revertants. ’Glowienke et al., 2004.” “Hakura et al., 1984.5 “NDF, no data found.
Table 3. Published Mutagenicity Data on Sulfonic Acids and Tosilate Anion
Table 3. Published Mutagenicity Data on Sulfonic Acids and Tosilate Anion
{Relative mutation frequency in TA100 at 1 mM; MMS = 1.00. Phosphate buffer at pH 7.4. Table 4. Mutagenic Potencies, Swain—Scott s Constants, and Hydrolysis Half-Lives for Some Alkyl Mesilates®?
{Relative mutation frequency in TA100 at 1 mM; MMS = 1.00. Phosphate buffer at pH 7.4. Table 4. Mutagenic Potencies, Swain—Scott s Constants, and Hydrolysis Half-Lives for Some Alkyl Mesilates®?
Table 5. Rationale Provided for Analysis of Alkyl Sulfonates in Sulfonic Acid Salts
Table 5. Rationale Provided for Analysis of Alkyl Sulfonates in Sulfonic Acid Salts
(4) Addition of an equimolar amount (in relation to MSA) of a tertiary amine non-nucleophilic base (2,6-lutidine), or using a slight molar excess of MSA in relation to the base, resulted in no detectable (<0.5 ppm) alkyl sulfonate (EMS) formation (Figure $). This finding confirms the need for strongly acidic conditions to achieve alcohol protonation before ester formation is feasible. Figure 3. EMS formation from MSA and anhydrous ethanol at different temperatures.
(4) Addition of an equimolar amount (in relation to MSA) of a tertiary amine non-nucleophilic base (2,6-lutidine), or using a slight molar excess of MSA in relation to the base, resulted in no detectable (<0.5 ppm) alkyl sulfonate (EMS) formation (Figure $). This finding confirms the need for strongly acidic conditions to achieve alcohol protonation before ester formation is feasible. Figure 3. EMS formation from MSA and anhydrous ethanol at different temperatures.
Figure 4. Effect of water on the extent of EMS formation at 70 °C.
Figure 4. Effect of water on the extent of EMS formation at 70 °C.
5.1. Sulfonic Acid Salt Synthesis. Since base protonation is an ultrafast reaction (particularly when the base form of the API has a pK, > 7 (Snodin et al.”°), as MSA (or other sulfonic Figure 5. Effect of base (2,6-lutidine) on the extent of EMS formation at 70 °C.
5.1. Sulfonic Acid Salt Synthesis. Since base protonation is an ultrafast reaction (particularly when the base form of the API has a pK, > 7 (Snodin et al.”°), as MSA (or other sulfonic Figure 5. Effect of base (2,6-lutidine) on the extent of EMS formation at 70 °C.
Organic Process Research & Development
Organic Process Research & Development
Figure 1. General perception regarding alkyl sulfonate byproduct formation. Figure 2. Mechanism of formation of alkyl sulfonates from a sulfonic acid and a short-chain aliphatic alcohol in a binary system.
Figure 1. General perception regarding alkyl sulfonate byproduct formation. Figure 2. Mechanism of formation of alkyl sulfonates from a sulfonic acid and a short-chain aliphatic alcohol in a binary system.
128,a Table 6. Physicochemical Data for Principal Alkyl Sulfonates of Interest
128,a Table 6. Physicochemical Data for Principal Alkyl Sulfonates of Interest
Table 7. Nominal Lifetime and Less-Than-Lifetime (LTL) Limits (mg/day) for Chloroalkanes*
Table 7. Nominal Lifetime and Less-Than-Lifetime (LTL) Limits (mg/day) for Chloroalkanes*
Table 8. Physicochemical Data for Principal Chloroalkanes of Interest'**
Table 8. Physicochemical Data for Principal Chloroalkanes of Interest'**
Table 9. Nominal Lifetime and Less-Than-Lifetime (LTL) Limits (ug/day) for Alkyl Mesilates and Alkyl Tosilates*
Table 9. Nominal Lifetime and Less-Than-Lifetime (LTL) Limits (ug/day) for Alkyl Mesilates and Alkyl Tosilates*
Figure 6. Nelfinavir mesilate. 6.1. Chemical and Pharmaceutical Aspects. In an incident occurring in 2007,°° significant levels (>0.1%) of EMS (>30 batches tested in 2001 showed <0.5 ppm EMS) were found in several batches of nelfinavir mesilate (Viracept drug product; Figure 6), and it seemed initially that regulatory risk
Figure 6. Nelfinavir mesilate. 6.1. Chemical and Pharmaceutical Aspects. In an incident occurring in 2007,°° significant levels (>0.1%) of EMS (>30 batches tested in 2001 showed <0.5 ppm EMS) were found in several batches of nelfinavir mesilate (Viracept drug product; Figure 6), and it seemed initially that regulatory risk
Table 11. EMS: Doses/NOELs and PK Parameters
Table 11. EMS: Doses/NOELs and PK Parameters
“M, mesilate; T, tosilate; B, besilate; MDE, maximum duration of exposure in months (m) or years (y); MDD, maximum daily dose. (MDE based on ICH M7 recommendations and Prescribing information; MDD, expressed as sulfonic acid salt, based on best estimates from prescribing information); N/A, not t applicable. ’Certificates of Suitability to the monographs of the European Pharmacopoeia (CEPs) [50 CEPs in total]. “Capped at 5000 ppm. “Alkyl tosilates/besilates. “Based on continuous dose of 15 yg/kg/min for 24 h in a SO kg patient. Acute treatment using intramuscular administration. ?Ph. Eur./USP limits for methyl besilate are 10/100 ppm, respectively. Table 12. ICH M7 Limits for Alkyl Mesilates, Tosilates, and Besilates in Sulfonic Acid Salts Listed in the Ph. Eur.“
“M, mesilate; T, tosilate; B, besilate; MDE, maximum duration of exposure in months (m) or years (y); MDD, maximum daily dose. (MDE based on ICH M7 recommendations and Prescribing information; MDD, expressed as sulfonic acid salt, based on best estimates from prescribing information); N/A, not t applicable. ’Certificates of Suitability to the monographs of the European Pharmacopoeia (CEPs) [50 CEPs in total]. “Capped at 5000 ppm. “Alkyl tosilates/besilates. “Based on continuous dose of 15 yg/kg/min for 24 h in a SO kg patient. Acute treatment using intramuscular administration. ?Ph. Eur./USP limits for methyl besilate are 10/100 ppm, respectively. Table 12. ICH M7 Limits for Alkyl Mesilates, Tosilates, and Besilates in Sulfonic Acid Salts Listed in the Ph. Eur.“
Table 15. ICH M7 Alkyl Sulfonate Limits for EU-Authorized Mesilate, Tosilate, and Besilate Salts (via Centralized, Decentralized, and Mutual Recognition Procedures)
Table 15. ICH M7 Alkyl Sulfonate Limits for EU-Authorized Mesilate, Tosilate, and Besilate Salts (via Centralized, Decentralized, and Mutual Recognition Procedures)
Figure 7. Summary of experiment with 2,6-lutidine + MSA.
Figure 7. Summary of experiment with 2,6-lutidine + MSA.
Related topics:
Organic Process Development
580 California St., Suite 400
San Francisco, CA, 94104
© 2025 Academia. All rights reserved