The (5R-cis)-toluene-4-sulfonic acid 5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-yl)methyltetrahydrofuran–3-ylmethyl ester is a stereochemically defined p-toluenesulfonate API intermediate used in the manufacture of oral and injectable azole antifungal drug substances. Its registry number is CAS 149809-43-8, with molecular formula C₂₁H₂₁F₂N₃O₄S and molecular weight 449.47 g·mol⁻¹. The molecule consists of a tetrahydrofuran core bearing a 2,4-difluorophenyl group and a 1H-1,2,4-triazol-1-ylmethyl group at the 5-position and a 4-methylbenzenesulfonyloxymethyl substituent at the 3-position in the cis configuration. The tosylate ester serves as a non-volatile, crystalline leaving-group donor for late-stage coupling to phenolic or amino side chains used in tablet, capsule, granule, and injection drug product pathways. The product differs from the free alcohol precursor and from methanesulfonate, halide, or 4-bromobenzenesulfonate analogues in molecular weight, crystallinity, leaving-group reactivity, and transferable impurities. Manufacturers typically provide this material under a drug master file or technical package with lot-to-lot data for identity, assay, chiral purity, residual solvents, elemental impurities, water content, and particle size distribution.

Model designation follows the (5R-cis) stereochemical prefix and the p-toluenesulfonate ester class. The cis descriptor excludes the corresponding trans racemate and other stereoisomers, which are treated as impurities during downstream purification. The CAS registry number is the stable model identifier; individual manufacturers may assign internal product codes that are not pharmacopeial identifiers. Because the compound is an intermediate rather than a final marketed drug product, release for tablet or injectable processing requires not only the manufacturer’s certificate of analysis but also incoming-material verification under 21 CFR 211.84 and applicable ICH quality expectations. The (5R-cis) assignment is critical because the cis geometry places the difluorophenyl and triazolylmethyl substituents on the same face of the tetrahydrofuran ring. In the trans isomer, the three-dimensional orientation of the azole and fluorinated aryl groups changes, which can affect downstream coupling selectivity. Chiral HPLC is therefore used not only to quantify the enantiomer but also to separate the cis and trans diastereomers; the undesired stereoisomer is typically controlled at not more than 0.5% by area normalization.

What specifications govern oral solid and injectable processing of the (5R-cis)-tosylate?

For direct compression and dry granulation, the material is characterized by powder flow, particle size distribution, and moisture content. The particle size distribution is measured by laser diffraction under USP <429>; typical acceptance uses D90 not more than 250 µm and D10 not less than 20 µm to limit segregation and to support content uniformity in low-dose tablet blends. If the final tablet has a drug loading below 2.0% w/w, a smaller D90 of 150 µm may be required to meet content uniformity under USP <905>. During dry granulation, compacted ribbons are milled and the granule fraction between 125 µm and 850 µm is used for compression; published data for this specific configuration is limited, so process settings are validated on a lot-by-lot basis. Karl Fischer titration under USP <921> controls water at not more than 0.5% w/w, because excess moisture promotes sulfonate hydrolysis and flow deterioration. Residual solvents are controlled under USP <467> and ICH Q3C; common solvents from the synthetic route include methanol, dichloromethane, and tetrahydrofuran. Elemental impurities are managed under ICH Q3D through USP <232>/USP <233>.

Residual solvent profiles are route-dependent. If the synthetic route uses dichloromethane as a reaction solvent, the limit for dichloromethane is 600 ppm according to ICH Q3C Table 2; if tetrahydrofuran is used, the limit is 720 ppm; methanol, if used in crystallization, is controlled at 3000 ppm. The actual limit set should be based on the manufacturing process and the drug substance’s maximum daily dose. For injectable-grade material, the residual solvent specification is often tightened below the oral limit because the final injectable dose may exceed the oral dose per kilogram body weight per day. Water content is controlled at not more than 0.5% w/w because the ester can undergo acid-catalyzed hydrolysis in the presence of residual water and trace acidic impurities. Karl Fischer coulometric or volumetric titration under USP <921> Method Ia or Method Ic is appropriate for this low-water crystalline solid.

Injectable-grade lots of the tosylate are controlled beyond oral solid specifications. The material is not marketed as a final sterile injectable; it is a pharma-grade starting material for further reaction and purification before sterile filtration. When it is used in an injectable drug substance route, bioburden and endotoxin controls are introduced before the final coupling step. Bacterial endotoxin testing by the limulus amoebocyte lysate method under USP <85> is performed on a lot-specific basis, with the acceptance criterion derived from the maximum allowable endotoxin level in the final injectable product rather than from an oral solid-dose limit. Process solutions are filtered through 0.22 µm polyethersulfone filters after dissolution in a validated solvent system. Filter compatibility is assessed for 24 h at 15–25 °C to identify extractables and leachables in the presence of the sulfonate ester. Because the tosylate can hydrolyze at elevated pH, solution hold times are monitored by an HPLC method capable of separating the free alcohol from the intact ester. Long-term storage is commonly recommended at 2–8 °C in tight, light-resistant double polyethylene bags under dry nitrogen; short-term shipping at 15–25 °C is acceptable when moisture protection is maintained. Published stability data for this specific configuration is limited, and the storage period should be supported by manufacturer stability studies.

Solvent compatibility studies usually include methanol, ethanol, acetonitrile, acetone, and dichloromethane; the solubility of this tosylate in aqueous media is low because of the difluorophenyl and tosyl groups. For injectable processing, the material is dissolved in an organic solvent, dried, and carried through a coupling step; residual water in the reaction solvent must be minimized because it can reduce coupling yield and increase the free alcohol impurity. Karl Fischer limits for reaction solvents are typically set at not more than 0.10% w/w before charging the tosylate. Filter compatibility under 24 h contact at 15–25 °C is evaluated by HPLC assay and by extractable profile; the filter membrane is flushed with the processing solvent and the flush is analyzed for total organic carbon and UV-absorbing leachables. Because the molecule is a sulfonate ester, the final drug substance is typically controlled for residual sulfonate ester content under ICH M7; the acceptable intake is derived from the threshold of toxicological concern of 1.5 µg/day. Published data for this specific compound is limited; typical LC-MS/MS methods for sulfonate esters achieve sub-ppm quantitation to support such limits.

When a less-hydrolytically reactive sulfonate is considered for coupling

Alternative sulfonate esters and the free alcohol differ in molecular weight, physical form, activation requirement, and purification behavior. The methanesulfonate analogue has a molecular weight of 373.38 g·mol⁻¹, lower than the p-toluenesulfonate at 449.47 g·mol⁻¹; the lower mass can improve molar yield per kilogram of starting alcohol, but the methanesulfonate analogue is often more water-sensitive and less readily isolated as a stable crystalline solid. The 4-bromobenzenesulfonate analogue has a molecular weight of 514.35 g·mol⁻¹ and introduces bromine into the waste stream, requiring additional environmental control. The free alcohol precursor has a molecular weight of 295.29 g·mol⁻¹ and requires activation, for example by sulfonylation or Mitsunobu-type coupling, before it can react with the phenolic or amino side chain. The (5R-cis)-p-toluenesulfonate is therefore preferred when a crystalline intermediate with direct SN2 reactivity is required and when recrystallization is used to reject the undesired stereoisomer.

The tosylate has a molecular weight increase of 154.18 g·mol⁻¹ relative to the free alcohol; the methanesulfonate increase is 78.09 g·mol⁻¹. This mass difference affects process mass intensity and batch cost. The p-toluenesulfonate group also absorbs UV at wavelengths near 254 nm, which supports HPLC quantification; the free alcohol has a weaker chromophore in the same region and may require refractive index or low-wavelength UV detection. The methanesulfonate analogue may not provide the same UV detection sensitivity. On a rotary tablet press with force feeder and 8 mm round tooling, blend compressibility is evaluated by bulk density, tapped density, and Hausner ratio. Published data for this specific intermediate is limited; manufacturers typically target a Hausner ratio below 1.35 to ensure uniform die fill, but the actual batch value is reported on the certificate of analysis.

During scale-up on production equipment, the tosylate is charged as a solid to reactor trains or vacuum conveyors; its crystalline habit reduces dusting relative to lower-melting sulfonates. However, nitrogen-blanketed transfer and local dust extraction are required because sulfonate esters may present sensitization and static-charge hazards. The tosylate should not be exposed to strong aqueous alkali or primary amines except when a coupling reaction is intended, because the sulfonate group is susceptible to hydrolysis at pH above 8.0 and to displacement by nucleophilic bases. In tablet and granule manufacturing, blend uniformity is evaluated under USP <905> for the final drug product; the intermediate itself is not a direct compression drug substance unless a regulatory authority approves its use as a prodrug or drug substance. For injectable use, the ester is processed through a controlled coupling step followed by purification, because residual sulfonate and the hydroxymethyl hydrolytic product are managed as process impurities. The product should be protected from light because the aromatic sulfonate may undergo photolytic discoloration; light-resistant containers are therefore consistent with ICH Q1B photostability guidance. The choice between this (5R-cis)-tosylate and alternative sulfonates is therefore based on crystallinity, molecular weight, impurity rejection, and the final API’s approved manufacturing route.