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Mesylate

Mesylate, also known as methanesulfonate, is the anion with the chemical formula CH₃SO₃⁻, serving as the conjugate base of methanesulfonic acid (CH₄O₃S), a strong organic acid with a pKa of approximately -1.9 that is miscible in water and used industrially as a catalyst and solvent.^[1] In chemistry, the term "mesylate" commonly refers to esters of this anion, such as alkyl methanesulfonates (ROSO₂CH₃), which are colorless, stable compounds prepared by reacting alcohols with methanesulfonyl chloride (MsCl) in the presence of a base like pyridine or triethylamine.^[1]^[2] One of the most notable applications of mesylates is in organic synthesis, where the mesylate group (–OMs) functions as an excellent leaving group in nucleophilic substitution (SN1 and SN2) and elimination (E1 and E2) reactions due to the resonance stabilization of the departing anion (CH₃SO₃⁻), which disperses the negative charge across three oxygen atoms, making it comparable in reactivity to chloride or bromide.^[2] This property allows mesylates to convert poor leaving groups like hydroxyl (–OH) from alcohols into highly reactive species without altering the stereochemistry at the carbon during formation, enabling efficient transformations such as the synthesis of ethers, amines, and halides.^[2] Mesylates are preferred over tosylates in some cases for their smaller size, which minimizes steric hindrance in crowded molecules.^[3] In pharmaceutical sciences, mesylate salts are widely employed to enhance the solubility, bioavailability, and stability of drug candidates, particularly for basic compounds, as methanesulfonic acid forms non-hygroscopic, crystalline salts that are compatible with oral and injectable formulations.^[4] Examples include osimertinib mesylate, an EGFR inhibitor for non-small cell lung cancer treatment; and paroxetine mesylate, a selective serotonin reuptake inhibitor for depression.^[5]^[6] However, short-chain alkyl mesylates (e.g., methyl or ethyl methanesulfonate) formed as impurities during salt preparation can be genotoxic alkylating agents, necessitating rigorous control in manufacturing to ensure drug safety below 1.5 µg/day intake limits.^[7]

Chemical Properties

Definition and Nomenclature

A mesylate is defined as any salt or ester derived from methanesulfonic acid, with the chemical formula CH_3SO_3H. The mesylate anion specifically refers to CH_3SO_3^-, also known as methanesulfonate, which serves as the conjugate base of methanesulfonic acid. It is important to distinguish between the term "mesylate," which denotes the anion CH_3SO_3^- or compounds containing it (such as salts or esters), and "mesyl," which refers to the methanesulfonyl functional group CH_3SO_2^- (abbreviated as Ms).^[8] The mesyl group is commonly used in organic chemistry to denote the CH_3SO_2- moiety in derivatives like mesyl chloride (CH_3SO_2Cl).^[9] The nomenclature for "mesyl" originated in 1938, when chemists Bernhard Helferich and Alfred Gnüchtel introduced the abbreviated term for the methanesulfonyl group in their work on sulfonate esters. This contraction paralleled earlier abbreviations like "tosyl" for the p-toluenesulfonyl group. In some pharmaceutical contexts, an alternative spelling "mesilate" is used; for example, the World Health Organization's International Nonproprietary Name (INN) for the drug imatinib is imatinib mesilate.^[10] According to IUPAC conventions, mesylate salts are named as alkanesulfonates (e.g., sodium methanesulfonate), while esters are designated as alkyl methanesulfonates (e.g., methyl methanesulfonate for CH_3SO_3CH_3).^[11] This systematic naming reflects the parent acid and the attached alkyl or metal group.^[9]

Structure and Reactivity

The mesylate anion, denoted as CH₃SO₃⁻, features a central sulfur atom bonded to a methyl group and three oxygen atoms, with the negative charge delocalized across the oxygen atoms through resonance, resulting in nearly equivalent S–O bond lengths. Crystal structures reveal typical S–O bond distances of approximately 1.45 Å and S–C bond lengths around 1.75 Å, with O–S–O angles near 113° and C–S–O angles about 106°.^[12] In mesylate esters of the general form ROSO₂CH₃, the structure includes two S=O double bonds (length ~1.42 Å), an S–O–R single bond (~1.56 Å), and the S–CH₃ bond (~1.74 Å), as determined from X-ray crystallographic data of specific derivatives like 4-tert-butylcyclohexyl methanesulfonates, where the ester C–O bond measures 1.48 Å.^[13] Methanesulfonic acid, the protonated form from which the mesylate anion derives, is a colorless, hygroscopic liquid with a melting point of 17–19 °C, a boiling point of 122 °C at 1 mmHg, and a density of 1.48 g/cm³ at 20 °C.^[1]^[14] It behaves as a strong acid with a pKa of –1.9, owing to the effective resonance stabilization of the conjugate base by delocalization of the negative charge over the three sulfonate oxygens.^[1] Spectroscopically, mesylates exhibit characteristic infrared absorptions for the S=O stretches at approximately 1350 cm⁻¹ (asymmetric) and 1170 cm⁻¹ (symmetric), attributable to the sulfonyl moiety.^[15] In ¹H NMR spectra, the methyl protons of the CH₃SO₂– group resonate at around 3.1 ppm in CDCl₃, reflecting the deshielding effect of the adjacent sulfonyl group.^[16] Mass spectrometry of mesylate-containing compounds often shows a prominent fragment at m/z 95 corresponding to the CH₃SO₃⁻ anion in negative-ion mode, arising from cleavage of the ester linkage.^[17] Mesylate esters function as excellent leaving groups in nucleophilic substitution reactions due to the resonance stabilization of the CH₃SO₃⁻ anion, which disperses the negative charge across the three oxygen atoms, lowering the energy barrier for departure.^[18] Compared to other sulfonate esters like tosylates, mesylates exhibit greater reactivity in hydrolysis under alkaline conditions because of reduced steric hindrance, though they remain relatively stable in neutral or mildly basic media.^[18] When the mesyl group is attached to nitrogen, as in methanesulfonamides, it demonstrates high stability and resistance to hydrolysis under both acidic and basic conditions, attributed to the strong S–N bond and lack of facile cleavage pathways.^[19]

Preparation

Synthesis of Methanesulfonyl Chloride

Methanesulfonyl chloride (MsCl), a key precursor in mesylate chemistry, is primarily synthesized in laboratory settings through the reaction of methanesulfonic acid with thionyl chloride. This method involves refluxing methanesulfonic acid (CH₃SO₃H) with thionyl chloride (SOCl₂) to produce MsCl, sulfur dioxide (SO₂), and hydrogen chloride (HCl), as shown in the equation:

\text{CH}_3\text{SO}_3\text{H} + \text{SOCl}_2 \rightarrow \text{CH}_3\text{SO}_2\text{Cl} + \text{SO}_2 + \text{HCl}

The reaction is typically carried out under anhydrous conditions to prevent hydrolysis, with excess thionyl chloride serving both as reagent and solvent; yields can reach up to 90% upon distillation of the crude product.^[20]^[21] This approach is favored due to its simplicity and the availability of starting materials, though it requires careful handling of the corrosive and lachrymatory byproducts.^[22] Alternative laboratory routes include the oxidation of methyl mercaptan (CH₃SH) with chlorine gas in the presence of water or an aqueous hydrogen chloride bath, which proceeds via chlorination and hydrolysis to yield MsCl directly. This continuous process achieves theoretical yields of around 92%, making it efficient for scaled preparations, though it demands precise control of gas feeds to minimize side products like dimethyl disulfide.^[23] Another variant involves chlorination of dimethyl sulfoxide (DMSO), where gaseous chlorine reacts with DMSO under anhydrous conditions followed by aqueous workup, affording deuterated MsCl in 52% yield when using DMSO-d₆, demonstrating the method's utility for isotopically labeled compounds.^[24] These oxidation-based syntheses are particularly useful when sulfur-containing precursors are readily available but may generate more complex waste streams compared to the thionyl chloride route.^[25] On an industrial scale, MsCl is produced via a free radical-initiated reaction of methane (CH₄) with sulfuryl chloride (SO₂Cl₂) in concentrated sulfuric acid at low temperatures (typically 0–30°C), selectively forming MsCl with HCl as byproduct and conversions up to 26% based on sulfuryl chloride. This gas-phase or liquid-phase process leverages inexpensive feedstocks like methane and chlorine-derived sulfuryl chloride, followed by purification through distillation under reduced pressure (boiling point approximately 62°C at 18 mmHg) to isolate high-purity MsCl. Yield optimizations, such as initiator selection (e.g., urea-H₂O₂ or metal catalysts), enhance selectivity and reduce over-chlorination, supporting large-scale production for pharmaceutical and agrochemical applications. Earlier practical methods from the mid-20th century, including mercaptan oxidation, laid the groundwork for these efficient modern processes.^[26]^[25]^[27]

Formation of Mesylate Esters

The standard method for the formation of mesylate esters involves the reaction of an alcohol (ROH) with methanesulfonyl chloride (MsCl) in the presence of a base such as triethylamine (Et₃N) or pyridine. This process generates the mesylate ester (ROSO₂CH₃) and hydrochloric acid (HCl), with the base neutralizing the HCl to prevent side reactions. The reaction is typically performed in an aprotic solvent like dichloromethane (DCM) or diethyl ether at temperatures ranging from 0°C to 25°C, often starting at low temperature to manage the exothermic nature of the sulfonylation. For instance, primary alcohols such as ethanol are efficiently converted to their mesylates in high yields (e.g., 96%) under these conditions, providing activated derivatives suitable for further transformations.^[28]^[29] The mechanism proceeds via nucleophilic substitution at the sulfur atom of MsCl. The oxygen lone pair of the alcohol attacks the electrophilic sulfur, displacing the chloride ion in an SN₂ fashion, which forms a protonated mesylate intermediate (ROH⁺-SO₂CH₃). Subsequent deprotonation by the base yields the neutral mesylate ester. This pathway occurs without involvement at the carbon center, resulting in retention of configuration at the alcohol's chiral carbon if present. Methanesulfonyl chloride, the primary reagent, is synthesized separately as outlined in the Synthesis of Methanesulfonyl Chloride section. Alternative approaches include the use of mesic anhydride (Ms₂O) for esterification, particularly when milder conditions are desired. Ms₂O reacts with the alcohol in the presence of a catalytic base like 4-(dimethylamino)pyridine (DMAP) to afford the mesylate, avoiding the generation of HCl and enabling reactions in more sensitive systems. Another variation involves in situ activation using methanesulfonic acid (MsOH) coupled with agents like dicyclohexylcarbodiimide (DCC), though this method is less prevalent and typically applied in specific synthetic contexts.^[30]^[31] Compared to tosylate esters, mesylates offer advantages due to the smaller methanesulfonyl group, which imparts less steric bulk and enhances suitability for subsequent SN₂ displacements without compromising reactivity. This makes mesylates particularly valuable for activating primary and secondary alcohols in concise synthetic sequences.^[32]

Formation of Mesylate Salts

Mesylate salts are ionic compounds formed by the neutralization of methanesulfonic acid (MsOH, \ce{CH3SO3H}) with a suitable base, yielding the mesylate anion \ce{CH3SO3-} paired with a cation such as an amine or metal ion.^[33] The general reaction proceeds as \ce{CH3SO3H + B -> B+ CH3SO3-}, where B represents the base, typically an organic amine, metal hydroxide, oxide, or carbonate, under controlled conditions to ensure complete proton transfer and salt formation.^[34] This acid-base neutralization is widely employed due to the strong acidity of MsOH (pKa ≈ -1.9), facilitating efficient salt generation in aqueous or organic solvents.^[33] In pharmaceutical applications, mesylate salts of basic drug candidates are prepared by reacting the free base with an equimolar amount of MsOH in polar solvents such as ethanol or acetone, often followed by heating to dissolve the components and subsequent cooling for crystallization.^[35] For instance, imatinib mesylate, a key tyrosine kinase inhibitor, is synthesized by suspending imatinib base in ethanol, adding MsOH dropwise, refluxing the mixture, and then cooling to precipitate the salt, achieving high purity through this solvent-mediated process.^[36] This method enhances the drug's solubility and stability compared to the free base, with reaction temperatures typically ranging from room temperature to reflux to optimize yield and polymorph control.^[37] Metal mesylate salts are commonly prepared by reacting MsOH with metal oxides or carbonates, which generates water or carbon dioxide as byproducts.^[33] A representative example is the formation of magnesium mesylate via the reaction of magnesium oxide with MsOH: \ce{MgO + 2 CH3SO3H -> Mg(CH3SO3)2 + H2O}, conducted in aqueous media with stirring to ensure homogeneity and often requiring evaporation or cooling for isolation. Similar procedures apply to other metals, such as lead or silver, using their oxides or carbonates to produce soluble salts suitable for applications in electroplating or catalysis.^[33] Purification of mesylate salts typically involves recrystallization from appropriate solvents to remove impurities like unreacted acid or base, with careful control of water content to manage hydrate formation.^[38] For hydrated forms, such as monohydrates or trihydrates, the solvent composition (e.g., aqueous methanol with 5-20% water) is adjusted during crystallization to stabilize the desired stoichiometry, followed by filtration and drying under vacuum.^[39] This step ensures pharmaceutical-grade purity, often exceeding 99%, by leveraging differences in solubility between the salt and contaminants.^[38]

Applications

In Organic Synthesis

Mesylate esters, denoted as ROMsO₂ or ROMs, serve primarily as activated derivatives of alcohols in nucleophilic substitution reactions, enabling both SN1 and SN2 pathways by converting the poor leaving group OH into the excellent leaving group mesylate anion (CH₃SO₂O⁻).^[40] This activation facilitates displacement by various nucleophiles, such as cyanide (CN⁻), iodide (I⁻), or azide (N₃⁻), to form corresponding substitution products with high efficiency, particularly for primary and secondary alkyl mesylates.^[41] For instance, primary mesylates undergo clean SN2 displacements under mild conditions, yielding alkyl cyanides or azides useful in further synthetic elaboration. The superior leaving group ability of mesylates stems from the stability of the mesylate anion, arising from resonance delocalization of the negative charge across the three oxygen atoms in the sulfonate moiety, which weakens the C-O bond in the ester.^[40] This results in significant rate enhancements compared to unactivated alcohols, often by orders of magnitude, as the reaction proceeds via direct nucleophilic attack without the need for additional activation.^[41] Representative applications include the Williamson ether synthesis, where an alkoxide nucleophile displaces the mesylate to form ethers, and epoxide formation from vicinal diols, involving selective mesylation of one hydroxyl followed by intramolecular cyclization under basic conditions.^[42] In comparison to other leaving groups, mesylates offer advantages over tosylates (p-toluenesulfonates) due to their smaller size and lower steric bulk from the methyl substituent versus the tolyl group, leading to faster reaction rates in crowded environments, especially for primary alcohols.^[41] Relative to alkyl halides, mesylates provide less basic byproducts (methanesulfonic acid versus HX), reducing side reactions in sensitive substrates, and are particularly suited for primary and secondary systems where elimination is minimized. Kinetic studies indicate that mesylate reactivity is lower than that of iodide and bromide but higher than that of chloride in polar aprotic solvents such as DMSO.^[41] Beyond substitution, mesyl groups function as protecting groups for amines, forming N-mesyl sulfonamides (R-NHMs) that mask nucleophilicity during multi-step syntheses and can be deprotected under reductive conditions. Additionally, mesylates participate in sulfonylation reactions, where methanesulfonyl chloride (MsCl) introduces the mesyl moiety to alcohols or amines, enabling further transformations like cross-coupling or oxidation.^[40]

In Pharmaceuticals

Mesylate salts are widely employed in pharmaceutical formulations to improve the physicochemical properties of basic active pharmaceutical ingredients, particularly by enhancing aqueous solubility, chemical stability, and oral bioavailability. For instance, the mesylate salt form of imatinib, known commercially as Gleevec, addresses the poor water solubility of the free base, rendering it soluble in aqueous buffers at pH below 5.5, which facilitates its absorption and efficacy in treating chronic myeloid leukemia (CML). This salt also demonstrates high stability in amorphous forms suitable for solid dosage formulations, contributing to consistent drug release and shelf-life. Similarly, the mesylate counterion promotes better bioavailability compared to the neutral form, as evidenced by studies on nano-emulsion delivery systems that leverage its solubility profile to overcome dissolution limitations in imatinib therapy. The mesyl group (-SO₂CH₃) is incorporated as a functional moiety in certain drug molecules, often attached to nitrogen atoms, to modulate pharmacokinetics and confer resistance to metabolic degradation. In antiarrhythmic agents like sotalol, a methane sulfonanilide derivative, the mesyl substituent on the aniline nitrogen enhances metabolic stability, as sotalol undergoes negligible hepatic metabolism via cytochrome P450 enzymes and is primarily excreted unchanged, achieving near-complete oral bioavailability of approximately 100%. This structural feature similarly applies to ibutilide, a methanesulfonamide analogue of sotalol, where the mesyl group supports its class III antiarrhythmic activity by aiding in the prolongation of action potential duration while contributing to its overall pharmacokinetic profile, including rapid distribution and hepatic metabolism into less active metabolites. Mesylate salts offer distinct formulation advantages over common alternatives like hydrochloride (HCl) salts, including reduced hygroscopicity, which minimizes moisture uptake and maintains tablet integrity during storage, and an odorless profile that improves handling and patient acceptability. Unlike HCl salts, which can introduce chloride ions potentially leading to corrosiveness in manufacturing equipment, mesylates provide higher solubility in some cases—up to fivefold greater than their HCl counterparts—without compromising stability. These properties have led to broad regulatory acceptance; the U.S. Food and Drug Administration (FDA) has approved numerous mesylate salts over the past seven decades, including 69 sulfonate variants, while the World Health Organization (WHO) recognizes them in essential medicines lists for their reliability in drug delivery. Prominent examples illustrate mesylate's pharmaceutical utility. Osimertinib mesylate, marketed as Tagrisso, serves as a first-line treatment for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, where the salt form ensures effective oral dosing and targets resistant tumor cells. In veterinary applications, tricaine mesylate (also known as MS-222) is the only FDA-approved anesthetic for finfish intended for human consumption, providing safe sedation and immobilization during procedures like transport or surgery, with a required 21-day withdrawal period to ensure residue-free tissue.

Occurrence and Safety

Natural Occurrence

Mesylates occur rarely in natural environments, with the most prominent example being the mineral ernstburkeite, magnesium methanesulfonate dodecahydrate (Mg(CH₃SO₃)₂ · 12H₂O), identified in solid inclusions within ice cores from Dome Fuji station in East Antarctica.^[43] These inclusions, typically ranging from 1 to 5 μm in grain size, are associated with gypsum and ice, and were confirmed through Raman microspectroscopy, revealing characteristic peaks for the methanesulfonate anion.^[43] The origin of MSA in these polar ice formations traces to the atmospheric oxidation of dimethyl sulfide (DMS), a biogenic gas released by marine phytoplankton through the breakdown of dimethylsulfoniopropionate.^[44] DMS oxidation by hydroxyl radicals and other oxidants yields MSA, which can then neutralize with cations like magnesium in aerosols before deposition into ice.^[44] Concentrations of methanesulfonate in Antarctic ice cores typically range from 0.02 to 0.8 μM, reflecting episodic marine productivity and transport efficiency under glacial conditions.^[45] While volcanic emissions of SO₂ contribute to broader sulfur cycling, MSA specifically derives from this marine biogenic pathway rather than direct reactions involving atmospheric methane.^[46] Beyond geological deposits, trace amounts of MSA appear in rainwater and atmospheric aerosols, particularly in marine-influenced regions, arising from the same DMS oxidation processes driven by algal activity.^[47] In polar ice samples, methanesulfonate is routinely detected using ion chromatography, enabling high-resolution analysis of anion profiles.^[48] These measurements serve as proxies in paleoclimate reconstructions, indicating historical variations in Southern Ocean productivity and sea ice extent over millennia.^[49]

Safety and Toxicology

Methanesulfonyl chloride (MsCl), a key precursor in mesylate synthesis, poses significant handling hazards due to its highly corrosive nature, causing severe skin burns, eye damage, and respiratory irritation upon contact. It is also toxic if inhaled, ingested, or absorbed through the skin, and acts as a lachrymator, inducing tearing and discomfort even at low concentrations.^[50] MsCl is extremely moisture-sensitive, reacting violently with water to generate hydrochloric acid and methanesulfonic acid, which can lead to exothermic reactions and toxic gas release; therefore, it must be handled exclusively in a fume hood under inert atmosphere, with appropriate personal protective equipment including gloves, goggles, and respiratory protection.^[51] Grounding of equipment is essential to prevent static discharge, as vapors can form explosive mixtures with air.^[27] Mesylate salts, such as those used as pharmaceutical counterions, generally exhibit low acute toxicity and are considered safe for human use when pure.^[52] However, certain alkyl mesylates, including methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS), are highly reactive alkylating agents that demonstrate genotoxic and mutagenic properties, capable of damaging DNA through alkylation. EMS is classified by the International Agency for Research on Cancer (IARC) as Group 2B (possibly carcinogenic to humans), based on sufficient evidence of carcinogenicity in experimental animals, while MMS falls under Group 2A (probably carcinogenic).^[53] These compounds are not typically used directly but can form as byproducts, necessitating strict controls to mitigate risks. In pharmaceutical manufacturing, residual alkyl mesylates represent critical impurities in mesylate salt drug substances, potentially arising from reactions between methanesulfonic acid and trace alcohols in solvents or starting materials; their genotoxic potential via DNA alkylation has prompted rigorous regulatory oversight. The FDA and EMA, through ICH M7 guidelines, recommend controlling such mutagenic impurities to the threshold of toxicological concern (TTC) of 1.5 μg per day for lifetime exposure, which often translates to limits below 0.15–3 ppm in the drug substance depending on the maximum daily dose and specific compound potency—for instance, EMS limits as low as 0.15 ppm were applied in response to contamination incidents like the 2007 Viracept recall.^[54] Analytical methods such as GC-MS are employed to ensure compliance, emphasizing the need for orthogonal testing to detect these trace levels.^[55] Methanesulfonic acid, the parent compound of mesylates, is environmentally favorable due to its ready biodegradability under aerobic conditions, breaking down into carbon dioxide, water, and sulfate via microbial action, with low potential for bioaccumulation owing to its high water solubility and low octanol-water partition coefficient (log Kow < -3).^[56] It exhibits minimal chronic toxicity to aquatic organisms at typical environmental concentrations. However, in pharmaceutical wastewater, elevated levels from production processes can pose acute aquatic toxicity and contribute to acidification, requiring monitoring and treatment in effluents to prevent localized impacts.^[57]

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[PDF] Agents Classified by the IARC Monographs , Volumes 1–123
Nov 9, 2018 · Group 1 with supporting evidence from other relevant data. 62-50-0 Ethyl methanesulfonate. 2B. 7, Sup 7. 1987. 62-53-3 Aniline. 3. 27, Sup 7.
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[PDF] ICH guideline M7(R1) on assessment and control of DNA reactive ...
Aug 25, 2015 · For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 ...Missing: mesylates | Show results with:mesylates
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Residues of genotoxic alkyl mesylates in mesylate salt drug ...
Mesylate esters of short-chain (n = 1–3) alcohols are reactive, direct-acting, genotoxic and possibly carcinogenic alkylating agents.
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Methanesulfonic acid (MSA) in clean processes and applications - NIH
This tutorial review acquaints chemists and metallurgists with the properties and industrial applications of methanesulfonic acid (MSA, CH 3 SO 3 H).
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US6063280A - Biodegradation of methanesulfonic acid
Therefore, MSA in wastewater poses significant environmental problems in the form of aquatic toxicity. A waste treatment system for MSA degradation to non ...