Isosorbide
Isosorbide is a bicyclic diol with the molecular formula C₆H₁₀O₄, consisting of two fused tetrahydrofuran rings formed as an acetal derivative of D-glucitol (sorbitol).[1]
It is produced industrially through the acid-catalyzed double dehydration of sorbitol, which itself is derived from the hydrogenation of glucose sourced from biomass or starch hydrolysis.[2][3]
As a versatile bio-based chemical, isosorbide serves primarily as a precursor for organic nitrate esters, including isosorbide dinitrate and isosorbide mononitrate, which are used to prevent and treat angina pectoris in coronary artery disease by promoting vasodilation.[4][5]
These nitrates function via biotransformation to nitric oxide, which stimulates guanylate cyclase in vascular smooth muscle, elevating cyclic guanosine monophosphate levels to induce relaxation and reduce cardiac preload and afterload.[6][4]
Isosorbide mononitrate, the active metabolite of dinitrate, exhibits higher bioavailability and a longer elimination half-life (approximately 5 hours versus 1 hour for dinitrate), enabling simpler once-daily dosing regimens.[4][7]
Beyond pharmaceuticals, isosorbide is employed as a renewable monomer in the production of polyesters, polycarbonates, and other eco-friendly polymers, leveraging its rigidity and chirality for enhanced material properties.[8][9]
History
Discovery and Early Synthesis
Isosorbide, or 1,4:3,6-dianhydro-D-glucitol, was first synthesized in 1948 by W. N. Haworth and L. F. Wiggins via acid-catalyzed double dehydration of D-sorbitol.[10] D-Sorbitol serves as the starting material, obtained through catalytic hydrogenation of D-glucose, which itself derives from the hydrolysis of starch.[10] This process involves sequential dehydration steps, first forming a sorbitan intermediate (1,4-anhydrosorbitol) followed by a second cyclization to the bicyclic diol.[11] Early structural insights emerged from the 1940 synthesis and analysis of isosorbide dinitrate, the 2,5-dinitrate ester of the diol, reported by researchers at the University of Maryland.[12] This derivative's preparation from sorbitol anhydrides highlighted the fused bicyclic framework, consisting of two tetrahydrofuran rings linked by an oxygen bridge, confirmed through chemical derivatization and solubility properties.[12] The precise bicyclic diol structure underwent empirical verification in the post-1950s era using advancing spectroscopic techniques, including infrared spectroscopy for functional group identification and emerging nuclear magnetic resonance for ring confirmation, building on initial degradative and synthetic proofs.[13] These methods corroborated the endo-exo orientation of the hydroxyl groups and the overall rigidity of the molecule derived from first-principles dehydration mechanisms of the linear polyol chain.[13]Development of Pharmaceutical Derivatives
In the 1950s, isosorbide dinitrate was independently synthesized in the United States by Harris and colleagues, marking a key advancement in nitrate derivatives for therapeutic applications.[14] Early pharmacological evaluations demonstrated its vasodilatory potency, with hemodynamic effects persisting for at least one hour, exceeding the duration observed with nitroglycerin in comparative studies.[15] These findings highlighted isosorbide dinitrate's potential for sustained action relative to other organic nitrates, prompting further exploration despite challenges like rapid tolerance development noted in initial trials.[16] Isosorbide itself emerged as an oral osmotic diuretic in the mid-1960s, with preclinical studies confirming its efficacy in promoting diuresis through hyperosmotic mechanisms without significant gastrointestinal irritation or toxicity at therapeutic doses.[17] By the 1970s, isosorbide dinitrate gained traction as an anti-anginal agent, with clinical investigations establishing its role in relieving exertional angina via coronary vasodilation, though adoption remained tempered by evidence of attenuated responses during prolonged administration.[18] The 1980s saw broader recognition of isosorbide nitrates in managing ischemic heart disease, including the development of isosorbide-5-mononitrate as a derivative designed to leverage its status as the primary active metabolite of dinitrate, aiming to reduce tolerance through once-daily dosing.[4] Initial limited uptake stemmed from pharmacokinetic data revealing rapid onset of tolerance, necessitating intermittent dosing strategies in early protocols. Commercial production advancements, such as Roquette Frères' initiation of pharmaceutical-grade isosorbide synthesis in a 2002 pilot unit, supported derivative scalability for medical applications.[19]Chemistry
Molecular Structure and Isomers
Isosorbide is a bicyclic acetal with the systematic name (3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol, corresponding to a 1,4:3,6-dianhydro-D-glucitol core.[1] This structure comprises two fused tetrahydrofuran rings formed by intramolecular dehydration of D-glucitol (sorbitol), eliminating water molecules between the 1- and 4- hydroxyl groups and the 3- and 6- hydroxyl groups, respectively.[20] The resulting framework positions two vicinal hydroxyl groups at carbons 2 and 5, one in an endo orientation and the other exo relative to the bicyclic system, conferring a rigid, V-shaped conformation absent in the flexible, acyclic parent hexitol.[21] As one of the isohexide stereoisomers, isosorbide exhibits distinct stereochemistry compared to isomannide (1,4:3,6-dianhydro-D-mannitol, with both hydroxyls endo) and isoidide (1,4:3,6-dianhydro-L-iditol, with both exo).[22] Derived specifically from D-glucitol, isosorbide's endo-exo configuration at the 2- and 5-positions introduces four chiral centers, enabling inherent chirality that influences molecular reactivity and packing, unlike the achiral or differently oriented isomers.[23] The molecular structure has been rigorously confirmed through X-ray crystallography, revealing the precise fused-ring geometry and stereocenters, and NMR spectroscopy, which verifies proton and carbon environments consistent with the bicyclic rigidity.[24] These techniques underscore the absence of conformational flexibility seen in acyclic polyols, attributing stability to the acetal bridges.[25]Physical and Chemical Properties
Isosorbide appears as a white to off-white crystalline solid that is hygroscopic and stable under inert atmosphere at room temperature.[26] Its melting point ranges from 60 to 63 °C.[26] [27] The boiling point is 175 °C at 2 mmHg pressure, reflecting low volatility with a vapor pressure of 0.007 Pa at 20 °C.[26] [28] Density is estimated at approximately 1.1 g/cm³.[26] It exhibits high water solubility exceeding 200 g/L at 20 °C and is also soluble in alcohols and ketones.[29] The specific optical rotation is +42° (c=3 in water), consistent with its chiral structure derived from D-sorbitol.[26]| Property | Value |
|---|---|
| Melting point | 60–63 °C |
| Boiling point | 175 °C (2 mmHg) |
| Density | ~1.1 g/cm³ |
| Water solubility | >200 g/L (20 °C) |
| Vapor pressure | 0.007 Pa (20 °C) |
| Optical rotation | [+42°] (c=3, H₂O) |