View source for Isosorbide

{{Use dmy dates|date=October 2022}}
{{chembox
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| verifiedrevid = 461781491
| ImageFile = Isosorbide.svg
| ImageSize = 150px
| PIN = (3''R'',3a''R'',6''S'',6a''R'')-Hexahydrofuro[3,2-''b'']furan-3,6-diol
| OtherNames = <small>D-</small>Isosorbide; 1,4:3,6-Dianhydro-<small>D</small>-sorbitol; 1,4-Dianhydrosorbitol
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = WXR179L51S
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 12077
| DrugBank = DB09401
| ChEBI = 6060
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1200660
| InChI = 1/C6H10O4/c7-3-1-9-6-4(8)2-10-5(3)6/h3-8H,1-2H2/t3-,4+,5-,6-/m1/s1
| InChIKey = KLDXJTOLSGUMSJ-JGWLITMVBP
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| StdInChI = 1S/C6H10O4/c7-3-1-9-6-4(8)2-10-5(3)6/h3-8H,1-2H2/t3-,4+,5-,6-/m1/s1
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| StdInChIKey = KLDXJTOLSGUMSJ-JGWLITMVSA-N
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| CASNo = 652-67-5
| PubChem = 12597
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| KEGG = D00347
| SMILES = O[C@@H]1[C@H]2OC[C@@H](O)[C@H]2OC1
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|Section2={{Chembox Properties
| C=6 | H=10 | O=4 
| Appearance = Highly [[hygroscopic]] white flakes
| Density = 1.30 at 25&nbsp;°C
| MeltingPtC = 62.5 to 63
| BoilingPtC = 160
| BoilingPt_notes = at 10 mmHg
| Solubility = in water (>850 g/L), [[Alcohol (chemistry)|alcohol]]s and [[ketone]]s
  }}
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| pronounce         = 
| tradename         = Ismotic, Isobide, others
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| DailyMedID        = Isosorbide
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'''Isosorbide''' is a [[Bicyclic compound|bicyclic chemical compound]] from the group of [[diol]]s and the [[Heterocyclic compound|oxygen-containing heterocycles]], containing two fused [[furan ring]]s. The starting material for isosorbide is [[D-sorbitol]], which is obtained by catalytic hydrogenation of [[D-glucose]], which is in turn produced by [[hydrolysis]] of [[starch]]. Isosorbide is discussed as a plant-based platform chemical from which biodegradable [[Derivative (chemistry)|derivatives]] of various [[Functionality (chemistry)|functionality]] can be obtained.

In 2022, it was the 119th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Isosorbide Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Isosorbide | access-date = 30 August 2024 }}</ref>

== Uses ==
=== Isosorbide ===
Because of its pronounced hygroscopicity, isosorbide is used as a humectant and in medicine as an osmotic diuretic for the treatment of [[hydrocephalus]] and acute angle-closure [[glaucoma]].<ref>{{pubChem|12597}}</ref><ref>{{Cite web |title=Angle-Closure Glaucoma - Eye Disorders - Merck Manuals Professional Edition |work=Merck Manuals Professional Edition |access-date=21 April 2021 |url=https://www.merckmanuals.com/professional/eye-disorders/glaucoma/angle-closure-glaucoma |archive-url=https://web.archive.org/web/20210421081913/https://www.merckmanuals.com/professional/eye-disorders/glaucoma/angle-closure-glaucoma |archive-date=21 April 2021 |url-status=live }}</ref> The two [[secondary hydroxy group]]s make isosorbide a versatile platform chemically-accessible from renewable resources. As a diol, isosorbide can be mono- or biderivatized using the standard methods of [[organic chemistry]], such as [[nitration]], [[esterification]], [[etherification]], [[tosylation]], etc., and converted into compounds with interesting properties or into monomeric units for novel polymers.<ref name="Rose">{{cite journal | vauthors = Palkovits R, Rose M | author-link1 = Regina Palkovits | title = Isosorbide as a Renewable Platform chemical for Versatile Applications – Quo Vadis? | journal = [[ChemSusChem]] | date = 2012 | volume = 5 | issue = 1 | pages = 167–176 | doi = 10.1002/cssc.201100580 | pmid = 22213713 | bibcode = 2012ChSCh...5..167R }}</ref>

[[File:Isosorbide reactions.svg|350px|center|Reaktionen von Isosorbid]]

=== Isosorbide nitrates ===
By nitration of isosorbide with [[concentrated nitric acid]], 2,5-[[isosorbide dinitrate]] (ISDN) can be obtained.  2,5-Isosorbide dinitrate is suitable (just like its major metabolite 5-[[isosorbide mononitrate]], ISMN<ref>{{cite book |title=Remington : the science and practice of pharmacy. |date=2006 |publisher=Lippincott Williams & Wilkins |location=Philadelphia |isbn=978-0-7817-4673-1 |edition=21st | page = 1359 | veditors = Tory DB }}</ref>)  for the treatment of [[Angina Pectoris|angina pectoris]] due to its [[Vasodilation|vasodilator effect]].<ref>{{cite book | veditors = von Claus JE, Schmidt H |title=Pharmakologie und Toxikologie für Studium und Praxis |date=2007 |location=Stuttgart | publisher = Schattauer Verlag |isbn=978-3-7945-2295-8 |edition=6th }}</ref>

=== Isosorbide esters ===
[[Esterification]] of isosorbide with [[fatty acid]]s gives access to isosorbide monoesters, which are useful as detergents in household cleaners, dishwashing detergents, and cosmetic preparations, because of their properties as surfactant.<ref>WIPO Patent Application WO/2010/115565, [http://patentscope.wipo.int/search/en/WO2010115565 Isosorbide monoesters and their use in household applications], invent1: C. Breffa et al., assign1: Cognis IP Management GmbH, veröffentlicht am 14. Oktober 2010</ref> The likewise readily available isosorbide diesters<ref>Deutksche Offenlegungsschrift DE 10 2007 028 702A1, [http://www.patent-de.com/20081224/DE102007028702A1.html Verfahren zur Herstellung von Dianhydrohexitol-Diestern] {{Webarchive|url=https://web.archive.org/web/20160304003419/http://www.patent-de.com/20081224/DE102007028702A1.html |date=4 March 2016 }}, invent1: M. Graß, M. Woelk-Faehrmann, assign1: Evonik Oxeno GmbH, offengelegt am 24. Dezember 2008</ref> are used as dispersants for pigments, preservatives, polymer stabilizers, as emulsifiers for cosmetics and as [[plasticizer]]s for [[vinyl polymer]]s (in particular [[polyvinyl chloride]], PVC). Isosorbide dioctanoate<ref>{{Cite patent|country = US|number = 2012220507|title = 2,5-Furan dicarboxylate derivatives, and use thereof as plasticizers|gdate =2012-08-30 |fdate = 17 August 2010|invent1 = M. Grass, H.G. Becker | assign1 = Evonik Oxeno GmbH}}</ref> is a diester of isosorbide and [[Octanoic Acid|octanoic acid]] (obtained from [[palm oil]], for example) and therefore made entirely from bio-based building blocks and has been used as Polysorb ID 37 by [[Roquette Frères]] for some time as a particularly non-toxic product.<ref>{{cite web | work = Healthy Building Network | title = Phthalate-free plasticizers in PVC | url = http://www.healthybuilding.net/uploads/files/phthalate-free-plasticizers-in-pvc.pdf }}</ref>

=== Isosorbide ethers ===
Isosorbide ethers (and in particular the simplest representative, 2,5-dimethylisosorbide, abbreviated DMI), are increasingly used as a renewable solvent for cosmetic and pharmaceutical preparations,<ref>{{cite web | work = Grant Industries | url = http://www.dimethylisosorbide.com/about-dimethyl-isosorbide.php | title = About Dimethyl Isosorbid | archive-url = https://web.archive.org/web/20120907234804/http://www.dimethylisosorbide.com/about-dimethyl-isosorbide.php | archive-date = 7 September 2012 }}</ref> as an electrolyte additive for lithium-ion accumulators<ref>US-Patentanmeldung US 2010/0183913 [https://patents.google.com/patent/US20100183913 Lithium cell with iron disulfide cathode and improved electrolyte], invent1: M. Sliger et al., assign1: The Procter & Gamble Co., veröffentlicht am 22. Juli 2010</ref> [18] and as a fuel additive for [[Diesel fuel|diesel]].<ref>US-Patentanmeldung US 2010/0064574A1 [https://patents.google.com/patent/US20100064574 Diesel cycle fuel compositions containing dianhydrohexitols and related products], invent1: R.M. de Almeida, C.R. Klotz Rabello, assign1: Petróleo Brasileiro S.A.-Petrobras, veröffentlicht am 18. März 2010.</ref>

=== Isosorbide phosphates ===
Phosphoric acid derivatives of isosorbide are explored as an environmentally friendly alternative to [[halogen-containing flame retardants]]. So far, [[Hexabromocyclododecane|1,2,5,6,9,10-hexabromocyclododecane]] (HBCD) has been widely used as a  flame retardant in [[Polystyrene|extruded polystyrene foam]] (XPS) in the construction and insulation sector, but it was as SVHC ([[substance of very high concern]]) banned from  manufacturing and application in May 2013. Phosphorus-based isosorbide compounds, such as isosorbide bis (diphenyl phosphate) [ISTP] are considered as a replacement.

[[File:Isosorbid-bis-(diphenylphosphate).svg|center|Isosorbid-bis(diphenylphosphate)]]

ISTP is readily accessible by [[transesterification]] of isosorbide with [[triphenyl phosphate]] in the presence of [[potassium carbonate]] at 150&nbsp;°C. The isosorbide-bis-diphenyl phosphate obtained in 88% yield as a yellowish oil contains about 20% dimers.<ref>Europäische Patentanmeldung EP 2,574,615: [https://patents.google.com/patent/EP2574615A1/de ''Verfahren zur Herstellung von Zucker(thio)phosphaten''], invent1: Ch. Fleckenstein, H. Denecke, assign1: BASF SE, veröffentlicht am 3. April 2013.</ref> The high [[decomposition temperature]] of ISTP allows a use in [[Polystyrene|XPS]], although the high softening effect is a drawback. The flame retardancy is particularly pronounced in the presence of sulfur-containing synergists such as bis(diphenylphosphinothionyl)disulfide (BDPS). This allows to reach the minimum requirement of fire protection (class B2) with only 3% ISTP.<ref>J. Wagner: [http://archiv.ub.uni-heidelberg.de/volltextserver/13576/1/Halogenfreie_Flammschutzmittelmischungen_fuer_Polystyrol_Schaeume.pdf ''Halogenfreie Flammschutzmittelmischungen für Polystyrol-Schäume''] (PDF; 15,5&nbsp;MB), Inauguraldissertation, Universität Heidelberg, Juni 2012.</ref>

=== Polymers from Isosorbide ===
Isosorbide has been examined as a potential platform chemical for the production of diverse polymers and resins.<ref name="Rose" /> The hydroxy groups can be converted into the  primary amino groups<ref name="Rose" /> via the [[tosylate]]s and [[azide]]s or by addition of acrylonitrile followed by hydrogenation into the corresponding aminopropyl derivatives.<ref>US-Patentanmeldung US 2010/0130759A1 [https://patents.google.com/patent/US20100130759 Novel functional compounds with an isosorbide or isosorbide isomer core, production process and uses of these compounds], invent1: J.-P. Gillet, assign1: Arkema Inc., veröffentlicht am 27. Mai 2010</ref> The latter have potential for the preparation of polyurethanes, as [[diamine]]s for the preparation of [[polyamide]]s, and as a [[hardener]] for epoxy resins.

When [[monoethylene glycol]] as a diol is replaced with isosorbide in the polyester [[polyethylene terephthalate]] (PET), [[polyisosorbide terephthalate]] (PIT) is obtained, which is characterized by an extreme thermal stability (up to 360&nbsp;°C under nitrogen). However, the inherently lower reactivity of the secondary hydroxyl groups in isosorbide cause in comparison lower molecular weights and high residual contents of [[terephthalic acid]], which leads to the insufficient chemical stability of the resulting polymers. Therefore, today's polyesters with isosorbide and monoethylene glycol are examined as diol components that show improved properties such as less discoloration.<ref>US-Patentanmeldung US 2006/0173154A1 [https://patents.google.com/patent/US20110077377 Process for making low color poly(ethylene-co-isosorbide) terephthalate polymer], invent1: L. Charbonneau, assign1: E.I. du Pont de Nemours and Company, veröffentlicht am 3. August 2006</ref><ref>{{cite journal | title = Efficiency Increase of Poly (ethylene terephthalate-co-isosorbide terephthalate) Synthesis using Bimetallic Catalytic Systems | year = 2011 | vauthors = Bersot JC, Jacquel N, Saint-Loup R, Fuertes P, Rousseau A, Pascault JP, Spitz R, Fenouillot F, Monteil V | journal = Macromolecular Chemistry and Physics | volume = 212 | issue=19 | pages = 2114–2120 | doi = 10.1002/macp.201100146 }}</ref>

Isosorbide is of also of interest as a precursor to [[polycarbonate]]s.<ref>{{cite journal | vauthors = Hani MA, Chatti S, Kricheldorf HR, Zarrouk H | title = Polycondensation of isosorbide and various diols by means of diphosgene characterization by a combination of MALDI and NMR. | journal = Recent Res. Devel. Organic Chem. | date = 2007 | volume = 11 | pages = 1–11 | url = http://www.trnres.com/ebook/uploads/oca185con/T_1292565005OCA185.pdf | isbn = 978-81-7895-294-9 | access-date = 15 March 2018 | archive-date = 4 March 2016 | archive-url = https://web.archive.org/web/20160304103803/http://www.trnres.com/ebook/uploads/oca185con/T_1292565005OCA185.pdf | url-status = dead }}</ref> It could in principle replace the [[bisphenol A]], which was identified as [[xenoestrogen]]. Limitations of isosorbide-based polycarbonates are their unsatisfactory temperature resistance and limited impact resistance, which can be improved though by the addition of comonomers to the isosorbide or by polymer blends.<ref>US-Patentanmeldung US 2011/0160422A1 [https://patents.google.com/patent/US20110160422 Isosorbide-based polycarbonates, method for making, and articles formed therefrom], invent1: J.H. Kamps et al., assign1: Sabic Innovative Plastics IP BV, veröffentlicht am 30. Juni 2011</ref>

Isosorbide, a diol, is a precursor to In polyurethanes.<ref>PCT-Patent WO 2012/163845 [http://patentscope.wipo.int/search/en/WO2012163845 Fibre composite component and a process for the production thereof], invent1: S. Lindner et al., assign1: Bayer IP GmbH, veröffentlicht am 6. Dezember 2012 (in {{language | nl}})</ref> or as a building block for the polyol<ref>{{cite book | vauthors = Feng X, East AJ, Hammond W, Jaffe M | chapter = Sugar-based chemicals for environmentally sustainable applications. | title = Contemporary Science of Polymeric Materials: A Symposium in honor of Professor Frank E. Karasz on the occasion of his 75th birthday | date = 2010 | pages = 3–27 | publisher = American Chemical Society | isbn = 978-0-8412-2602-9 }}</ref> [29] It could be converted to the diisocyanate component<ref>{{cite journal | vauthors = Bachmann F, Reimer J, Ruppenstein M, Thiem J | journal =[[Macromolecular Chemistry and Physics]]|title=Synthesis of Novel Polyurethanes and Polyureas by Polyaddition Reactions of Dianhydrohexitol Configurated Diisocyanates|volume=202|issue=17|pages=3410–3419|date=2001|language=German|doi=10.1002/1521-3935(20011101)202:17<3410::AID-MACP3410>3.0.CO;2-Q0|doi-broken-date=1 November 2024}}</ref> as well as a chain extender.<ref>US-Patentanmeldung US 2011/0015366 A1 [https://patents.google.com/patent/US20110015366 Novel chain extenders for polyurethane elastomer formulations], invent1: G. da Costa et al., veröffentlicht am 20. Januar 2011</ref>

By reacting isosorbide with [[epichlorohydrin]], isosorbide bis-glycidyl ether<ref>US-Patent US 7,619,056B2 [https://patents.google.com/patent/US7619056 Thermoset epoxy polymers from renewable resources], invent1: A.J. East et al., assign1: New Jersey Institute of Technology, erteilt am 17. November 2009</ref> (a bis-epoxide) is formed, which could be used as a replacement for the analog bisphenol A bis-epoxide. Isosorbide bis-glycidyl ether can be crosslinked to a thermosetting epoxy resins with suitable curing agents, such as polyamines or cyclic [[acid anhydrides]]. These resins are used as adhesives, paints or coatings for food cans.<ref>Press Release NEWARK, 24 February 2010: [http://www.njit.edu/news/2010/2010-053.php NJIT Patent May Be Able To Replace BPA; Make Consumer Products Safer] {{Webarchive|url=https://web.archive.org/web/20100707074643/http://www.njit.edu/news/2010/2010-053.php |date=7 July 2010 }}</ref> Furthermore, polyoxazolidones are described which can be obtained by reaction of isosorbide diglycidyl ethers with diisocyanates.<ref>US-Patentanmeldung US 2010/0298520A1 [https://patents.google.com/patent/US20100298520 Polyoxazolidones derived from dianhydrohexitols], invent1: A.J. East et al., assign1: New Jersey Institute of Technology, veröffentlicht am 25. November 2010</ref> Polyoxazolidones could find use as rigid, highly branched and solvent-resistant thermoset plastics in the electrical and electronics industry.

==Production==
[[Hydrogenation]] of glucose gives [[sorbitol]]. Isosorbide is obtained by acid-catalyzed [[dehydration reaction|dehydration]] of D-[[sorbitol]] which yields the monocyclic furanoid [[sorbitan]],<ref name="Rose" /> which in turn forms by further dehydration the bicyclic furofuran derivative isosorbide.<ref>{{Cite patent |country=US |number=9120806 |title=Dianhydrosugar production process |gdate=2015-09-01 |invent1=David James Schreck, Marion McKinley Bradford, Nye Atwood Clinton, Paul Aubry |assign1=Iowa Corn Promotion Board}}</ref>

[[File:Sorbitol-Sorbitan-Isosorbid.svg|upright|1,4-Sorbitan aus <small>D</small>-Sorbit und Weitereaktion zum Isosorbid]]

The reaction gives about 70 to 80% isosorbide in addition to 30 to 20% of undesirable by-products which have to be removed costly by distillation, recrystallization from alcohols, recrystallization from the melt,<ref>{{Cite patent |country=US |number=6670033 |title=Process and products of purification of anhydrosugar alcohols |gdate=2003-12-30 |inventor = Hubbard MA, Wohlers M, Witteler HB, Zey EG, Kvakovszky G, Shockley TH, Charbonneau LF, Kohle N, Rieth J |assign1=E.I. du Pont de Nemours and Company}}</ref> by a combination of these methods or by deposition from the vapor phase.<ref name="Bhatia">{{Cite patent |country=US |number=6867296 |title=Recovery and purification of anhydro sugar alcohols from a vapor stream |gdate=2005-03-15 |inventor = Bhatia KK |assign1=E.I. du Pont de Nemours and Company}}</ref> A high purity product (> 99.8%<ref name="Bhatia" />) is essential for the use of a monomer when uncoloured, high molecular weight polymers shall be obtained.

== Properties ==
Isosorbide is a white, crystalline, highly hydrophilic solid. The two secondary hydroxy groups in the V-shaped bicyclic system possess different orientations leading to different chemical reactivities. This allows a selective monoderivatization of isosorbide. The hydroxy group in 5-position is [[Endo-exo isomerism|''endo'' oriented]] and forms a [[hydrogen bond]] with the oxygen atom in the adjacent furan ring. This makes the hydroxy group in 5-position more nucleophilic and more reactive than the ''exo'' oriented hydroxy group in 2-position; however, it is more shielded from the attack of sterically demanding reactants.<ref>{{cite journal | vauthors = Flèche G, Huchette M | title = Isosorbide. Preparation, properties and chemistry. | journal = Starch | date = 1986 | volume = 38 | issue = 1 | pages = 26–30 | doi = 10.1002/star.19860380107 | language=German }}</ref>

=== Safety ===
With an LD<sub>50</sub> value of 25.8 g·kg<sup>−1</sup> (rat, oral<ref name="ACROS">{{cite web|author=Datenblatt |url=https://www.acros.com/DesktopModules/Acros_Search_Results/Acros_Search_Results.aspx?search_type=ProductNumber&SearchString=351910050 |title=Isosorbide|work=Acros|accessdate=6 January 2013}}</ref>), isosorbide is similarly nontoxic as D-glucose (also with an LD<sub>50</sub> of 25.8 g·kg<sup>−1</sup>, rat, oral<ref>{{cite web|author=Datenblatt |url=https://www.carlroth.com/downloads/sdb/de/X/SDB_X997_DE_DE.pdf|title= D-Glucose|publisher={{ill|Carl Roth (Unternehmen)|de|lt=Carl Roth}}|accessdate=24 August 2010}}</ref>) and is classified by the [[Food and Drug Administration]] FDA as GRAS ("[[generally recognized as safe]]").<ref>{{cite journal | vauthors = Feng X, East A, Hammond W, Ophir Z, Zhang Y, Jaffe M | title = Thermal analysis characterization of isosorbide-containing thermosets: Isosorbide epoxy as BPA replacement for thermosets industry. | journal = Journal of Thermal Analysis and Calorimetry | date = September 2012 | volume = 109 | issue = 3 | pages = 1267–1275 | doi = 10.1007/s10973-012-2581-2 | s2cid = 94674402 }}</ref>

==References==
{{reflist}}

[[Category:Antianginals]]
[[Category:Diols]]
[[Category:Furofurans]]
[[Category:Multiple Chemboxes|X]]