- Active oxygen responsive antioxidant nitric oxide donor, and preparation method and application thereof
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The invention relates to the field of medicinal chemistry, and especially relates to an active oxygen responsive antioxidant nitric oxide donor, and a preparation method and application thereof. The donor has a structural formula shown in the specification. The preparation method comprises the following steps: reacting PBAP with CDI to obtain PBAP-CDI; and reacting with ISN under the action of a catalyst to obtain the antioxidant nitric oxide donor. The active oxygen responsive antioxidant nitric oxide donor disclosed by the invention is good in stability and long in half-life period in a physiological environment, can be decomposed and released only under the stimulation of high-concentration active oxygen in inflammatory tissues, and does not generate side effects on normal tissues. Meanwhile, active oxygen can be effectively removed, and the anti-oxidation effect is achieved; and the antioxidant nitric oxide donor can promote the growth of endothelial cells and inhibit the growth of smooth muscle cells, is beneficial to rapid endothelialization of heart and blood vessels, has diversified functions, can be widely applied to drug development, and has popularization and application values.
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Paragraph 0028
(2021/08/14)
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- Synthesis method and application of isosorbide mononitrate
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The invention belongs to the field of medicine synthesis, and discloses a synthesis method and application of isosorbide mononitrate. The synthesis method of the isosorbide mononitrate provided by the invention adopts a one-pot method and comprises the following steps: adding sorbitol into concentrated sulfuric acid, dehydrating and cyclizing, adding nitrate, carrying out nitration reaction, and adding zinc powder to carry out reduction reaction, thereby obtaining the isosorbide mononitrate. The synthesis method has the advantages of simple process flow, high raw material utilization rate and production cost saving. The method is suitable for synthesizing the isosorbide mononitrate, and the obtained isosorbide mononitrate is used for preparing the isosorbide mononitrate for injection.
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Paragraph 0032-0040
(2021/07/14)
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- A 5 - isosorbide Mononitrate preparation method (by machine translation)
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The present invention provides a 5 - isosorbide Mononitrate synthetic method. The method includes the steps of: in order to isosorbide as raw materials, with the nitrates TMSCl nitrating agent in three of the aluminum chloride under the action of selective nitration sorbitan 5 - hydroxyl, completion of the reaction, the reaction liquid is poured into ice water, adjusting the pH value to neutral, filtering precipitation, phase separation, the aqueous phase of the liquid organic solvent extraction, the organic phase into the drying agent and, decolorized with active carbon, concentrated under reduced pressure to dry, to obtain high-purity of 5 - isosorbide Mononitrate. The scheme of this invention mild reaction conditions, nitration high selectivity, after treatment is simple, high product yield and purity, is suitable for industrial production. (by machine translation)
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Paragraph 0020; 0037-0052
(2019/11/14)
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- An Improved Process for Industrial Production of Isosorbide-5-mononitrate: Recycling of Wastes
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Different schemes were studied for the recovery of wastes generated during the industrial production of isosorbide-5-mononitrate (IS-5-MN). For the wastewater, disposal was achieved by hydrolysis of isosorbide-2-mononitrate (IS-2-MN) to the starting material isosorbide (IS) utilizing its alkaline environment, where NaOAc was also recovered effectively in the form of the trihydrate. For the solid waste, two different schemes were investigated: direct crystallization and catalytic hydrogenation. The former afforded useful isosorbide dinitrate (ISDN) efficiently, and the latter provided an efficient and scalable route to synthesize IS-5-MN from ISDN. The combinations of unit operations were evaluated on a 100 kg scale and proved to be feasible and robust. The waste recycling strategy provides an eco-friendly complement for the industrial-scale preparation of IS-5-MN, which minimizes waste emission during the process.
- Zhu, Shi-Guo,Yang, Jiang-Tao,Zhang, Gui-Min,Chen, Cheng-Fu,Zhang, Fu-Li
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supporting information
p. 991 - 995
(2018/08/03)
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- Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors
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The invention belongs to the field of medicine synthesis, and particularly discloses a method for synthesizing 5-isosorbide mononitrate by the aid of micro-channel reactors. The method includes pumping nitrification reagents and isosorbide liquid into the micro-channel reactors and carrying out hybrid reaction; allowing products to flow out from outlets of the micro-channel reactors after the reaction is completely carried out; carrying out after-treatment on the products and separating and purifying the products to obtain the 5-isosorbide mononitrate which is a target product. The method hasthe advantages that the method is short in reaction time and is safe as compared with the traditional processes, and the yield of the 5-isosorbide mononitrate can be greatly increased.
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Paragraph 0048-0078; 0095; 0097
(2018/10/19)
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- A 5 - isosorbide Mononitrate preparation method
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The invention provides a preparation method for isosorbide 5-mononitrate. The preparation method comprises the following steps: with isosorbide dinitrate as a raw materials and Pd/C as a catalyst in a special mixed solvent, carrying out selective hydrogenation reduction on 2-nitro, filtering after reaction, steaming to remove ethyl alcohol in filtrate, extracting residual concentrated liquid through ethyl acetate, washing extracting liquid through dilute acid, washing to be neutral through water, drying through anhydrous magnesium sulfate, filtering to remove a drying agent and steaming to remove ethyl acetate so as to obtain high-purity isosorbide 5-mononitrate. Compared with the prior art, the synthetic method provided by the invention is simple and easy to operate, impurities are easy to remove, the yield and purity are higher, the cost is reduced since the Pd/C and the solvent can be recycled and reused, isosorbide generated through over reduction can be recycled and the preparation method is suitable for industrial production.
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Paragraph 0039; 0040; 0047; 0048
(2017/09/01)
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- Preparation method of 5-isosorbide mononitrate
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The invention provides a preparation method of 5-isosorbide mononitrate. The synthetic method comprises the following steps: selectively nitrating 5-site hydroxyl radicals in a dried organic solvent by taking sorbitan as a raw material and a silver nitrate/sulfoxide chloride system as a nitrating agent, after the reaction is finished, carrying out suction filtration on reaction liquid, filtering precipitates, pouring filtrate into water, washing the filtrate to be neutral, adding a drying agent into an organic phase for drying, carrying out activated carbon decoloration, and carrying out reduced pressure concentration until the liquid is dried, so as to obtain high-purity 5-isosorbide mononitrate. The scheme provided by the invention has the beneficial effects that reaction conditions are mild, the nitrating selectivity is high, post-treatment is simple, the yield and purity of a product are high, and the preparation method is suitable for industrial production.
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Paragraph 0042-0057
(2017/09/01)
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- A 5-isosorbide Mononitrate the synthesis and purification method
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The invention provides a method for synthesizing and purifying 5-isosorbide mononitrate. The method comprises the steps of: (1) preparing a nitrifying reagent from concentrated nitric acid, acetic acid and acetic anhydride, and directly nitrifying isosorbide to obtain an isosorbide nitride mixture; (2) adding water to arouse a quenching reaction, separating out 2,5-isoscrbide dinifrate at a temperature ranging from 0 to 5 DEG C, and filtering out the 2,5-isoscrbide dinifrate; (3) reacting the filtrate with sodium hydroxide to prepare an isosorbide mononitrate sodium salt aquo-complex, filtering, and hydrolyzing the sodium salt; and (4) extracting, concentrating and recrystallizing to obtain high-purity 5-isosorbide mononitrate. The preparation method provided by the invention is simple, safe, easy to operate and short in reaction period; impurities are easy to remove, and the yield and the purity are high; therefore, the method lays a foundation for industrial production.
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Paragraph 0045-0051
(2017/01/23)
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- Synthesis of 2-[18F]Fluoro-2-deoxyisosorbide 5-mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET)
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Herein we disclose the synthesis of 2-fluoro-2-deoxyisosorbide 5-mononitrate (2F-IS-5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). X-ray structural data for IS-5MN and its C2-epimeric congener IM-5MN are presented together with structural data for 2F-IS-5MN. Radioisotope labeling of 2F-IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice. Visualization breakthrough: Herein we disclose the synthesis of a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). Radioisotope labeling of 2F- IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice.
- Santschi, Nico,Wagner, Stefan,Daniliuc, Constantin,Hermann, Sven,Sch?fers, Michael,Gilmour, Ryan
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p. 1724 - 1732
(2015/10/06)
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- VASODILATOR-ENHANCED CARDIOPULMONARY RESUSCITATION
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A method for increasing blood flow to vital organs during cardiopulmonary resuscitation of a person experiencing a cardiac arrest may include performing standard or active compression decompression cardiopulmonary resuscitation on a person to create artificial circulation by repetitively compressing the person's chest such that the person's chest is subject to a compression phase and a relaxation or decompression phase. The method may also include administering one or more vasodilator drugs to the person to improve the artificial circulation created by the cardiopulmonary resuscitation. The method may also include binding at least a portion of the person's abdomen, either manually or with an abdominal compression device. Performing cardiopulmonary resuscitation on a person may include ventilating the person with either an impedance threshold device or a intrathoracic pressure regulator.
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- SYNTHESIS OF ISOSORBIDE MONONITRATE
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A method of synthesising a compound of formula (1), in which each of R and R is independently selected from H or optionally substituted straight or branched chain C1-C30 alkyl, C1-C30 carboxyalkyl, C1-C30 sulphoxyalkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C3-C30 carboxycycloalkyl, C3-C30 sulphoxycycloalkyl, C3-C30 cycloalkoxy, heterocyclic, carboxyheterocyclic, sulphoxyheterocyclic, oxyheterocylic, C3-C30 cycloalkenyl, carboxycycloalkenyl, sulphoxycycloalkenyl or cycloalkenoxy, C8-C30 cycloalkynyl, carboxycycloalkynyl, sulphoxycycloalkynyl or cycloalkynoxy, C2-C30 alkynyl, carboxyalkynyl, sulphoxyalkynyl or alkynoxy group, C4-C30 aromatic, carboxyaromatic, sulphoxyaromatic or aryloxy, C4-C30 heteroaromatic, carboxyheteroaromatic, sulphoxyheteroaromatic or heteroaryloxy group, wherein in any of the hereto atom-containing groups the hetero atom is selected from O, S, and N; comprises treating a compound of formula (2) with a reducing system effective to reduce preferentially the compound of formula (2) at the 2-position to produce the compound of formula (1), wherein the reducing system comprises (i) hydrogen in the presence of a platinum-containing catalyst, or (ii) a hybride source in the presence of a transition metal phthalocyanine or polyphthalocyanine in which the transition metal is iron and/or cobalt.
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- New preparative routes to isosorbide 5-mononitrate
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Three new methods for the preparation of the vasodilator isosorbide 5-mononitrate are described. In the first method enzymatic regioselective acetylation of isosorbide gave isosorbide 2-butyrate. Nitration and deprotection of this material afforded isomerically pure isosorbide 5-mononitrate in high overall yield. Secondly, regioselective hydrogenation of isosorbide dinitrate over platinum oxide (PtO2) furnished the 5-mononitrate in 45% yield. Similarly, regioselective reduction of the dinitrate was achieved using sodium borohydride (NaBH4) activated with cobalt or iron phthalocyanine. All three methods show advantages over existing procedures. The Royal Society of Chemistry 2000.
- Brown, Chris,Marston, Richard W.,Quigley, Paul F.,Roberts, Stanley M.
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p. 1809 - 1810
(2007/10/03)
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- A highly chemoselective reduction of isosorbide-2,5-dinitrate mediated by tetrathiomolybdate
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In an interesting reaction mediated by benzyltriethylammonium tetrathiomolybdate, [(PhCH2NEt3)2MoS4] isosorbide-2,5-dinitrate undergoes selective reduction to isosorbide-5-mono-nitrate in good yield.
- Bhar, Debjani,Chandrasekaran, Srinivasan
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p. 793 - 795
(2007/10/03)
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- Process for the enzymatic production of isomerically pure isosorbide-2 and 5-monoesters as well as their conversion into isosorbide-2- and 5-nitrate
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Process for the enzymatic production of isomerically pure compounds having the general formulae I and II STR1 in which the substituents R have the meanings stated in the claims, as well as their use for the production of isomerically pure isosorbide-2-nitrate having the formula V and isosorbide-5-nitrate having the formula VI, STR2 which are both important as therapeutic agents for coronary diseases.
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- Highly chemoselective reduction of 2,5-dinitro-1,4:3,6-dianhydro-D-glucitol with titanium(III) tetrahydroborates: Efficient synthesis of isomerically pure 2- and 5-nitro-1,4:3,6-dianhydro-D-glucitols
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It has been found that the reduction of 2,5-dinitro-1,4:3,6-dianhydro-D-glucitol (1) with titanium(III) tetrahydroborate (2) (- 78 → 0 °C) affords exclusively 2-nitro-1,4:3,6-dianhydro-D-glucitol (3). On the other hand, reduction of dinitrate 1 with diisopropoxytitanium(III) tetrahydroborate (4) (- 78 → 0 °C) yields 5-nitro-1,4:3,6-dianhydro-D-glucitol (5) as the only product.
- Ravikumar,Chandrasekaran
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p. 1032 - 1034
(2007/10/02)
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- Hydrolases in organic synthesis: Preparation of enantiomerically pure compounds
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Esterhydrolases (Esterases, Lipases) are highly (chemo-, regio- and enantio-) selective biocatalysts for the transformation of racemic and achiral substrates into enantiomerically pure compounds.Numerous examples for their application in the preparation of synthetically useful chiral auxiliaries and building blocks for flavour compounds, pheromones and several pharmaceuticals including β-adrenergic blockers, antidepressants and ACE inhibitors are presented.
- Ader, U,Andersch, P,Berger, M,Goergens, U,Seemayer, R,Schneider, M
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p. 145 - 150
(2007/10/02)
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- Enzymatic preparation of isomerically pure 1,4:3,6-dianhydro-D-glucitol monoacetates - Precursors for isoglucitol 2- and 5-mononitrates
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Using a highly selective lipase from Pseudomonas sp. (SAM II) the isomerically pure title compounds 3 and 4 were prepared either by enzymatic hydrolysis (alcoholysis) of the diacetate 2 or by enzymatic esterification of the diol 1, respectively. They were further converted into the pharmaceutically important, isomerically pure 1,4:3,6-dianhydro-D-glucitol-2- and 5-nitrates 6 and 7.
- Seemayer,Bar,Schneider
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p. 1123 - 1126
(2007/10/02)
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- Method for the preparation of isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate as a precursor thereof
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A novel and efficient method is proposed for the preparation of isosorbide-5-nitrate which is a promising medicinal compound for several diseases due to disorder in heart. The method comprises direct nitration of isosorbide with a concentrated nitric acid in a specific reaction medium containing an aromatic hydrocarbon solvent, e.g. benzene, in addition to conventional acetic acid and acetic anhydride. After neutralization of the reaction mixture and removal of the dinitrate as a byproduct therefrom, the reaction mixture is admixed with an aqueous solution of sodium hydroxide so that a sodium salt of isosorbide-5-nitrate is precipitated in the form of a hydrate, which is a novel compound not known in the prior art. This hydrate sodium salt is then decomposed with an acid to give the desired isosorbide-5-nitrate in a high yield.
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- Process for the preparation of isosorbide-5-nitrate
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In a process for preparing isosorbide-5-nitrate, isosorbide is reacted with an aliphatic carboxylic acid, with the formation of an acylation mixture. The acylation mixture is then nitrated, and the resulting nitration mixture is hydrolyzed and/or transesterified in order to split off acyl groups. The product is used in treatment of angina pectoris.
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- Differences in the production of methemoglobin during high-dose treatment with isosorbide dinitrate or isosorbide 5-mononitrate
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12 patients with coronary heart disease were studied to see whether high doses of isosorbide dinitrate (ISDN, Corovliss) or isosorbide 5-mononitrate (IS-5-MN, Ismo) increase the erythrocyte methemoglobin production in an acute experiment and after 4 days of medication. The patients were divided into two groups. Group 1 (6 patients) was given a single dose of 80 mg ISDN on the morning of day 1 and Group 2 (6 patients) was given 80 mg IS-5-MN as a single oral dose. Under the influence of the IS-5-MN no change was observed from the initial methemoglobin (met-Hb) value (0.81% of the total Hb) at measurements performed 1 and 2 h after the administration of the drug. In Group 1 (ISDN) the initial met-Hb value was 0.58% of the total Hb, a slight increase to 0.70% being observed after 1 h and to 0.77% after 2 h (p0.05). The patients were then treated as follows for a further 4 days: Group 1 480 mg ISDN/d, Group 2 480 mg IS-5-MN/d. On day 5 the initial met-Hb values in both groups were unchanged compared to day 1. The patients were then given first 80 mg ISDN (Group 1) or 80 mg IS-5-MN (Group 2) and 4 h after a single dose of 160 mg of the appropriate substance. In Group 2 (IS-5-MN) the met-Hb content remained unaffected. In Group 1 a slight increase of the met-Hb to 0.79% occurred 1 h after 80 mg ISDN and to 0.9% after 2 h (p0.05). The plasma concentrations of IS-5-MN at the times of the methemoglobin determinations were about half as high during ISDN therapy as during IS-5-MN therapy. The concentrations of unchanged ISDN and of isosorbide 2-mononitrate were respectively about 10-30 and 4-10 times below the IS-5-MN levels. This shows that - in contrast to IS-5-MN - the bulk of the ISDN is already metabolized during absorption or the first liver passage. The nitrite ions thus formed may be responsible for the slight rise of the methemoglobin. Overall, it can be said that therapeutic doses of ISDN approaching the maximum doses effect a slight increase of the met-Hb, although in patients with intact erythrocyte metabolism this is only a little over 1%. No such increase of the met-Hb occurs after equal doses of IS-5-MN.
- Schneider,Stahl,Kaltenbach,Bussmann
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p. 1779 - 1782
(2007/10/02)
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- Process for the production of isosorbide-5-nitrate
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This invention relates to a process for the production of isosorbide-5-nitrate comprising (a) subjecting an acylation mixture of isosorbide containing varying proportions of isosorbide, isosorbide-2-acylate, isosorbide-5-acylate and/or isosorbide-2,5-diacylate, or pure isosorbide-5-acylate or an equimolar mixture of isosorbide-2,5-diacylate and isosorbide to a transacylation reaction in the presence of a catalyst and removing the isosorbide-2-acylate present from the reaction mixture by fractional distillation; (b) optionally subjecting the separated isosorbide-2-acylate to a further purification step; (c) esterifying the obtained isosorbide-2-acylate with nitric acid; and (d) partially hydrolyzing the obtained isosorbide-2-acylate-5-nitrate.
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- Process for selectively producing isosorbide-5-nitrate
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The present invention is related to a new process for selectively preparing isosorbide-5-nitrate (1.4-3.6-dianhydrosorbitol-5-nitrate) by subjecting isomannide (1.4-3.6-dianhydromannitol) in an organic solvent or an aqueous-organic reaction medium to reaction with the equivalent amount of an acid halogenide or the anhydride of a benzene or naphthalene sulfonic acid possibly substituted by lower alkyl, lower alkoxy and/or halogen, of a perfluoro - lower alkane-sulfonic acid, of a lower alkanesulfonic acid or of a perfluoro - lower - alkanoic acid or with the equivalent amount of an acid halogenide of a carbamic acid or of sulphurous acid; subjecting the resulting isomannide-2-ester in the presence of a solvent and possibly with heating, to reaction with an alkali metal salt or an ammonium salt of a benzoic acid possibly substituted by lower alkyl, lower alkoxy and/or halogen or of a lower alkanoic acid; converting the hydroxy group in the 5-position of the resulting isosorbide-2-ester into the nitric acid ester group in manners known per se by reaction with nitric acid; and subjecting the resulting isosorbide-2-ester-5-nitrate to selective hydrolysis and/or reesterification in an organic or aqueous-organic solvent with an alkali metal hydroxide in manners known per se.
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