87-33-2

Basic information

• Product Name: Isosorbide dinitrate
• Synonyms: 1,4:3,6-dianhydro-,dinitrate,d-glucito;1,4:3,6-dianhydro-d-glucitodinitrate;1,4:3,6-dianhydrosorbitol2,5-dinitrate;cardis;carvanil;carvasin;cedocard;claodical
• CAS NO: 87-33-2
• Molecular Formula: C₆H₈N₂O₈
• Molecular Weight: 236.14
• EINECS: 201-740-9
• Product Categories: chiral;Nitric Oxide Reagents;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 87-33-2.mol

Chemical Properties

• Melting Point: 700C
• Boiling Point: 378.59°C (rough estimate)
• Flash Point: 186.6 °C
• Appearance: White crystalline powder
• Density: 1.7503 (rough estimate)
• Vapor Pressure: 3.19E-05mmHg at 25°C
• Refractive Index: 1.5010 (estimate)
• Storage Temp.: -20?C Freezer
• Solubility: Undiluted isosorbide dinitrate is very slightly soluble in water, very soluble in acetone, sparingly soluble in ethanol (96 per cent). The solubility of the diluted product depends on the diluent and its concentration.
• Water Solubility: 549.7mg/L(25 oC)
• CAS DataBase Reference: Isosorbide dinitrate(CAS DataBase Reference)
• NIST Chemistry Reference: Isosorbide dinitrate(87-33-2)
• EPA Substance Registry System: Isosorbide dinitrate(87-33-2)

Safety Data

• Hazard Codes: Xn
• Statements: 5-22
• Safety Statements: 36
• RIDADR: UN 2907
• HazardClass: 1.1A
• PackingGroup: II
• Hazardous Substances Data: 87-33-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Isosorbide dinitrate is used as an antianginal agent for the prevention of angina pectoris attacks in patients with chronic cardiac insufficiency. Its long-lasting action provides sustained relief and management of angina symptoms.
Used in Cardiovascular Therapy:
As a nitric oxide (NO) donor, Isosorbide dinitrate is utilized to enhance the production of nitric oxide in the body, which in turn promotes vasodilation. This action helps to improve blood flow and reduce the workload on the heart, offering therapeutic benefits for individuals suffering from various cardiovascular conditions.

Originator

Isordil,Ives,US,1959

Manufacturing Process

An aqueous syrup of 1,4:3,6-dianhydro-D-glucitol is slowly added to a cooled mixture of HNO3 and H2SO4. After standing a few minutes the mixture is poured into cold water and the precipitated product is collected and recrystallized from ethanol.

Air & Water Reactions

Highly flammable. Slightly soluble in water.

Reactivity Profile

Nitroalkanes, such as Isosorbide dinitrate, range from slight to strong oxidizing agents. If mixed with reducing agents, including hydrides, sulfides and nitrides, they may begin a vigorous reaction that culminates in a detonation. Nitroalkanes are milder oxidizing agents, but still react violently with reducing agents at higher temperature and pressures. Nitroalkanes react with inorganic bases to form explosive salts. The presence of metal oxides increases the thermal sensitivity of nitroalkanes. Nitroalkanes with more than one nitro group are generally explosive. Nitroalkanes are insoluble in water. This heart drug is detonable when dry, but non-explosive with 30% of water.

Health Hazard

Fire may produce irritating and/or toxic gases. Contact may cause burns to skin and eyes. Contact with molten substance may cause severe burns to skin and eyes. Runoff from fire control may cause pollution.

Fire Hazard

Flammable/combustible material. May be ignited by friction, heat, sparks or flames. Some may burn rapidly with flare burning effect. Powders, dusts, shavings, borings, turnings or cuttings may explode or burn with explosive violence. Substance may be transported in a molten form at a temperature that may be above its flash point. May re-ignite after fire is extinguished.

Clinical Use

Vasodilator: Prophylaxis and treatment of angina Left ventricular failure

Safety Profile

Moderately toxic by ingestion, intraperitoneal, intramuscular, and subcutaneous routes. Experimental reproductive effects. Mutation data reported. A flammable solid. When heated to decomposition it emits toxic fumes of NOx. A coronary vasodilator. See also NITRATES.

Synthesis

Isosorbiddinitrate, 1,4:3,6-dianhydrosorbate-2,5-dinitrate (19.1.4), is synthesized by intermolecular dehydration of D-sorbite into isosorbide (19.1.3) using paratoluenesulfonic acid and subsequent nitration of the two hydroxyl groups by nitric acid.

Veterinary Drugs and Treatments

Isosorbide mononitrate (ISMN) and dinitrate (ISDN) are organic nitrates potentially useful as preload reducing agents in treating heart failure in small animals, however, research and clinical experience demonstrating clinical efficacy are lacking in dogs or cats. Limited research indicates that dogs may require much higher dosages of isosorbide dinitrate to achieve therapeutic effects than do humans. In humans, isosorbide nitrates are used for treating or preventing angina, treating esophageal spasm, and as an adjunctive treatment in CHF.

Drug interactions

Potentially hazardous interactions with other drugs Avanfil, sildenafil, tadalafil, vardenafil: hypotensive effect significantly enhanced - avoid concomitant use. Riociguat: avoid concomitant use due to risk of hypotension.

Metabolism

Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver. It is taken up by smooth muscle cells of blood vessels and the nitrate group is cleaved to inorganic nitrite and then to nitric oxide. It is also rapidly metabolised in the liver to the major active metabolites isosorbide 2-mononitrate and isosorbide 5-mononitrate. Isosorbide mononitrate is metabolised to inactive metabolites, including isosorbide and isosorbide glucuronide. Only about 2% of isosorbide mononitrate is excreted unchanged in the urin

InChI:InChI=1/C6H8N2O8/c9-7(10)15-3-1-13-6-4(16-8(11)12)2-14-5(3)6/h3-6H,1-2H2/t3-,4+,5-,6-/m1/s1

Synthetic route

Isosorbide (652-67-5) → isosorbide dinitrate (87-33-2)

Conditions	Yield
With nitric acid; acetic anhydride In acetic acid at 5 - 10℃; for 2h;	92%
With nitric acid In acetic anhydride; acetic acid at 5 - 10℃; for 2h; Nitration;	92%
With sulfuric acid; nitric acid
With nitric acid; acetic anhydride; acetic acid at 20℃; for 0.0194444h; Flow reactor;	92 %Chromat.

Isosorbide (652-67-5) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + isosorbide dinitrate (87-33-2)

Conditions	Yield
Stage #1: Isosorbide With nitric acid; acetic anhydride; acetic acid at 0 - 12℃; for 6h; Stage #2: With sodium hydroxide at -5℃; for 1h; pH=13; Temperature;	A 41.53% B n/a

Isosorbide (652-67-5) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + isosorbide-2-mononitrate (16051-77-7) + isosorbide dinitrate (87-33-2)

Conditions	Yield
With nitric acid; acetic anhydride
With nitric acid; acetic anhydride In 2-methyltetrahydrofuran; acetic acid at -10℃; for 0.0105556h; Temperature; Solvent; Flow reactor; Overall yield = 65.5 %;	A 214.2 g B n/a C n/a
With nitric acid; acetic anhydride In 2-methyltetrahydrofuran; acetic acid at -10℃; for 0.0105556h; Temperature; Solvent; Flow reactor; Overall yield = 49.4 %;	A 161.5 g B n/a C n/a

isosorbide dinitrate (87-33-2) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + Isosorbide (652-67-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; triethylamine In ethanol; water at 0℃; under 2250.23 Torr; for 12h; Autoclave;	A 81.55% B 16.1%

isosorbide dinitrate (87-33-2) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; diethylamine In ethanol; water at 0℃; under 2250.23 Torr; for 12h; Catalytic behavior; Temperature; Pressure; Reagent/catalyst; Autoclave;	78.11%
With benzyltriethylammonium tetrathiomolybdate In N,N-dimethyl-formamide at 20℃; for 30h; Hydrolysis;	70%
With titanium(IV) dichlorodiisopropylate; Benzyltriethylammonium borohydride In dichloromethane at -78 - 0℃; for 2h;	57%
Multi-step reaction with 4 steps 1: NaBH4; cobalt phthalocyanine / methanol / 0.17 h 2: 62 percent / Subtilisin Carlsberg / tetrahydrofuran / 26 h 4: Na2CO3 / methanol View Scheme

isosorbide dinitrate (87-33-2) → isosorbide-2-mononitrate (16051-77-7)

Conditions	Yield
With Benzyltriethylammonium borohydride; titanium tetrachloride In dichloromethane at -78 - 0℃; for 2h;	71%
With iron(II) sulfate; water In methanol at 20℃; Reflux;	69.65%

isosorbide dinitrate (87-33-2) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + isosorbide-2-mononitrate (16051-77-7) + Isosorbide (652-67-5)

Conditions	Yield
With sodium tetrahydroborate; cobalt(II) phthalocyanine In methanol for 0.166667h; Reduction;	A 52% B n/a C n/a

isosorbide dinitrate (87-33-2) → isosorbide mononitrate (16106-20-0, 16908-90-0, 16908-91-1, 35993-37-4, 38709-03-4, 114718-64-8, 127001-76-7, 16051-77-7) + isosorbide-2-mononitrate (16051-77-7)

Conditions	Yield
metabolism study in patients with coronary heart desease after dosage of 80 mg p.o.;

isosorbide dinitrate (87-33-2) → isosorbide 2-O-butanoate (84207-83-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4; cobalt phthalocyanine / methanol / 0.17 h 2: 62 percent / Subtilisin Carlsberg / tetrahydrofuran / 26 h View Scheme

isosorbide dinitrate (87-33-2) → isosorbide 2-butyrate-5-mononitrate

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBH4; cobalt phthalocyanine / methanol / 0.17 h 2: 62 percent / Subtilisin Carlsberg / tetrahydrofuran / 26 h View Scheme

Upstream product

• 652-67-5 Isosorbide 

Downstream Products

• 16106-20-0 isosorbide mononitrate 
• 16051-77-7 isosorbide-2-mononitrate 
• 652-67-5 Isosorbide 

Relevant articles and documents

METHOD FOR PREPARING NITRATE ESTER

A method for preparing a nitrate ester is provided. The method includes providing a first solution including a compound (which has at least one hydroxyl group) and a carboxylic acid having 2-5 carbon atoms; providing a second solution including nitric acid, acetic anhydride, and acetic acid; and transferring the first solution and the second solution to a microreactor, obtaining a nitrate ester after a residence time. In particular, the ratio of the weight of nitric acid to the total volume of the acetic anhydride and acetic acid is 1:1 to 1:3.5. The ratio of the molar amount of nitric acid to the hydroxyl group equivalent of the compound is from 1:1 to 15:1.

An Improved Process for Industrial Production of Isosorbide-5-mononitrate: Recycling of Wastes

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.

Method for synthesizing 5-isosorbide mononitrate by aid of micro-channel reactors

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.

NANOEMULSIONS HAVING REVERSIBLE CONTINUOUS AND DISPERSED PHASES

A nanoemulsion having reversible continuous and dispersed phases. The nanoemulsion includes an aqueous phase and an oil phase, a weight ratio of the aqueous phase to the oil phase being 1:40-100:1. In the nanoemulsion, the aqueous phase is dispersed as nanosized droplets in the oil phase or the oil phase is dispersed as nanosized droplets in the aqueous phase. The aqueous phase contains water or a water solution and a water-soluble organic nanostructure stabilizer. The oil phase contains an oil or an oil solution, an organic gel thickener, and a hydrophilic surfactant having a hydrophilic-lipophilic balance value greater than 8.0. Also disclosed is a method for preparing the above-described nanoemulsion.

A 5-isosorbide Mononitrate the synthesis and purification method

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.

VASODILATOR-ENHANCED CARDIOPULMONARY RESUSCITATION

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.

SYNTHESIS OF ISOSORBIDE MONONITRATE

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.

A highly chemoselective reduction of isosorbide-2,5-dinitrate mediated by tetrathiomolybdate

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.

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

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.

Pharmaceutical preparations and a method of manufacturing them

A sustained-release composition, which comprises (a) a substance which forms a gel in water, (b) a fat and/or oil which is solid at room temperature and (c) a pharmaceutical, said composition having a specific gravity of not more than about 1.