Mannitol dehydration

The osmotic diuretics are contraindicated in patients with known hypersensitivity to the drags, electrolyte imbalances, severe dehydration, or anuria and those who experience progressive renal damage after instituting therapy (mannitol). Mannitol is contraindicated in patients with active intracranial bleeding (except during craniotomy). 

Sugihara and Schmidt49 reported the isolation of 2,5-anhydro-D-glucitol in crystalline form its preparation on a relatively large scale has been described in the patent literature,50 and consists in the thermal dehydration of D-mannitol. The process leads to the formation of 1,4-anhydro-D-mannitol, 1,5-anhydro-D-mannitol, 1,4 3,6-dianhydro-D-mannitol, and 2,5-anhydro-D-glucitol, which is isolated as the crystalline 1,3-O-isopropyIidene derivative (35). 

Anhydro-D-mannitol is also obtained by a novel route from 1,6-dibenzoyl-D-mannitol. When this compound is heated with p-tolu-enesulfonic acid in acetylene tetrachloride, it suffers partial dehydration and one of the products is a dibenzoyl derivative of mannitan. On debenzoylation of this substance it yields crystalline 1,4-anhydro-D-mannitol.67 The formation of dibenzoyl-1,4-anhydro-D-mannitol has involved the migration of at least one benzoyl group and Hockett and coworkers6 believe that the initial product is either 2,6- or 3,6-dibenzoyl-1,4-anhydro-D-mannitol. 

Crystalline 1,4-anhydro-D-sorbitol is of much more recent origin than 1,4-anhydro-D-mannitol, inasmuch as its preparation was first recorded in 1946.10 It was obtained by the restricted dehydration of D-sorbitol and has been given the trivial name arlitan. Two groups of workers simultaneously effected proof of its constitution. Hockett and coworkers11 treated the anhydride with lead tetraacetate and since its rate of oxidation coincided with that of ethyl D-galactofuranoside and since one molecular proportion of formaldehyde was formed, the authors concluded that the ring must involve Cl and C4 of a hexitol chain. Assuming that no other carbon atoms are involved, sorbitan is either 1,4-anhydro-D-sorbitol or 1,4-anhydro-D-dulcitol (Walden inversion at C4 of the sorbitol molecule). They therefore synthesized 3,6-anhydro-D-dulcitol (enantio-morphous with 1,4-anhydro-L-dulcitol) but found it to be different from arlitan. 

Summarizing, it appears that D-mannitol with boiling hydrochloric acid first suffers dehydration between Cl and C4 (because when the treatment is interrupted after only a few hours duration, 1,4-anhydro-D-mannitol is obtained), then between C3 and C6. The dehydration is probably achieved by the catalytic influence of the chloride ion. Dehydration is accompanied by the formation of smaller amounts of other ring compounds and by substitution of secondary hydroxyl groups by chlorine. With fuming hydrochloric acid, D-mannitol gives mainly 1,6-dichloro-... 

The simultaneous preparation of both isosorbide and isomannide from sucrose has been achieved.57 This process entailed the hydrogenation of sucrose to a mixture of D-mannitol and D-sorbitol and the subjection of this mixture to dehydration in the presence of acid catalysts followed by fractional distillation.68... 

Exubera (see also Exhibit 4.14) Exubera is an inhalable insulin for the treatment of type I and II diabetes. Each dose consists of 1 or 3 mg insulin in a powder formulation with sodium citrate (dehydrate), mannitol, glycine, and sodium hydroxide. 

Isomannide or 1,4 3,6-dianhydromannitol (IV) is an isomer of isosorbide. It has been prepared by dehydration of mannitol (V) according to a procedure similar to that for the preparation of isosorbide (6) which has been described previously. 

A development of some promise lies in the dehydration of mannitol and sorbitol to give anhydro compounds. Mannitol can be dehydrated to give 1,4-anhydro-mannitol (XIII) (mannitan) and isomannide, shown to be 1,4 3,6-dianhydro-mannitol (XIV) by Wiggins. Similarly,... 

Mannitol (OsmitroL others) [Osmotic Diuretic] Uses Cerebral edema, T lOP/ICP, renal impair, poisonings Action Osmotic diuretic Dose Test dose 0.2 g/kg/dose IV over 3-5 min if no diuresis w/in 2 h, D/C Oliguria 50-100 g IV over 90 min T lOP 0.5-2 g/kg IV over 30 min Cerebral edema 0.25-1.5 g/kg/dose IV >30 min Caution [C, ] w/ CHF or volume overload Contra Anuria, dehydration, HE, PE Disp Inj SE May exacerbate CHF, N/V/D Interactions t Effects OF cardiac glycosides X effects OF barbiturates, imipramine, Li, salicylates EMS Monitor ECG for hypo-/hyperkalemia (T wave changes) OD May cause dehydration, t urine frequency/amount hypotension and CV collapse symptomatic and supportive... 

Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatremia. As water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalemia. 

Isosorbide and isomannide are important by-products of the starch industry, arising from dehydration of D-sorbitol and D-mannitol. These commercial starting materials provide an easy and inexpensive access to optically pure functionalized tetrahydrofurans like 04,05-isopropylidene-1-iodo-3,6-anhydro-1-deoxy-D-glucitol and 04,05-isopropylidene-l-iodo-3,6-anhydro-1-deoxy-Q-mannitol. This procedure describes a preparation of the former compound and the epoxide derived therefrom. 

Peds. Cardiac arrest w/ torsades 25-50 mg/kg/dose IV Caution [B, +] Contra Heart block Disp Inj 10, 20, 40, 80, 125, 500 mg/mL bulk powder SE CNS depression, D, flushing, heart block Interactions T CNS depression W/ antidepressants, antipsychotics, anxiolytics, barbiturates, hypnodcs, narcotics EtOH T neuromuscular blockade W/ aminoglycosides, atracurium, gallamine, pancuronium, tubocurarine, vecuronium EMS Monitor ECG for changes Mannitol (Osmitrol) [Osmotic Diuretic] Uses Tx cerebral edema (T ICP) Action Diuretic Dose Adults. 0.5-2 g/kg slow IV Peds. 0.2-0.5 g/kg IV over 60 min Caution [C, ] Contra Pulm edema, CHF, cerebral bleeding Disp Inj, sol 5% (50 mg/mL) 10% (100 mg/mL) 15% (150 mg/mL) 20% (200 mg/mL) 25% (250 mg/mL) SE N/V, HA, dizziness, edema, blurred vision, diuresis, dehydration Interactions Interferes w/ blood transfusions EMS Use caution to prevent extravasation (use large vein) rebound T in ICP has been noted about 12 h post administration... 

Dehydration of mannitol with formic acid yields 2-methylpyran (20LA(422)133). 

Esterification is effected in the cold in presence of alkali or by heating the alcohol and anhydride together, usually in presence of a dehydrating agent—e.g., fused zinc chloride, anhydrous sodium acetate, etc. Preparation 204.—Mannitol Hexacetate. 

During gas-liquid chromatographic-mass spectrometric analysis of the acid-catalyzed dehydration reaction of D-mannitol, 1,4 3,6-dianhydro-2-chloro-2-deoxy-D-mannitol was found among the reaction products.35 Contrary to the postulated Sn2 mechanism, according to which 2,5-di-endo oriented leaving-groups are substituted by different nucleophiles, resulting... 

---