Ammonium hydrobromide

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

The methylation of 51.4 parts by weight of D,L-3-hydroxy-N-methyl-morphinan is carried out with a methylating solution obtained from 51.5 parts by weight of phenyl-trimethyl-ammonium-chloride. The D,L-3-methoxy-N-methyl-morphinan is isolated in the form of its hydrobromide, which melts with 1 mol of water at 92°-94°C, without water at 239°-240°C. The base isolated from the aqueous solution by means of sodium carbonate melts at 81°-83 C. 

A) Preparation of 4-Acetyl-7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-5H-1,4-Bemodiazepin-5-one A mixture of 68.5 g (0.37 mol) of 5-chloro-N-methylanthranilic acid, 51 g (0.51 mol) of calcium carbonate, 76 g (0.37 mol) of bromoethylamine hydrobromide and 2.5 liters of water was stirred and heated under reflux for 3 hours. A solution of 23.4 g (0.26 mol) of anhydrous oxalic acid in 250 ml of water was slowly added to the refluxing mixture. The precipitated calcium oxalate was filtered off, and the filtrate adjusted to pH 7 with concentrated ammonium hydroxide. The filtrate was then concentrated to dryness in vacuo and the residue heated on the steam bath with 400 ml of 6 N ethanolic hydrogen chloride until the residue was crystalline. Filtration gave 122 g of N-(aminoethyl)-5-chloro-N-methylanthranilic acid hydrochloride as a solid. 

As these solid agents, some quaternary ammonium tribromides such as pyridinium hydrobromide perbromide (ref. 1), phenyltrimethylammonium tribromide (ref. 2), tetramethylammonium tribromide (ref. 3), and tetrabutyl-ammonium tribromide (ref. 4) have already been reported as mild and selective brominating agents (Fig. 1). 

Hydrobromide. A complex process takes place in the first step of weight loss of melamine hydrobromide (250-400 C) as shown by the DTG curve of Figure 6. The products evolved in this step were shown to be a mixture of melamine hydrobromide (IR) and ammonium bromide (IR and X-ray). The IR spectrum of the residue (55% at 400 0 which is compared with the original salt in Figure 7, is identical with that of reference melam hydrobromide. Furthermore, the IR of the residue... 

Melam hydrobromide undergoes thermal degradation between 450-550 0 (2nd step, Figure 6) with complete elimination of bromine either through evolution of ammonium bromide, which is the major product, or melamine hydrobromide as shown by IR. Also a small amount of free ammonia is evolved in this step in which melon is formed as shown by the IR of the residue at 550 0 (ca. 35% of original melamine hydrobromide). 

Similarly to melamine hydrobromide, in the second step of weight loss (370-450 0, Figure 8), IR data show that melam nitrate evolves further ammonium nit rate,ammonia and melamine nitrate giving melon which decomposes completely to volatile products above 500 C. The degradation scheme is then ... 

Ammonia is evolved here in the condensation process of melamine to melam whereas the respective ammonium salts are evolved in the case of the hydrobromide and nitrate. Reactions 9 and 9b show that ammonia should be neutralised by pyrosulphuric acid groups. In TG we have found that diammonium pyrosulphate eliminates ammonia above 350 C, with however complete decomposition ... 

The residue consists of a syrup (largely glycine hydrobromide) mixed with crystals of ammonium bromide. It has a strong odor of formaldehyde. 

A further small quantity of impure glycine can be isolated by concentrating the filtrates obtained on recrystallization. The liquors from the first precipitation, containing ammonium bromide, pyridine hydrobromide, excess pyridine, and alcohol-soluble by-products, may be treated as follows The mixture is first acidified with mineral acid and the methyl alcohol recovered by distillation with a column. The residue is rendered strongly alkaline and the bulk of the ammonia removed by boiling under a reflux condenser wet pyridine can be recovered by downward distillation and treatment of the distillate with solid sodium hydroxide. 

Of the procedures cited in Section 3, procedures (1), (3), and (4) have been examined by the submitters for comparison with the present procedure. Of these, the present procedure and that based on the Delepine reaction (1) appeared to be the most satisfactory for preparative purposes. Yields by the two procedures were comparable however, the Delepine reaction could be run somewhat more conveniently on a larger scale (provided that one was willing to accept a tedious extraction of the product from the copious quantity of ammonium salts with which it is mixed). The Delepine reaction also makes a lesser demand on the skill and technique of the operator. On the other hand, attempts in the submitters laboratory to extend the Delepine reaction to sec-bromides have been unsuccessful therefore the Delepine reaction appears to lack the generality of the present procedure, which shares such generality, apparently, with procedures (2), (3), (7). and (8). Furthermore, the Delepine reaction gives a mixture of phenacylamine hydrochloride and hydrobromide M0 (although the submitters have found that by careful fractional crystallization from isopropyl alcohol-hydrochloric acid solution about 50% of the pure hydrochloride can be obtained). 

A mixture of 4 parts of 2-iminothiazoline, 8.3 parts of bromomethyl-2-thienylketone and 40 parts of absolute ethanol is stirred and refluxed for 2 hours in a water-bath. After cooling, the precipitated hydrobromide is filtered off. From this salt the free base is liberated on treating with ammonium hydroxide solution and it is extracted with chloroform. The organic extract is separated, treated with activated charcoal, filtered and the filtrate is first dried over magnesium sulfate and then evaporated. The solid residue is recrystallized from 24 parts 2-propanol, to yield 2-imino-3-[(2-thienylearbonyl)-methyl]-thiazoline MP 117.5°-118.5°C. 

To a stirred mixture of 13 parts of 2-(acetylimino)-3-(2-thienylcarbonyl)methyl]thiazoline hydrobromide and 64 parts of ethanol are added portion wise 3 parts of sodium borohydride (exothermic reaction). After the addition is complete, the whole is stirred and refluxed for one hour. The solvent is evaporated. The solid residue is dissolved in hydrochloric acid 4 N. After keeping at room temperature, it crystallizes again. The solid is filtered off and dissolved in water. The aqueous solution is rendered alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract is dried over magnesium sulfate and evaporated. The solid residue is recrystallized twice first from 4-methyl-2-pentanone and once more from 400 parts of water. After drying in vacuum, DLI-2-(acetylimino)-3-[2-hydroxy-2-(2-thienyl)ethyl]thiazoline is obtained MP 132.5°-133°C. 

To a stirred slurry of 63.47 g (0.177 mole) of 3 -[(2-imino-3-thiazolidinyl) acetyl]acetanilide hydrobromide in 1 L of 95% ethanol, maintained at 5°C, is added 5.70 g (0.15 mole) of sodium borohyride. After stirring 40 min an additional 4.10 g of sodium borohydride is added and the mixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue is partitioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 6.77 g (48%) of 3 -[l-hydroxy-2-(2-imino-3-... 

A mixture of 3.44 g (9.63 mmoles) of 4-(2-di-n-propylaminoethyl)-7-hydroxy-2(3H)-indolone hydrobromide (U. S. Pat. No. 4,314,944), 22 cc of dimethylformamide, 1.79 g (9.91 mmoles) of 5-chloro-l-phenyl-lH-tetrazole, 220 cc of acetone, 10 cc of water and 2.90 g (21 mmoles) of anhydrous potassium carbonate was refluxed for about 3 hours at which time thin layer chromatographic analysis (silica gel GF, 75-23-2 ethyl acetate-methanol-conc. ammonium hydroxide) indicated that the reaction was complete. 

The bromination of imidazole derivatives is more complicated. Imidazole, treated with an equimolecular amount of bromine in chloroform, yields, after removal of solvent and boiling the residue with water, 2,4,5-tribromoimidazole hydrobromide, ammonium bromide, and a very small amount of 4,5-dibromoimidazole.92... 

The dicyclopropyl ketimine 198 prepared from the 0,N-cyclopropanone hemiacetal 194 (vide supra, Sect. 4.9, Eq. (62)), heated in xylene with ammonium chloride for 4 hr underwent ring expansion exclusively to the enamine 399 followed by isomerization to the cyclopropyl pyrroline 400. Although further ring expansion was not observed on prolonged heating, 400 was converted to the hydrobromide 401 with anhydrous HBr 2091 which upon heating to 140 °C for 10 min experienced a second cyclopropyl imine rearrangement to provide the pyrrolizidone 403 in 51 % yield, most probably via the HBr adduct 401 by cyclization to the pyrroline 402 followed by acid-induced hydrolysis, Eq. (95) 129). 

Anisodamine hydrobromide Bulk TLC MeOH Aluminum methanol (1% ammonium hydroxide) (98 2) CHClj-dehydrated EtOH Dilute K, CP, other alkaloids, [1138... 

The addition of hydrogen to C-2 (instead of the heteroatoms discussed so far) leads directly to 2-deoxyglycosides. Various sulfonic acids have been used as activators for this purpose, including MsOH [601], CSA [602-604], pTsOH [605], and dehydrated AG50 WX2 resin [606]. In addition to these, triphenylphosphine hydrobromide [607], BCI3 or BBr3 [608], and ceric ammonium nitrate (CAN) [609] are effective for this purpose. 

The synthesis of (+)-cucurbitin (26) may be achieved starting from 1-carbe-thoxy-3-pyrrolidone (180). Reaction of 180 with KCN and ammonium chloride in aqueous methanol gives an adduct which is refluxed with 48% HBr to afford cucur-bitin hydrobromide. Resolution of (+)-cucurbitin with (+)-camphoric acid yields (-) 26-(+)-camphorate (m.p. 195-96°C) from which free base is liberated to give (-)-cu-curbitin (26) [126b]. 

The 1,4-thiazepine 178 was synthesised from 3-aminocrotonitrile 175 and the thiazolidine hydrobromide 176 by heating in acetonitrile or via the thiazolidine 177 by heating in the presence of the proton source, ammonium chloride. Two multistep mechanistic scenarios are proposed for the formation of 178 which hinge on the equilibrium between 176 and its ring opened imino thiol tautomer <05SL239>. 

Quaternary ammonium perhalogenides, being solid compounds, constitute halogen sources which are very convenient to handle. Of the different compounds studied and examples of their use which have been reported, pyridinium hydrobromide perbromide is the most popular. Phenyltrimethyl-ammonium trihromide (PTT), the utility of which was recognized by Marquet and Jacques, has the advantage of high stability and ease of preparation. The procedure herein described is a modification of that of Vorlander and Siebert. ... 

General procedure (cf. Hagemann1150) A solution of the amine in dry ether, CHC13, or benzene is added gradually to the BrCN solution (fume cupboard ). The reaction is exothermic. The mixture of amine and BrCN (1-1.1 moles per moles of amine) may also be warmed on a water-bath. By-products, mostly precipitated when a solvent is used, may contain the hydrobromide of the tertiary amine as well as the quaternary ammonium bromide (see above), the requisite HBr being liberated by olefin formation. When no solvent is used, the reaction mixture is extracted with ether. The unused amine and the salts are removed by shaking the solution of A-substituted cyanamide with dilute aqueous acid. 

Sample preparation 10 mL Urine -I- 500 pL 100 p,g/mL nalorphine hydrobromide in MeOH -I- 1 mL concentrated HCl, heat at 100° for 1 h, cool, add 500 p-L saturated ammonium sulfate solution, adjust pH to 9 with 25% NaOH, dilute to 20 mL with water, add mixture to an Extrelut 20 column, let stand for 10 min, elute with 40 mL dichloromethane isopropanol 85 15. Add the eluate to 3 mL 200 mM HCl, extract, repeat extraction. Combine the aqueous phases and add them to 500 p.L saturated ammonium sulfate solution, adjust pH to 9.2 with 25% NaOH, dilute to 20 mL with water, add to another Extrelut 20 column, let stand for 10 min, elute with 40 mL dichloromethane isopropanol 85 15. Evaporate the eluate to dryness under a stream of nitrogen at 40°, reconstitute the residue in 100 p-L mobile phase, iiyect a 20 p-L aliquot. 

Arecolidine, CgHi302N (80), which is isomeric with arecoline, was isolated in small quantity from the mother liquors from the technical preparation of arecoline hydrobromide (80). It crystallizes from ether as colorless needles, m.p. 105°, but after sublimation the base melts at 110°. It forms stable salts (Table 1) and a methiodide, yellow needles, m.p. 264° (dec.) which behaves towards alkalies as a quaternary ammonium salt. The methiodide may be transformed to a methaurichloride, m.p. 252° (dec.). Arecolidine is not hydrolyzed by alkalies and it was suggested by Emde (80) that it is probably 3,4-dimethoxy-l-methyl-l,2-dihydropyridine. However, the evidence is inadequate to support such a structure. 

The raeemie mixture dl) of l-(p-hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydro-isoquinoline may be obtained exactly in the same manner as described for levorphanol tartrate (in 1 above). This is now resolved to get the J-enantiomorph and then treated with phenyltrimethyl ammonium hydroxide to cause methylation and yield the dextromethorphan base. Treatment of the base with appropriate amount of hydrobromide gives the eorresponding hydrobromide. 

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