Ammonium chloride, 523 reaction

The synthesis of losartan potassium (1) by the process research chemists at Merck is outlined in the following (Griffiths et ak, 1999 Larsen et al., 1994). Phenyltetrazole (8) is protected as the trityl phenyltetrazole 9 (Scheme 9.3). Ortho-lithiation of 9 followed by quenching with triisopropyl borate afforded boronic acid 10 after treatment with aqueous ammonium chloride. Reaction of glycine (11) with methyl pentanimidate (12) in a methanol/water mixture yielded (pentanimidoylamino) acetic acid (13), which underwent a Vilsmeier reaction with phosphorous oxychloride in DMF followed by hydrolysis to give imidazole-4-carbaldehyde 14 in moderate yield. 

Other preparations include the treatment of KNO2-AICI3 melts with ammonium chloride, reaction of nitric acid with HCl in aqua regia, or the reactions of metal chlorides with nitric acid. 

Notice the diversity in structure of lhe.se proton dunurs. They include the classical hydrochloric acid (reaction a). Ihc weakly acidic dihydrogen phosphate anion (reaction b). the ammonium cation as is found in ammonium chloride (reaction c), the carboxylic acetic acid (reaction d). Ihc cnolic form of phenobarbital (reaction e), Ihe carboxylic acid moiety of indomelhacin (reaction j), Ihc imidc of saccharin (reaction g). and the prolonaied amine of ephedrine (reaction h). Because all are proton donors, they mu.st be treated as acids when calculating the pH uf a solution or percent ionization of the drug. At the same lime, as nuted below, there are important differences in the pharmaceutical properties of ephedrine hydrochloride (an acid salt of an amine) and lho.se of indomelhacin. phenobarbital. or saccharin. 

Hydrogen chloride. Method 1 from concentrated sulphuric acid and fused ammonium chloride). The most convenient procedure is to allow concentrated sulphuric acid to react with lumps of fused ammonium chloride in a Kipp s apparatus. The gas may be dried by passage through a wash bottle containing concentrated sulphuric acid the latter should be followed by an empty wash bottle or flask as a precaution against sucking back of the contents of the reaction vessel. 

Now run in a solution of 52 g. (53-5 ml.) of pure diethyl carbonate (1) in 70 ml. of anhydrous ether, with rapid stirring, over a period of about one hour. A vigorous reaction sets in and the ether refluxes continually. When the diethyl carbonate has been added, heat the flask on a water bath with stirring for another hour. Pour the reaction mixture, with frequent shaking, into a 2 litre round-bottomed flask containing 500 g. of crushed ice and a solution of 100 g. of ammonium chloride in 200 ml. of water. Transfer to a separatory funnel, remove the ether layer, and extract the aqueous solution with two 176 ml. portions of ether. Dry... 

Reflux a mixture of 1 g. of the ester, 3 ml. of benzylamine and 0 1 g. of powdered ammonium chloride for 1 hour in a Pyrex test-tube fltted with a short condenser. Wash the cold reaction mixture with water to remove the excess of benzylamine. If the product does not crystallise, stir it with a httle water containing a drop or two of dilute hydrochloric acid. If crystallisation does not result, some unchanged ester may be present ... 

Mix 100 g. of ammonium chloride and 266 g. of paraformaldehyde in a 1-litre rovmd-bottomed flask fitted with a long reflux condenser containing a wide inner tube (ca. 2 cm. diameter) the last-named is to avoid clogging the condenser by paraformaldehyde which may sublime. Immerse the flask in an oil bath and gradually raise the temperature. The mixture at the bottom of the flask liquefies between 85° and 105° and a vigorous evolution of carbon dioxide commences at once remove the burner beneath the oil bath and if the reaction becomes too violent remove... 

Vinylacetic acid. Place 134 g. (161 ml.) of allyl cyanide (3) and 200 ml. of concentrated hydrochloric acid in a 1-htre round-bottomed flask attached to a reflux condenser. Warm the mixture cautiously with a small flame and shake from time to time. After 7-10 minutes, a vigorous reaction sets in and the mixture refluxes remove the flame and cool the flask, if necessary, in cold water. Ammonium chloride crystallises out. When the reaction subsides, reflux the mixture for 15 minutes. Then add 200 ml. of water, cool and separate the upper layer of acid. Extract the aqueous layer with three 100 ml. portions of ether. Combine the acid and the ether extracts, and remove the ether under atmospheric pressure in a 250 ml. Claisen flask with fractionating side arm (compare Fig. II, 13, 4) continue the heating on a water bath until the temperature of the vapour reaches 70°. Allow the apparatus to cool and distil under diminished pressure (compare Fig. II, 20, 1) , collect the fraction (a) distilling up to 71°/14 mm. and (6) at 72-74°/14 mm. (chiefly at 72 5°/ 14 mm.). A dark residue (about 10 ml.) and some white sohd ( crotonio acid) remains in the flask. Fraction (6) weighs 100 g. and is analytically pure vinylacetic acid. Fraction (a) weighs about 50 g. and separates into two layers remove the water layer, dry with anhydrous sodium sulphate and distil from a 50 ml. Claisen flask with fractionating side arm a further 15 g. of reasonably pure acid, b.p. 69-70°/12 mm., is obtained. 

Dissolve 0-5 g. of the substance in 10 ml. of 50 per cent, alcohol, add 0-5 g. of solid ammonium chloride and about 0 -5 g. of zinc powder. Heat the mixture to boiling, and allow the ensuing chemical reaction to proceed for 5 minutes. Filter from the excess of zinc powder, and teat the filtrate with Tollen s reagent Section 111,70, (i). An immediate black or grey precipitate or a silver mirror indicates the presence of a hydroxyl-amine formed by reduction of the nitro compound. Alternatively, the filtrate may be warmed with Fehling s solution, when cuprous oxide will be precipitated if a hydroxylamine is present. Make certain that the original compound does not aflfect the reagent used. 

In a 2 litre bolt-head flask, equipped with an efficient mechanical stirrer, place 60-5 g. (50 ml.) of pure nitrobenzene and a solution of 30 g. of ammonium chloride in 1 litre of water. Stir vigorously and add 75 g. of a good quality zinc powder (about 90 per cent, purity) in small portions over a period of 5 minutes. The main reaction occurs about 5 minutes after the addition and the temperature rises. When the temperature reaches about 65°, add enough ice to the weU-stirred mixture to reduce the temperature to 50-55°. Filter the solution through a Buchner funnel twenty minutes after the first portion of zinc powder was introduced wash the zinc oxide residues with 600-700 ml. of boiling water. 

The way the chemist knows that she has methylamine and not ammonium chloride is that she compares the look of the two types of crystals. Ammonium chloride crystals that come from this reaction are white, tiny and fuzzy. The methylamine hydrochloride crystals are longer, more crystalline in nature and are a lot more sparkly. The chemist leaves the methylamine crystals in the Buchner funnel of the vacuum filtration apparatus and returns the filtrate to the distillation set up so it can be reduced one last time to afford a second crop. The combined methylamine hydrochloride filter cake is washed with a little chloroform, scraped into a beaker of hot ethanol and chilled. The methylamine hydrochloride that recrystallizes in the cold ethanol is vacuum filtered to afford clean, happy product (yield=50%). 

Place 250g of Ammonium Chloride and 500g of technical Formaldehyde (37%, Formalin). Rig the flask for simple distillation such that a thermometer extends into the reaction mixture, and a Liebig... 

To a solution of 0.30 mol of ethyllithium (note 1) in about 270 ml of diethyl ether (see Chapter II, Exp. 1) v/as added 0.30 mol of methoxyallene at -20°C (see Chapter IV, Exp. 4) at a rate such that the temperature could be kept between -15 and -2Q°C. Fifteen minutes later a mixture of 0.27 mol of >z-butyl bromide and 100 ml of pure, dry HMPT ivas added in 5 min with efficient cooling, so that the temperature of the reaction mixture remained below 0°C. The cooling bath was then removed and the temperature was allowed to rise. After 4 h the brown reaction mixture was poured into 200 ml of ice-water. The aqueous layer was extracted twice with diethyl ether. The combined solutions were washed with concentrated ammonium chloride solution (which had been made slightly alkaline by addition of a few millilitres of aqueous ammonia, note 2) and dried over potassium carbonate. After addition of a small amount (2-5 ml) of... 

In 400 ml of anhydrous liquid ammonia (note 1) (drawn from a cylinder) in the 3-1 flask were dissolved 25 g of K0-tert.-Ci,tig (see Exp. 4, note 2). 1,4-Dimethoxy--2-butyne (Chapter VIII-6, Exp. 8) (0.60 mol) was poured into the solution. The reaction mixture was allowed to stand (with occasional swirling) for 25 min, after which 50 g of powdered ammonium chloride were introduced in 5 min with manual swirling. The ammonia was driven off by placing the flask in a water bath at 40 C. 

To a mixture of 0.20 mol of 1,1,4-triethoxy-2-butyne [see Chapter III, Exp. 40), 60 ml of dry THF and 50 ml of dry diethyl ether was added at -45 to -50°C a solution of 0.42 mol of ethyllithium in about 280 ml of diethyl ether (see Chapter II, Exp. 1). Stirring at -5o°C was continued for 30 min, then the reaction mixture was poured into 300 ml of saturated ammonium chloride solution. After shaking, the layers were separated and the aqueous layer was extracted twice with small portions of diethyl ether. The combined ethereal solutions were dried over magnesium sulfate and concentrated in a water-pump vacuum and the residue wasdistilled at about... 

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