Hydrochloride Preparation

Intermediate Chemicals Chapter 24 Methylamine Hydrochloride Preparation by Emil Alphonse Werner 

The proportions of ammonium chloride and formaldehyde (40 per cent, formalin) recommended by Brochet and Gamier, namely, one part by weight of the former, and two parts by weight of the latter, were found after several trials to give the best results. Since about 35 per cent, of ammonium chloride has always been recovered unchanged, the molecular ratios NH4C1 2CH20 required by theory are very closely represented by the above proportions. 

After cooling, 96 grams of methylamine hydrochloride were separated after further concentration a second crop (18 grams) was obtained. The filtrate was now concentrated as far as possible at 100° and was left for twenty-four hours in a vacuum over sodium hydroxide, after which the semi-soft residue was digested with chloroform, when 20 grams of methylamine hydrochloride which had been washed with chloroform to remove the dimethylamine hydrochloride, were obtained. The total yield was 128 grams. Source Werner 1917 

22 Germany 040922-02 A5 Autobahn, near Frankfurt-am-Main. About 20 tonnes of methylamine spilled after a Netherlands-registered tanker was struck by another truck. Incidents, Week 39 2004 

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Chloromethyl)pyridine hydrochloride [1822-51-1] M 164.0, m 170-175°, 172-173°, pK , -5.6. Purified by recrystn from EtOH or EtOH-dry Et20. It melts between 171° and 175° and the clear melt resolidifies on further heating at 190° and turns red to black at 280° but does not melt again. The picrate-hydrochloride (prepared in EtOH) has m 146-147°. The free base is an oil, [Mosher and Tessieri J Am Chem Soc 73 4925 1951.]... 

A mixture consisting of 2 grams of 2-hydroxy-3-(N,N-diethylcarboxamido)-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-1 Ib-H-benzopyridocoline (OH-axial) hydrochloride (prepared by treating the base with hydrogen chloride gas in absolute ether) dissolved in 7 ml of acetic anhydride containing 3 ml of pyridine was heated at 100°C for 2 hours under a nitrogen atmosphere. At the end of this period, a crystalline precipitate had formed and the resultant mixture was subsequently diluted with an equal volume of diethyl ether and filtered. 

The free base was then dissoived in absolute methanol, and the resulting solution was then adjusted to an acid pH value with an ethereal hydrochloric acid solution. The acidified solution was purified with charcoal and then dry ether was added thereto until crystallization took place. The hydrochloride, prepared in this customary manner, had a melting point of 305°C according to U.S. Patent 3,202,660. 

The mixture is cooled, the organic phase washed with water and dried over sodium sulfate. The toluene Is evaporated and the residue taken up in 2 liters of normal acetic acid, with cooling. It is allowed to crystallize in the cold, filtered to remove the insoluble portion and the base precipitated from the filtrate by the addition of sodium carbonate this is extracted with dichloroethane and the organic phase dried over sodium sulfate. After evaporation of the solvent an oil is distilled, BP 225° to 230°C/0.1 mm, weight 340 grams, yield 58%. The hydrochloride prepared by the action of gaseous hydrogen chloride on this oil in ethyl ether melts at 140°C. 

One route is described in U.S. Patent 3,412,193 as follows. To a mixture of o-(p-chloro-phenoxy)aniline hydrochloride (prepared from 32 g of the base) in 50 ml of pyridine is added gradually while heating under reflux, 25 ml of ethyl chloroformate. After the addition is completed, the mixture is heated under reflux for one hour longer, and then evaporated under reduced pressue to an oily residue. The residue is taken up in 300 ml of water, and extracted with ether (approximately 200 ml). 

After cooling, the reaction mixture is agitated (with a mixture of (water (40 cc) and a normal solution of methanesulfonic acid (70 cc), the xylene layer is removed and the acid liquors are (washed (with ether (200 cc). The aqueous phase is then made alkaline (with sodium hydroxide (d = 1.33 10 cc) and the liberated base Is extracted (with ether. The ethereal solution is dried over anhydrous potassium carbonate and concentrated at normal pressure. On distillation of the residue under reduced pressure 3-(3-methoxy-10-phenthi-azinyl)-2-methyl-1-dimethylaminopropane (11.3 g) is obtained, MP 103°C, BP 182° to 191°C/0.15 mm Hg. The hydrochloride prepared in isopropanol melts at about 90°C. 

The corresponding hydrochloride prepared in ethyl acetate and recrystallized from a mixture of ethanol and isopropanol melts at 250°C. 

Experiments.—Being a primary hydrazide (of carbamic acid), semicarbazide reduces ammoniacal silver solutions and Fehling s solution. It reacts readily with aldehydes and ketones with the elimination of water and formation of semicarbazones, which, since they are more easily hydrolysed than are phenylhydrazones and oximes, are to be preferred to the latter for purposes of separation and purification of carbonyl compounds. Shake an aqueous solution of the hydrochloride (prepared as described above) with a few drops of benzaldehyde, isolate the semicarbazone and purify it by recrystallisation from alcohol. Melting point 214° decomp. Benzaldehyde semicarbazone is decomposed into its constituents by gentle warming with concentrated hydrochloric acid. 

A -Unsubstituted 1,2,4-diazaphospholes (4) undergo A -alkylation by reaction with alkyl vinyl ether, sulfur ylides, and diazo compounds <95HAC403>. They react with acyl chlorides in a 2 1 molar ratio to give a mixture of the A -acylated diazaphosphole and the diazaphosphole hydrochloride. Preparative A -acyclation is achieved in presence of a tertiary amine. Sulfonyl chlorides and phosphorus trichloride also give A -substitution reactions (Scheme 2) <87TH 422-01 >. 

The product of the simpler synthesis was compared in detail with the product of the RR-amine process. In particular, the Research Quality Control Unit searched for the presence of different polymorphs and new impurities (e.g., the dialkylation byproduct from the first step). They compared the stabilities of both products and also compared the hardness and dissolution rates of tablets made from both products. Since the DBTA resolution, crystallization, and product isolation steps, as wll as the final dilevalol hydrochloride preparation step, were the same for both the RR-amine process and the simpler synthesis, it was anticipated that these steps should protect against the introduction of new impurities or changed physical parameters in the final crystalline product. Such proved to be the case. 

Side Note 7.2. Chemistry of Imidic Acid Ester Hydrochlorides Preparation of Orthoesters and Amidines... 

When isolation of the imine is required [16], care has to be taken to minimize contact with aqueous acid, though in some cases the hydrochloride may be obtained even from aqueous acid, as in the following procedure. Where the imine is more sensitive, it may be isolated as the hydrochloride, prepared under anhydrous conditions [16, A], or protonation of the adduct by methanol may be used to furnish the free imine ... 

Watanabe, K., Yakou, S., Takayama, K., Isowa, K., and Nagai, T. (1996), Rectal absorption and mucosal irritation of rectal gels containing buprenorphine hydrochloride prepared with water-soluble dietary fibers, xanthan gum and locust bean gum,/ Controlled Release, 38,29-37. 

These nitroso nitro compounds were converted to amines and diamines, probably as mixtures of isomers. For example, the 2,3-dihydro-l /f-indene-1,2-diamine hydrochloride prepared via 2,3-dihydro-2-nitro-l/f-inden-l-one oxime has mp 280 °C (dec)92, while the authentic cis-iso-mer93 has mp 304-308 °C. Furthermore, 2,3-dihydro-l-methyl-l//-inden-2-amine obtained by direct hydrogenation of the l-methyl-17/-indene derivative92 has the same melting point (201 — 202 "C) as the 1 1 mixture of the cis- and trans-isomers94. 

A solution of 157 g. (1.20 moles) of 3-diethylamino-1-propanol in 260 ml. of chloroform is added (1 hour) to an ice-cold solution of 290 g. (2.44 moles) of thionyl chloride in 1200 ml. of chloroform. The reaction mixture is heated under reflux for 3 hours, after which the solvent and excess thionyl chloride are distilled off and the solid residue made alkaline with 40% aqueous sodium hydroxide solution. The reaction mixture is cooled during the addition of the alkali. Ether extraction followed by distillation of the extracts gives 131 g. (73%) of colorless oil boiling at 73-75°/20 mm. The hydrochloride (prepared by passing dry hydrogen chloride through an ether solution of the oil) is a white powder, m.p. 66-68°. The free base is unstable and should be stored in a refrigerator. 

Although primarily used as a suspending agent, xanthan gum has also been used to prepare sustained-release matrix tablets. ° Controlled-release tablets of diltiazem hydrochloride prepared using xanthan gum have been reported to sustain the drug release in a predictable manner and the drug release profiles of these tablets were not affected by pH and agitation rate.< >... 

The base is liberated from 10 g of the bitartrate with concentrated caustic soda solution, yield 5 g, and the hydrochloride prepared from this in acetonitrile with etherified hydrochloric acid. Yield 4.5 g, melting point 170-171 °C. The resolution is [alD26=—30° (2% solution in water). 

The dehydrochlorination of diphenylcyclopropenone oxime hydrochloride, prepared from 2,3-diphenylcyclopropenone and hydroxylamine hydrochloride in methanol, with aqueous hydrogen carbonate gave 2,3-diphenylcyclopropenone oxime (1) in 98% yield. ... 

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