Methylamine production

Other cholesterol derivatives include cholesteryl-3 /3-oxy-succinamido-ethylenedi-methylamine (product 1 in Figure 15.6) and cholesteryl-3 /3-carboxyamidoethylene-dimethylamine (product 2 in Figure 15.6)... 

Egly and Smith have studied the effect of operating variables on methylamine production from methanol and ammonia over activated alumina. Nine reactions are postulated as probable under commercial operating conditions. These include reaction of methanol with di- and trimethylamines as well as decomposition of the amines. Optimum space velocities were found for a given temperature and pressure at which maximum conversion was obtained (e.g., a 97 per cent conversion of alcohol to a product consisting of 54 per cent mono-, 26 per cent di-, and 20 per cent trimethylamine was attained at 50 C with a space velocity of 720 per hr). The existence of optimum space-velocity conditions was interpreted qualitatively on the basis of the rate of the various possible reactions. Trimethylamine in the product can be reduced by adding water to the feed or eliminated by recycling. 

Aminofulvenes. Startg. m. allowed to react at room temp, with methanolic methylamine product. Y ca. 100%. Also with NH3 and f. methods s. F.-G. Fick and K. Hartke, Tetrah. Let. 1975, 1133. 

Methyl iodide easily undergoes Sfj2 reactions since it is very unhindered amines are weak nucleophiles, and reaction gives the ammonium intermediate which is deprotonated to give the methylamine product. 

This methylamine product is a weak base and good nucleophile, better in fact than the starting material as a result of inductive electron release of the N substituents the alkylation reaction therefore repeats to give the dimethylamine. 

Another synthesis of substituted amines mixes formic acid with an amine and formaldehyde. If 3-aminohexane (15) is treated with formaldehyde in the presence of formic acid, the initial product is iminium salt, 16. In the presence of formic acid, the n-bond of the imine donates electrons to the acidic proton to give an AT-methylamine product, 3-(AT-methylamino)hexane, 17. This particular reaction is called the Eschweiler-Clarke reaction, after Wilhelm Eschweiler (Germany 1860-1936) and Hans Thacher Clarke (England 1887-1972). It is also possible to mix formaldehyde and an amine in the presence of hydrogen... 

The absence of ammonium chloride and methylamine hydrochloride may be shown by the complete solubility of the product in chloroform. 

Bromosafrole is a great stepping stone to final product and was, in fact, the exact precursor used by Merck who was the first person to synthesize MDMA. Until very recently it was the defacto method that most underground chemists started out with (Someone-Who-Is-Not-Strike included) because, at first glance, it seems so simple and uses basic chemicals and equipment. Once someone has the bromosafrole, all one has to do is just swap out that Br with simple ammonia or methylamine and the deed is done. 

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%). 

Purification of the Methylamine HCI is in order now, so transfer all of the crude product to a 500mL flask and add either 250mL of absolute Ethanol (see end of FAQ for preparing this) or, ideally, n-Butyl Alcohol (see Footnote 4). Heat at reflux with a Calcium Chloride guard tube for 30 minutes. Allow the undissolved solids to settle (Ammonium Chloride) then decant the clear solution and cool quickly to precipitate out Methylamine HCI. Filter rapidly on the vacuum Buchner funnel and transfer crystals to a dessicator (see Footnote 3). Repeat the reflux-settle-cool-filter process four... 

If the crystals are opaque white and do not deliquesce quickly in air of average humidity (65% rh), they may be contaminated with some Hex amine. Washing 100g of the crude product with lOOmL of Chloroform by stirring in a beaker then filtering, repeated as many times as necessary, will remove Hex amine. Methylamine HCI is insoluble in Chloroform whereas Hexamine Is at the rate of 1g to 10mL. 

Furthermore, treatment of the aminopalladation product with bromine affords aziridines[176]. The aziridine 160 was obtained stereoselectively from methylamine and 1-decene in 43% yield. The aminopalladation of PdCl2 complexes of ethylene, propylene, and 1-butene with diethylamine affords the unstable ir-alkylpalladium complex 161, which is converted into the stable chelated acylpalladium complex 162 by treatment with CO[177],... 

Du Pont has lepoited an alternative catalytic process for the production of MIC starting with methylamine [74-89-5J (32). 

Naphthol is mainly used in the manufacture of the insecticide carbaryl (59), l-naphthyl A/-methyicarbamate/ iJ-2j5 - (Sevin) (22), which is produced by the reaction of 1-naphthol with methyl isocyanate. Methyl isocyanate is usually prepared by treating methylamine with phosgene. Methyl isocyanate is a very toxic Hquid, boiling at 38°C, and should not be stored for long periods of time (Bhopal accident, India). India has developed a process for the preparation of aryl esters of A/-alkyl carbamic acids. Thus l-naphthyl methylcarbamate is prepared by refluxing 1-naphthol with ethyl methylcarbamate and POCl in toluene (60). In 1992, carbaryl production totaled > 11.4 x 10 t(35). Rhc ne-Poulenc, at its Institute, W. Va., facihty is the only carbaryl producer in United States. 

Fig. 3. Synthesis of fluoxetine (31). 3-ChIoro-I-phenyl-I-propanol reacts with sodium iodide to afford the corresponding iodo derivative, followed by reaction with methylamine, to form 3-(methyl amin o)-1-phenyl-1-propan 0I. To the alkoxide of this product, generated using sodium hydride, 4-fluorobenzotrifluoride is added to yield after work-up the free base of the racemic fluoxetine (31), thence transformed to the hydrochloride (51)...

Other Polyimides. In 1979, Rohm Haas introduced Kamax resin, which was thought to be an /V-methylamine imidization product of poly(methyl methacrylate) (118). The product was then withdrawn, but was reintroduced in the late 1980s. The partly imidized resins are similar to poly(methyl methacrylate) but have a higher glass-transition temperature. 

One-electron cleavage of the oxaziridine ring is especially useful in the case of the oxaziridine (114), easily obtained from cyclohexanone, methylamine and hypochlorite. The radical formed from (114) by uptake of one electron from the iron(II) ion can be trapped, for example, by acrylonitrile to form products derived from radical (297) (68TL5609). 

This explanation has been revised recently by Bickel, who has shown that the product, C,Hii03N, first formed in this reaction, is the monohydrate of iV-methyl-3-methoxypyridone-4, MeO. CgHjONMe, H2O, the chloride, C,Hio02NCl, is the hydrochloride, MeO. C HgONMe, HCl of the same base, and the substance formed when the chloride is heated is N-methyl-3-hydroxypyridone-4. The constitution of the latter had already been established by Wibaut and Kleipol, who had synthesised it by the action of methylamine on meconic acid (V) and decarboxylation of the resulting product (VI) to the desired substance (VII = IV). 

Merck and Maeder have patented the manufacture of arecaidine by loss of water from l-methyl-4-hydroxypiperidine-3-carboxylic acid. A method of producing the latter has been describd by Mannich and Veit and has been developed by Ugriumov for the production of arecaidine and arecoline. With the same objective, Dankova, Sidorova and Preobrachenski use what is substantially McElvain s process,but start by converting ethylene oxide, via the chlorohydrin and the cyanohydrin, into -chloropropionic acid. The ethyl ester of this with methylamine in benzene at 140° furnishes methylbis(2-carbethoxyethyl) amine (I) which on refluxing with sodium or sodium Moamyloxide in xylene yields l-methyl-3-carbethoxy-4-piperidone (II). The latter is reduced by sodium amalgam in dilute hydrochloric acid at 0° to l-methyl-3-carbethoxy-4-hydroxypiperidine (III) which on dehydration, and hydrolysis, yields arecaidine (IV R = H), convertible by methylation into arecoline (IV R = CH3). 

The importance of tropinone as a possible starting-point for the production of the therapeutically valuable alkaloids atropine, hyoscyamine, cocaine, tropacocaine and the artificial tropeines (p. 73) led Robinson to consider the possibility of preparing this substance by a simple method. Starting with the idea that the formula for tropinone (XXX) may be regarded as made up of the formulae of the residues of succindialdehyde (XXVII), methylamine (XXV III) and acetone (XXIX), he found that a mixture of these substances in water, when allowed to stand for thirty minutes produced tropinone, which could be detected by means of its characteristic dipiperonylidene derivative (bright yellow needles, m.p. 214°). 

Br. GHj. GH2. GBr(G02. G2H5)2. This reacts with methylamine orming two products both derived from ZV-methylpyrrolidir e-2 2-dicarboxylic acid, viz., the dimethylamide (XIV) and the diethyl ester. 

The intermediate products (I) and (II) lose water, forming hydrohydrastinine and oxyhydrastinine respectively. Alkaline permanganate converts oxyhydrastinine into hydrastinic acid (III), C HgOgN, needles, m.p. 164° this in turn is oxidised by dilute nitric acid to hydrastic acid methylimide (IV), CJ0H7O4N, m.p. 227-8°, which, when warmed with potassium hydroxide solution, furnishes methylamine and hydrastic acid (V). 

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