Our First Ever Ephedrine Section
Why did it take Strike so long to get with the program? Because Strike does not do speed and Strike has never worked on ephed-rine. But for some crazy reason there are a few people out there that do. Since Strike has nothing to say about it, Strike bows to the superior knowledge of those that do.
Naturally there are a trillion reduction methods for ephedrine, pseudoephedrine and phenylpropanolamine to final product. These methods have been used and abused ad nauseam. So as to not tread on the banal work of yesterday's chemist, the advanced underground chemists associated with this book are here to give you the next cutting edge methods for your reading pleasure. Osmium emailed Strike the journal references. She and others discovered them Strike believes. The first recipe here is a nifty little way to actually make phenylpropanolamine from the very safe propiophenone [96-98], The intermediate made from propio-phenone is called isonitrosopropiophenone. It is then subsequently reduced with palladium. Although Strike would imagine that a zillion different reducing agents could be employed:
Isonitrosopropiophenone was prepared from propiophenone and butyl nitrite. Slater11 used methyl nitrite, a gas: butyl nitrite, a liquid, was found more convenient. In a 1-liter 3-necked, round-bottomed flask, fitted with stirrer, reflux and delivery tube for hydrogen chloride, was placed a solution of 80 g. of propiophenone (0.6 mol) in 400 cc. of ether; hydrogen chloride gas was passed through the stirred solution at the rate of 2-3 bubbles per second, stirring and addition of acid being continued throughout the reaction; then freshly distilled butyl nitrite, b.p. 75-81° , was added through the reflux condenser in 2-3 cc. portions until a total of 61.8 g. (0.6 mol) was added. After addition of the first portion the reaction mixture slowly became a yellow-brown and after several more minutes a light yellow color, after which a second portion was added; now the color change took place more rapidly, whereupon a third portion was added, etc. The mixture gradually warmed up and the ether began to reflux gently. The total time required for the addition of the nitrite was about ninety minutes. Stirring and bubbling of hydrogen chloride were continued for another fifteen minutes and the mixture then was allowed to stand overnight, during which time it became quite dark. The next day the ethereal solution was slowly stirred into dilute sodium hydroxide containing pieces of ice and the ethereal layer was repeatedly extracted with cold alkali until no more product was obtained. The alkaline extracts were slowly stirred into concentrated hydrochloric acid containing sufficient ice to keep the reaction mixture cold. In this manner white crystals of isonitrosopropiophenone were obtained: these were recrystallized from toluene and melted at 106.0-106.5°; 21 yield, 71 g., or 72.5% of the theoretical. When treated with hy-droxylamine (hydrochloride) in alkaline solution for several hours it formed, on acidifying, a voluminous precipitate which was recrystallized from alcohol and melted at 230.5-231. (f.
Phenylpropanolamine. - With catalyst prepared as previously described from 0.5g of palladium chloride and 3g of charcoal, it was possible to reduce two portions of 9.8g of isonitrosopropiophenone (0.06 mol), dissolved in 150 cc. of absolute alcohol containing 7.0g of hydrogen chloride, to phenylpropanolamine in from 145 - 190 minutes with yields of the isolated chloride from 9.4g to 11. Og, or 84 to 98% of the theoretical. After recrystallization from absolute alcohol the salt melted at 191° . The free base was obtained by treating an aqueous solution of the hydrochloride with alkali; on cooling, the liberated amino alcohol solidified and after recrystallization from water melted at 103°."
With Phenylpropanolamine at hand (or ephedrine and pseudo-ephedrine) one would next need to reduce that alpha carbon OH group to get the final amine. Strike understands that the current favorite methods for doing this involve lithium and amine, HI and red P or other iodine related protocols. So when you meth heads ruin every aspect of those methods as well, what will you do then? The following are a couple of OH reduction methods (Strike thinks) that have applicable use [99-100],
"Direct Borohydride Reduction of Alcohols to Alkanes with Phosphonium Anhydride Activation: N-Proovlbenzene.: To a solution of 5.56 g (20 mmol) of triphenylphosphine oxide in 30mL of dry methylene chloride at CfC was added dropwise a solution of 1.57 mL (10 mmol) of triflic anhydride in 30mL of dry methylene chloride. After 15 min when the precipitate appeared, a solution of 1.36g (10 mmol) of 3-phenyl-1-propanol in 10 mL of dry methylene chloride was added and the precipitate vanished in 5 min. An amount of 1.5g (40 mmol) of sodium borohydride was added as a solid all at once and the slurry was stirred at room temperature for -203 -
4.5 h. The mixture was washed twice with 1N HCI [may want to skip the HCI or wash with -5% NaOH afterwards when using this on an amine such as PPA etc.] and then water and brine, dried over MgS04, and passed thru a short plug of silica to remove tri-phenylphosphine oxide. Evaporation afforded 1.07g (89%) of phenylpropane as a colorless liquid."
"Me3SiCi - Nal - CH3CN as an Efficient and Practical Reducing Agent for Benzylic Alcohols. A typical procedure for the present reduction is as follows: To a mixture of Me3SiCI (1.54 ml, 12 mmol), Nal (1.8 g, 12 mmol), and acetonitrile (0.6 ml, 12 mmol) was added a solution of 1-phenylethanol (244 mg, 2 mmol) in hexane (2 ml). The mixture was stirred for 24 h at room temperature. Dilution with water, extraction with ether and subsequent isolation process gave ethylbenzene (158 mg) with sufficient purity in 75% yield."
Wow! Strike ought to consider taking up speed as a second habit. Those reductions looked freaking easy!
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