Many bees have reported interesting and strange details to the patent literature, both new and old.
In regards to inventions of mechanical or industrial processes, such as a new method for eliminating pollution from contaminated sites, such examples of the patent literature fall a bit short of detail. This may occur for any number of reasons, the most typical ones perhaps surrounding the necessity of providing limited information about the process, construction, and overall function of the invention itself. My guess is that the vagueness in detail of many current inventions is for the purpose of securing the potential profits said invention may yield through it's application in the global market.
But patents detailing standard chemical processes, such as a new reaction protocol for synthesizing any one of many commercial reagents or substances, typically seem to be quite accurate in that they appear to have only a marginal promise of profitability, and seem more an extension of the inventor's desire to report and promote his/her/their most recent contribution to science. In short, these patents, both new and old, oftentimes are very detailed and, at least on the surface, appear to be accurate, and according to heresay, generally provide positive results.
However, patents detailing potentially "controversial" inventions--that for any one of many reasons, political, scientific, ethical, or perhaps even those based on someone's desire to "hint" to possible future buffs of patent history that they, the researcher, author, transcriber, or sponsor of the patent, knew more about the particular invention in question and, equally importantly, about the manner in which it was published--seem to retain an air of mystery that perhaps the typical casual reader who tends to refrain from probing and asking questions, would miss.
My point is quite simple: Many patents (and scientific articles as well) that I have read have strangely been marred by errors which seem difficult to dismiss as simple oversights. Since the primary focus here at the Hive is to explore various aspects to the drug phenomena, I will cite just a few examples of particularly strange errors in the pharmaceutical and chemical patent literature, that, to the best of my memory, are inexcusable as common and so-called expected "mistakes".
The Parke-Davis U.S. Patent detailing the synthesis of l-methcathinone from l-ephedrine indicates an over-usage of sulfuric acid in the chromic acid oxidation phase. I believe the required decimal point that would have accurately indicated the correct volume/weight of sulfuric acid required to prepare the Jones Reagent, is missing. To the inexperienced experimentor, following the instructions in the patent to the letter/number would likely, as has unfortunately been reported here at the Hive numerous times, lead to an overly acidic reaction which would in turn would make the subsequent processing and purification steps difficult.
Also, it has been reported time and again, that the 4-6 hour length of time mandated in the experimental section of the patent will NOT be enough for the oxidation to reach completion. In other words, an excessive amount of starting material (l-ephedrine, in the case of both the British Patent and U.S. Patent) would be present in the final product in what would likely be in an unacceptably and potentially dangerous excess.
Furthermore, the danger of condensation of two methcathinone base molecules to form the pyrazine derivative is not even hinted at in any of the three patents. This, I suspect, is either because the pyrazine would naturally be expected to be removed by a skilled experimentor through common prudent purification steps accompanied by the appropriate use analytical devices to determine purity. In this light, it is possible that the authors of the patents did not care about--or possibly were not even aware of--the ramifications the pyrazine contaminant would have on the future problem of social methcathinone use/abuse in what is, and has been, and will likely continue to be for quite some time, a drug prohibitionist society. Either way, the authors of the U.S. Patent, at least--if so inclined, and if they were alive--could argue that the inconsistencies found in the final draft of their published patent were a result of their commitment to and respect for the former literature from which they obtained their information, and that, in their view, at least, the simplist explanation to the issue of misreporting, is that they--the reseachers from Parke-Davis--directly copied their information from the previously published British Patent, detailing the same reaction scheme in the same vague and inaccurate way.
The British Patent--again, if I remember correctly--is focused primarily on the chemisty and synthesis of l-methcathinone; the U.S. Patent, on the other hand, appears to actually be a report on l-methcathinone clinical trails with results of toxicity laboratory experiments performed on rats. Maybe the synthesis of l-methcathinone was published in the U.S. Patent just for the sake of maintaining an air of professionality, via, of course, the inclusion of a concise and detailed experimental section. For all we know, the U.S. Patent research staff may have gotten their samples of l-methcathinone straight from the British. Huh. But I doubt that very much.
Strangely enough, the authors of the British Patent got their information from, I believe, a German Patent detailing the synthesis of l-ephedrine from the chromic acid oxidation of d-pseudoephedrine, which was then subsequently reduced by sodium metal (I think) to the l-ephedrine. Basically, the patent is a synthesis of l-ephedrine from d-pseudoephedine. I've done the math, and the exact same proportions of reactants are used in the German patent as are used in the British and U.S. Patents. The only difference is that the German patent uses both a much larger scale of reactants and a standing--yes, STANDING not STIRRING--reaction of six or so days as the time interval required to complete the chromic acid oxidation. The yield was reported to be about 80% l-methcathinone, which actually represented the intermediate to the final l-ephedrine product, which was the main focus of the patent.
The British patent and the U.S. patent use stirring for a 4 to 6 hr period of time to complete the oxidation of l-ephedrine to l-methcathinone. Strangely enough AGAIN, no yields are reported.
According to the much more detailed process of chromic acid oxidation of both ephedrine and pseudoephedrine as reported in the 1994 volume of Journal of Chromatographic Science (J. of C.S.)--I'll get the actual paper later for more details--the chromic acid oxidation should proceed through stirring of the reaction matrix for--if I remember correctly--12 to 18 hrs. However, in the J. of C.S. report, seemingly more useful experimental details are offered that, at least on cursory inspection, appear to fill in the gaps and limitations of the three former examples cited in the patent literature. In point of fact, the suggested reaction time, the purifaction protocol whereby the toluene solution is gassed by anhydrous HCl, distilled off under vacuum until a small quantity of toluene and the solubilized methcathinone-HCl is left. Then, the solution is quenched with anhydrous ether and the precipitated product filtered and recrystallized with IPA/acetone. This report is quite detailed compared to that reported in the former literature. It unfortunately is devoid of the unquestionably beneficial step of adding a minimal quantity of IPA to reduce the excess chromic acid to the amphoteric chromium hydroxide. The completely uniform green or blue solution can then be basified to liberate the methcathinone free base, a step which will also simultaneously solubilize the chromium hydroxide formed. Unfortunately, in lieu of this step, the author of the J. of C.S. adheres to the classic method of basification which, at the completion of the reaction, causes the time and again reported--inconvenient, and tediously removed--insoluble chromium hydroxide to precipitate out as a water insoluble chromium amphoteric hydroxide sludge.
Unfortunately, this article too offers what appears to be an erroneous and likely problematic step wherein a ridiculously excessive amount of sulfuric acid is called for (not a typo like in the British and U.S. Patents; merely a modification--a bad one, in my opinion, that would most likely be scorned by the Hive community at large). Why such a modification was suggested is certainly a good question as the recommended sulfuric acid concentration seems to be so excessive as to perhaps account for about more than 50% of the aqueous solution. As a matter of speculation, perhaps the authors of the J. of C.S. article were actually promoting a very prudent technique that would allow the overall chromic acid oxidation scheme to work in an optimal manner. Although this could be the case, it certainly doesn't look that way.
I would suspect that--based on the current knowledge of the general chromic acid oxidation--the quantity of sulfuric acid called for in the J. of C.S. periodical is either an accidental or intentional mistake. Perhaps in the instances so far mentioned, the authors have been, or presently are, either sympathetic or hostile to the cause of drug experimentation and research; therefore it is logical to assume they possibly had the wisdom to foresee both positive and negative commercial applications of their research.
Or perhaps, even more interestingly, the authors of the publications in question reported their information in such a manner that would allow only those individuals who were both knowledgeable, skilled, and qualified to "read between the lines" and make the necessary inferences about the patents secrets, thus implying the need to take certain productive and intelligent steps based on the available evidence.
Another simple yet compelling theory is that the authors of such patents and scientific articles--then as well as today--are bound by some governmental type of limitations in terms of how the experimental segments of scientific papers (particularly those written about the subject of illicit or potentially future illicit substances) are to be reported. Such a model would obviously favor qualitative evidence as the primary focus of scientific research while quantitative evidence would either be marginalized or altogether absent.
And last but not least, maybe the inventors of said erroneous patents were (are) just lazy about dotting every "i" and crossing every "t", and simply didn't catch the typos. However, in all honesty, I find this last possible explanation hard to swallow as the typo in question had appeared more than once (as a reminder, in both the British and U.S. Patents). The recurrence of such a big mistake, which would obviously affect the outcome of just about any application to research of the information contained therein, would obviously, at the very least, cause time consuming and costly mistakes, and at most, cause harm to a potential experimentor wishing to reproduce the results of the patent's claims.
To me, the whole thing smakes of some undisclosed political or ethical agenda, dating back all the way to the earlier half of the twentieth century.
BTW, this is a little off the subject,but I thought it worth mentioning that the molar ratios of the dichromate oxidation used to convert l-ephedrine/d-pseudoephedrine to l-methcathinone are completely equimolar to eachother in all three patents, meaning that just enough sulfuric acid is added to the sodium or potassium dichromate to make just enough chromic acid to oxidize the exact amount of ephedrine/pseudoephedrine in solution.
As for the stereochemical consistency of the dichromate oxidation of ephedrine/pseudoephedrine, it is correctly reported in the J. of C.S., but suspiciously incorrectly reported in the J. of Forensic Sciences article covering the subject of methcathinone also indicated to be known as "Jeff", "Mulka", and "Ephedrone". It would seem, therefore, that a 100% yield from this reaction would be out of the question, as much of the chromic acid oxidant is reported to consume much of the desired methcathinone product, accounting for the 20% excess of the ephedrine enatiomer starting material left over. But, on the good side, l-ephedrine (1R,2S) and d-pseudoephedrine (1S, 2S) DO both in fact yield, upon direct oxidation with any number of oxidants, the more potent levo isomer of methcathinone. Racemization can occur due to the enolizable carbonyl group, but harsh reaction conditions and/or strongly basic conditions would have to exist for this to occur. This is merely interesting as this property is very much akin to the reduction of ephedrine/pseudoephedrine to the stronger dextro isomer of methamphetamine, in that the enantiomers, ephedrine/pseudoephedrine, upon clean oxidation or reduction, yield only one isomeric product, namely the most potent one.
More interesting but possibly irrelevant and off-topic information for the Hive masses:
Accidental application of excess sulfuric acid in dichromate aminoalcohol oxidations to aminoketones and the subsequent attempt to remedy the situation by basifying a bit to compensate for said excess, and then extending the length of the reaction to twice the amount indicated to compensate for the excessive volume of liquid in the reaction matrix, has been reported to lead to low yields and difficulty in reducing, at the end of the reaction, the excess chromic acid in solution with the standard application of a minimal quantity of 2-propanol (IPA). Surprisingly, and symptomatic of this particular problem, is that the solution does not change its appearance in color to that of the expected opaque green or opaque blue in the expected amount of time (2-3 minutes). Furthermore, the subsequent basification step is rendered difficult due to the formation of solids, most likely the typical insoluble chromium hydroxide salts that normally accompany the classic basification method to the aminoketone base liberation/isolation step essential to this and pretty much any other general alkylamino/aminoketone synthesis.
The above mentioned problem is reported to normally be avoided by the simple use of the appropriate ratio of reagents to that of the substrate (everything appears to be equimolar, according to former calculations). Also, the exact amount of sodium hydroxide required to effect basification (the details of which are absent in all of the patents) falls somewhere--again, according to previous reports--to a dramatically lesser degree than has been both assumed and even reported by members here at the Hive. I believe I read somewhere that the proper amount of base--for both the British and U.S. Patent basification step--is somwhere around 2.1 g of sodium hydroxide in enough water to form a 20% solution. This amount--I'm going by memory as I read these figures a long time ago--is necessary for either every 1 g of sodium or potassium dichromate or for every 1 g of aminoalcohol-HCl used in the oxidation reaction. I don't remember which. More research in this area is obviously called for.
I obviously got sidetracked from the main topic of this thread, but I do have other striking examples of perculiar errors in the patent literature and a host of wild theories as to why they made it to final publication. But I'm tired of typing, so that part of my report will have to wait for now.
Until sometime in the near future, use your time wisely and respond to my post. And, of course, take care!
PK