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There are many procedures out there for the production of N-methyl-amphetamines (methamphetamines) from various starting materials, such as phenyl-2-propanone (P2P) or ephedrine, but what if you already have an amphetamine (or phenethylamine) and wanted to add a methyl group to the nitrogen atom? If you would use the first reaction that comes to mind for the conversion, to alkylate the amphetamine with methyl iodide or dimethylsulfate, you would be disappointed, as you would get a mixture of products, most important the N,Ndimethyl-amphetamine (of very low activity), as once the amphetamine has been methylated to methamphetamine, the molecule is much more succeptible to another alkylation, and thus the dimethyl- amphetamine is formed much faster than the remaining amphetamine is alkylated to methamphetamine. Actually, in the reaction mix you would find unreacted amphetamine, Nmethylamphetamine, N,N-dimethyl- amphetamine and even some of a quaternary N,N,Ntrimethylamphetammonium salt. To avoid this happening, we must usually resort to indirect methods of introducing the methyl group. One way is to react the amphetamine with formaldehyde (either as an aqueous solution, or as paraformaldehyde) to get the amphetamine formaldehyde imine, which can then be reduced to the N-methylamphetamine using a several different reducing agents, for example Al/Hg or Pt/H2.
Amphetamine can also from an amide with formic acid, N-formylamphetamine, if boiled in a Dean-Stark apparatus where the formed water in the reaction is continously removed, thus driving the formation of the amide forward. The amide can then be reduced by for example lithium aluminum hydride.
Another way is to react the amine with benzaldehyde to form an imine, which then can safely be alkylated with methyl iodide or dimethyl sulfate, and after hydrolysis of the resulting compound, N-Methylamphetamine is formed.
5 hr.25-0. The selectivity might be somewhat lower with methylations than with the butylation described in the last synthesis of this document. (0.5 g. since an exact amount could be weighed. but this gave no improvement in yield after reduction. 4. which was converted to the phosphate salt. (0. but 5 g of 5% rhodium on carbon did prove satisfactory. Thus. of platinum oxide (Note 4) were added. When low boiling components are to be mixed.25 mole) of glacial acetic acid (Note 3). Palladium on carbon was not used in this experiment. Originally about 20 ml of 37% formaldehyde solution was added (0. it must be said that using exotic reagents like cesium salts.25 mole). When hydrogen absorption was complete. Strong acids should not be used with rhodium because they act as inhibitors of its activity. a mixture of 1 mole amphetamine freebase (136g) and 1 mole aqueous formaldehyde (81ml 37% or 75ml 40%) in 350 ml alcohol and an excess of aluminum amalgam was reduced for several hours. it is best to cool the solution of amine while the aldehyde is added to prevent loss of amine or aldehyde from the exothermic reaction. When the aldehyde and base were mixed. it might be possible to directly mono-methylate amphetamine without too much overalkylating taking place. converted to the hydrochloride. and hydrogenation was carried out at room temperature and 3 atm.5 g. it appeared safer to use paraformaldehyde. the mixture was warmed slightly and allowed to stand before reduction. Other acids should also be satisfactory as long a they do not cause reversal of the formation of imine.Finally. and the filtrate and washings concentrated to dryness. When reduction was too slow. Additional ethanol (100 ml). aluminum hydroxide filtered off. When no heat developed in the reaction of aldehyde and amine. A solution of 30. for complete reaction. The reaction rate in this reduction was slower in the absence of acetic acid. After standing. FORMALDEHYDE AND ALUMINUM AMALGAM1 N-Methyl-amphetamines were prepared by the reaction of the corresponding amphetamine with formaldehyde and reduction in the absence of acid. PARAFORMALDEHYDE. PLATINUM OXIDE AND HYDROGEN2 This procedure is for the methylation of 2-phenethylamine. but it can easily be adapted for use with any amphetamine. the catalyst was removed. 1-Phenyl-2aminopropanol similarly yielded ephedrine. while not perfect it is pretty good for one step with no reduction necessary. The solution was allowed to stand for 0. In some cases the mixture was allowed to stand overnight. and the freebase separated by means of alkali yielding phenyl-Nmethylisopropylamine. dried and distilled to give an 80-90% yield of N-methyl 2-phenethylamine (Note 6). and 0. Many reductive alkylations were carried out successfully with platinum or palladium in the absence of acid. 15 g. the mixture can then be hydrogenated. Freifelder states there is little doubt that 5 g of 5% .25 mole) of 2-phenylethylamine and 7. 70g damphetamine in alcohol with aluminum and 1 mole formaldehyde gave dmethamphetamine. Notes: 1.25 mole) of paraformaldehyde (Note 1) in 50 ml of 95% ethanol was allowed to stand for a short period (Note 2). Hydrogen uptake was usually complete within 2 hr or less. mp 140°C. extracted with ether. interruption for addition of the required amount of acid did speed hydrogen uptake. Similarly. 2. The residue was treated with sodium hydroxide solution (Note 5). You get an approximate 9:1 ratio of secondary amine to tertiary amine. the solution acidified and evaporated. the solution became warm. water added.25 g (0. 3. In view of the reported danger of dimethylation of primary amines when formaldehyde is used.
neutralized with concentrated HCl.8 g. on standing. addition of alkali and extraction of base are unnecessary. without cooling. This solution was extracted with 3x100 mL dilute HCl. Two Et2O exts of the basic aqueous phase were added to the amine layer which separated. aq NaOH. leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine. the aqueous layer was washed twice with Et2O to remove unreacted benzaldehyde and made strongly basic with 50% aq NaOH.66 mole) of benzaldehyde.5 g of a nearly white residue which was distilled at 100-110°C at 0. and the residue dissolved in 200 mL CH2Cl2. A mildly exothermic reaction began at once.4-methylenedioxyamphetamine (MDA) as the free base and 2. Removal of the volatiles yielded an oil that set up to white crystals. A solution of 7. there was the deposition of fine white crystals of 3. A reaction such as this is actually a reduction of the imine in situ. formed crystals of N-formyl-3. washed first with dilute HCl.536 mole) of the hydrochloride by stirring with conc. . This was dissolved in 25 mL IPA. This material was dissolved in 500 ml of 20% abs EtOH-Et2O and treated with 50 ml of conc HCl with swirling and cooling to yield the white. Removal of the solvent gave an 8. treated with 200 ml of H2O. and finally once again with dilute acid.4-methylenedioxyamphetamine in 25 mL anhydrous THF was added dropwise to a well stirred and refluxing solution of 7. When acid is not used. The yield was 83 g (77%). 5. an attached Dean-Stark trap was removed and a soln of 82 g (0. The 2-phase mixt was heated for 90 min on the steam bath. cooled slightly. After being brought to room temperature. There was obtained 6. then with dilute NaOH. and the pooled extracts were stripped of solvent under vacuum.8 g of an amber oil which was dissolved in 100 mL CH2Cl2.4-methylenedioxy-N-methylamphetamine hydrochloride (MDMA) which were removed by filtration. After cooling in ice.5-186. The reaction mixture was held at reflux for 4 days. mp 185. and heated for an addn 20 min. generated from 100 g (0. giving a final weight of 4. washed with Et2O. The mixt was heated under reflux until no more H2O was present in the condensate (ca.4 g LAH in 600 mL anhydrous THF under an inert atmosphere.8 g. The solids were removed by filtration. and 1. then. 1 hr). and the filter cake washed with additional THF.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no further H2O was generated (about 20 h was sufficient.4 mm/Hg to give 5.4-methylenedioxyamphetamine. the excess hydride was destroyed with 7. cryst hydrochloride. On continued stirring.4 mL H2O in an equal volume of THF. The combined filtrate and washes were stripped of solvent under vacuum. An alternate process for the synthesis of this amide involved holding at reflux for 16 h a solution of 10g of MDA as the free base in 20 mL fresh ethyl formate. 6. and these extracts pooled and made basic with 25% NaOH.5°C.7 g of an amber oil that.palladium on carbon or an equal amount of 5% platinum on carbon would work as they had in other reductive alkylations. followed by 7.65 mole) of Me2SO45 in 200 ml of benzene (toluene could be substituted) was added through the condenser at such a rate as to maintain reflux (15 min). which was washed thoroughly with ice-cold 20% EtOH-Et2O and dried. weighing 7.7 g N-formyl-3. and the resulting solution was evacuated at the aspirator for 30 min. a very useful procedure that may be used in alkylations with other aldehydes. Extraction with 3x75 mL CH2Cl2 removed the product. was treated with 100 ml of benzene (toluene could be substituted) and 70 g (0.55 g of 3. followed by the addition of sufficient anhydrous Et2O to produce a lasting turbidity. BENZALDEHYDE AND DIMETHYLSULFATE4 p-Methoxyphenethylamine.4 mL H2O was collected). and air dried.4 mL of 15% NaOH and then another 22 mL H2O. FORMIC ACID AND LITHIUM ALUMINUM HYDRIDE3 A solution of 6.0 g of a colorless oil. The solvent was removed under vacuum giving 7.
CA 52:20055e. Alexander Shulgin. Med. Syn.N-dibutyl phenethylamine (40 mg. Other alkali hydroxides produced moderate yields of the desired product along with a considerable amount of the tertiary amine. but also inhibited the formation of tertiary amines. whereas cesium hydroxide allowed for a greater selectivity of 9:1 in preference for the monoalkylation product. favoring mono-N-alkylation over dialkylation. Representative Experimental Procedure To activated powdered 4 Å molecular sieves (500 mg) in anhydrous N. Interestingly. 1. Chem. Catalytic Hydrogenation in Organic Synthesis: Procedures Commentary. N-butyl phenethylamine (260 mg. Kiefer.0 mmol) was added into the white suspension. Among the cesium bases examined..21 mL. Under our cesium base promoted N-alkylation conditions. Keil et al. D. comparative studies between cesium bases and other bases were performed. S. Edgar F. 10%) as a pale yellow oil. defined by the enhanced reactivities in the presence of cesium salts.. gave the highest yields and selectivities although cesium carbonate also worked well. 98-101. and P. 44. the intended alkylation of a secondary amine (N-butylphenethylamine) was very sluggish under our conditions. J. Korosec. filtered. J.7 mmol) was added and followed by additional 30 min of stirring. and extracted with EtOAc (4 x 20 mL). was added cesium hydroxide monohydrate (280 mg. 1.N-dibutyl-phenethylamine was obtained along with the recovery of 25% of N-butyl-phenethylamine in absence of cesium hydroxide after the same duration. suggesting that the improvement of chemoselectivity would stem mainly from the retarded overalkylation or reversal of normally observed alkylation rates. 2. and rinsed several times with EtOAc. REFERENCES 1. 1-bromobutane (0. According to our experiments. depending on substrates. A.Ndimethylformamide (8. After the filtrate was concentrated to a nominal volume by blowing air. N. A cesium base not only promoted monoalkylations of primary amines but also suppressed overalkylations. After phenethylamine (0. the residue was taken up in 1 N NaOH.3 mL). 15(2). affording the tertiary amine (N. 9:1 v/v) afforded the secondary amine.7 mmol). Lucier. Freifelder.155 (1953).-phenylethylamines. The combined organic layers were washed with brine. 89%) as a colorless oil as well as tertiary amine. primary and secondary amines exhibited opposing reactivities. 2. N-Monomethyl.CESIUM HYDROXIDE PROMOTED MONOALKYLATION6. cesium hydroxide monohydrate. in general.21 mL. use of amino acid derivatives afforded the desired secondary amines exclusively. and then the white suspension was vigorously stirred for 10 min.Ndibutyl-phenethylamine) in only 10% yield. Harris. 214 (1972) 5. 72 (1964) and .5 mmol. To confirm the possible cesium effect. 1. and concentrated in vacuo. demonstrating that cesium hydroxide was superior to other alkali bases tried with the regard to the observed chemoselectivities. the next comparative study implied that the cesium base not only promoted N-alkylation of primary amines. 3. Flash column chromatography (EtOAc-EtOH.17 mmol. German Pat. filtered to remove the molecular sieves and undissolved inorganic salts. Various amines and alkyl bromides were examined. It was apparent that an unprecedented "cesium effect" in N-alkylation was observed as seen in O-alkylation. J. In particular. and the preliminary results demonstrated this methodology was highly chemoselective.7 Selective N-alkylation of primary amines was developed using cesium hydroxide to prepare various secondary amines efficiently. dried over anhydrous sodium sulfate. The reaction was stirred for 20 h. 0. Org. 871. Pihkal #109 (MDMA) 4. whereas 72% of N.
stirring method. at this smaller scale it gets pretty filled up!). A chooses to perform this reaction on is half-scale to the scale in the Ritter writeup. losses. lacked details about the many nuances that. The first thing I'd like you to look at is the array of interrelating variables in this reaction that make it so delicate.6. flat.5g aluminum and 25g MDP-2-P. With this writeup. Finally.in the end . 4. 7. much discussion has taken place about it but.) amount of HgCl2 used in relation to the amount of aluminum addition rate of the MeNO2/MDP-2-P size of the reaction vessel in relation to the scale of the reaction ability to effectively stir the reaction coldness of the water through the reflux condenser (yes.5g Reynolds Wrap Heavy Duty aluminum foil 25g MDP-2-P 20 mL MeNO2 of 99+% purity . Patent WO 50377 Reductive Amination of MDP2P with Al/Hg + Nitromethane by Methyl Man INTRODUCTION Since the appearance of Ritter's writeup of this method in Total Synthesis II. etc. 2. The subject found for his own personal reasons that this smaller scale was much easier to manage (not the least of which is that even with a huge 4-liter separatory funnel. and probably other elements.e. 5. There's no doubt that the original larger scale can be successfully applied. while inspiring. even that!) The above factors are sort of submitted in an order of importance (#1 being most important). but in reality they are all inextricably related. once understood. MATERIALS y y y AND APPARATUS 27. A as he struggled to match up the correct combination of ratios and conditions that would allow a smooth. Gonzo using this method can be found here. after lots of frustration. Thus I have tried with this writeup to help the neophyte who has only physical observations and scant written material to guide him (although I suspect and hope that it may even help a few more seasoned cooks as well). A. allow the amateur chemist to really understand this reaction's dynamics. consistent reaction and predictable results every time. 1(12). 1893-1896 (1999) 7. little has been clarified. although it would require adjustments in the glassware capacity. 3. They are as follows: 1. the the the the the the the thickness/type of the aluminum consistency (i. Ritter's original writeup. and . the perfect set of elements was hit upon and recorded. Lett. I hope to provide a clearer view of the method and to allow others to benefit from the hard-won experience of someone (not me) whom we'll call Mr. The scale Mr. Org. it has sometimes seemed. Therefore this writeup will illustrate the reaction on a scale of 27. 6. I observed firsthand the trials and tribulations of Mr. which was 55g aluminum and 50g MDP-2-P. This is due in large measure to the sensitivity of this reaction to even the most minor changes in its many variables. A photo-essay by Dr.a revelation. confusion. ground.
Fill the coffee grinder only loosely (about two thirds full . Also.don't stuff it! That will adversely change the consistency of the ground foil). Place a 3" stirbar in your 2L flat bottom flask and onto your stirplate. the foil does not get "ground. If it is compressed too heavily. It will probably take about 4 to 5 "loads" in your grinder to do the whole 25g of foil. I believe that doing this really helps facilitate the amalgamation process that is about to occur. After about 5 minutes or so. the inner surfaces of the foil nuggets may be rendered inaccessible to the Hg/MeOH solution. 4.) When properly done. like champagne bubbles. 3.y y y y y y 750 mL MeOH + 50 mL more for addition funnel + additional small amounts that will be needed later to thin the mixture 400mg HgCl2 2-liter 2-neck flat bottom flask reflux condenser (400mm preferable) 250mL or 500mL addition or separatory funnel cooling setup (bucket. Combine the 25g MDP-2-P. it will easily stir. the foil should be in gnarled little nuggets about the size of sunflower seeds (shell included) and should NOT look super-tight and small." but rather. Add the foil nuggets to the flask and then proceed to set up your glass. This is the magic moment when you want to begin dripping in your MDP-2-P/MeNO2/MeOH mixture.75". i. It is around this same time that the appearance of the aluminum will change from its normal shiny silver color and start to take on a dull gray look. long sleeves and a Hail Mary if you're Catholic). attach the inflow and outflow tubes to the reflux condenser. each individual piece just gets compacted and compressed. Set this solution aside. 6. Carefully add the 400mg HgCl2 to 750mL MeOH to a tightly sealable bottle and shake to dissolve all HgCl2. 2. changing the timing of the amalgamation and maybe even causing an incomplete or failed reaction. 5. Settle down with this task with a good CD or TV show because it is tedious and will take about 30-40 minutes. prepare your cooling. tubing. Rinse your beaker (or whatever you used) with a tiny bit of additional MeOH to get the residual ketone and add it to this MDP-2-P/MeNO2/MeOH solution. Then after a few minutes you will see them joined by larger bubbles closer to the size of those seen in boiling water. water pump. Give it a few more 5-second stirs over the next few minutes. With a coffee grinder. using a large funnel. accompanied by a gray cloudy look that begins forming in the MeOH. glasses.e. 20mL MeNO2. Turn the stirring on full blast for a 5-second burst to intimately mix the solution and the foil. and 50mL MeOH and pour them into the addition/sep funnel. You can speed it up a bit later to accelerate the reaction if desired. you will begin to see bubbles popping up on the surface of the MeOH solution. "grind" these pieces of foil for durations of about 10 seconds. (In actuality. . Weigh 27. If you have prepared the foil as described above. 8. pour the HgCl2/MeOH solution from step 4 down the condenser.5g of Reynolds Wrap Heavy Duty aluminum foil (NOTE: it HAS to be Reynolds and it must be the heavy duty stuff) and then tear it by hand or cut it with scissors into small rectangles approximately 1" by . 1 bag ice) PROCEDURE 1. depending on the size of your grinder. Set a drip rate of approximately 1 drop per second at this point and no faster. Very slowly and carefully (w/gloves. 7. support and clamps so that the reflux condenser and addition/sep funnel are securely affixed and your flask is well-centered on the stirplate (this will be critical when you begin to attempt stirring!). At first they will be tiny.
At a point maybe 30 minutes or so post-addition. you could be lazy and just leave the addition at a steady 1 drop/second the whole time. and you find yourself adding your beautiful ketone to impotent sludge. It is a light shade. NOTE: This is where you can take advantage of Mr. turn on/off the stirring intermittently as you did earlier. you will observe that the aluminum is breaking up fairly rapidly. crank the stirring to 10 and leave it on. but with a little experience and intuition you'll get the hang of it. The extra headroom in the glass provides a nice zone of "breathing room" for the reaction and facilitates good refluxing. A's trial and error regarding this reaction's parameters. and it isn't pretty. Add more ice to your bucket as needed. If you used the kind of foil specified. Place about 3 lbs ice into your bucket. but if the amalgamation peters out way before your addition is finished. That is to say. 10. where a dark metallic gray with definite green overtones (from unreacted ketone) was noted. Use the 2-liter." When the reaction is clearly starting to get vigorous and hot. with the MeOH literally pouring down out of the condenser. this is good. This time it is to assure distribution of the added ketone/nitromethane in the reaction flask but also because the amalgamation seems to gain its vital momentum more effectively if given some significant blocks of time (meaning about 30 sec at a time) in between "stirring bursts. At this point you can sort of control the reaction rate by slowing down or speeding up the addition rate a bit. Trust me. This is in contrast to what I saw in failures resulting from using too thick of aluminum and not enough HgCl2. Your reflux should be unnervingly vigorous as the amalgamation really starts to pick up speed. I've seen this reaction get out of hand in a 1000mL flask. While monitoring the growing intensity of the bubbling amalgamation. A note about color at this point is helpful too. and imprecise. I know it's hard to believe. quickly add about 2. You will also see sludge already starting to settle at the bottom and forming a ring on the glass around the top surface of the spinning mess. don't cry to me. prepared it as specified. The consistency will get thicker by the minute. and . but I'd say with a very slight suggestion of a blue hue in there as well. The addition should take about 40-45 minutes in total. Of course the reaction is already barreling along. This is good. as it were. and will result in perfectly processed aluminum amalgam sludge. used no more than the specified 400mg HgCl2. As the reaction progresses only a few minutes after the addition was started. In fact the reaction should by now (~45 minutes after addition was started) look like a really thick. believe me. the state of the aluminum should be about 95% broken down. But be careful with the addition rate at this point. At this scale. I'm telling you. akin to the color of common gray sweat pants.5 liters water to the bucket (or an appropriate amount to make very ice-heavy ice water) and plug in the pump." It is a hard thing to describe shades of gray. Sure. Comparing successful reactions to failed ones. When you can feel exothermic warmth begin by feeling the outside of the flask. LOTS of trial and error came before this writeup. the reaction takes on a color that I would describe as being "light steely gray with blue overtones. with the breakdown of the foil as it amalgamates and gets turned into sludge. NOTE: Another point I would like to make about the timing of the addition against the breakdown of the aluminum is that Mr. 12. and used a 2-liter and NOT a smaller flask. You will probably even need to add an extra 20-30mL of MeOH down the condenser at this point (or before) to help it keep stirring effectively. but I will try. and as it's finishing. you can breathe easy knowing that the reaction is going to hum along nicely but will not get out of control. In other words. steely-gray chowder with only minor small slivers of undissolved aluminum visible if any at all.9. so you won't want to speed it up much. as long as you have the ketone/nitro mixture dripping in at a good rate of about 1drop per second. there is a peak that it builds up to and then comes down from. You may think that a 2-liter flask is oversized for this reaction. The concept here is that you want the addition of the ketone/nitromethane to be paced neck-and-neck. It's tricky. A found that there was a definite "spike" curve to the amalgamation reaction which was easily observed by watching the reflux rate. 11. but this is what you want. but that is precisely the point. you have to watch those two things and sort of adjust the addition so that they proceed at approximately the same rate. I have observed that there is a distinctive color to the mixture early on that indicates healthy amalgamation and foretells a successful run. as a rate that is much faster than this could easily send the reaction into overdrive (not good). This is no problem.
and/or in variations using methylamine and not nitromethane. Adding the NaOH will cause the mixture to warm up a bit as the very last bits of the aluminum are dissolved. dismantle your setup. When the mixture in the sep funnel has cooled down. the garbage gets a lot less mobile and it is easy to decant the toluene away from it. That's right. do as Mr. pour your nice gray reaction mixture. So at only about 20-25 minutes after you first started feeling the amalgamation heating up. It will reach this state at about one hour 45 minutes to two hours after addition was started. When finish time has arrived. you will lose the very last 2 or 3 mL. If you chose to apply external heat. no "uneaten" aluminum is visible and the solution is a thick. set aside your reaction flask. Also. you may need to add small amounts of MeOH to thin it to a pourable consistency.. The toluene/product layer will of course be on top since toluene floats on water. NOTE: Your extractions will contain a tiny amount of the base/metal/garbage from the bottom layer. but that's life. that buildup to peak and subsequent slowdown occurs over approximately 25 minutes or so -. A does it just to be sure). this is inevitable but easily worked around in this way: when you have collected your combined toluene/product extractions in a bottle. If you like. At one hour and 15 minutes after you first started the addition. it is easy to tell when it's okay to separate because the interface of small toluene bubbles finally resolves and you have a nice clean line between the layers. 15. the reflux has slowed to almost no reflux at all B.very fast. Slowly pour the NaOH solution into the sep funnel (gloves and glasses! no excuses!). you could filter it through a paper towel. uniform gray soup. If your mixture is really thick. Alternatively. Just be vigilant while pouring the last 50 mL or so and avoid letting that glob of crap rejoin the toluene. not drops. 14. 17. Basifying should be a gentle process. so you be sure to shake long and hard (at least 3 min) during these extractions (I don't have to tell you to vent do I?!). and it probably doesn't even need that much time. Wash the final residue out of the reaction flask with a few mLs of MeOH and add it to the funnel also. A does and finish off with a final small extraction of 50-60 mL toluene just to get the last of the stuff. 13. and make 750 mL 35% NaOH solution (750 mL H2O + 262. Mr. Just get over it and move on! . turn it off at 30 minutes before the targeted finish time.the reaction has essentially finished.5g NaOH) and let it cool to room temp or below (safety glasses!). and doesn't want to be! Why would someone want to make a reaction take any more time than it needs? Beats me! I'm mystified! The approach illustrated in this writeup optimizes this reaction to finish in 3 hours 45 minutes from beginning to end. it will have slowed to a reflux of about 2 drops per second. Into a separatory funnel no smaller than 2000mL capacity. extract it once with 400mL toluene followed by once with 100mL toluene.. You could add a bit of external heat at this point but it's probably not even needed (Mr. Finally. being very careful to keep the stirbar from falling into the sep funnel and breaking it (that would be ugly). the reflux will have slowed to a very calm 1 drop per 2 seconds or so. A. That yummy stinky methylamine smell tells you that the reaction was successful. Nevertheless. When cold. Swirl it a couple times and give it about 10 minutes to cool down to something closer to ambient temperature. Otherwise you will have to wait an extra 30 minutes for it to cool for the next steps.. if you stop the stirring you do not see any small bubbles anymore C. when. Yeah.. don't dump it in wholesale. One reason I bring this all up is that there has been lots of talk about how this reaction needs 8 hours or 24 hours or even 36 hours to run! But those time frames apply only in cases where much thicker aluminum is used. be sure to give the separations ample time to happen (at least 15 min). you will leave it stirring happily for a total of three hours after the addition was finished to assure that the reaction has run its full course and the conversions that you desire have had ample time to take place. 16. but you will still lose the same amount when the towel absorbs it. This is perfectly fine. A was never successful in using thicker aluminum. chill that bottle in the freezer for 30 minutes or so. . These are the critical moments for your yield now. If you bully those molecules they may decide they're being disrespected and choose not to cooperate. after having been at a peak with a reflux rate so furious it is a stream.using the exact materials described herein. which is fine.
in Strike.18. Wash the toluene/product 4 times (or more) in your sep funnel with 400 or 500mL H2O and a final time with 500mL of a saturated NaCl solution to remove any traces of solvated HgCl2. In a 2L: beaker. Total Synthesis II. Once in the lab. Weep with joy as a bumper crop of white precipitate crashes out of solution. and maybe it was not a good thing. That may be true. After the 30 minutes. but insisted that they modify the procedure ever so slightly. Then add 55 gm of aluminum squares (appx 1" sq) that have been cut from pie tins. Filter the solution and gas it with that good ol' HCl bubbler setup. They finally agreed and implemented the following procedure. 20. Snoopy wanted to try the nitromethane Al/Hg procedure as outlined in TS II. they only had 38 mL to work with). then add 850 mL of MeOH to the amalgum and set aside for a moment. Mr.5 grams HgCl2 in 1500 mL of distilled water. Reference: Ritter. Be smart and use just enough muriatic (31% HCl) to wet the salt but not enough to make any puddles. If you haven't already. 85 mL of 60% nitromethane racing fuel (60% nitromethane/40% MeOH). Using a wooden chopstick (they had chinese for lunch) stir this mess around and let the Al amalgamate for appx 30 minutes. You should see effervensence and the less should turn a dirty gray color. Shake the excess moisture off the Al amalgum and transfer to a clean 2L beaker. In another beaker combine 38 mL MD-P2P (you can use up to 50 mL with this recipe. but I know for a fact that it doesn't need to be added.5g raw odoriferous product that will purify via careful recrystallization to 17-18g of beautiful snow-white MDMA! Ain't life grand? One thing that I want to mention in hindsight here since I know it's probably going to come up. Expected yield: approximately 20-21. A is superstitious so he lets it sit for an hour). drain the garbage layer out of your sep funnel into a storage bottle or something. is the issue of added water. and put a wad of drying agent wrapped in tissue paper in line somehow between the reaction flask and the tube leading to your pipette end. maybe there is some trace water in the MeOH Mr. etc. and wash the garbage residue out your sep funnel with water. Dry your toluene/product solution with 30g of your favorite drying agent (MgSO4 recommended) in an acetone-cleaned. Shake it a few times during this period. It's been emphatically stated several times that some water is needed in this reaction for imine formation etc. heat-dried bottle for no less than 30 minutes (Mr. But he likes how it's going now. He picked up the Big Bad Wolf from the forest who had just made MD-P2P (see MD-P2P via modified KRV thread) and the two of them headed for their laboratory along with the vial of MD-P2P. and 190 mL of methanol. dissolve 1. [This is the equivalent of the amounts listed in TSII] . I don't know. page 104-107 Reductive amination of MDP2P with Al/Hg using nitromethane as in situ amine source. 19. A uses (Heet) that is fulfilling this function. by Entropy (02-05-99) While Charlie Brown and Linus were away at school. Before. Snoopy decided to have some fun. 21. The Wolf agreed. A was adding about 25 mL. But he doesn't add it anymore and it definitely doesn't hurt anything. dump the contents of the beaker into a strainer and rinse thoroughly with distilled water to remove as much of the mercury salts as possible. they were puzzled as to which way to go to produce their honey. He donned his Red Baron attire and jumped into his plane. and maybe it's even in all MeOH except expensive absolute anhydrous stuff. That is to say.
the cis-permetrinic acid. Among them the O. While the reaction was underway. and the 2phenoxypropionic acid. 428±430 (2001). A STATUS REPORT WITH FAMILIES OF . NOTE: If there is unreacted Al amalgum. The garbage bottom layer was removed and the top layer was transferred to a flask and the methanol evaporated leaving the impure amine. Procedures for the Resolution of Racemic Amphetamines [ Back to the Chemistry Archive ] METHAMPHETAMINE OPTICAL RESOLUTION DIASTEREOISOMERIC SALT FORMATION BY DISTILLATION AFTER PARTIAL Solvent-free optical resolution of N-methylamphetamine was developed by distillation after partial diastereoisomeric salt formation. The reaction started immediately.74 is in the range of the industrial-scale resolutions and not worse than the efficiency achieved by optical resolution via fractional crystallization. After this time two layers were observed. O. make sure the pieces of Al are removed or decant the sludge from the remaining amalgum.O'-dibenzoyltartaric acid in water-free form provided the more effective resolution.O'-di-ptoluoyltartaric acid. this time as a methylamine generator. They tossed in a 3" stirbar and placed it on a magnetic stirrer. the reaction was beginning to boil vigorously. 6-methoxy-alpha-methyl-2-naphthaleneacetic acid (Naproxen). Chirality 13. Snoopy freaked out.O'-dibenzoyltartaric acid. FEATURE ARTICLE: DUTCH RESOLUTION: SEPARATION OF ENANTIOMERS RESOLVING AGENTS. This was mixed well and allowed to sit undisurbed for about an hour. of course) and there is not much you can do to stop it except hold your nose and wait or made a mad dash to the toilet. Once the reaction time had elapsed. Within 7 minutes. five provide by this method resolution: O. the sludge from the reaction was dumped into a large (2L) sep funnel along with the the liter of 35% NaOH solution . ran and got an ice bucket with ice and placed the beaker on ice for a few minutes until the reaction was under control (a matter of 1-2 minutes) then the beaker was placed back on the stirrer and the reaction allowed to continue for 3 hours. This does not have to be added slowly. this mess starts reacting again. To the remaining DCM solution was added 50 mg of MgSO4 and this allowed to sit for 30 minutes. Snoopy nodded with agreement. "Not too shabby for a first run" the Wolf muttered. the Wolf prepared 1 liter of a 35% NaOH solution and put it into the fridge to chill. They added it over a 5 minute period of time. From the 18 chiral acids tested by this method. The impure amine was then dissolved in 250 mL of DCM and washed with several portions of distilled water and finally with a saturated NaCl solution. precisely the compound you were trying to avoid making (except for the in situ generation. If there are unreacted pieces of Al amalgam left when the NaOH is added.Now add the nitro/MeOH/MD-P2P mixture to the amalgum methanol solution. The DCM solution was then decanted and bubbled with HCL gas yielding 23 gm (60%) of beautiful MDMA crystals. The efficiency of this resolution S = 0.
And in those methods. particularly with regard to the separation of l-amphetamine by means of d-tartaric acid. Again. By using l-tartaric acid in such method. the method according to this invention is applicable to mixtures rich in the laevo form. Broadly. I have discovered a method whereby both optically active forms of amphetamine. However while those processes are operable chemically. This novel method greatly simplifies the process and makes the therapeutically useful isomers readily available. Synthesis (10). the l-amphetamine l-bitartrate is obtained as a crystalline material by fractional crystallisation. Chem. in that while d-tartaric acid is readily available and comparatively cheap. Where it is desired to effect separation of the laevo form from a mixture a mixture rich in the dextro form. Practical aspects of Dutch Resolution in particular and resolutions in general are discussed. they have serious disadvantages. the separation of the desired isomer is effected by the fractional crystallisation of acid tartrates.methylphenethylamine. in the form of their neutral salts with d-tartaric acid. D. But in such prior methods. the method according to this invention comprises the separation of l-amphetamine from dl-amphetamine by treatment with d-tartaric acid for the production of a mixture of neutral d-tartrates and crystallisation from a solution. all as more fully hereinafter set forth and as claimed. Kellogg et. it will usually be necessary to first effect separation of a part of the dextro form by methods heretofore known and then to apply the method in accordance with this invention to the remaining mixture. as free base. in the form of its neutral salt with dtartaric acid. such as result from initial separation of the dextro form by methods heretofore known. the neutral d-tartrate of the laevo amine being obtained as a crystalline material.Richard M. .1055/s-2003-40508 Abstract Dutch Resolution is the term given to the use of mixtures (families) of resolving agents in classical resolutions. ltartaric acid is 'unnatural'). d-tartaric acid is used to obtain the dextro amine and l-tartaric acid to prepare the laevo amine. The method according to this invention may be applied to. from such neutral salt. al. the acid tartrate may be decomposed with caustic alkali and the free base recovered by distillation in vacuo. Thus by the method outlined above d-amphetamine may be readily and cheaply prepared while the laevo form can only be obtained at great expense. for example. are separated by the fractional crystallisation from an alcohol solution of such salts. it having been found that l-amphetamine may be readily separated by crystallisation from a solution of the neutral d-tartrates. RESOLUTION OF RACEMIC AMPHETAMINE My invention relates to a novel method for the separation of the optically active isomers of amphetamine and it compromises methods wherein the laevo and dextro isomers. 1626-1638 (2003) DOI: 10. Gesell. by reacting the racemic amine with sufficient d-tartaric acid to form a mixture of the tartrates of the d. either dextro or laevo -amphetamine have been previously obtained from the racemic form by certain known prior methods. The concept of families is discussed as well as the factors that come into play on use of families. In this status report an overview is given of the latest results and new (possible) families of resolving agents are introduced. That is.and l. This acid tartrate may likewise be decomposed with alkali to obtain the l-amine as a free base. by crystallisation from a solution of a mixture of acid d-tartrates. To obtain the d-amine as the free base. racemic amphetamine. and it more particularly relates to the separation of the laevo-isomer. (1932) p664) that d-amphetamine d-bitartrate may be obtained as a crystalline acid tartrate. and the recovery of the laevo amine. as. or to any mixture of the optically active isomers thereof in which the laevo form is present in amount not substantially less than the dextro form. from the racemic (. and especially the laevo form may be prepared by the use of d-tartaric acid alone. It is known in the art (Ber.amine and then fractionally crystallising the bitartrate of the d-amine from an alcohol solution of the mixture of acid tartrates so obtained. for example. l-tartaric acid at the present time is both difficult to obtain and expensive in pure form (d tartaric acid comes from fruit.
Neutralisation of the excess tartaric acid may be effected where. From the solution so formed l-amphetamine d-tartrate may be separated by repeated crystallisation and the free base may be recovered as described above. where the l-amphetamine is to be separated from a mixture of the optically active isomers in which the dextro form is in substantial excess. for example.5 is obtained in a concentration of 8 grams per 100 cc of aqueous solution. Thus. The neutral salt thus obtained is fully dissolved by the addition of sufficient. it will now be understood that the method in accordance with this invention comprises essentially the separation of lamphetamine from a racemic amphetamine and from the various mixtures of d. or from any mixture of the optically active isomers in which the dextro form is not in substantial excess. caustic potash and then adding the free base to the other portion of the mother liquors with heating to forma solution. removing. for example. and that following the separation of the laevo form the dextro form may be recovered from the mother liquors by the addition thereto of d-tartaric acid for the formation of acid d-tartrates and crystallisation. the method in accordance with this invention. one mol of racemic amphetamine base is reacted with 1. The crystals are filtered off and will be found to contain a preponderance of the laevo enantiomorph. or in preponderance. The product thus obtained is pure d-amphetamine dbitartrate. while primarily of the greatest advantage for effecting separation of l-(-methylphenethylamine. by the use of d-tartaric acid alone and with separation also of d-amphetamine. as will now be evident. as for example. 80% ethanol. yielding a further fraction of l-amphetamine d-tartrate which may be purified by recrystallization. yielding a further fraction of damphetamine d-bitartrate which may be purified by recrystallisation. and heating to about boiling point. provides also procedure for the separation of d-amphetamine. On recrystallisation the preponderance of the l-enantiomorph is increased and the process is repeated until no further change in optical rotation is effected and a reading of [(]20(D = -6. by evaporation. The product thus obtained is l-amphetamine d-tartrate.As will be appreciated.. As more specifically illustrative of the method in accordance with this invention for the separation of the l-enantiomorph form. The solution is then allowed to cool to room temperature with occasional stirring to effect crystallisation.8 are obtained in a concentration of 8 grams per 100cc of aqueous solution. Again. the mother liquors comprise alcoholic solutions by dividing the total volume of the mother liquors into equal parts. Repeated crystallisation is then carried out until crystals having an optical rotation [(]20(D = +30. which may now be separated by effecting neutralisation of the excess of d-tartaric acid present with production of neutral tartrates and effecting separation of the l-amphetamine d-tartrate by crystallisation. as in the case of the example above. Following the procedure according to this invention it will be apparent that the l-enantiomorph may be initially separated from the racemic amphetamine. adding excess alkali. in addition to the tartrates initially obtained.2 mols of tartaric acid and the resulting bitartrate is dissolved in. with an organic or inorganic acid corresponding to the salt desired. a neutral salt. of absolute ethanol. etc. the dextro form will first be separated by crystallisation following treatment with d-tartaric acid to form d-bitartrates and the laevo form will then be recovered by crystallisation following neutralisation with the formation of neutral d-tartrates. The residual solid in the mother liquors now remaining comprises a preponderance of l-amphetamine d-bitartrate. may be obtained by exact neutralisation of either optically active base with the acid corresponding to the desired salt. hydrochlorides. Following the procedure in accordance with this invention. the following procedure may be employed and will be found to be efficient. Two mols. any desired organic or inorganic salt of the optically active isomers. by way of example. The residual solid in the mother liquors is repeatedly and systematically crystallised. separates as an oil. The solution is then allowed to cool to about 60(C and filtered hot. as has been indicated. which will cause the base to separate as an oil which may be recovered and purified by any well known procedure. as for example. the alcohol from one part. liberating the free base. The residual solid in the mother liquors is repeatedly and systematically crystallised. other salts of the optically active isomers may be obtained from the free bases of the isomers by exact neutralisation of either base. Such procedure will result in the formation of a neutral d-tartrate solution. The free base of either optically active isomer may be obtained by addition to the d-tartrate in the case of the laevo isomer and the d-bitartrate in the case of the dextro isomer of alkali in excess. sulphates. As a further example. which. of racemic amphetamine base are reacted with one mol (150 grams) of d-tartaric acid. thereby forming a dl-amphetamine d-tartrate. for example. say about 1 litre. d-amphetamine may be readily recovered from the mother liquors by the addition of tartaric acid thereto for the formation of acid tartrates and separation of d-amphetamine d-bitartrate by crystallisation. by the addition of an aqueous solution of caustic soda. with heating almost to the boiling point. 270 grams. racemic amphetamine. separating and drying the free base with for example. for example.and l-amphetamine in which the laevo form is present in amount not substantially less than the dextro form with the use of d-tartaric acid for the formation of neutral d-tartrates . oleates. Thus.
1711 OCDS Vol. The free base of either optical isomer may be obtained by addition to the d-tartrate in the case of the levo isomer and the dbitartrate in the case of the dextro isomer of alkali in excess. 1 p. 1450. The neutral salt thus obtained is fully dissolved by the addition of sufficient. and heating to about the boiling point.P. 270 grams. The crystals are filtered off and will be found to contain a preponderance of the levo enantiomorph. or a mixture in which the dextro form is not in substantial excess. thereby forming dl-amphetamine d-tartrate. Reference: US patent 2. for example.S.276.N. resulting in separation of the free base as an oil which may be recovered and purified by any well known method. by the addition of an aqueous solution of caustic soda. as. as in the case of mixtures in which the dextro form predominates. whether the procedure be for the initial separation of the lamphetamine d-tartrate. say about 1 liter..757 RESOLUTION OF RACEMIC AMPHETAMINE Two mols. U. The solution is then allowed to cool to room temperature with occasional stirring to effect crystallization. d-amphetamine may be readily recovered from the mother liquors by the addition of tartaric acid thereto for the formation of acid tartrates and separation of d-amphetamine d-bitartrate by crystallization.508 RESOLUTION OF RACEMIC METHAMPHETAMINE 85 parts of racemic methamphetamine are introduced into a solution of 100 parts of d-tartaric acid in 1000 parts of methyl alcohol. or is preceded by preliminary separation of the dextro form by known methods. of absolute ethanol. 301 REM p. l-amphetamine may be readily obtained from the l-amphetamine d-tartrate by treatment of the d-tartrate with alkali in excess. . which will cause the base to separate as an oil which may be recovered and purified by any well-known procedure.and separation of l-amphetamine d-tartrate by crystallisation . F. After protracted standing about 100 parts of the precipitated salt are aspirated off and extracted with hot ethyl alcohol.276. p. Since the d-tartrate of dextrorotary methamphetamine is readily soluble in both methyl and ethyl alcohol whereas the d-tartrate of levorotary methamphetamine is sparingly soluble both in methyl alcohol and hot ethyl alcohol an extremely simple separation of the d-tartrates of the optical antipodes of the base is effected. for example. a neutral salt.881 Nabenhauer. References y y y y y Merck Index 2918 PDR pp. The residual solid in the mother liquors is repeatedly and systematically crystallized. Reference: British Patent 508.508. March 17. It will be understood that proceeding in accordance with this invention the free base. of racemic amphetamine base are reacted with one mol (150 grams) of d-tartaric acid. The base is exactly neutralized with sulfuric acid to give the sulfate. yielding a further fraction of amphetamine d-tartrate which may be purified by recrystallization. 1942.70 (1977) I. as from racemic amphetamine. Patent 2.
O-Dibenzoyl-2R. Selective Extraction of d-Methamphetamine with d-Tartaric Acid: Rusznak et al. Teljes.l or (+. The resulting suspension was stirred at 5°C overnight. 1. The precipitated salt were dissolved in 30ml 2N NaOH and extracted with 3x25ml dichloromethane.50 g. The racemic mixtures may be referred to as d. Appl. and 18. Using 3ml methanol in the above procedure gave d(+)-methamphetamine in 93% yield and 85% optical purity. C. which can be dissolved in diethyl ether and bubbled with dry HCl gas to obtain the crystalline hydrochloride salt. d-tartaric acid 82. Selective Crystallization of Methamphetamine with d-Tartaric Acid: Rusznak et al. (+). A mixture of phenylisopropylmethylamine 150.1 mole (13.8ml methanol gave 78% yield in 98% optical purity. 0.4-6 moles hydrogen chloride. D or S isomer.05 mole dtartaric acid (7. below which utilizes a selective extraction rather than the usual crystallization.C07B).516.520. C07B). After drying over MgSO4. and 2 g sodium hydroxide (reagent grade or titrated equivalent) in 3 ml water was kept 4 hours with intermittent shaking. then filtered. the methamphetamine freebase was obtained. The D-enantiomer (58 g as the HCl salt) was isolated from the filtrate.O-DIBENZOYL- Using O. and the organic phase evaporated to give 98% L-phenylisopropylamine. Hung.A.A. 1976. methamphetamine base) in 60 ml benzene. L or R isomer.RESOLUTION EXTRACTION OF RACEMIC METHAMPHETAMINE USING SELECTIVE The dextro isomer of amphetamine and methamphetamine is the d. p.5. 518 (1976).4g (25 mmol) O.52 g. Phenylisopropylamines and phenylisopropylmethylamines and various substituted amines were resolved with 0. p.O-Dibenzoyl-2R. . RESOLUTION OF RACEMIC METHAMPHETAMINE R. 28 Sep. Teljes.) in 30 ml water. Resolution of 1-Phenylisopropyl methyl amine. 12. The precipitate was washed on the filter three times with 5°C dichloroethane and air dried under a heat lamp.. and H2O 330 g was treated with HCl to pH 4 to deposit 120 g L-phenylisopropylmethylamine-d-tartrate salt.4-6 moles of dextro tartaric acid in water or aqueous ethanol containing 0. 518 (1976). 85: 192337q. 1976. 08 Nov..5 mole sodium hydroxide or potassium hydroxide by selective extraction of either enantiomer. 85: 192335n. The aqueous phase was extracted with benzene at pH 13 and evaporated to give 96% D-enantiomer. Resolution of Phenylisopropylamines. Appl.3R-Tartaric Acid (made by acylating L(+)-tartaric acid with benzoyl chloride) in dichloroethane/methanol/water.210 (Cl. (-). Classical resolution techniques are often tedious and usually afford poor yields. Hung. Experimental 15.R-TARTARIC ACID USING O. 28 Sep. with an optical purity of 85-98%. racemic methamphetamine can be resolved in 80-95% yield. The best published procedure seems to be that of Rusznak et al. 1974. 1. the levo isomer is the l.5 mole tartaric acid in benzene-water containing 0. C. 12.208 (Cl. 04 Dec. 1974. A solution of 9.3R-tartaric acid in 40ml of dichloroethane and methanol (see amounts below) was added to the two-phase solution during 30 minutes at room temp. From the stirred solution the crystallization starts in 10-15 minutes. filtering and evaporation of the solvent.92 g. Phenylisopropylmethylamine was resolved by treatment with 0.0g (100 mmol) of racemic methamphetamine freebase was dissolved in a mixture of 20ml dichloroethane and 15ml water.-) or DL or (R)(S).) phenylisopropylamine (or 14. which gave 88 g L-phenylisopropylmethylamine. A mixture of 0.
4315-4319 (1999) .Reference: Synthetic Communications 29(24).