Anthranilic acid from Phtalimide

When it comes to Quaalude chemistry we still have one major victory left: An useful/simple/OTC anthranilic acid from naphthalene synthesis. Rhodium has a long time ago pointed out that phthalimide could probably be converted to anthranilic acid using a commercial NaOCl solution such as "Clorox". So I called my friend Dr Dream, authorized researcher in Europe.

He told me he had not used "Clorox" but a product called "Alclorite", this is pretty much the same as I understand it. But "Alclorite" is preferred (perhaps essential!) because "Clorox" contains tensides (sp?) that we don't need for our purposes. BTW Alclorite is supposed to contain 3.5% (w/w) NaOCl.

In great detail Dr Dream told me about three more or less successful tests:

Test #1

225ml Alclorite and 10.0g NaOH were mixed in a 500ml Erlenmeyer. 8.0g NaOH and 80ml H2O were mixed in another 250ml Erlenmeyer. 15.0g phthalimide was grinded to a very fine powder. The Alcorite solution was cooled to about 0°C, perhaps a bit cooler. Half of the phthalimide was added in portions, the solution was again cooled in the freezer before the rest was added, in portions. When it was all dissolved the solution was a bit yellow-orange.

The 80ml NaOH solution from above was added and the temperature was raised to 80°C and held there for two minutes. Brought it back to room temperature using cold water.

Transferred the mixture to a 1000ml beaker and neutralized it with about 110ml of 10% hydrochloric acid. The pH was 7.0-7.5. A precipitate formed and it was removed by filtration. (After drying in an oven the amount was 1.93g). Now glacial acetic acid was added to the solution, a total of 22ml was used. A lot of CO2 was formed. A mess precipitated and the solution was filtered. Rather dirty but not hopelessly dirty "crystals" were collected. They were dried in an oven at 100°C (darkened a little bit) and before further purification the yield was 8.48g (60,6%).

Test #2

260ml Alclorite (15-2/15 = 225/260, just a thought) and 12.0g NaOH were mixed as above and cooled to -10°C. A NaOH solution in water was prepared just as above and cooled to +4°C. 15.0g Phthalimid was grinded into a very fine powder and added in portions, while stirring fast, to the Alclorite solution. When it had all dissolved the solution was not more (Alclorite is slightly yellow) colored at all, quite the opposite in fact. The temperature of the solution was now +5°C. Added the 80mls of NaOH solution and begun to heat the mixture. At 30°C it quickly turned rather deep orange/red/brown. Heated it up to 90°C let it cool to 80°C over 5 minutes and then cooled it actively. The solution was much more colored then in Test #1. Neutralized the solution in a 1000ml beaker with a little less then 50ml 30% hydrochloric acid. A precipitate was formed, proceed as above and got 2.34g dirty phthalimide back (It "must" be phthalimide, it will not dissolve in water, has no taste at all (slightly salty but that is because of the NaCl solution it came from), and it look like phthalimide).

Now GAA was added as above, 20ml, which was more than enough. Filtered, dried, and ended up with 11.83g of very, very dirty crystals. 11.83g was more then possible if we consider the >2g phtalimide we got back, and the fact that the solution was colored as hell. Well, the yield of PURE crystals from this will be much lower.

Test #3

210ml cold Alclorite and 8.0g was mixed in a 500ml Erlenmeyer and we cooled it to -10°C. 80ml ~10% NaOH solution was prepared as before and cooled to +5°C. 15.0g Phthalimide as a very, very fine powder was added, all at once, and the flask was plugged and stirred at 1600rpm. The solution became as above not more colored then before, rather less colored. Cooled it again to +3°C. Added the NaOH solution and put the solution in the cold fridge (+3°C). I stood there overnight (yes, even Dr Dream sleeps). Now it was placed in room temperature and left there for 3.5 hours. At ~20°C it was just as achromatic as before. Heated it to 85°C and kept it there for 5 minutes, the solution hardly darkened at all! (2 minutes at 80°C would possibly not be noticeable!). Cooled fast to room temp, then further to +5°C. Neutralized with 31.5ml 30% hydrochloric acid (this made the solution yet a bit more colored, but not much compared to Test #1). Solution got cloudy, filtered, 2.07g when dry. Now GAA was added (solution in 1000ml beaker!), 15ml was probably enough, but we added 20ml. Nice crystals formed! filtered and dried. Only very slightly yellow/brown, maybe pure enough for whatever uses. The yield was a fair 9.42g (67.4%). When we subtracted for the 2g phthalimide we got back, the effective yield of almost pure crystals was 77.7%!

So if you do just as Dr Dream did, everything should be just fine, but the nice doctor also e-mailed me this step by step method:

1. In a 250ml Erlenmeyer mix 80ml H2O and 8.0g NaOH, cool to about +5°C and don't mess with it until later. To another 500ml Erlenmeyer add 210ml Alclorite (or other ~3.5% NaOCl solution, 215ml is 0.1mol) and cool this to +5°C or cooler. Then add 8.0g (0.2mol) NaOH to the now cold Alclorite solution, by precooling it we prevent the temperature from getting too high. Cool the NaOH/Alclorite solution to -10°C in the freezer (If you check the pH of the Alclorite you will find it to be 12-13, but this doesn't mean that I contains much NaOH from the beginning, a 0.05% solution has pH 12).
2. Grind 15.0g (0.1mol) phthalimide to a very, very fine powder. Now add this to the cold (-10°C) Alclorite solution, plug the flask and mix with magstirrer on fastest setting (or shake). The phthalimide will dissolve within 5 min and the solution will not be more colored than before. Place in the freezer again for at least 30 minutes.
3. Now add the cold NaOH solution prepared above to the cold (not over +5°C) Alclorite solution, nothing happens. Let stand in room temperature until it reaches 20°C. Now heat to 80-85°C over 10 minutes and hold there for at least two minutes but not more then five. The solution will be a little less achromatic now, but only slightly. Cool in water to room temperature or preferable below so the awaiting hydrochloric acid addition will not heat it up to much.
4. Transfer the solution to a 1000ml beaker, keep some (~20-30ml) in the Erlenmeyer flask. Stir at medium speed on a magstirrer. Now begin to add hydrochloric acid, the ~30% OTC version will do more then fine. You can probably add the first 25ml rather careless. But now you must measure pH, by adding acid drop by drop and using the saved solution (the 20-30ml above) as backup you should eventually have a nice pH 7.0 solution (if you mess this up, a pH above 7.0 is MUCH better then getting it below 7.0). The solution will become a little more colored when you add the hydrochloride acid.
5. At this point your solution has probably become cloudy because of a precipitate, this must be unreacted phthalimide (about 2g) so filter (suction!) and save it. Now you will have a clear solution again.
6. Again add your solution to a 1000ml beaker, make sure the temperature is about +20°C or below. Strirr at medium speed and begin to slowly add glacial acetic acid. If foaming has not begun after the two first milliliters, you probably should have neutralized better above, but just keep adding acid. A lot of CO2 is formed so add it slowly. 15ml will probably be enough, but some extra milliliters will do no harm. The antharanilic acid will precipitate, as you add the GAA.
7. Filter (Buchner, plastic cover to such away solution) and dry the crystals in an oven at +50°C (higher temperature might darken the crystals) for several hours. The resulting powder should be slightly yellow/brown but NOT much. The yield at this point would probably be over 9g. Recrystallisation from water with some decolorizing carbon present will give nice clean crystals.
8. After some runs you can grind up the saved phthalimide and reflux it in water (10-15ml/g, it will not dissolve) for half an hour, then cool and filter to get pure phthalimide ready to be reused.

There might be even better ways to perform this, don't lock your thinking bees. Always assume that every synthesis you find can be improved!

-Methaco(s)mic (send PGP key or no replay)

Anthranilic acid to quaalude, by Methaco(s)mic

So Dr. Dream picked up those small glass jars he had in the fridge and begun to play. The crappy product from "Test #2" was soon discarded, that run was fucked up good. The second runner up product from "Test #1" was another story. First a simple recrystallization from a dH2O/EtOH mixture, then recrystallization from the same type off mixture but with decolorizing carbon present (about 300mg). This was messy; Dr. Dream has not been working with carbon in quite some time.

The result from "Test #1" was 6.24g nice glistering flake-like crystals, even though they looked nice the colour was not so nice, like "brown sugar" (not heroin ;). Sloppy carbon usage technique, I believe. More correctly the individual crystals were a bit like needles, but they formed flakes by grouping side-by-side.

The product from "Test #3" was worked up in similar manner, but the first recrystallization was omitted. The result was 6.83g of product that looked exactly as the one described above. No doubt it was the same thing.

In both cases the product was allowed to dry for 24 hours on a glass dish in room temperature, prior to weighting and further procedures.

In retrospect, knowing more than the reader does so far, I think the best thing is to; perform the Step-by-step in my "last paper", when the non reacted phthalimide precipitates add some (2-300mg) decolorizing carbon and see what happens. Then filter and proceed, use the product for The Next Step without yield lowering post synthesis purification.

The Next Step:

The first 6.24gs was placed in a 100ml RB flask. 5.0ml Acetic Anhydride was added, 4.7ml would have been 1:1, but it was an old bottle, the air is not dry this season and so on. Just after the entire dry material had turned damp, things went really hot, there was a reaction going on for sure! I "stirred" with a glass rod; no external heat was applied, after half an hour of doing this, things had cooled down. The slightly gray product looked dry but the smell of Acetic Acid was strong. Left it in room temperature for 24 hours, after this most of the Acetic Acid smell was gone.

In a similar manner the 6.83gs with origin from "Test #3" was put into another 100ml RB flask ~5.5ml Acetic Anhydride was added; again this was more than enough. Things went hot, and this time external heat was applied. Everything was wetter in this run, compared to the previous one. The lightly grayish product was left overnight, but was not dry (free from Acetic Acid) when The Last Step was performed.

If the modification I proposed above is used, I assume this product will not be very pure. To make The Last Step more foolproof, recrystallization from dH20/EtOH (50/50 as invented by Cheapskate) could probably be worth the extra time and work. Anyhow, I did not purify my suspected N-acetyl-anthranilic acid after this step.

The Last Step:

To the first of the two RB flasks above was added 6.0ml o-Toluidine. As soon as this was done the RB flask was emerged in an oil bath preheated to 190°C. The reaction begun after just a few minutes, after only an hour (with the temperature held between 189-193°C) the reaction died. Another 1.0ml o-Toluidine was added and the mixture held at about 190°C for another 30 minutes. Now the mixture was poured into a 250ml beaker with 100ml 0.2% NaOH (200mg NaOH added) solution. After some hours in the fridge "the mess" was almost solid and the water was poured off. 50ml Acetone was added, and it was slightly heated to make "the mess" dissolve. 2.0ml 37% HCl was added. After a night in the fridge, no crystals, added another 1.0ml 37% HCl and about 15ml Acetone and put the beaker in the freezer (-10°C). Crystals precipitated in the same manner as I have seen before using this method. Left it there for 24 hours to ensure complete precipitation. Filtered and boiled in Acetone to get 4.34g Methaqualone that was pure enough for consumption.

To the second RB flask 6.5ml o-Toluidine was added, everything got wet (the powder was damp already, remember?). After ~10 minutes at room temperature it had solidified (!?). After this delay it was emerged in a 190°C oil bath. The temperature was about 195°C, after 30 minutes it was 220°C, by mistake (my corn-oil smoked ;). Brought it back down to 200°C and kept it there until the total time was 90 minutes. At the one hour point the reaction was dead though. The mixture was dumped into a weak NaOH solution in the same manner as above. This time "the mess" was a bit browner and not so much the usual purple tint, that 220°C top sure was overkill. I might add that I use a Claisen adapter on the RB flask as some kind of condenser, the water leaves just fine even with it on. It almost solidified in the fridge as above and the same method was used. Off with the NaOH solution, mixed with ~60ml Acetone and added 3ml 37% HCl, put in the freezer for 24 hours. Just as before, crystals appeared after many hours in the freezer. Again I filtered and boiled in Acetone to get 4.80g rather pure Methaqualone.

The yield in the last step was rather low (this has been the case for Dr. Dream when using N-acetyl anthranilic acid made using the KMnO4 oxidizing method too). I think the best thing to do is to recrystallize the N-acetyl anthranilic acid using EtOH/dH2O then grind the crystals to a very fine powder. After this, the powder is placed in a RB flask and 1.20mol% o-Toluidine is added and the flask swirled until all the powder is wet. Then emerge in preheated oil (~170°C), when the reaction dies at this temperature raise it fast to 190°C and keep it there until the reaction again dies.

-Methaco(s)mic (send PGP key or no replay)

Phthalimide to anthranilic acid by Cheapskate

Go to the great big building supply house and pick up a couple of gallons of swimming pool chlorination liquid. This stuff is 5% sodium hypochlorite. Yep, the same stuff as Clorox bleach but twice as strong and several times less expensive. Now go to the chemicalsupply and get a pound or so of phthalimide. This stuff costs about US$5.00 a pound and is unwatched and uncontrolled. Quantities can be purchased also in 25 pound bags, but you have to wait for it to come in.

In a 2 liter erlinmeyer flask put 200ml of the hypochlorite solution and 400ml of water. Mix well and cool to less than 30C, 20C is a perfect temperature. Now add 40g of phthalimide all at once. This is about 4 rounded tablespoons for the scale impared out there. Stir this mess rapidly. The phthalimide will not dissolve, it will get wet and mix in the solution. It'll also try to crawl up the sides of the flask a half inch or so. After a couple of minutes of stirring (the warmer the solution, the less the time. Remember cooler is better) the reaction will happen. The solution's temperature will rise and start to release gas. It will appear to boil with the phthalimide changing into anthranilic acid and foaming on the top of the now yellow colored liquid. Shake the flask and try to keep it all wet. Let the reaction proceed for 3 minutes shaking often, add an equal volume of cold water, stir to cool down and vacuum filter to collect the solids. One thing to note here is that you should use two coffee filters to filter this. This is concentrated anthranilic acid and bleach, it will eat right through the filter if you take too long filtering it. So filter quick and get the filter paper out and lay it on a couple of paper towels to wick away more of the solution. Discard the filtered yellow solution, there isn't enough product in there to bother with.

The anthranilic will try to cling to the sides of the flask and you'll have to rinse the flask a few times to get it all into the filter paper, this is ok since it will also rinse away the rest of the bleach solution leaving slightly yellow crystals.

You now have quite a pile of slightly impure anthranilic acid that needs to be recrystalized to purify. Don't you just love it when people say, "recrystalize from water."? You try this and either nothing happens and you lose your product or it comes out dirtier than when you started. To clean this stuff dissolve it in boiling water, filter and let the water cool to recrystalize the anthranilic. However, it is not very soluble in boiling water and almost not at all in cold water, so it will take a heck of a lot of water to do the job.

Do it like this: put the anthranilic in a 1 liter flask, add 300ml of water and boil. Be careful, watching it for boil over. The anthranillic acid forms long thin needle crystal that just love to attach to bubbles forming in the boiling water and foam up. This foam will easily boil out of the flack if you don't pay attention. Pour the boiling solution through 2 coffee filter using only gravity. When the boiling solution starts to cool, it will immediately crystalize into pretty white crystals. As it cools off, more will form until at around 25C it's all out of solution. The residual powder in the filter and flask needs another boiling water treatment to get some more anthranilic acid. Keep this put-powder-in-flask, boil, filter operation going until you don't get crystals in the filtered water. After all the solutions (you'll have multiple containers) have cooled, vacuum filter and dry the powder. This operation will take as much as 4 liters of water, so be patient and keep with it.

Possiblities of screw up. Heat is your enemy in the first part of the reaction, start off cool, be sure to add the water to cool it off and filter it quickly to make sure the operation doesn't proceed to far. If it gets too hot it'l turn dark and clean up is horrible. When recrystalizing don't boil the solution too long or it will turn dark. Just bring it to a boil and filter, then do the next boiling operation. DO NOT try to dissolve all of it in the water, you may be able to do it, but it will certainly turn dark and ruin the batch. Some one may read how the solubility of the anthranillic in water can be increased by adding NaOH to the water. This is true, but it will also result in the anthranilic decomposing. Keep the NaOH in the cupboard on the other side of the room. It would be best if you take it a half mile away just to be sure.

The crystals when dry are mostly small needles, that fluff up and take a lot of space for the weight. Needless to say there is substantial mechanical loss to this procedure, and it can be a pain in the butt. The yield is only around 50%, but at US$5.00 for the phthalimide and almost nothing for the sodium hypochlorite it is really cost effective and provides one with a good source of this controlled substance.