A-PHP Synthesis

This is designed for the home chemist.
Literally everything I used, I bought online for cheap.

Stuff you will need:

Equipment (all from eBay):

Hotplate stirrer
Cold water circulator apparatus (bucket of ice water with a pump and 2 hoses attached to a condenser)
250 ml flat bottom flask
Magnetic stirbar
Mercury thermometer
Sepratory funnel
Pipette
Graduated cylinder

Chemicals (& sources!):

L-proline (commonly sold as vitamin on Amazon or eBay)
Benzene (eBay)
Caproic acid (as fishing bait scent aroma on eBay)
Anhydrous aluminum trichloride (eBay)
Phosphorus pentoxide (eBay)
Water (preferably distilled from CVS)
Sodium Bromide (Spa additive eBay)
TCCA (trichlorocyanauric acid - pool chlorinator search "TCCCA" on eBay. Yes it's a typo)
Dichloromethane (eBay or can be distilled from paint stripper)
Hydrochloric acid (eBay or hardware store)
Acetophenone (eBay)
Sodium hydroxide (powdered drain opener)

Making hexanophenone (caprophenone):
To a 250ml round bottom flask with medium stirring was added 50ml of DRY benzene. Then 30 grams of anhydrous aluminum Chloride and 19 grams of phosphorus pentoxide. This was stirred for a minute until a nice suspension is formed. Next attach a condenser with no water flowing through it yet. Measure out 15g of caproic acid. Add this slowly dropwise and let it drip through the condenser. Then quickly turn on the water flow with ice cold water flowing. Reflux for 2 hours. If the mixture becomes too thick, mix temporarily with something metal. Detach the flash from the condenser and allow to cool to room temperature. The flask will be a mess. There will be this gross black goop inside. Don't worry this is normal. Once cooled, add a few drops of ice water to the flask. There will be some fizzing. This is the water reacting with the left over ACl3 and PO5. One the fizzing is died down add a little more. Stick in a thermometer then slowly add about 100ml more of water. The water will boil. Then add 12ml of 36% HCL. Make sure the temperature is above 32C if not, warm on a hotplate. You should have 2 layers and a precipitate at the bottom. Working quickly with the temp above 32C. Pour into a sepratory funnel. The hexanophenone will be the top brown layer. Empty out the bottom layer and discard it. Empty the top layer into a clean container and place in the fridge for 3 hours. Filter the crystals on a vacuum pump and wash with 5 × 50ml of ice cold water. You should have some brown crystals. Put the crystals in a dish and let them melt. Once melted you can move to the next step or wash them a few times with water in a sepratory funnel if needed.

Making the pyrrolidine:
NOTE: You can skip this if you have pyrrolidine. I searched everywhere and can't find it so here's how to make it.
Measure out 20g of L-proline. Use a scale and don't you dare eyeball it. This stuff is very light and you will need a lot more than it looks. Next measure out 75ml of acetophenone. Put this in a 2-neck round bottom flask and get this stirring. Set up a hot oil bath (metal container with cooking oil) place the flask in the and attach a condenser with water flowing. Heat this up to 150C. If you have trouble getting the temperature this high, wrap the flask in some tin foil, but make sure nothing escapes out the condenser! The mixture will begin to reflux. At about 135C, you can start to smell the pyrrolidine. There will be lots of bubbling of CO2 and the mixture will turn orange. After 45min have passed remove the oil bath and let the flask cool. Not measure out 30ml of 36% HCL. And add water to the HCL until it's adds to 100ml. Add this to the cooled flask and stir for 15 min. Put into a sepratory funnel and drain the lower layer. This has the pyrrolidine in it. Keep the top layer in the sep funnel and add 50ml of water to it. Shake and then drain off the bottom layer into the pyrrolidine that you collected before. Do this one more time then discard the the upper layer. So now you should have the seamen smelling layer with the two 50ml extracts in it. Put this back in the sep funnel. Make a strongly basic mixture by adding 20g of NaOH to 30ml of water. Stir this until it dissolves. This will get hot, let it cool some. Then add this to the pyrrolidine-water mixture in the sep funnel. There will be some slight fizzing and stuff. Let this die down and then separate the bottom layer and discard the top layer. Now set up for distillation. Yes this will be the only distillation you will do (be thankful). Keep the column at 88-94C keep it as low as possible. We do not want water to distill over. Although there will be an inevitable little amount water in the distillate no matter what you do. But we want to keep it at an absolute minimum. After distillation, there will be some black tar in the boiling flask and some lovely smelling distillate.

Making alpha-php:

Introduction: This 2 step synthesis produces Alpha-pyrrolidinohexanophenone. The first step is brominating the second carbon on the skeleton of hexanophenone to form a-2-bromo-hexanophenone. Then in the second step, rearranging the Br with the nitrogen of the pyrrolidine to form the product.  The specific quantities used in this synthesis are not recommended for economical use. The small amounts are to test the skills of the chemist performing the synthesis. Once familiar with the procedure, the quantities can be scaled up, greatly increasing yields.

1) To a 100ml RBM with a flat bottom with medium stirring, add 1.5g of hexanophenone. Wash the beaker with 5ml of DCM that contained the hexanophenone and add it to the flask.

2) Add a room temperature water bath to the apparatus. Next, add a vacuum tube into the flask on low suction to suck out the HBR gas that will be produced in the next step. Measure out 4g of bromine solution.

3) Add one drop (0.5ml) to the flask and wait for the bromine color to disappear. Then add the next drop and wait. Continue this process until all 4g of bromine solution is added. Full addition time should take about 15 minutes. Stir for an additional 20 minutes. Then gently heat until all DCM has evaporated and left with a small amount of amber liquid. Allow to cool to RT. This is our a-2-bromohexanophenone intermediate compound.

3) Next, with strong stirring, inject 1.125g of pyrrolidine into the flask. This route of addition is recommended so that little to no pyrrolidine is wasted.

4) Attach a Liebig or Allihn water condenser to the flask and heat to boiling (approx. 90C) Reflux for 1 hour. A precipitate will form. If a boiling point cannot be reached, remove the water bath although this can result in loss of product.

5) After 30 min, allow to cool to RT. Add the contents of the flask to a vacuum filter and wash the reaction flask with 10 ml of benzene and add to the vacuum filter. Filter the contents on the pump and wash the precipitate 2 × 10ml of benzene. Keep the pump running until dry. Approximately 600mg of freebase product is obtained.

6) To convert the product to the HCL salt, make a solution of the product in 25ml of ethyl acetate. Bubble HCL gas through the solution and vacuum filter the precipitate. Wash the precipitate with 2 × 10ml of ether. Dry the product and collect to yield around 500mg of Alpha-pyrrolidinohexanophenone HCL (alpha-PHP)