Olivetol is an important precursor for tetrahydrocannabinol and its analogues. But since it's one of the DEA watched chemicals, not a lot of clandestine chemists are interested in classic tricyclic cannabinoid synthesis. there are several ways to synthesize olivetol, but most of them accompanies exotic chemicals and complicated lab techniques. This one I'll share uses relatively acquirable precursors and glasswares with reasonable yields. I've done this several times in lab and usually the purity doesn't go lower than 90% (via GC/MS). It's still quite complicated but it's the best bet IMO. Use of various condensers and vacuum distillation required.
I'm pretty sure you can buy olivetol directly from some chemical suppliers. And I usually does so too. Synthesizing it is for the last resort.
Part 1 : synthesis of 3-hydroxy-nonan-2-one
1, 159.4 g(1 L) of acetone and 200 mL of 10% aquous KOH is reacted in 3 L 3 neck RBF for 0.5h, 30'C with sturring, reflux condencer, thermometer, and one neck with stopper
2, While the reaction 1 proceeds, prepare n-hexanal and acetone solution by mixing 81.5 g hexanal and 79.7 g acetone.
*normal-hexanal is used in perfume industry and can be purchased from chemical suppliers. It's also known as "Aldehyde-C6"
3, Add the solution made in step 2 to three neck RBF in step 1 using dropper funnel under 1 hr period. Keep the temperature in 30'C.
4, After the addition is complete, let the reaction proceed for 100 mins. after that, adjust the ph to 7 to stop overreaction, using phosphoric acid.
5, Let the phase divide and separate the organic phase. distill off the residual acetone(bp 56'C).
Part 2 : conversion of alcohol to alkene
1, Take 20 g of above prouct in 250 ml RBF. add 9 g of water, and adjust ph to 2 with phosphoric acid.
2, Attach the reflux condenser and slowly heat the mixture under reflux for 2 hrs.
3, After the reaction, the product was extracted with ethyl acetate 3 times.
4, Combine all organic layers and remove the solvent by distillation. - discard the solvent or redistill it for other uses(not recommended)
5, Pull the vacuum and distill the ketone(bp about 62~65'C under 3 mmHg).
6, The resulting ketone is mixture of 3-nonen-2-one and 5-undecane-5-carboxaldehyde by 10:1. Physical properties of both are pretty similar and difficult to separate.
but it can be used in next process without further purification.
Part 3 : Cyclic ketone intermediate.
Now where it gets hard(kinda).
1, Make solution of 32.4 g of sodium methoxide and 90 g dimethyl malonate in 230 ml of anhydrous methanol.
*sodium methoxide can be prepared by reacting sodium metal with anhydrous methanol. Dimethyl malonate can be hard to come by, but quite a lot of chemical suppliers have it in stock.
2, 75g of 3-nonen-2one from part 2 is added to 500ml RBF. with magnetic stiring, solution from 1 is added dropwise.
3, The reaction mixture is refluxed 3 h under nitrogen atmosphere.
*use anhydrous CaCl2 or silica gel tube to dry nitrogen gas from cylinder.
4, After the reaction is done, solvent is distilled off and residue is dissolved in 350 ml of water.
5, There'll be slurry of white crystals in clear solution. Extract them with 80 ml of chloroform 3 times(let the crystals stay in aquous solution) and acidify the aquous solution to ph 4 with hcl.
6, the crystals are filtered and dried to give methyl 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2ene-1-carboxylate at 90~95% yield.
Part 4 : Olivetol
1, Make solution of 58.4 g of above ketone in 115 ml of DMF. Refridgerate the solution to ice cold.
2, Make the solution of 37.9 g of bromine in 60 ml of DMF
3, 500ml 3 neck RBF is charged with ice cold ketone solution 1. Put magnetic stirring, thermometer and reflux condenser. And the bromine solution is added dropwise.
4, At the end of the addition(about 90 mins), reaction mixture is slowly heated to 80'C. The carbon dioxide evolution will become quite vigorous. Keep the reaction temperature in 80'C until the gas evolution ceases.
5, Mixture is heated to 160'C. Hold this temperature for 10 hrs.
6, DMF is removed by distillation and residue is treated with 80 ml of water.
7, the solution is extractd with 250 ml ether 2 times and combined ether layer is washed with 2X80 ml 10% aquous NaHSO3, and 2X80 ml 10% aquous acetic acid.
8, the ether is removed by distillation and remaining viscous oil which solidifies on itself is our product.
9, the oil itself is reasonably pure but you can purify it by recrystallization or distillation with vigreux column. Yield is about 50~60%
And there it is. Olivetol! It's quite difficult and time consuming process. Maybe later I can write up some different olivetol derivatives for possibly legal THC analogues and classical cannabinoids synthesises from olivetol.
Huge thanks for the read!
I'm pretty sure you can buy olivetol directly from some chemical suppliers. And I usually does so too. Synthesizing it is for the last resort.
Part 1 : synthesis of 3-hydroxy-nonan-2-one
1, 159.4 g(1 L) of acetone and 200 mL of 10% aquous KOH is reacted in 3 L 3 neck RBF for 0.5h, 30'C with sturring, reflux condencer, thermometer, and one neck with stopper
2, While the reaction 1 proceeds, prepare n-hexanal and acetone solution by mixing 81.5 g hexanal and 79.7 g acetone.
*normal-hexanal is used in perfume industry and can be purchased from chemical suppliers. It's also known as "Aldehyde-C6"
3, Add the solution made in step 2 to three neck RBF in step 1 using dropper funnel under 1 hr period. Keep the temperature in 30'C.
4, After the addition is complete, let the reaction proceed for 100 mins. after that, adjust the ph to 7 to stop overreaction, using phosphoric acid.
5, Let the phase divide and separate the organic phase. distill off the residual acetone(bp 56'C).
Part 2 : conversion of alcohol to alkene
1, Take 20 g of above prouct in 250 ml RBF. add 9 g of water, and adjust ph to 2 with phosphoric acid.
2, Attach the reflux condenser and slowly heat the mixture under reflux for 2 hrs.
3, After the reaction, the product was extracted with ethyl acetate 3 times.
4, Combine all organic layers and remove the solvent by distillation. - discard the solvent or redistill it for other uses(not recommended)
5, Pull the vacuum and distill the ketone(bp about 62~65'C under 3 mmHg).
6, The resulting ketone is mixture of 3-nonen-2-one and 5-undecane-5-carboxaldehyde by 10:1. Physical properties of both are pretty similar and difficult to separate.
but it can be used in next process without further purification.
Part 3 : Cyclic ketone intermediate.
Now where it gets hard(kinda).
1, Make solution of 32.4 g of sodium methoxide and 90 g dimethyl malonate in 230 ml of anhydrous methanol.
*sodium methoxide can be prepared by reacting sodium metal with anhydrous methanol. Dimethyl malonate can be hard to come by, but quite a lot of chemical suppliers have it in stock.
2, 75g of 3-nonen-2one from part 2 is added to 500ml RBF. with magnetic stiring, solution from 1 is added dropwise.
3, The reaction mixture is refluxed 3 h under nitrogen atmosphere.
*use anhydrous CaCl2 or silica gel tube to dry nitrogen gas from cylinder.
4, After the reaction is done, solvent is distilled off and residue is dissolved in 350 ml of water.
5, There'll be slurry of white crystals in clear solution. Extract them with 80 ml of chloroform 3 times(let the crystals stay in aquous solution) and acidify the aquous solution to ph 4 with hcl.
6, the crystals are filtered and dried to give methyl 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2ene-1-carboxylate at 90~95% yield.
Part 4 : Olivetol
1, Make solution of 58.4 g of above ketone in 115 ml of DMF. Refridgerate the solution to ice cold.
2, Make the solution of 37.9 g of bromine in 60 ml of DMF
3, 500ml 3 neck RBF is charged with ice cold ketone solution 1. Put magnetic stirring, thermometer and reflux condenser. And the bromine solution is added dropwise.
4, At the end of the addition(about 90 mins), reaction mixture is slowly heated to 80'C. The carbon dioxide evolution will become quite vigorous. Keep the reaction temperature in 80'C until the gas evolution ceases.
5, Mixture is heated to 160'C. Hold this temperature for 10 hrs.
6, DMF is removed by distillation and residue is treated with 80 ml of water.
7, the solution is extractd with 250 ml ether 2 times and combined ether layer is washed with 2X80 ml 10% aquous NaHSO3, and 2X80 ml 10% aquous acetic acid.
8, the ether is removed by distillation and remaining viscous oil which solidifies on itself is our product.
9, the oil itself is reasonably pure but you can purify it by recrystallization or distillation with vigreux column. Yield is about 50~60%
And there it is. Olivetol! It's quite difficult and time consuming process. Maybe later I can write up some different olivetol derivatives for possibly legal THC analogues and classical cannabinoids synthesises from olivetol.
Huge thanks for the read!