For those who's interested in tryptamine analogues might be familiar with DMT synthesis by N,N-dimethylation of tryptamine with formaldehyde and NaBH3CN.
This method is the best for clandestine lab environment due to easy access to reagents. The only drawback is the formation of tricyclic impurities when the reaction temperature gets too high.
To prevent this, reaction temperature is kept low by ice bath or dry ice-methanol bath. This reduces the formation of impurities, but it makes it harder to process large scale synthesis since it slows down the entire reaction and lowers the yield(about 30~40% on multi-hundred grams reaction. not THAT bad, to be honest).
If you have access to industrial chemicals and lab glasswares and want to synthesize DMT with high purity, the procedure using Fischer indole synthesis might be more ideal.
These procedures are from published papers and I've done it several times with different batch sizes under lab enironment. Most of them are reasonably scalable but requires lab equipments and vacuum distillation.
Part 1 : Synthesis of chlorobutanal
You can buy chlorobutanal from chemical suppliers but it can be difficult to come by.
1, 3 L 3 neck RBF is charged with 450 ml of DCM, 100 g of butane chlorohydrin(4-chloro-butan-1-ol), 360mg of free radical TEMPO. Cool the mixtur with Ice-salt bath.
2, Prepare 900ml of sodium hypochlorite bleach(7.5% - test the concentration of bleach using hydrogen peroxide and use molar equivalent of it) and use NaHCO3 solution to set pH to 6.0~8.5.
3, The bleach solution is added to flask during 10-15 minutes. Two phases will seperate and stirring must be kept strong. Keep the temperature below 25'C and let the mixture react for 2 hrs.
4, Organic layer was separated and aquous layer is extracted with 3*150 ml DCM. Combined organic layer is dried under MgSO4.
5, DCM is separated off by distillation, and product aldehyde is distilled under reduced pressure (bp 55-56'C under 16mmHg). Yield about 70%
Part 2 : Synthesis of 4-(N,N-dimethylamino)butanal diethyl acetal
Usually Fischer indole synth is done by addition of normal aldehyde to phenylhydrazines. But since dimethylamine side chain lowers the total yield, the process needs suitable modified addition group.
1, 100g of chlorobutanal is mixed with 250 ml of DCM and 138ml of ethanol. the mixture is stirred for 15 mins in 500 ml RBF.
2, Concentrated sulfuric acid is added dropwise over 0.5 hr at 25~30'C. Sulfuric acid acts as a catalyst so exact volume is not measured.
3, The solution is stirred for 3 hrs and filtered. Filtrate is washed with 300 ml of 5% aqueous NaHCO3 solution and 500ml of 10 % NaCl solution.
4, Organic layer is dried with sodium sulfate and fraction distilled. (bp 90'C under 15mmHg)
5, 100g of above product is dissolved in 200ml aquous dimethylamine solution and stirred for 15 mins. And warmed to 50'C for another 3h stirring.
6, After the reaction mixture cooled to rt, product is extracted with 2*250ml DCM. And combined organic layer is washed with 2*100 ml NaHCO3 solution and 2*100 ml brine solution.
7, Solvent is removed by distillation and residue is fraction distilled. (bp 85'C under 15mmHg). Yield about 75%
Part 3 : Synthesis of phenylhydrazine hydrochloride
Phenylhydrazine and its hydrochloride salt can be easily purchased from chemical suppliers. In case you can't afford it...
1, 10 g of freshly distilled aniline is added to solution of 30g of conc hydrochloric acid in 30ml of water. A solution of 8g sodium nitrite in 30ml of water is added with stirring over a period of 15 mins. Keep the temperature around 0'C. The solution is further stirred for another 15 mins.
2, Mixture of 60 g stannous chloride in cold 25g conc hydrochloric acid is slowly added at the rate the temperature doesn't exceed 3'C.
3, After the addition, the reaction mixture is further stirred for 4 hrs under low temperature.
4, The solid precipitate is filtered off and washed with brine solution.
5, Resulting phenylhydrazine HCl can be purified further by freebasing it with excess sodium carbonate followed by filtration and distllation and re-salt formation with HCl solution. Yield about 90%
Unfortunately, scaling up this procedure results in lower yields and more impurities due to the temperature control issues and stannous chloride hydrolysis.
Part 4 : Synthesis of N,N-DMT
1, 120 g of phenylhydrazine HCl solution in 1.45 L water is charged in 5L 4 neck RBF. Stirring, reflux condencer and thermometer is attatched. The flask is flushed with nitrogen and stirred at 30~35'C.
2, To the suspension, 47.7 ml of conc. sulfuric acid is cautiously added under N2 atmosphere over 10 mins while maintaining the temperature below 40'C.
3, The solution (might be brown or red) is heated to 35~40'C and stirred for additional 10 mins.
4, While the reaction proceeds, a solution of 165.0g 4-(N,N-dimethylamino)butanal diethyl acetal in 580ml acetonitrile.
5, After 10 mins, solution 4 is added dropwise over 60 mins while temperature is maintained at 35~40'C. After addition, addition funnel is rinsed with acetonitrile(about 140ml) and added dropwise to the reactor.
6, The contents are stirred for additional 4 hrs while temperature is maintained at 40'C.
7, The mixture was cooled to rt and washed with 2*2L 2-methyl-THC(optional)
8, To acidic aquous layer(whole acidic reaction mixture if not washed), 650ml of NaOH solution is added dropwise while maintaining the temperature at 20~25'C, bringing the pH to 11-12 with milky suspension.
9, suspension is extracted with 3*1.45 L 2-Me-THF, which can be substituted by isopropyl acetate or DCM.
10, The organic layers ar combined and solvented is striped off by distillation. The remaining oily residue is redissolved in solvent and reconcentrated(to remove water azeotrope).
11, Resulting residue is dried under vacuum(preferably rotary evaporator) to provide N,N-DMT freebase. Yield about 65%, purity about 95% by HPLC.
DMT with this high purity actually have no advantages over root-extracted DMT for trips. But it's one of the few scalable operation for synthetic DMT and can be used for various tryptamine analogues.
Someone might ask if it's possible for 5-MeO and 4-OH substituted tryptamine analogues. Methoxy compounds can be synthesized with 4-methoxy-phenylhydrazine but it's extremely difficult to obtain and you may have to synthesize it yourself with 4-anisidine. 4-MeO-phenylhydrazine is quite unstale in it's freebase form and its salt should be kept at low temperature.
Unfortunately it can't be done for OH substituted compounds since the acetal readily reacts with hydroxy groups on substituted phenylhydrazine.
This method is the best for clandestine lab environment due to easy access to reagents. The only drawback is the formation of tricyclic impurities when the reaction temperature gets too high.
To prevent this, reaction temperature is kept low by ice bath or dry ice-methanol bath. This reduces the formation of impurities, but it makes it harder to process large scale synthesis since it slows down the entire reaction and lowers the yield(about 30~40% on multi-hundred grams reaction. not THAT bad, to be honest).
If you have access to industrial chemicals and lab glasswares and want to synthesize DMT with high purity, the procedure using Fischer indole synthesis might be more ideal.
These procedures are from published papers and I've done it several times with different batch sizes under lab enironment. Most of them are reasonably scalable but requires lab equipments and vacuum distillation.
Part 1 : Synthesis of chlorobutanal
You can buy chlorobutanal from chemical suppliers but it can be difficult to come by.
1, 3 L 3 neck RBF is charged with 450 ml of DCM, 100 g of butane chlorohydrin(4-chloro-butan-1-ol), 360mg of free radical TEMPO. Cool the mixtur with Ice-salt bath.
2, Prepare 900ml of sodium hypochlorite bleach(7.5% - test the concentration of bleach using hydrogen peroxide and use molar equivalent of it) and use NaHCO3 solution to set pH to 6.0~8.5.
3, The bleach solution is added to flask during 10-15 minutes. Two phases will seperate and stirring must be kept strong. Keep the temperature below 25'C and let the mixture react for 2 hrs.
4, Organic layer was separated and aquous layer is extracted with 3*150 ml DCM. Combined organic layer is dried under MgSO4.
5, DCM is separated off by distillation, and product aldehyde is distilled under reduced pressure (bp 55-56'C under 16mmHg). Yield about 70%
Part 2 : Synthesis of 4-(N,N-dimethylamino)butanal diethyl acetal
Usually Fischer indole synth is done by addition of normal aldehyde to phenylhydrazines. But since dimethylamine side chain lowers the total yield, the process needs suitable modified addition group.
1, 100g of chlorobutanal is mixed with 250 ml of DCM and 138ml of ethanol. the mixture is stirred for 15 mins in 500 ml RBF.
2, Concentrated sulfuric acid is added dropwise over 0.5 hr at 25~30'C. Sulfuric acid acts as a catalyst so exact volume is not measured.
3, The solution is stirred for 3 hrs and filtered. Filtrate is washed with 300 ml of 5% aqueous NaHCO3 solution and 500ml of 10 % NaCl solution.
4, Organic layer is dried with sodium sulfate and fraction distilled. (bp 90'C under 15mmHg)
5, 100g of above product is dissolved in 200ml aquous dimethylamine solution and stirred for 15 mins. And warmed to 50'C for another 3h stirring.
6, After the reaction mixture cooled to rt, product is extracted with 2*250ml DCM. And combined organic layer is washed with 2*100 ml NaHCO3 solution and 2*100 ml brine solution.
7, Solvent is removed by distillation and residue is fraction distilled. (bp 85'C under 15mmHg). Yield about 75%
Part 3 : Synthesis of phenylhydrazine hydrochloride
Phenylhydrazine and its hydrochloride salt can be easily purchased from chemical suppliers. In case you can't afford it...
1, 10 g of freshly distilled aniline is added to solution of 30g of conc hydrochloric acid in 30ml of water. A solution of 8g sodium nitrite in 30ml of water is added with stirring over a period of 15 mins. Keep the temperature around 0'C. The solution is further stirred for another 15 mins.
2, Mixture of 60 g stannous chloride in cold 25g conc hydrochloric acid is slowly added at the rate the temperature doesn't exceed 3'C.
3, After the addition, the reaction mixture is further stirred for 4 hrs under low temperature.
4, The solid precipitate is filtered off and washed with brine solution.
5, Resulting phenylhydrazine HCl can be purified further by freebasing it with excess sodium carbonate followed by filtration and distllation and re-salt formation with HCl solution. Yield about 90%
Unfortunately, scaling up this procedure results in lower yields and more impurities due to the temperature control issues and stannous chloride hydrolysis.
Part 4 : Synthesis of N,N-DMT
1, 120 g of phenylhydrazine HCl solution in 1.45 L water is charged in 5L 4 neck RBF. Stirring, reflux condencer and thermometer is attatched. The flask is flushed with nitrogen and stirred at 30~35'C.
2, To the suspension, 47.7 ml of conc. sulfuric acid is cautiously added under N2 atmosphere over 10 mins while maintaining the temperature below 40'C.
3, The solution (might be brown or red) is heated to 35~40'C and stirred for additional 10 mins.
4, While the reaction proceeds, a solution of 165.0g 4-(N,N-dimethylamino)butanal diethyl acetal in 580ml acetonitrile.
5, After 10 mins, solution 4 is added dropwise over 60 mins while temperature is maintained at 35~40'C. After addition, addition funnel is rinsed with acetonitrile(about 140ml) and added dropwise to the reactor.
6, The contents are stirred for additional 4 hrs while temperature is maintained at 40'C.
7, The mixture was cooled to rt and washed with 2*2L 2-methyl-THC(optional)
8, To acidic aquous layer(whole acidic reaction mixture if not washed), 650ml of NaOH solution is added dropwise while maintaining the temperature at 20~25'C, bringing the pH to 11-12 with milky suspension.
9, suspension is extracted with 3*1.45 L 2-Me-THF, which can be substituted by isopropyl acetate or DCM.
10, The organic layers ar combined and solvented is striped off by distillation. The remaining oily residue is redissolved in solvent and reconcentrated(to remove water azeotrope).
11, Resulting residue is dried under vacuum(preferably rotary evaporator) to provide N,N-DMT freebase. Yield about 65%, purity about 95% by HPLC.
DMT with this high purity actually have no advantages over root-extracted DMT for trips. But it's one of the few scalable operation for synthetic DMT and can be used for various tryptamine analogues.
Someone might ask if it's possible for 5-MeO and 4-OH substituted tryptamine analogues. Methoxy compounds can be synthesized with 4-methoxy-phenylhydrazine but it's extremely difficult to obtain and you may have to synthesize it yourself with 4-anisidine. 4-MeO-phenylhydrazine is quite unstale in it's freebase form and its salt should be kept at low temperature.
Unfortunately it can't be done for OH substituted compounds since the acetal readily reacts with hydroxy groups on substituted phenylhydrazine.
