LSZ is one of the lysergamide designer drug with substituted amide group. Dimethylazetidine's stereoisomeric properties affect the potency of the LSZ as trans(S,S) isomer being most potent.
Stereoselective synthesis of dimethylazetidine requires chiral reaction mediating molecules and prescious metal catalyst. So I'll just depict the synthesis of trans (R+S) form of dimethylazetidine.
Synthesis of trans-dimethylazetidine.
Part 1, 4-aminopentan-2-ol (cis-trans mixture)
1, Reflux the solution of 10 g of 3,5-dimethylisoxazole in 250ml of 1-pentanol. Add 24g of sodium metal pieces over 6 hrs.
2, Add 150ml of water and organic layer is separated. Aqueous phase is extracted with 4*15ml of chloroform to pull off remaining alcohol and products.
3, Combined chloroform layer is distilled, and residue is added to separated alcoholic layer. Product is extracted from alcohol with 75ml of 6 N hydrochloric acid, and washed twice with 10 ml portions of ether.
4, The acid solution is made strongly alkaline with KOH pellets, and extracted with 10*10ml chloroform.
5, Combined chloroform is distilled and fraction at 72-75'C at 20~25mmHg is collected with yield of 40%
Part 2, 4-(p-toluenesulfonamido)-2-pentyl p-toluenesulfonate. and semi-resolution of it.
1, 18.5g of p-toluenesulfonyl chloride is added to a ice cold solution of 4-aminopentan-2-ol in 100 ml of dry pyridine and solution is kept at -15'C for 4 days.
2, Mixture is poured onto 400 g of ice and separated red oil is washed with dilute hydrochloric acid. Oil is dissolved in chloroform and dried with NaSO4 with treatment with activated carbon.
3, After filtration, addition of petroleum ether gives tan oil of ditosylate product which solidifies slowly. Yield about 63%.
Resolution
1, 140 g of above product is dissolved in 300 ml of warm methanol and refrigerated at -20'C for 20 hrs. Precipitated crystal is cis form of product.
2, trans form of the product is not obtained in pure form, but as enriched material from mother liquor. You can repeat the crystallizing procedure and obtain more enriched trans isomer.
Part 3, trans-2,4-dimethyl-p-toluenesulfonazetide.
1, To a refluxing solution of 2.5 g of sodium ethoxide in 500 ml ethanol, solution of 11.5 g of trans-4-(p-toluenesulfonamido)-2-pentyl p-toluenesulfonate in 300ml ethanol is added over 40 hrs.
2, The solution is heated for additional 10 hrs and concentrated to volume 200 ml. Hot solution is poured onto 600 g of ice to precipitate product. Yield 75%
Part 4, trans-2,4-dimethylazetide.
1, To a refluxing solution of 10.4 g of trans-2,4-dimethyl-p-toluenesulfonazetide in 300ml of 1-pentanol, 23g of sodium metal was added over 6 hrs.
2, 150ml of water was added to the cooled solution and aquous layer is fraction distilled. Distillate under 100'C is collected and added to alcoholic phase.
3, Amine is extracted with hydrochloric acid, washed with ether, made strongly basic and fraction distilled. KOH pellets is added to first 20 ml of distillate and resulting oil is redistilled to afford product (bp 84~86). Yield about 89%.
The resulting amine is unstable and hygroscopic. It's advised to storing it in hydrochloric or acetic acid salt form.
Synthesis of LSZ - from the original paper.
All proedure should be done under red light or dark environment.
1, 220 mg of lysergic acid monohydrate, 426 mg of PyBOP and 109 mg of 2,4-dimethylazetide is suspended in 20ml of DCM. 193 mg of diisopropylethylamine is added and stirred for 3 hrs.
2, Mixture is quenched by addition of 20ml of 7.5M amminium hydroxide solution. DCM layer is separated and aquous layer is extracted with 10ml of DCM.
3, Combined organic layer is washed with 2*30 ml water, 15ml of brine and dried with MgSO4.
4, Filtered solution is dried under vacuum to form product. It can be further purified by column chromatography under N2 atmosphere.
Lysergamides in its freebase form are unstable and highly light sensitive. It's advised to storing it in tartrate or maleate/fumarate salt
Stereoselective synthesis of dimethylazetidine requires chiral reaction mediating molecules and prescious metal catalyst. So I'll just depict the synthesis of trans (R+S) form of dimethylazetidine.
Synthesis of trans-dimethylazetidine.
Part 1, 4-aminopentan-2-ol (cis-trans mixture)
1, Reflux the solution of 10 g of 3,5-dimethylisoxazole in 250ml of 1-pentanol. Add 24g of sodium metal pieces over 6 hrs.
2, Add 150ml of water and organic layer is separated. Aqueous phase is extracted with 4*15ml of chloroform to pull off remaining alcohol and products.
3, Combined chloroform layer is distilled, and residue is added to separated alcoholic layer. Product is extracted from alcohol with 75ml of 6 N hydrochloric acid, and washed twice with 10 ml portions of ether.
4, The acid solution is made strongly alkaline with KOH pellets, and extracted with 10*10ml chloroform.
5, Combined chloroform is distilled and fraction at 72-75'C at 20~25mmHg is collected with yield of 40%
Part 2, 4-(p-toluenesulfonamido)-2-pentyl p-toluenesulfonate. and semi-resolution of it.
1, 18.5g of p-toluenesulfonyl chloride is added to a ice cold solution of 4-aminopentan-2-ol in 100 ml of dry pyridine and solution is kept at -15'C for 4 days.
2, Mixture is poured onto 400 g of ice and separated red oil is washed with dilute hydrochloric acid. Oil is dissolved in chloroform and dried with NaSO4 with treatment with activated carbon.
3, After filtration, addition of petroleum ether gives tan oil of ditosylate product which solidifies slowly. Yield about 63%.
Resolution
1, 140 g of above product is dissolved in 300 ml of warm methanol and refrigerated at -20'C for 20 hrs. Precipitated crystal is cis form of product.
2, trans form of the product is not obtained in pure form, but as enriched material from mother liquor. You can repeat the crystallizing procedure and obtain more enriched trans isomer.
Part 3, trans-2,4-dimethyl-p-toluenesulfonazetide.
1, To a refluxing solution of 2.5 g of sodium ethoxide in 500 ml ethanol, solution of 11.5 g of trans-4-(p-toluenesulfonamido)-2-pentyl p-toluenesulfonate in 300ml ethanol is added over 40 hrs.
2, The solution is heated for additional 10 hrs and concentrated to volume 200 ml. Hot solution is poured onto 600 g of ice to precipitate product. Yield 75%
Part 4, trans-2,4-dimethylazetide.
1, To a refluxing solution of 10.4 g of trans-2,4-dimethyl-p-toluenesulfonazetide in 300ml of 1-pentanol, 23g of sodium metal was added over 6 hrs.
2, 150ml of water was added to the cooled solution and aquous layer is fraction distilled. Distillate under 100'C is collected and added to alcoholic phase.
3, Amine is extracted with hydrochloric acid, washed with ether, made strongly basic and fraction distilled. KOH pellets is added to first 20 ml of distillate and resulting oil is redistilled to afford product (bp 84~86). Yield about 89%.
The resulting amine is unstable and hygroscopic. It's advised to storing it in hydrochloric or acetic acid salt form.
Synthesis of LSZ - from the original paper.
All proedure should be done under red light or dark environment.
1, 220 mg of lysergic acid monohydrate, 426 mg of PyBOP and 109 mg of 2,4-dimethylazetide is suspended in 20ml of DCM. 193 mg of diisopropylethylamine is added and stirred for 3 hrs.
2, Mixture is quenched by addition of 20ml of 7.5M amminium hydroxide solution. DCM layer is separated and aquous layer is extracted with 10ml of DCM.
3, Combined organic layer is washed with 2*30 ml water, 15ml of brine and dried with MgSO4.
4, Filtered solution is dried under vacuum to form product. It can be further purified by column chromatography under N2 atmosphere.
Lysergamides in its freebase form are unstable and highly light sensitive. It's advised to storing it in tartrate or maleate/fumarate salt