Synthesis of N-Methylisopropylamine

This is an easy synth of N-Methylisopropylamine. This amine can be used to synthetise the MIPT family of tryptamines (MIPT, 5-Meo-MIPT and 4-MeO-MIPT) by S_N2 displacement on brominated or tosylated tryptophols, alternatively through indole-3-glyoxylchlorides (made from indoles and oxalyl chloride).

Experimental Part

To 59 g (one mole) anhydrous isopropylamine (stirred and cooled with an external ice bath), there was added 85.7 g (one mole) 35% aqueous formaldehyde solution. During the addition, an oily layer of 1,3,5-tris(isopropyl)hexahydro- 1,3,5-triazine is formed.

After 15 min the oily layer is separated and dried over anhydrous K2CO3 for 12 hours in the refrigerator (4°C), yield: 83% of theory.

40 grams of the triazine is added slowly to a cooled (-5°C) acidic (no further specification of "acidic") suspension of 70 grams Zn dust in 200 ml H₂0 with strong stirring. During the addition, simultaneous 320 ml concentrated HCl is added, dropwise at -5°C. After complete addition, one hour further stirring, filter off the residual Zn dust and add the filtrate to a 40% NaOH solution (90°C hot) in a three-necked-RBF equipped with a stirrer and a liebig condenser. The liberated N- methylisopropylamine (b.p. 50-60°C @ normal pressure) is trapped in a cooled recieving flask and finally fractionally redistilled with a 30 cm vigreux column. The main fraction has a bp of 49-51°C . The picrate has a mp of 135°C, but requires 3-4 days for crystallization from Et₂O/EtOH.

Traces of isopropylamine can be seen with GC analysis (shorter retention time) and N,N-dimethylisopropylamine (longer retention time).

Notes from Nemo_Tenetur:

This is a valuable synthesis. N-Methylisoproylamine is hard to get (only a few suppliers) and outrageous expensive. Five years ago I've bought 50 ml from Sigma-Aldrich for almost 90$ ! Unfortunately, the above recipe gave no final yield claim, but the required chemicals are cheap, so it does pay even with a moderate final yield. The N-methyl-N-isopropyl substitution pattern is a good choice!

Reference: Arch. Pharm. 314, p 644, (1981)