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Synthesis of N-Methylisopropylamine

Translated from German by Nemo_Tenetur


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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 SN2 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 (4C), yield: 83% of theory.

40 grams of the triazine is added slowly to a cooled (-5C) 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 -5C. After complete addition, one hour further stirring, filter off the residual Zn dust and add the filtrate to a 40% NaOH solution (90C hot) in a three-necked-RBF equipped with a stirrer and a liebig condenser. The liberated N- methylisopropylamine (b.p. 50-60C @ 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 49-51C . The picrate has a mp of 135C, 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)