Report on the preparation method of N,N,N’,N’-tetramethylchloroformamidine hexafluorophosphate_Industrial Additives

Background and overview^[1]

N,N,N’,N’-tetramethylchloroformamidine hexafluorophosphate (TCFH) is a good non-hygroscopic coupling reagent for peptide synthesis and a starting material for other coupling reagents. As a general activating reagent in solid-phase chemistry, TCFH mainly promotes the formation of carboxylic acid amine derivatives rather than amides during the coupling process of amino acids. It is very useful for the coupling of very hindered amino acids, and has the characteristics of simple and convenient synthesis process and long shelf life.

Preparation^[1-2]

Report 1,

(1) Synthesis of tetramethyl chloroformamidine dichlorophosphate: Add 0.086 mol of tetramethyl urea liquid into the reaction kettle, bathe in ice, and when the system temperature reaches 0°C, add 0.086 mol of tetramethyl urea liquid dropwise For POCl3 liquid, the dropping time is 30 minutes. After the addition is completed, move the reaction kettle to the oil bath, raise the temperature to 100°C, react for 60 minutes, and cool to room temperature to obtain a transparent yellow liquid.

(2) Synthesis of N,N,N’,N’ silicone coating additive-tetramethylchloroformamidine hexafluorophosphate (TCFH): Add 100mL to the reaction solution obtained in step (1) of methylene chloride, under ice bath conditions, use a peristaltic pump to drop 2 antioxidants 16800mL of potassium hexafluorophosphate aqueous solution (number of moles: 0.083 mol), the dropping time is 15 minutes, after the dropwise addition is completed, under the ice bath Continue to stir vigorously for 30 minutes, separate the liquids, wash the organic phase three times with 200 mL of deionized water, separate the liquids again, dry the organic phase with magnesium sulfate, spin evaporate the organic phase at 50°C, crystallize, and dry to obtain a white solid, yield 63.66 %, melting point 106.9~107.6℃.

Report 2,

After 2 minutes, add a small portion of oxalyl chloride (2.0 mL, 23 mmol) to the 1,1,3,3-tetramethylurea (2.5 mL, 21 mmol)/10 mL toluene solution, while adding The reaction mixture was stirred at ice-water bath temperature. After stirring at room temperature for 18 hours, the reaction mixture was concentrated to a volume of approximately 5 mL under reduced pressure, and the resulting precipitate was collected by filtration. The collected solid was dissolved in approximately 20 mL of water and then treated with potassium hexafluorophosphate (3.8 g, 21 mmol)/50 mL of water solution while the mixture was stirred vigorously at room temperature to obtain a white precipitate. The precipitate was collected by filtration and dried under vacuum. The solid was then treated with approximately 8 mL of acetone and filtered to remove insoluble material. The obtained filtrate was added to 60 mL of diethyl ether in small portions while stirring vigorously at room temperature. The desired product was collected by filtration and dried under vacuum to give 4.5 g (76 %) of white solid.