Preparation of purified phosphorodiamidite
View Patent ↗The instant invention relates to a method of phosphorodiamidite production that comprises: (E1) preparing a purified solution of a dialkylamine in a polar solvent as follows: —the dialkylamine dissolved in a polar solvent is contacted with a quantity of phosphorus trihalide that is sufficient to react with the alcohol impurities contained in the dialkylamine but sufficiently low to leave a major part of the dialkylamine unreacted, whereby a mixture is obtained that contains the dialkylamine in the polar solvent and reaction products of the impurities with the phosphorous trihalide; —the unreacted dialkylamine and polar solvent present in the mixture obtained in step (E1.1.) are extracted from the solution S by their difference of volatility, typically by distillation, whereby the purified solution of the dialkylamine in the polar solvent is obtained; (E2) the purified solution of dialkylamine in a polar solvent as obtained in step (E1) is reacted with a phosphorus trihalide, whereby an intermediate compound is formed; (E3) the intermediate compound obtained in step (E2) is reacted with a hydroxyalkyl compound in the presence of a non-polar co-solvent.
1. A method of phosphorodiamidite production, the method comprising:
(E1) preparing a purified solution of a dialkyl amine in a polar solvent as follows:
(E1.1.) the dialkylamine dissolved in a polar solvent is contacted with a quantity of phosphorus trihalide that is sufficient to react with the alcohol impurities contained in the dialkylamine, and optionally with other impurities contained in the dialkylamine or in the polar solvent, but sufficiently low to leave a major part of the dialkylamine unreacted, whereby a mixture is obtained that contains the dialkylamine in the polar solvent and reaction products of the impurities with the phosphorus trihalide;
(E1.2.) the unreacted dialkylamine and polar solvent present in the mixture obtained in step (E1.1.) are extracted from the solution S by their difference of volatility whereby the purified solution of the dialkyl amine in the polar solvent is obtained;
(E2) reacting the purified solution of dialkyl amine in a polar solvent as obtained in step (E1) with a phosphorus trihalide whereby an intermediate compound is formed;
(E3) reacting the intermediate compound obtained in step (E2) with a hydroxyalkyl compound in the presence of a non-polar co-solvent.
2. The method of claim 1 , wherein the dialkyl amine is a diisopropylamine comprising isopropanol as an impurity.
3. The method of claim 2 , wherein the dialkyl amine furthermore contains N-ethyl, N-isopropyl amine and N-(1-propyl), N-isopropyl amine as impurities.
4. The method of claim 2 , wherein the prepared phosphorodiamidite is 2-Cyanoethyl N,N,N′,N′-tetraisopropylphosphorodiamidite.
5. The method of claim 1 , wherein the phosphorus trihalide is phosphorus trichloride.
6. The method of claim 1 , wherein the polar solvent is a nitrile compound.
7. The method of claim 6 , wherein the nitrile compound is acetonitrile.
8. The method of claim 6 , wherein the polar solvent is propionitrile or benzonitrile.
9. The method of claim 1 wherein the hydroxyalkyl compound is hydroxypropionitrile.
10. The method of claim 1 wherein the hydroxyalkyl compound is methanol or tert-butyl alcohol.
11. The method of claim 1 wherein the co-solvent is a C 5 to C 9 aliphatic hydrocarbon.
12. The method of claim 1 wherein the co-solvent is an alicyclic hydrocarbon.
13. The method of claim 1 , wherein the unreacted dialkylamine and polar solvent present in the mixture obtained in step (E1.1.) are extracted from the solution S by distillation.