Preparation of purified phosphorodiamidite

Abstract

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.

Claims

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.sub.5 to C.sub.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.

Description

EXAMPLES

(1) The process of the invention has been carried out in the following conditions, in a clean and dried apparatus maintained under inert atmosphere.

Example 1

(2) First Step:

(3) PCl.sub.3 (8.09 g; 0.0589 moles) was added slowly to a mixture of MeCN (200 g) and diisopropylamine (DIPA) (120.84 g; 1.194 moles). The resultant mixture was stirred for 5 hours. The reaction mixture obtained was then vacuum distilled, whereby a purified DIPA/MeCN solution was obtained (163.97 g, namely 41 wt % DIPA determined by 1H NMR).

(4) Second Step:

(5) PCl3 (15.07 g; 0.110 moles) was added slowly to the purified DIPA/MeCN solution obtained in the first step (95.89 g MeCN/66.63 g DIPA, 0.658 moles). The reaction mixture was left stirring overnight.

(6) Third Step:

(7) Heptane (110 g) was added to the reaction mixture obtained in the second step and then cyanoethanol (7.64 g, 0.107 moles) was added slowly.

(8) Recovery of the Phosphorodiamidite

(9) Solid by-products of the reaction were removed by filtration and the filtrate was then washed (1 H.sub.2O wash and then 2 MeCN/H2 washes and then a final MeCN wash).

(10) Heptane was removed under vacuum to give the crude product as a clear colourless liquid.

Example 2

(11) First Step:

(12) PCl3 (8.47 g; 0.0617 moles) was added slowly to a mixture of MeCN (200 g) and DIPA (122.16 g; 1.207 moles). The resultant mixture was stirred for 5 hours. The reaction mixture obtained was then vacuum distilled, whereby a purified DIPA/MeCN solution was obtained (215.06 g, namely 41 wt % DIPA determined by 1H NMR).

(13) Second Step:

(14) PCl3 (14.81 g; 0.108 moles) was added slowly to the purified DIPA/MeCN solution obtained in the first step (94.25 g MeCN/65.50 g DIPA, 0.658 moles). The reaction mixture was left stirring overnight.

(15) Third Step:

(16) Heptane (107 g) was then added to the reaction mixture and then cyanoethanol (7.60 g, 0.107 moles) was added slowly.

(17) Recovery of the Phosphorodiamidite

(18) Solid by-products of the reaction were removed by filtration and the filtrate was then washed (1 H2O wash and then 2 MeCN/H2O washes and then a final MeCN wash).

(19) Heptane was removed under vacuum to give the crude product as a clear colourless liquid.

COMPARATIVE DATA

(20) For seek of comparison, a control has been made, wherein second and third steps of Example 1 have been carried out, without the purification of the first steps.

(21) The Table 1 below reports the effect of the purification steps on the impurities content in the final products, and shows a clear decrease.

(22) Three impurities have been analyzed, namely: the impurity due to isopropanol (isopropyl impurity); the impurity due to N-ethyl, N-isopropyl amine (ethyl isopropyl impurity) the impurity due to N-(1-propyl), N-isopropyl amine (isopropyl propyl impurity)

(23) The Table 1 reports the area percentage from .sup.31P NMR analysis of the phosphorodiamidite and of the three impurities, that shows that the purification step: eliminates the isopropyl impurity substantially reduce (by 90%) the two other impurities

(24) TABLE-US-00001 TABLE 1 Composition of the final product (.sup.31P NMR) Ethyl Isopropyl isopropyl isopropyl propyl phosphorodiamidite impurity impurity impurity Control 98.571% 0.010% 0.208% 0.102 Example 1 99.541% Not detected 0.026% 0.010% Example 2 99.614% Not detected 0.026% 0.011%