Process for manufacturing purified phosphorodiamidite
View Patent ↗A scalable process for purification of phosphorodiamidite includes steps of solubilizing a crude phosphorodiamidite in an apolar organic solvent, contacting the non-polar organic solvent with a polar phase comprising a polar organic solvent to remove impurities from the solubilized phosphorodiamidite, and removing the non-polar organic solvent from the phosphorodiamidite.
1. A process of producing a purified phosphorodiamidite, said process comprising the steps of:
a. dissolving a crude phosphorodiamidite containing at least one impurity in an apolar phase; and
b. contacting the apolar phase with a polar phase comprising a polar organic solvent, whereby at least a portion of the impurity is transferred into the polar phase and the purified phosphorodiamidite is produced in the apolar phase;
wherein said phosphorodiamidite is represented by formula I:
G 1 is OR 1 ;
R 1 is cyanoethyl;
each G 2 is independently —NR 2 R 3 , and
R 2 and R 3 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl.
2. The process of claim 1 , wherein the phosphorodiamidite is the most lipophilic solute in the apolar phase of step (a).
3. The process of claim 1 , wherein the apolar phase comprises a liquid hydrocarbon.
4. The process of claim 3 , wherein the apolar phase comprises alkanes.
5. The process of claim 1 , wherein the polar phase comprises acetonitrile, N,N-dimethylformamide (DMF), ethylene glycol, glycerol, acetamide, ethylene diamine, N,N,-dimethylacetamide, N-methylacetamide, N-methylformamide, dimethylsulfoxide, ethanolamine, diethanolamine, triethanolamine, caprolactam, 3-hydroxypropiononitrile, hexamethylphosphoric triamide, dimethylurea, tetramethylurea, 2-pyrrolidinone, N-methylpyrrolidinone or 2-imidazolidone.
6. The process of claim 5 , wherein the apolar phase comprises hexanes.
7. The process of claim 6 , wherein the polar phase comprises acetonitrile.
8. The process of claim 7 , wherein the polar phase further comprises water.
9. The process of claim 8 , wherein the polar phase comprises a mixture of acetonitrile and water in the range of about 50:50 to about 90:5 (v/v).
10. The process of claim 9 , wherein the polar phase comprises a mixture of acetonitrile and water in the range of about 50:50 to about 80:20 (v/v).
11. The process of claim 3 , wherein the apolar phase comprises toluene.
12. The process of claim 11 , wherein the polar phase comprises acetonitrile, N,N-dimethylformamide (DMF), ethylene glycol, glycerol, acetamide, ethylene diamine, N,N,-dimethylacetamide, N-methylacetamide, N-methylformamide, dimethylsulfoxide, ethanolamine, diethanolamine, triethanolamine, caprolactam, 3-hydroxypropiononitrile, hexamethylphosphoric triamide, dimethylurea, tetramethylurea, 2-pyrrolidinone, N-methylpyrrolidinone or 2-imidazolidone.
13. The process of claim 1 , further comprising at least one additional step of contacting a polar phase with the apolar phase.
14. The process of claim 1 , wherein the apolar phase and the polar phase are contacted at room temperature.
15. The process of claim 1 , wherein the apolar phase and the polar phase are contacted with agitation.
16. The process of claim 1 , further comprising the following step (c):
(c) separating the apolar phase from the polar phase.
17. The process of claim 1 , further comprising the following steps (c) and (d):
(c) separating the apolar phase from the polar phase; and
(d) removing the apolar organic solvent from the purified phosphorodiamidite.
18. The process of claim 1 , wherein the phosphorodiamidite is the most hydrophobic compound in the apolar phase.
19. A process of purifying a phosphorodiamidite compound of formula Va:
said process comprising the steps of:
a. dissolving the phosphorodiamidite of formula Va and at least one impurity in an apolar organic solvent to form an apolar phase; and
b. contacting the apolar phase with a polar phase comprising a polar organic solvent, whereby at least a portion of the impurity partitions into the polar phase, thereby producing the purified phosphorodiamidite in the apolar phase.
20. The process of claim 19 , wherein the apolar phase comprises hexanes.
21. The process of claim 19 , wherein the polar phase comprises acetonitrile.
22. The process of claim 21 , wherein the polar phase further comprises water.
23. The process of claim 22 , wherein the polar phase comprises acetonitrile and water in a ratio within the range of about 50:50 to about 95:5 (v/v).
24. The process of claim 23 , wherein the polar phase comprises acetonitrile and water in a ratio within the range of about 50:50 to about 80:20 (v/v).
25. The process of claim 19 , wherein the proccss is carried out at about room temperature.
26. The process of claim 19 , further comprising at least one additional step of contacting a polar phase with the apolar phase.
27. The process of claim 19 , wherein the apolar phase and the polar phase are contacted at room temperature.
28. The process of claim 19 , wherein the apolar phase and the polar phase are contacted with agitation.
29. The process of claim 19 , further comprising the following step c.:
c. separating the apolar phase from the polar phase.
30. The process of claim 19 , further comprising the following steps c. and d.:
c. separating the apolar phase from the polar phase; and
d. removing the apolar organic solvent from the purified phosphorodiamidite.
31. The process of claim 19 , wherein the phosphorodiamidite of formula Va is the most lipophilic compound in the apolar phase of step a.
32. The process of claim 19 , wherein the phosphorodiamidite is the most lipophilic compound in the apolar phase of step a.
33. A process of making a purified phosphorodiamidite, said process comprising
a. obtaining a crude phosphorodiamidite composition comprising phosphorodiamidite and at least one impurity;
b. dissolving said crude phosphorodiamidite composition in an apolar organic solvent to form an apolar phase;
c. contacting said apolar phase with a polar phase comprising a polar organic solvent, whereby at least a portion of said impurity partitions into the polar phase; and
d. separating the apolar phase from the polar phase, whereby a purified phosphorodiamidite is obtained in the apolar phase wherein said phosphorodiamidite is represented by formula I:
G 1 is OR 1 ;
R 1 is cyanoethyl;
each G 2 is independently —NR 2 R 3 , and
R 2 and R 3 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl.
34. The process of claim 1 , wherein said apolar phase is hexane and said polar phase is a mixture of acetonitrile and water.