Process for producing phosphine oxide vitamin D precursors
A process for producing a compound of the formula: including reacting of a compound of the formula: with diphenyl phosphine oxide using a binary phase reaction mixture including diphenyl phosphine oxide in an organic solvent, a basic aqueous solution, and a phase transfer catalyst, to obtain the compound of formula 1, wherein Ph is phenyl, X 1 and X 2 are both hydrogen or X 1 and X 2 taken together are CH 2 , R 1 is a protecting group, R 2 is fluorine, hydrogen, or OR 3 , wherein R 3 is a protecting group, and the squiggly line represents a bond that results in the adjacent double bond being in either the E or Z configuration, is disclosed.
1. A process for producing a compound of formula (1):
comprising reacting a compound of formula (2):
with diphenyl phosphine oxide using a binary phase reaction mixture comprising diphenyl phosphine oxide in an organic solvent, a basic aqueous solution, and a phase transfer catalyst selected from the group consisting of a quaternary salt, a crown ether, and a mixture thereof, to obtain the compound of formula 1,
wherein Ph is phenyl, X 1 and X 2 are both hydrogen or X 1 and X 2 taken together are CH 2 , R 1 is a protecting group, R 2 is fluorine, hydrogen, or OR 3 , wherein R 3 is a protecting group, and the squiggly line represents a bond that results in the adjacent double bond being in either the E or Z configuration.
2. The process claim 1 wherein R 1 is a silyl protecting group.
3. The process of claim 2 , wherein R 1 is a tert-butyl dimethyl silyl group.
4. The process of claim 1 , wherein R 2 is fluorine.
5. The process of claim 1 , wherein R 2 is tert-butyl dimethyl silyl oxide.
6. The process of claim 1 , wherein R 2 is fluorine or tert-butyl dimethyl silyl oxide.
7. The process of claim 1 , wherein X 1 and X 2 taken together are CH 2 .
8. The process of claim 1 , wherein the organic solvent is selected from the group consisting of diethyl ether, methoxyphenyl ether, ethylphenyl ether, methylpropyl ether, ethylvinyl ether, a haloethyl ether, benzyl ether, dibutyl ether, dipropyl ether, butylphenyl ether, butylvinyl ether, cyclohexylvinyl ether, t-butylmethyl ether, and mixtures thereof.
9. The process of claim 1 , wherein the organic solvent comprises t-butylmethyl ether.
10. The process of claim 1 , wherein the basic aqueous solution comprises an inorganic base.
11. The process of claim 10 , wherein the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, potassium hydroxide, and mixtures thereof.
12. The process of claim 10 , wherein the inorganic base is potassium hydroxide.
13. The process of claim 1 , wherein the basic aqueous solution comprises an organic base.
14. The process of claim 13 , wherein the organic base is selected from the group consisting of Me 4 NOH, Et 4 NOH, BnMe 3 NOH, and mixtures thereof.
15. The process of claim 1 , wherein the phase transfer catalyst comprises one or more quaternary ammonium salts.
16. The process of claim 15 , wherein the phase transfer catalyst comprises tetra-n-butylammonium bromide.
17. The process of claim 1 , wherein the reaction is performed at a temperature in a range of about 0° C. to about 40° C.
18. The process of claim 17 , wherein the reaction is performed at a temperature in a range of about 10° C. to about 30° C.
19. The process of claim 18 , wherein the reaction is performed at room temperature.