Methods and intermediates for the preparation bile acid derivatives
The present invention relates to methods and novel intermediates useful in the preparation of a compound of formula (A) or a pharmaceutically acceptable salt thereof, comprising converting the aldehyde of a compound of formula (B) with a reducing agent to prepare a compound of formula (C) and converting the compound of formula (C) with a sulfating reagent to prepare a compound of formula (A). An objective of the present invention is to provide methods of preparing bile acid derivatives and novel intermediates. A use of the methods and intermediates described relates to the synthesis of bile acid derivatives which activate both FXR and TGR5.
1. A method of preparing a sodium salt of a compound of formula (A)
wherein R 1 is H or C 1 -C 6 alkyl, the method comprising the steps of:
(a) dissolving an ammonium salt of the compound of formula (A) in an aqueous solution; and
(b) passing the aqueous solution through a cation-exchange resin, wherein the cation-exchange resin is Na + form
wherein the compound of formula (A) is prepared through the steps of
converting the aldehyde of a compound of formula (B) with a reducing agent to prepare a compound of formula (C)
wherein R 2 is a protecting group;
converting the compound of formula (C) with a sulfating reagent to prepare a compound of formula (D)
or a pharmaceutically acceptable salt thereof; and
deprotecting the C-3 hydroxyl of the compound of formula (D) to form a compound of formula (A).
2. The method of claim 1 , further comprising lyophilization of the sodium salt of the compound of formula (A).
3. The method of claim 2 , further comprising purifying the sodium salt of the compound of formula (A) by reverse phase chromatography.
4. The method of claim 1 , wherein R 1 is C 1 -C 4 alkyl, and the C-7 hydroxyl is in the alpha-orientation.
5. The method of claim 1 , wherein R 2 is —C(O)C 1 -C 4 alkyl.
6. The method of claim 1 , wherein the reducing reagent in step (a) is selected from NaBH 4 , NaCNBH 3 , LiBH 4 , (i-Bu 2 AlH) 2 , and an organoborane.
7. The method of claim 1 , wherein the sulfating reagent in step (b) is selected from sulfur trioxide pyridine, sulfur trioxide trimethylamine, sulfur trioxide triethylamine, sulfur trioxide N,N-dimethylformamide, poly(4-vinylpyridine) sulfur trioxide, chlorosulfonic acid, oleum, and sulfamic acid.
8. The method of claim 1 , wherein R 2 is acetyl and the deprotection in step (c) is performed under acidic conditions.
9. The method of claim 1 , further comprising converting a compound of formula (E) to prepare the compound of formula (B):
10. The method of claim 9 , further comprising protecting the C-3 hydroxyl of a compound of formula (F) to prepare the compound of formula (E):
11. The method of claim 10 , further comprising converting a compound of formula (G) to prepare the compound of formula (F):
12. The method of claim 11 , further comprising converting a compound of formula (H) to prepare the compound of formula (G):
wherein R 3 is C 1 -C 6 alkyl.
13. The method of claim 12 , further comprising converting a compound of formula (I) to afford the compound of formula (H):
wherein R 3 is C 1 -C 6 alkyl.
14. The method of claim 1 , wherein the compound of formula (A) is compound 7,
wherein the method further comprises converting compound 7B to compound 7C:
and
further converting compound 7C to compound 7.