Process for preparing budesonide
A process is described for preparing budesonide which comprises the steps of: a) preparing an aqueous hydrochloric acid solution; b) reacting 16α-hydroxyprednisolone and butyraldehyde within the solution prepared in step a), in an inert atmosphere; c) quenching the reaction of step b) with water. The process of the invention enables the ratio between the A and B epimers of budesonide to be controlled.
1. Process for preparing budesonide of formula (I),
which comprises the steps of:
a) preparing an aqueous hydrochloric acid solution;
b) reacting 16α-hydroxyprednisolone and butyraldehyde within the solution prepared in step a), in an inert atmosphere;
c) quenching the reaction of step b) with water or an aqueous solution.
2. Process according to claim 1 , wherein the hydrochloric acid solution in step a) is prepared from concentrated hydrochloric acid and water in a concentrated hydrochloric acid/water ratio within the range, from 6/4 to 9/1.
3. Process according to claim 1 , wherein the hydrochloric acid/water ratio is about 7/3.
4. Process according to claim 1 , wherein the hydrochloric acid/water ratio is about 8/2.
5. Process according to claim 1 , wherein the aqueous hydrochloric acid solution is a solution obtainable from fuming or concentrated commercial hydrochloric acid at 36-37% and water.
6. Process according to claim 1 , wherein the reaction temperature of step b) varies within the range from −5 to +15° C.
7. Process according to claim 1 , wherein the reaction time of step
b) varies within the range from 60 to 240 minutes.
8. Process according to claim 1 , wherein in step b) the butyraldehyde reactant is used in slight excess over 16α-hydroxyprednisolone.
9. Process according to claim 1 , wherein in step c) an aqueous solution of sodium acetate is used for quenching the reaction of step b).
10. Process according to claim 1 wherein the process of the invention further comprises the steps of:
d) recovering the crude budesonide reaction compound from the reaction mixture of step c);
e) neutralizing and dehydrating;
f) crystallizing from isopropyl ether to obtain crystallized crude budesonide;
g) crystallizing the crystallized crude budesonide with methanol to obtain pure budesonide.
11. Process according to claim 10 , wherein recovery of the reaction compound of step c) takes place by extraction with the solvent methylene chloride.
12. Process according to claim 10 , wherein step g) of crystallization with methanol comprises the following substeps:
1) boiling crude budesonide from step f) in a volume of methanol to achieve total dissolution;
2) distilling the methanol;
3) cooling the suspension obtained.
13. Process according to claim 10 , wherein after step g) of crystallization from methanol budesonide is obtained with 44%<Epimer A<51%.
14. Process according to claim 12 , wherein after step g) of crystallization from methanol budesonide is obtained with 44%<Epimer A<51%.
15. Process according to claim 6 , wherein the reaction temperature of step b) varies within the range from 0 to +5° C.
16. Process according to claim 7 , wherein the reaction time of step b) varies within the range from 120 to 180 minutes.
17. Process according to claim 12 , wherein said substep 2) of distilling the methanol is carried out at atmospheric pressure.