Processes for the preparation of rocuronium bromide and intermediates thereof
View Patent ↗A novel process for preparing (2β,3α,5α,16β,17β)-17-acetoxy-3-hydroxy-2-(4-morpholinyl)-16-(1-pyrrolidinyl) androstane, a known intermediate in the synthesis of the skeletal muscle relaxant rocuronium bromide, is disclosed.
1. A process of preparing a compound having Formula I:
the process comprising:
reacting a compound having Formula II:
with a molar excess of an acetylating agent, to thereby obtain a reaction mixture including a compound having Formula III:
and
contacting said reaction mixture with an aqueous solution of an acid, to thereby selectively deacetylate an acetoxy group at position 3 of said compound having Formula III, thereby obtaining the compound having Formula I.
2. The process of claim 1 , wherein said acetylating agent is selected from acetyl chloride and acetic anhydride.
3. The process of claim 1 , wherein said molar excess of said acetylating agent ranges from about 1.1 molar equivalents to about 5 molar equivalents per one mol of said compound having said formula II.
4. The process of claim 3 , wherein said molar excess of said acetylating agent is about 1.35 molar equivalents per one mol of said compound having said formula II.
5. The process of claim 1 , wherein said reacting is performed in the presence of an organic solvent.
6. The process of claim 5 , wherein said organic solvent is selected from dichloromethane and acetonitrile.
7. The process of claim 1 , wherein said acid is selected from an organic acid and an inorganic acid.
8. The process of claim 7 , wherein said acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid and phosphoric acid.
9. The process of claim 7 , wherein said acid is selected from formic acid and a carboxylic acid.
10. The process of claim 5 , wherein said contacting said reaction mixture with said aqueous solution of said acid is performed at a reflux temperature of said organic solvent.
11. The process of claim 1 , further comprising purifying the compound having Formula I.
12. The process of claim 11 , wherein said purifying comprises recrystallizing the compound having Formula I.
13. process of claim 1 , wherein the compound of Formula I is obtained in a purity of at least 90 %.
14. The process of claim 12 , wherein the compound of Formula I is obtained in a purity of at least 99 %.
15. A process of preparing rocuronium bromide, the process comprising:
reacting a compound having Formula II:
with a molar excess of an acetylating agent, to thereby obtain a reaction mixture including a compound having Formula III:
contacting said reaction mixture with an aqueous solution of an acid, to thereby selectively deacetylate an acetoxy group at position 3 of said compound having Formula III, to thereby provide a compound having Formula I
reacting said compound having said Formula I with allyl bromide, thereby obtaining rocuronium bromide.
16. The process of claim 15 , wherein said acetylating agent is selected from the group consisting of acetyl chloride and acetic anhydride.
17. The process of claim 15 , wherein said molar excess of said acetylating agent ranges from about 1.1 molar equivalents to about 5 molar equivalents per one mol of said compound having said formula II.
18. The process of claim 17 , wherein said molar excess of said acetylating agent is about 1.35 molar equivalents per one mol of said compound having said formula II.
19. The process of claim 15 , wherein said reacting is performed in an organic solvent.
20. The process of claim 19 , wherein said organic solvent is selected from the group consisting of dichloromethane and acetonitrile.
21. The process of claim 15 , wherein said acid is selected from an organic acid and an inorganic acid.
22. The process of claim 21 , wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid and phosphoric acid.
23. The process of claim 21 , wherein said acid is selected from formic acid and a carboxylic acid.
24. The process of claim 19 , wherein said contacting of said product with said aqueous solution of said acid is performed at a reflux temperature of said organic solvent.
25. The process of claim 1 , further comprising purifying the compound having Formula I.
26. The process of claim 25 , wherein said purifying comprises recrystallizing the compound having Formula I.
27. The process of claim 25 , further comprising converting the compound of formula I into rocuronium bromide.
28. The process of claim 27 , comprising reacting the compound of formula I with allyl bromide to produce the rocuronium bromide.