Process for the preparation of arformoterol or salt thereof
Provided is an improved process for the preparation of arformoterol L-(+)-tartrate, and more specifically provided is a novel process for the preparation of arformoterol L-(+)-tartrate via arformoterol D-(−)-tartrate.
1. A process for the preparation of arformoterol L-(+)-tartrate, a compound of Formula Ia,
wherein the level of compounds of formula A or B, is less than 0.15% w/w relative to the amount of arformoterol L-(+)-tartrate as determined by HPLC,
composing: a) reacting crude arformoterol, a compound of Formula I
with D-(+)-tartaric acid to form arformoterol D-(−)-tartrate, a compound of formula II; and
b) reacting the arformoterol D-(−)-tartrate, the compound of formula II, with a base and L-(+)-tartaric acid, to form arformoterol L-(+)-tartrate, a compound of Formula Ia.
2. The process of claim 1 , wherein arformoterol D-(−)-tartrate, a compound of formula II, is subjected to purification.
3. The process of claim 2 , wherein arformoterol D-(−)-tartrate, a compound of formula II, is subjected to purification by crystallization in a solvent system.
4. The process of claim 3 , wherein the solvent system comprises ether and water.
5. The process of claim 1 , wherein arformoterol D-(−)-tartrate, a compound of formula II has a chemical purity of at least 95% as determined by HPLC.
6. The process of claim 1 , wherein in step b) the arformoterol D-(−)-tartrate, the compound of formula II, is reacted with a base to obtain arformoterol, followed by reacting the arformoterol with L-(+)-tartaric acid in a mixture of toluene and isopropanol to form arformoterol L-(+)-tartrate.
7. The process of claim 6 , wherein the isopropanol and toluene are used in the ratio of 8:2 v/v.
8. The process of claim 6 , wherein an aqueous solution of L-(+)-tartaric acid is used.
9. The process of claim 8 , wherein the aqueous solution of L-(+)-tartaric acid is used in a proportion such that isopropanol:toluene:water is in the ratio of 8:2:1 v/v, for 1 part by weight of arformoterol D-(−)-tartrate.
10. The process of claim 9 , wherein the arformoterol L-(+)-tartrate, to compound of Formula Ia, is isolated in crystalline polymorphic Form B.
11. The process of claim 1 , wherein arformoterol D-(−)-tartrate, the compound of formula II, is thereafter convened to arformoterol L-(+)-tartrate, a compound of Formula Ia.