(−)-Huperzine A processes and related compositions and methods of treatment
The invention provides (1) processes for making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; (2) compositions useful in making substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives; and (3) methods of treating or preventing neurological disorders using substantially-pure (−) huperzine A and substantially-pure (−) huperzine A derivatives.
1. A process for making substantially pure (−) huperzine A having the formula:
comprising subjecting an amide of the formula:
to modified Hofmann reaction in an aqueous or alcohol solvent and in the presence of bis(trifluoroacetoxyiodo)benzene (PIFA) to form an intermediate, deprotecting the intermediate to form (−) huperzine A in an amount of at least 80% by weight of a combined mixture of (−) huperzine A and (+) huperzine B, and optionally, further purifying the (−) huperzine A from said mixture.
2. The process of claim 1 , wherein the alcohol solvent is methanol and the (−) huperzine A is further purified by crystallization or flash column chromatography.
3. The process of claim 1 , wherein the substantially pure (−) huperzine A contains less than about one percent by weight of (+) huperzine A.
4. A process for making substantially pure (−) huperzine A or a derivative thereof having the formula (III):
wherein:
R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl and substituted or unsubstituted ether;
R 2 and R 5 are independently selected from the group consisting of H and substituted or unsubstituted C 1 -C 6 alkyl;
R 3 at each occurrence is independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, ether, amino, and alkoxy;
R 4 is selected from the group consisting of H and Si(CH 3 ) 2 Ph;
R 7 is substituted or unsubstituted C 1 -C 6 alky, ester, or substituted or unsubstituted aryl;
A is N; and
n is 1;
comprising subjecting an amide having the formula (IV):
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , A, and n are as defined in the compound of formula (III), to a modified Hofmann reaction in an aqueous or alcohol solvent and in the presence of bis(trifluoroacetoxyiodo)benzene (PIFA) to form an intermediate, optionally deprotecting the intermediate to form (±) huperzine A or (±)huperzine A derivative, and purifying the (±) huperzine A or (±)huperzine A derivative to yield substantially pure (−) huperzine A or a substantially pure (−) huperzine A derivative, wherein the substantially pure (−) huperzine A or huperzine A derivative contains less than about twenty percent by weight of (+) huperzine A or a (+) huperzine A derivative.
5. The process of claim 4 , wherein the alcohol solvent is methanol and the (±) huperzine A or (±) huperzine derivative is purified by flash column chromatography.
6. The process of claim 4 , wherein the substantially pure (−) huperzine A or derivative thereof contains less than about one percent by weight of (+) huperzine A or a (+) huperzine A derivative.
7. The process of claim 4 wherein R 4 is H and R 1 is CH 3 .
8. The process of claim 7 wherein R 3 is H, CH 3 or OCH 3 .
9. The process of claim 7 wherein R 7 is CH 3 .
10. The process of claim 8 wherein R 7 is CH 3 .
11. The process of claim 8 wherein R 2 is H or CH 3 and R 5 is H or CH 3 .
12. The process of claim 8 wherein R 3 is H, and R 2 and R 5 are both H.