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US 11,142,503 B2Granted
(−)-huperzine A processes and related compositions and methods of treatment
AssigneeYale University
InventorsSeth Herzon, Maung Kyaw Moe Tun
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Abstract
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.
Claims4
A process of making an olefination product which is in substantially E isomer form and which has the formula:
- comprising deprotonating an addition alkylation product of the formula:
- by reacting the addition alkylation product with lithium bis(trimethylsilyl) amide (LHMDS) or lithium diisopropyl amide (LDA) and an electrophilic source of cyanide (e.g., para-toluenesulfonyl cyanide or cyanogen bromide) an organic solvent to form an α-cyanoketone, subjecting the α-cyanoketone to palladium-catalyzed intramolecular enolate heteroarylation in the presence of a base and a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium or tris(dibenzylidene acetone) dipalladium, palladium bis(tri-tert-butylphoshpine) to form a cyclized product, and stereoselectively olefinating a ketone function of the cyclized product in a Wittig olefination reaction in the presence of a base and in an organic solvent to form an olefination product, wherein the stereoselective olefination of the cyclized product kinetically favors formation of the olefination product in E-isomer form, wherein the process is conducted one-pot or in steps.
A process for making substantially pure (−) huperzine A comprising:
- (a) in one pot, reacting (R)-4-methyl-cyclohex-2-ene-1-one with lithium dimethylphenylsilylcuprate in a conjugate addition reaction to form an incipient enolate and alkylating the incipient enolate with 3-bromo-2-(bromomethyl)-6-methoxypyridine) to form an addition alkylation product having the formula:
- (b) in one pot, deprotonating the addition alkylation product by reacting the addition alkylation product with lithium bis(trimethylsilyl) amide (LHMDS) or lithium diisopropyl amide (LDA) in an organic solvent to form an α-cyanoketone, subjecting the α-cyanoketone to palladium-catalyzed intramolecular enolate heteroarylation in the presence of a base to form a cyclized product, and stereoselectively olefinating a ketone function of the cyclized product in a Wittig olefination reaction in the presence of a base and in an organic solvent to form an olefination product, wherein the stereoselective olefination of the cyclized product kinetically favors formation of the olefination product in E-isomer form and wherein the olefination product has the formula:
- (c) subjecting the olefination product to oxidative disilylation by (1) reaction with a boron trifluoride-acetic acid complex or a Bronsted acid in an inert solvent, or (2) through use of Fleming-Tamao oxidation to form a cyanoalcohol having the formula:
- (d) in one pot, dehydrating the cyanoalcohol in an organic solvent under heated conditions and in the presence of a Burgess reagent to form a dehydration product, and subjecting the dehydration product to thermolysis in an alcohol and in the presence of a platinum catalyst to form the amide having the formula:
- and
- (f) subjecting the amide to modified Hoffmann reaction in an aqueous or alcohol solvent and in the presence of bis(trifluoroacetoxyiodo)benzene (PIFA) to form an intermediate, globally deprotecting the intermediate to form (−) huperzine A, and optionally, further purifying the (−) huperzine A to yield substantially pure (−) huperzine A having the formula:
3 more elements
Dependencies are inferred from the claim text.