Crystal forms and methods of synthesis of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine
The disclosure provides a method for synthesizing free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine. In an embodiment synthesis of (2R,6R)-hydroxynorketamine (HNK) includes preparation of (R)-norketamine via chiral resolution from racemic norketamine via a chiral resolution with L-pyroglutamic acid. The disclosure also provided crystal forms of the corresponding (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine hydrochloride salts.
1. A method for the manufacture of (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a salt thereof, the method comprising
treating a compound of Formula Ia or Formula Ib with a base, then with a trialkylsilylchloride, then with a peroxy compound, and then optionally with an acid or a fluoride source, to provide a compound of Formula II if Formula Ia was treated or a compound of Formula IIb if Formula Ib was treated, wherein the compound of Formula IIa or Formula IIb contains a carbamate linkage;
and cleaving the carbamate linkage in the compound of Formula IIa or Formula IIb to provide (2R,6R)-hydroxynorketamine if the carbamate linkage of the compound of Formula IIa was cleaved, or (2S,6S)-hydroxynorketamine if the carbamate linkage of the compound of Formula IIb was cleaved
wherein R′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, benzyl, 4-methoxybenzyl, or 2-trimethylsilylethyl.
2. The method according to claim 1 , wherein R 1 is tert-butyl and wherein cleaving the carbamate linkage comprises treatment of the compound of Formula IIa or Formula IIb with acid.
3. The method according to claim 2 , wherein the acid is trifluoroacetic acid.
4. The method according to claim 1 , additionally comprising treating (2R,6R)-hydroxynorketamine with hydrochloric acid to manufacture (2R,6R)-hydroxynorketamine hydrochloride salt, or treating (2S,6S)-hydroxynorketamine with hydrochloric acid to manufacture (2S,6S)-hydroxynorketamine hydrochloride salt.
5. The method according to claim 1 , wherein the base is lithium diisopropylamide, sodium hexamethyldisilazane, potassium hexamethyldisilazane, or sec-butyllithium, and the compound of Formula Ia or Formula Ib is treated with the base at a temperature below 0° C.
6. The method according to claim 1 wherein treating the compound of Formula Ia or Formula Ib with a base comprises treating the compound of Formula Ia or Formula Ib with lithium diisopropylamide at a temperature below −50° C.
7. The method according to claim 1 wherein the trialkylsilylchloride is trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, or triisopropylsilyl chloride.
8. The method according to claim 7 wherein the trialkylsilylchloride is trimethylsilyl chloride.
9. The method according to claim 1 , wherein the peroxy compound is a peroxy acid or a peroxide.
10. The method according to claim 9 , wherein the peroxy compound is meta-chloroperoxybenzoic acid, peroxybenzoic acid, peracetic acid, dimethyldioxirane, tert-butylhydroperoxide, or hydrogen peroxide.
11. The method according to claim 1 , wherein after treatment with the peroxy compound the compound of Formula Ia or Formula Ib is treated with tetra-n-butylammonium fluoride.
12. The method according to claim 1 , further comprising
generating the compound of Formula Ia or Formula Ib by reacting (R)-norketamine with (R 1 O 2 C) 2 O or R 1 O 2 C-X to generate a compound of Formula Ia, or reacting (S)-norketamine with (R 1 O 2 C) 2 O or R 1 O 2 C-X to generate a compound of Formula Ib; wherein X is a halogen.
13. The method according to claim 12 wherein R 1 is tert-butyl, and wherein generating the compound of Formula Ia comprises reacting (R)-norketamine with (tert-butyl-O 2 C) 2 O, and generating the compound of Formula Ib comprises reacting (S)-norketamine with (tert-butyl-O 2 C) 2 O.
14. The method according to claim 1 , comprising
treating a compound of Formula Ia with lithium diisopropylamide at a temperature below −50° C., then with trimethylsilylchloride, then with meta-chloroperoxybenzoic acid, and then with tetra-n-butylammonium fluoride, to provide a compound of Formula IIa, wherein R 1 is tent-butyl,
and cleaving the carbamate linkage in Formula IIa by treatment with acid to provide (2R,6R)-hydroxynorketamine
15. The method according to claim 1 , comprising
treating the compound of Formula Ib with lithium diisopropylamide at a temperature below −50° C., then with trimethylsilylchloride, then with meta-chloroperoxybenzoic acid, and then with tetra-n-butylammonium fluoride, to provide a compound of Formula IIb, wherein R 1 is tert-butyl,
and cleaving the carbamate linkage in Formula IIb by treatment with acid to provide (2S,6S)-hydroxynorketamine