Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use
AssigneeUnity Biotechnology, Inc.
InventorsThomas W. von Geldern, Bradley Backes, Bing Chen
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Abstract
This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective crystallization. Both enantiomers can be cyclized into the desired cis-imidazoline by complementary pathways. Compounds can be synthesized according to the invention with an enantiomeric excess as high as 99%. Cis-imidazolines such as Nutlin-3a prepared according to this invention may be used for treating cancer, killing senescent cells, or treating senescence-associated conditions.
Claims18
A method for chemically synthesizing a cis-imidazoline with an enantiomeric excess (ee) of at least 90%, the method comprising:
- (a) obtaining a racemic mixture of a precursor according to Formula (A);
- wherein X1 and X2 are both halogen, the first nitrogen is bonded to R1 which is a first substituent having the formula —C(═O)—R2 where R2 an optionally substituted carbocycle or heterocycle group, and the second nitrogen is a primary amine;
- (b) combining the racemic mixture of the precursor with a chiral aromatic acid according to Formula (B):
- HOOC—CH(OH)—R3 (B)
- wherein R3 is an optionally substituted aryl or heteroaryl group,
- whereby a first stereoisomer of the precursor associates with the chiral aromatic acid, and a second stereoisomer of the precursor does not;
- (c) separating and recovering the first stereoisomer from the chiral aromatic acid;
- (d) selectively derivatizing the second nitrogen of the first stereoisomer with a second substituent having the formula —C(═O)—R4, wherein R4 is an optionally substituted carbocycle or heterocycle group;
- and then
- (e) performing a ring closing reaction in which the first nitrogen joins with the second nitrogen, thereby forming the cis-imidazoline with an enantiomeric excess (ee) of at least 90%.
A method for chemically synthesizing a cis-imidazoline with an enantiomeric excess (ee) of at least 90%, the method comprising:
- (a) obtaining a racemic mixture of a precursor according to Formula (A),
- wherein X1 and X2 are both halogen, the first nitrogen is bonded to R1 which is a nitrogen protecting group, and the second nitrogen is a primary amine;
- (b) combining the racemic mixture of the precursor with a chiral aromatic acid according to Formula (B),
- HOOC—CH(OH)—R3 (B)
- wherein R3 is an optionally substituted aryl or heteroaryl group,
- whereby a first stereoisomer of the precursor associates with the chiral aromatic acid, and a second stereoisomer of the precursor does not;
- (c) separating and recovering the first stereoisomer from the chiral aromatic acid;
- (d) selectively derivatizing the second nitrogen of the first stereoisomer with a second substituent having the formula —C(═O)—R4, wherein R4 is an optionally substituted carbocycle or heterocycle group;
- (e) deprotecting the first nitrogen;
- (f) selectively derivatizing the first nitrogen of the first stereoisomer with a first substituent having the formula —C(═O)—R2, wherein R2 is an optionally substituted carbocycle or heterocycle group, and then
- (g) performing a ring closing reaction on the first stereoisomer in which the first nitrogen joins with the second nitrogen, thereby forming the cis-imidazoline with an enantiomeric excess (ee) of at least 90%.
A method for enantiomerically enriching a cis-imidazoline precursor, comprising:
- (a) combining a racemic mixture of a precursor according to Formula (A) with a chiral aromatic acid under conditions whereby crystals selectively form between a first stereoisomer of the precursor and the chiral aromatic acid, leaving a second stereoisomer of the precursor in solution;
- (b) separating the crystals from the solution;
- and
- (c) recovering the first stereoisomer from the crystals, thereby enantiomerically enriching the cis-imidazoline precursor;
- wherein X1 and X2 are both chloride, R1 is —C(═O)—R2 or an amine protecting group, and R2 is an optionally substituted carbocycle or heterocycle group;
- and
- wherein the chiral aromatic acid is HOOC—CH(OH)—R3 wherein R3 is a substituted or an unsubstituted aryl or heteroaryl group.
Dependencies are inferred from the claim text.