Process for preparing a conjugate linking moiety
AssigneeCybrexa 2, Inc.
InventorsRobert John Maguire, Michiel Christian Alexander van Vliet, Willem Robert Klaas Schoevaart
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Abstract
The present invention relates to processes for preparing linkers that are useful in the conjugation of therapeutic molecules (e.g., cytotoxic agents) with targeting moieties (e.g., proteins, peptides, antibodies, nanoparticles, nucleic acids). During said processes lipases like lipase B from Candida antarctica were used for enantioselective resolution of (S,S)-2-benzylthiocyclohexanol or (S,S)-2-benzylthiocycloheptanol in presence of acylating agent which are reduced for deprotection to yield (S,S)-2-mercaptocyclohexanol or (S,S)-2-mercaptocyclopentanol which can then be used for linking therapeutic with targeting moieties.
Claims62
A process for preparing a compound of Formula (A1)
- or a salt thereof, wherein ring A is C5-7 cycloalkyl or 5-7 membered heterocycloalkyl, comprising:
- a) treating a compound of Formula (A4)
- or a salt thereof, wherein Z is a protecting group, with Ak1, wherein Ak1 is an acylating reagent, in the presence of an enzyme to provide a mixture of a compound of Formula (A2) and a compound of Formula (A3);
- or salts thereof;
- wherein RB is C1-6 alkyl optionally substituted with COOH;
- and
- b) deprotecting the compound of Formula (A2), or a salt thereof, to provide a compound of Formula (A1), or a salt thereof.
A process for preparing a compound of Formula (1)
- or a salt thereof, wherein m is 0, 1, or 2, comprising:
- a) treating a compound of Formula (4)
- or a salt thereof, wherein Z is a protecting group, with Ak1, wherein Ak1 is an acylating reagent, in the presence of an enzyme to provide a mixture of a compound of Formula (2) and a compound of Formula (3);
- or salts thereof;
- wherein RB is C1-6 alkyl optionally substituted with COOH;
- and
- b) deprotecting the compound of Formula (2), or a salt thereof, to provide a compound of Formula (1), or a salt thereof.
A process for preparing a compound of Formula (8):
- or a salt thereof, wherein m is 0, 1, or 2, and RC is C6-10 aryl or 5-10 membered heteroaryl;
- wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;
- and wherein the C6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, halo, CN, NO2, OH, and OCH3, comprising reacting a compound of Formula (7)
- or a salt thereof, with Ak2, wherein Ak2 is an acylating reagent, in the presence of an enzyme to provide a mixture of a compound of Formula (8) and a compound of Formula (9);
- or salts thereof, wherein RD is C1-6 alkyl optionally substituted with COOH.
Dependencies are inferred from the claim text.