Method for synthesis of diazabicyclo[6.2.0]decane related compounds

A method of making a compound of Formula VIII:

• wherein for the compound of Formula VIII:
• R1 is —I, —Cl, —Br, or
• R6 and R7 are independently the same or different, and are selected from —H, —OH, alkyl, —Oalkyl, or wherein R6 and R7 together with the atoms to which they are attached form a ring system protecting group for a diol;
• R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• R10 is —H, a straight chain or branched alkyl, —C(O)alkyl, —C(O)O-alkyl, —C(O)NH— alkyl, —C(O)aryl, —C(O)O-aryl, —C(O)NH-aryl, —C(O)heteroaryl, —C(O)O-heteroaryl, and —C(O)N-heteroaryl;
• wherein said aryl is a phenyl group optionally substituted with 1-3 groups of —OCH3, —OH, and halogen;
• and said heteroaryl is selected from the group consisting of triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl;
• wherein the method comprises:
• (i) forming a solid compound given by Formula I:
• by reacting a reactant of Formula II:
• with a base and resolving the racemic mixture by crystallization with a chiral reagent,
• wherein for the solid compound of Formula I and the reactant of Formula II:
• R1 is —I, —Cl, —Br, or
• R2 is C(O)R3;
• wherein R3 is —O— and a positive counterion ionically associated with Formula I;
• and
• P1 is —C(O)CF3;
• (ii) forming a lactone of Formula V from the compound of Formula I:
• wherein for the lactone of Formula V:
• R1 is —I, —Cl, —Br, or
• and
• P1 is selected from the group consisting of 9-fluorenylmethyl carbamate and —C(O)CF3;
• (iii) reducing the lactone of Formula V into a compound of Formula VI:
• wherein for the compound of Formula VI:
• R1 is —I, —Cl, —Br, or
• and
• P1 is selected from the group consisting of 9-fluorenylmethyl carbamate, —C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and H;
• (iv) converting the two alcoholic groups of Formula VI into mesylate leaving groups to form an intermediate of Formula VII or Formula VIIb:
• wherein for Formula VII and Formula VIIb:
• R1 is —I, —Cl, —Br, or
• and
• P1 is selected from the group consisting of 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl;
• (v) reacting the compound of Formula VII or Formula VIIb with phthalimide to generate a compound of Formula IV:
• wherein for the compound of Formula IV:
• R1 is —I, —Cl, —Br, or
• P1 is either —H or a nitrogen protecting group selected from the group consisting of 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl;
• and
• NP2 forms:
• and
• (vi) reacting the compound of Formula IV with a substituted γ-hydroxyaldehyde of formula:
• to produce an intermediate of Formula X:
• wherein for the intermediate of Formula X:
• R1 is —I, —Cl, —Br, or
• and
• NR8R9 forms:
• (vii) oxidizing the intermediate of Formula X to produce an intermediate of Formula XI:
• wherein for the intermediate of Formula XI:
• R1 is —I, —Cl, —Br, or
• and
• NR8R9 forms:
• (viii) cyclizing the intermediate of Formula XI to create an intermediate of Formula XII:
• wherein for the intermediate of Formula XII:
• R1 is —I, —Cl, —Br, or
• and
• NR8R9 forms:
• and
• (ix) reducing the intermediate of Formula XII to create the compound of Formula VIII.

A compound or a pharmaceutically acceptable salt thereof of Formula XV:

• wherein R1 is —I, —Cl, —Br, or
• and
• wherein Z is selected from the group consisting of:
• wherein P1 is either —H or a nitrogen protecting group selected from the group consisting of 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl;
• and
• NP2 forms:
• or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• wherein the alkyl is substituted by one or more halogens or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• wherein the alkyl is substituted by one or more halogens, or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• wherein the alkyl is substituted by one or more halogens, or a pharmaceutically acceptable salt thereof;
• and
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• wherein the alkyl is optionally substituted by one or more halogens, or a pharmaceutically acceptable salt thereof.

A compound or pharmaceutically acceptable salt thereof wherein the compound has Formula XV:

• wherein R1 is —I, —Cl, —Br, or
• wherein Z is selected from the group consisting of:
• wherein R2 is C(O)R3;
• R3 is —O— and a positive counterion ionically associated with Formula XVI, or R3 is —OH;
• and
• P1 is —C(O)CF3, 9-fluorenylmethyl carbamate or —H;
• wherein P1 is —C(O)CF3, 9-fluorenylmethyl carbamate or —H;
• wherein P1 is 9-fluorenylmethyl carbamate, —C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or H;
• wherein P1 is 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or —H;
• and
• wherein P1 is 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or —H;
• or a pharmaceutically acceptable salt thereof.