Methods and intermediates for preparing macrolactams
View Patent ↗A first aspect of the present invention describes a compound selected from group consisting of: wherein R is either H, C(O)R A , or C(O)NHCH(X)COOH; provided that X is a C 2 -C 6 alkyl, or a C 3 -C 8 cycloalkyl and R A is a C 1-6 alkyl or aryl; These compounds are used to make Compound A
1. A compound selected from the group consisting of:
wherein R is either H, acetyl, or C(O)NHCH(X)COOH, and X is a C 2 -C 6 alkyl, or a C 3 -C 8 cycloalkyl,
and salts thereof, wherein Y is a protecting group or H and wherein PG is a protecting group.
2. The compound of claim 1 , wherein said compound is
3. A method of making Compound 6, comprising the step of reacting
(Compound 5) with an acetylating agent to produce
(Compound 6).
4. The method of claim 3 , wherein Compound 5 is produced by reacting
(Compound 4)with a metal acetylide to produce Compound 5.
5. The method of claim 4 , wherein Compound 4 is produced by oxidizing
(Compound 3).
6. The method of claim 5 , wherein Compound 3 is produced by reacting
(Compound 2) with an alkyl zinc reagent, an acid and a dibalomethane in a balogenated solvent at a temperature between 0° C. and 40° C., followed by addition of an acidic aqueous solution and separation of the organic layer to obtain Compound 3.
7. A method of making a compound of Formula I
wherein R is C(O)NHCH(X)COOH, X is a C 2 -C 6 alkyl, or a C 3 -C 8 cycloalkyl; or a salt thereof; comprising the step of reacting
(Compound 7) with
to produce Compound 8.
8. A method of producing Compound 13, comprising the step of reacting Compound 11 with Compound 12 to produce Compound 13:
wherein PG is a protecting group.
9. The method of claim 8 , comprising steps of reacting Compound 9 with HCl and oxalic acid to produce Compound 10 and further reacting Compound 10 with POCl 3 to produce Compound 11 or salts thereof:
10. A method of producing Compound 14 comprising the step of reacting Compound 13 with Compound 8 to produce Compound 14 or salts thereof:
wherein PG is a protecting group.
11. The method of claim 10 , wherein the reaction uses tri tert-butylphosphine tetra fluoroborate salt in a solvent, and Compound 8 is provided as either a dibenzylamine salt or a t-butylamine salt.
12. The method of claim 10 , further comprising the steps of:
or salts thereof, wherein PG is a protecting group and Compound A is