Process for the preparation of tert-butyl 4-((2S ,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate and analogs thereof

1. A process for preparing a compound of Formula I:

or a pharmaceutically acceptable salt thereof; comprising:

(a) reacting a compound of Formula (II):

with a compound of formula (X)

and a base to obtain a compound of Formula (III) or (IV), or a mixture thereof;

(b) treating the compound of formula (III) or (IV), or the mixture thereof, with phosgene or a phosgene equivalent to obtain a compound of formula (V) or (VI), or a mixture thereof

and

(c) treating the compound of formula (V) or (VI), or a mixture thererof, with a hydrolysis reagent to obtain the compound of formula (I);

wherein

Z is O or —NR 5 ;

k is an integer equal to 0, 1, or 2;

R 2 and R 3 are defined as follows:

(a) R 2 is H, C 1-6 alkyl, —O—C 1-6 alkyl, —O—Si—(C 1-6 alkyl) 3 , or

—O—Si—(C 1-6 alkyl)(phenyl) 2 , and

each R 3 is H or C 1-6 alkyl; or

(b) alternatively and with the proviso that k is 1 or 2, R 2 and the R 3 adjacent to R 2 together with the carbon atoms to which each is attached form C 5-7 cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently C 1-6 alkyl, —O—C 1-6 alkyl, —O—Si—(C 1-6 alkyl) 3 , or

—O—Si—(C 1-6 alkyl)(phenyl) 2 ; and any other R 3 is H or C 1-6 alkyl;

R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, —C 1-6 alkyl-aryl, heteroaryl, —C 1-6 alkyl-heteroaryl, or

R 6 and R 8 are independently H, C 1-3 alkyl, —O—C 1-3 alkyl, or —N—(C 1-3 alkyl) 2 ;

each R 7 and R 9 is independently H or C 1-6 alkyl;

P G2 is an amine protecting group selected from carbamates, benzylamines, sulfonamides and amides;

R 10 is benzyl or allyl, wherein the benzyl or allyl is optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, fluoro, or —NO 2 ;

R 11 and R 12 are C 1-6 alkyl or aryl; or

R 11 and R 12 together with the silane to which they are attached form a 4-to 6-membered saturated monocyclic ring containing 0 or 1 heteroatoms selected from N and O, which is optionally fused with 1 or 2 aromatic rings each optionally containing 0 or 1 heteroatoms selected from N and O;

R 13 is a leaving group;

p is 0, 1, or 2;

q is 0, 1, or 2;

p+q=0, 1, 2, or 3; and

R a and R b are halo.

2. The process of claim 1 , wherein Z is —NR 5 .

3. The process of claim 1 , wherein k is 1.

4. The process of claim 1 , wherein R 2 and R 3 are H.

5. The process of claim 1 , wherein R 5 is H or

6. The process of claim 4 , wherein R 5 is

7. The process of claim 1 , wherein P G2 is t-Boc.

8. The process of claim 1 , wherein the compound of Formula X is a dihalodialkylsilane, dihalodiarylsilane, or dihaloalkylarylsilane.

9. The process of claim 8 , wherein the compound of Formula X is dichlorodimethylsilane.

10. The process of claim 1 , wherein the base is Hunig's base.

11. The process of claim 1 , wherein the phosgene equivalent is carbonyldiimidazole.

12. The process of claim 1 , wherein the hydrolysis reagent is a protic solvent, acid, or fluoride source.

13. The process of claim 12 , wherein the hydrolysis reagent is a protic solvent.

14. The process of claim 13 , wherein the protic solvent is isopropyl alcohol.

15. The process of claim 1 , wherein the compound of Formula (I) is tert-butyl 4-((2S,5R)-7-oxo-6-benzyloxy-1,6-diazabicyclo [3.2.1]octane-2-carboxamido)piperidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

16. A compound which is:

wherein

Z is 0 or —NR 5 ;

k is an integer equal to 0, 1, or 2;

R 2 and R 3 are defined as follows:

(a) R 2 is H, C 1-6 alkyl, —O—C 1-6 alkyl, —O—Si—(C 1-6 alkyl) 3 , or —O—Si—(C 1-6 alkyl)(phenyl) 2 , and each R 3 is H or C 1-6 alkyl; or

(b) alternatively and with the proviso that k is 1 or 2, R 2 and the R 3 adjacent to R 2 together with the carbon atoms to which each is attached form C 5-7 cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently C 1-6 alkyl, —O—C 1-6 alkyl, —O—Si—(C 1-6 alkyl) 3 , or

—O—Si—(C 1-6 alkyl)(phenyl) 2 ; and any other R 3 is H or C 1-6 alkyl;

R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, C 1-6 alkyl-aryl, heteroaryl, C 1-6 alkyl-heteroaryl, or

R 6 and R 8 are independently H, C 1-3 alkyl, —O—C 1-3 alkyl, or —N—(C 1-3 alkyl) 2 ;

each R 7 and R 9 is independently H or C 1-6 alkyl;

P G2 is an amine protecting group selected from carbamates, benzylamines, sulfonamides, and amides;

R 10 is benzyl or allyl, wherein the benzyl or allyl is optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, fluoro, or —NO 2 ;

R 11 and R 12 are C 1-6 alkyl or aryl; or

R 11 and R 12 together with the silane to which they are attached form a 4-to 6-membered saturated monocyclic ring containing 0 or 1 heteroatoms selected from N and O which is optionally fused with 1 or 2 aromatic rings each optionally containing 0 or 1 heteroatoms selected from N and O;

R 13 is a leaving group;

p is 0, 1, or 2;

q is 0, 1, or 2;

p+q=0, 1, 2, or 3.

17. The compound of claim 16 , wherein Z is —NR 5 .

18. The compound of claim 16 which is:

or a salt thereof.