Process for the preparation of chiral tert-butyl 4-((1R,2S,5R)-6(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carb derivatives and (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

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

which comprises:

(A) contacting a lactone of Formula II:

with an azacycloalkylamine of formula II-Am:

followed by contact with a sulfonyl halide of formula II-Su:

R 4 −SO 2 W  (II-Su)

in the presence of tertiary amine base to obtain a compound of Formula III wherein:

P G1 is a first amine protecting group which forms with the amino nitrogen to which it is attached a carbamate, a benzylamine, or a sulfonamide;

P G2 is a second amine protecting group selected from (i) carbamates and (ii) benzylamines;

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 4 is

(1) phenyl optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, Cl, Br, F, or NO 2 ;

(2) C 1-4 alkyl; or

(3) C 1-4 haloalkyl;

R 5 is H or C 1-3 alkyl;

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

W is halogen;

p is 0, 1, or 2;

q is 0, 1, or 2; and

p+q=2.

2. The process according to claim 1 , which further comprises:

(A) contacting a compound of Formula I:

with a P G1 -producing agent in the presence of an organic or inorganic base to obtain Compound II.

3. The process according to claim 1 , which further comprises:

(A) contacting a compound of Formula I:

with a P G1 -producing agent in the presence of an aqueous base followed by addition of a tertiary base to obtain Compound II.

4. The process according to claim 1 , which further comprises:

(C) treating Compound III with N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine in the presence of a base, followed by treatment with a thiol to obtain compound of Formula IV, or a pharmaceutically acceptable salt thereof:

5. The process according to claim 1 , which further comprises:

(D) contacting Compound (IV) with phosgene, diphosgene, triphosgene, carbodiimidazole or haloformate in the presence of a amine base, and then quenching with aqueous medium to obtain a compound of Formula V:

6. The process according to claim 1 , which further comprises:

(D) contacting Compound (IV) with phosgene, diphosgene, or triphosgene in the presence of a tertiary amine, and then adding an aqueous solution of acid to obtain a compound of Formula V:

7. The process according to claim 5 , which further comprises:

(E) contacting Compound V with a source of hydrogen in the presence of a hydrogenolysis catalyst and in the presence of a Boc-producing agent to obtain a compound of Formula VI:

8. The process according to claim 7 , which further comprises:

(F) contacting compound VI with a sulfating agent in the presence of an organic base to obtain a compound of Formula VII, or a pharmaceutically acceptable salt thereof:

9. The process according to claim 8 , which further comprises:

(G) treating compound VII with acid to obtain a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof.

10. A process according to claim 1 , wherein the compound of Formula III is Compound 3:

which comprises:

(B) contacting a lactone 2:

with an azacycloalkylamine 2-Am:

followed by contact with a sulfonyl halide 2-Su:

in the presence of 4-dimethylaminopyridine.

11. The process according to claim 9 , which further comprises:

(A) contacting a compound 1, or a pharmaceutically acceptable salt thereof:

with 2-nitrobenzene-1-sulfonyl chloride in the presence of an organic or inorganic base to obtain compound 2.

12. The process according to claim 10 , which further comprises:

(A) contacting a compound 1, or a pharmaceutically acceptable salt thereof:

with 2-nitrobenzene-1-sulfonyl chloride in the presence of an aqueous base followed by addition of TEA, DIPEA or diethylisopropylamine to obtain compound 2.

13. The process according to claim 11 , which further comprises:

(C) treating Compound 3 with N-4-nitrobenzenesulfonyl-O-benzylhydroxylamine in the presence of a base, followed by treatment with a thiol to obtain compound 4, or a pharmaceutically acceptable salt thereof:

14. The process according to claim 13 , which further comprises:

(D) contacting compound 4 with phosgene, diphosgene, triphosgene, carbodiimidazole or haloformate in the presence of an amine base, and then quenching with aqueous medium to obtain a compound 5:

15. The process according to claim 13 , which further comprises:

(D) contacting compound 4 with phosgene, diphosgene, or triphosgene in the presence of a tri-C 1-4 alkylamine, and then adding an aqueous solution of acid to obtain a compound 5:

16. The process according to claim 14 , which further comprises:

(E) contacting compound 5 with hydrogen in the presence of a Pd catalyst to obtain compound 6:

17. The process according to claim 16 , which further comprises:

(F) contacting compound 6 with a sulfating agent selected from the group consisting of pyridine-SO 3 complex, chlorosulfonic acid and DMF-SO 3 complex in the presence of 2-picoline to obtain compound 7, or a pharmaceutically acceptable salt thereof:

18. The process according to claim 16 , which further comprises:

(F) contacting compound 6 with a sulfating agent selected from the group consisting of pyridine-SO 3 complex, chlorosulfonic acid and DMF-SO 3 complex in the presence of picoline to obtain compound 7, or a pharmaceutically acceptable salt thereof:

19. The process according to claim 17 , which further comprises:

(G) treating Compound 7 with acid to obtain Compound 8:

or a pharmaceutically acceptable salt thereof.

20. The process according to claim 19 , wherein the acid is trimethylsilyl iodide (TMSI).

21. The process according to claim 20 , wherein the TMSI is in the presence of N,O-Bis(trimethylsilyl)acetamide (BSA) or N, O-bis(trimethylsilyl)trifluoroacetamide (BSTFA).

22. The process of claim 19 , wherein Compound 8 is directly crystallized as a monohydrate from the reaction mixture.

23. A compound selected from the group consisting of:

wherein:

P G1 is a first amine protecting group which forms with the amino nitrogen to which it is attached a carbamate, a benzylamine, or a sulfonamide;

P G2 is a second amine protecting group selected from the group consisting of (i) carbamates or (ii) benzylamines

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 4 is:

(1) phenyl optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, Cl, Br, F, or NO 2 ;

(2) C 1-4 alkyl; or

(3) C 1-4 haloalkyl;

R 5 is H or C 1-3 alkyl;

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;

W is halogen;

p is 0, 1, or 2;

q is 0, 1, or 2; and

p+q=2.

24. A compound according to claim 23 , which is selected from the group consisting of: