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-carboxylate derivatives and (2s,5r)-7-oxo-n-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Patent metadata

Field	Value
Publication number	US-2016122350-A1
Application number	US-201414897290-A
Country	US
Kind code	A1
Filing date	Jun 5, 2014
Priority date	Jun 10, 2013
Publication date	May 5, 2016
Grant date	—

Abstract

A process for the preparation of N-protected 6-(piperidin-4-ylcarbamoyl)piperidin-3-yl sulfonates of Formula (III): which comprises 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, wherein P G1 and P G2 are amine protective groups; k, p and q are 0, 1, or 2, and W, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are defined herein. Additional embodiments add a series of process steps leading to the synthesis of 7-oxo-1,6-diazabicyclo[3.2.1]octanes suitable for use as β-lactamase inhibitors.

First claim

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=0, 1, 2, or 3.

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

Assignees

• Miller Steven P
• Limanto John
• Zhong Yong-Li
• Yasuda Nobuyoshi
• Liu Zhijian
• Merck Sharp & Dohme

Inventors

• Miller Steven P
• Limanto John
• Zhong Yong-Li
• Yasuda Nobuyoshi
• Liu Zhijian

Classifications

• C07D471/08 Primary

  Bridged systems · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D211/62

  attached in position 4 · CPC title

• C07D491/08

  Bridged systems · CPC title