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

Patent metadata

Field	Value
Publication number	US-10053460-B2
Application number	US-201515532788-A
Country	US
Kind code	B2
Filing date	Nov 30, 2015
Priority date	Dec 2, 2014
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The present invention relates to processes for preparing compounds of Formula I. Such compounds include interme-diates in the manufacture of 7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide beta-lactamase inhibitors such as (2S,5R)-7-oxo-N-5 piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. The present invention also relates to novel intermediates formed i these processes. The present invention relates to a process for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

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.

Assignees

• Merck Sharp & Dohme

Inventors

• Liu Zhijian
• Yasuda Nobuyoshi
• Yang Lu
• Klapars Artis
• Campos Kevin R
• Reibarkh Mikhail

Classifications

• C07F7/10

  containing nitrogen {having a Si-N linkage} · CPC title

• C07F7/1868

  Chemistry & Metallurgy · mapped topic

• C07D471/08 Primary

  Bridged systems · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title