Methods of preparing hydroxylamine derivatives useful in the preparation of anti-infective agents

Patent metadata

Field	Value
Publication number	US-10472345-B2
Application number	US-201716074141-A
Country	US
Kind code	B2
Filing date	Jan 30, 2017
Priority date	Feb 4, 2016
Publication date	Nov 12, 2019
Grant date	Nov 12, 2019

Abstract

The present invention relates to processes for the preparation of N-protected 4-((2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-1-carboxylates. Such compounds have application in the preparation of beta-lactamase inhibitors such as 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamides and esters, in particular, the beta lactamase inhibitor, (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. The present invention also encompasses intermediates useful in the disclosed processes and methods for their preparation.

First claim

What is claimed is:

1. A process for preparing a compound of Formula I, or a salt thereof:

which comprises a reduce/couple sequence or a couple/reduce sequence,
wherein:
the reduce/couple sequence comprises
(E1) reducing a compound of Formula V

 or an acidic or basic salt thereof,
to obtain a compound of Formula VI

 or an acidic or basic salt thereof; and
(F1) coupling the compound of Formula VI, or an acidic or basic salt thereof, with a compound of formula VII

 or a salt thereof;
to form the compound of Formula I, or a salt thereof;

the couple/reduce sequence comprises
(E2) coupling a compound of Formula V:

 or an acidic or basic salt thereof,
with a compound of Formula VII

 or a salt thereof,
to obtain a compound of Formula VIII

 or a salt thereof; and
(F2) reducing the compound of Formula VIII, or a salt there, to form the compound of Formula I, or a salt thereof;

PG 1 is an amine protecting group which forms with the amino nitrogen to which it is attached a carbamate, a benzylamine, or a sulfonamide; and
PG 2 is an oxygen protecting group selected from acetyl (Ac), benzyl (Bn), 4-MeOBn, benzoyl (Bz), and tert-Butyldimethylsilyl ether (TBS).

2. The process according to claim 1 , wherein the reduction step in step E1 or F2 is conducted with a mono or bidentate phosphine in the presence of 1) a transition metal in a polar solvent or 2) a borohydride reagent and a protic or Lewis acid in a suitable solvent.

3. The process according to claim 2 , wherein the phosphine is bis(dicyclohexylphosphino)-ferrocene, triphenylphosphine, tricyclohexylphosphine, or 1,1′-Bis(diphenylphosphino)ferrocene.

4. The process according to claim 2 , wherein the reaction is conducted in the presence of a transition metal in a polar solvent and the transition metal is Rh(I), Ru, Pd, Ni, or Cu.

5. The process according to claim 4 , wherein the transition metal is Rh(I) in the form of bis(norbornadiene)rhodium(I) tetrafluoroborate.

6. The process according to claim 2 , wherein the reaction is conducted in the presence of a borohydride reagent, and an acid in a suitable solvent including water, the borohydride reagent is NaBH 4 , the suitable solvent is ethanol or an ethanol/triglyme mixture, the acid is a Lewis acid selected from a Fe(III) halide or a Fe(III) salt, wherein the water can be in the form of a hydrate salt of Fe(III) halide or Fe(III) salt.

7. The process according to claim 2 , wherein the reaction is conducted in the presence of a borohydride reagent and a protic acid in a polar solvent, the borohydride reagent is a carboxylic acid modified NaBH 4 , the polar solvent is acetonitrile or ethyl acetate, and the protic acid is H 2 SO 4 .

8. The process according to claim 1 , wherein the coupling step in step E2 or F1 is conducted in the presence of a coupling reagent in a non-nucleophilic solvent system and optionally a peptide coupling additive and optionally an acid or a base additive.

9. The process according to claim 8 , wherein the coupling reagent is 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC.HCl).

10. The process of claim 8 wherein the non-nucleophilic solvent system comprises one or more of CH 3 CN, NMP, toluene or DMF.

11. The process of claim 8 wherein the peptide coupling additive is HOPO.

12. The process of claim 8 wherein the additive is CF 3 CO 2 Na.

13. The process of claim 8 wherein the base additive is lutidine.

14. The process of any one of claims 1 to 13 , wherein PG 1 is Boc and PG 2 is benzyl.

15. The process according to claim 1 , which further comprises preparing a compound of Formula V

 or an acidic or basic salt thereof,
by Step C1 followed by Step D1

(C1) cyclizing a halooxime of Formula III:

 or an acidic or basic salt thereof, wherein X is bromo or chloro,
by addition of a base in a solvent to obtain a compound of Formula IV

 or an acidic or basic salt thereof; and
(D1) deprotecting the compound of Formula IV, or a salt thereof, to form a compound of Formula V, or an acidic or basic salt thereof.

16. The process of claim 15 , wherein the base is KOtBu.

17. The process of claim 15 , wherein the solvent is THF, DMF, or toluene.

18. The process of claim 15 , wherein the deprotection step is conducted with a protic acid, Lewis acid or nucleophilic base in a solvent.

19. The process of claim 18 , wherein the deprotection step is conducted with a Lewis acid, and optionally BSA, in a solvent, wherein the Lewis acid is TMSBr or TMSI.

20. The process according to claim 1 , which further comprises preparing a compound of Formula V

 or an acidic or basic salt thereof,
by Step C2 followed by Step D2

(C2) deprotecting a compound of Formula III in a strong acid in a non-nucleophilic solvent:

 or a salt thereof
to obtain a compound of Formula IX

 or an acidic or basic salt thereof; and
(D2) cyclizing the compound of Formula IX, or an acidic or basic salt thereof, with a base to form a compound of Formula V, or an acidic or basic salt thereof;
wherein X is bromo or chloro.

21. The process of claim 20 , wherein the acid is MsOH.

22. The process of claim 20 , wherein the solvent is CH 2 Cl 2 .

23. The process of claim 20 , wherein the base is NaOH.

24. The process of claim 20 , wherein the solvent is CH 2 Cl 2 /H 2 O.

25. The process according to claim 1 or 2 , which further comprises preparing a compound of Formula III

 or a salt thereof, wherein X is bromo or chloro,

through Steps A and B below:
(A) reacting SM of Formula

 or a salt thereof,
with a sulfur reagent to obtain a sulfur ylide compound of Formula II

Assignees

• Merck Sharp & Dohme

Inventors

• Dumas Aaron M
• Scott Jeremy P
• Shevlin Michael
• Liu Zhijian
• Chung John Y L
• Xu Feng
• Meng Dongfang

Classifications

• C07C251/38

  to carbon atoms of a saturated carbon skeleton · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C381/00

  Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00 · CPC title

• C07D211/78

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07C249/08

  by reaction of hydroxylamines with carbonyl compounds · CPC title