Process for preparing N-hydroxyformamido-propyl pyrrolidin compounds and intermediates
The present invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial N-formyl hydroxylamine compounds which are peptide deformylase inhibitors. The process makes use α β-lactarn intermediate. Certain optically pure intermediates are also claimed.
1. A process for preparing a compound of the formula (VIII)
comprising step A:
contacting a compound of the formula (I)
with a compound of the formula (II)
Y—O—NH 2 (II)
in the presence of a carboxy activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III)
followed by step B:
contacting compound (III) with a compound of the formula (XIII)
R′—SO 2 —X′ (XIII)
in the presence of a base in a suitable solvent, under conditions suitable to form a compound of the formula (IV)
followed by Step C:
contacting compound (IV) with a base in a suitable solvent under conditions suitable to form a compound of the formula (V)
followed by Step D:
contacting compound (V) with a compound of the formula (VI)
in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII)
followed by Step E:
contacting compound (VII) with a formylating agent in a suitable solvent under conditions suitable to form compound (VIII);
wherein
Y is a hydroxy protecting group;
Each of R 2 , R 3 , R 4 and R 5 , independently, is hydrogen or an aliphatic group;
X is —CH 2 ;
G is —OH or —O ⊖ M ⊕ , wherein M is a metal or an ammonium moiety;
R 1 is aryl or heteroaryl;
X′ is halo;
R′ is alkyl or aryl; and
n is 1.
2. The process of claim 1 , followed by additional Step F which comprises contacting the compound of formula (VIII), wherein R 1 is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding N-oxide derivative.
3. The process of claim 1 , followed by the additional step of removing the hydroxyl-protecting group by contacting compound (VIII) with a palladium catalyst to form the compound of formula (IX)
wherein R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
4. The process of claim 1 , wherein each of R 2 , R 3 and R 5 is hydrogen; R 4 is butyl; X is —CH 2 —; n is 1; Y is benzyl or t-butyldimethylsilyl; and R 1 is of the formula
wherein
R 6 and R 9 are hydrogen;
R 7 is hydrogen or C 1-7 alkyl; and
R 8 is hydrogen, halogen or C 1-7 alkyl.
5. The process of claim 4 , wherein R 7 is hydrogen; and R 8 is fluoro.
6. The process of claim 4 , wherein R 7 is C 1-7 alkyl; and R 8 is hydrogen.
7. The process of claim 1 , wherein R 1 is of the formula (XIa)
wherein
R 6 , R 7 and R 9 are hydrogen; and
R 8 is halogen or C 1-7 alkyl.
8. The process of claim 7 , wherein R 8 is fluoro.
9. The process of claim 1 , carried out at a temperature of about 0° C. to about 80° C., a pH of about 2 to about 12, and in one or more solvents selected from the group consisting of dioxane, methylene chloride, dichloromethane, toluene, acetone, methyl ethyl ketone, THF, isopropyl acetate, DMF and an alcohol.