Synthetic route to anti-viral agents

Patent metadata

Field	Value
Publication number	US-9809576-B1
Application number	US-201514802372-A
Country	US
Kind code	B1
Filing date	Jul 17, 2015
Priority date	Jul 18, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides methods of synthesizing a viral protease inhibitor in high yield, without using expensive catalysts or challenging reaction conditions.

First claim

We claim:

1. A method comprising one or more of steps A, C, D, E, E′, F, F′, G, G′, H, I, J, K, L, M, and N:
(A)

wherein the reaction takes place in a sixteenth solvent, thereby forming a thirteenth product mixture comprising

(C)

wherein Step 1 of the reaction takes place in a thirteenth solvent in the presence of a seventh base; and Step 2 of the reaction takes place in a fourteenth solvent, thereby forming an eleventh product mixture comprising

(D)

wherein the reaction takes place in a twelfth solvent in the presence of a second acid, thereby forming a tenth product mixture comprising

(E)

wherein the reaction takes place in an eleventh solvent in the presence of a sixth base, thereby forming a ninth product mixture comprising

(E′)

wherein step (1) takes place in a nineteenth solvent in the presence of an eighth base, and step (2) takes place in a twentieth solvent in the presence of a ninth base, thereby forming a sixteenth product mixture comprising

(F)

wherein the reaction takes place in a tenth solvent in the presence of a fifth base, thereby forming an eighth product mixture comprising

(F′)

wherein the reaction takes place in a eighteenth solvent in the presence of a reagent, thereby forming an fifteenth product mixture comprising

(G)

wherein the reaction takes place in a ninth solvent in the presence of a fourth base, thereby forming a seventh product mixture comprising

(G′)

wherein the reaction takes place in a seventeenth solvent in the presence of an oxidant, thereby forming a fourteenth product mixture comprising

(H)

wherein the reaction takes place in an eighth solvent, thereby forming a sixth product mixture comprising

(I)

wherein Step 1 of the reaction takes place in a sixth solvent at a sixth temperature to effect a Claisen rearrangement, and Step 2 of the reaction takes place in a seventh solvent at a seventh temperature, thereby forming a fifth product mixture comprising

(J)

wherein the reaction takes place in a fifth solvent in the presence of a first acid and a hydrogen source, thereby forming a fourth product mixture comprising

(K)

wherein Step 1 of the reaction takes place in a third solvent in the presence of a second base; and Step 2 of the reaction takes place in a fourth solvent in the presence of a third base, thereby forming a third product mixture comprising

(L)

wherein the reaction takes place in a second solvent in the presence of a first enzyme, thereby forming a second product mixture comprising

(M)

wherein the reaction takes place in a first solvent in the presence of a first base, thereby forming a first product mixture comprising

or
(N)

wherein:
LG is a leaving group; and
the second reagent comprises one or more reagents sufficient to replace the OH with group LG.

2. The method of claim 1 , comprising the reaction of Scheme N, wherein LG is Br, and the second reagent comprises PPh 3 and Br 2 .

Assignees

• Abbvie Inc

Inventors

• Cink Russell D
• Lukin Kirill A
• Leanna Marvin R
• Pelc Matthew J
• Towne Timothy B
• Welch Dennie S
• Engstrom Kenneth M
• Ravn Matthew M
• Bishop Richard D
• Zhao Gang
• Mei Jianzhang
• Kallemeyn Jeff M
• Hill David R
• Abrahamson Michael J
• Morrill Westin H

Classifications

• C12P41/005

  by esterification of carboxylic acid groups in the enantiomers or the inverse reaction · CPC title

• C07D241/44

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

• C07C269/04

  from amines with formation of carbamate groups · CPC title

• C07C271/34

  with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title