Difluoroalkylcyclopropyl amino acids and esters, and syntheses thereof

Patent metadata

Field	Value
Publication number	US-9809534-B1
Application number	US-201514802392-A
Country	US
Kind code	B1
Filing date	Jul 17, 2015
Priority date	Jul 21, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides methods of synthesizing compounds in an asymmetric or enantioenriched fashion, wherein the compounds are useful intermediates in the synthesis of viral protease inhibitors.

First claim

We claim:

1. A compound, or a salt thereof, having a structure selected from:

wherein, independently for each occurrence,
R is ethyl or n-propyl.

2. The compound of claim 1 , wherein the compound is

3. The compound of claim 1 , wherein the compound is selected from

4. The compound of claim 1 , wherein the compound is

5. The compound of claim 1 , wherein the compound is selected from

6. The compound of claim 1 , wherein the compound is

7. The compound of claim 1 , wherein the compound is

8. A method comprising any one of steps (i)-(vi), or a combination thereof:
(i)
contacting, in an eighth solvent, a compound of formula I with a fifth base, thereby forming a compound of formula J;
wherein
formula I is

formula J is

or a salt thereof; and
R is ethyl or n-propyl;
(ii)
subjecting a compound of formula F to simulated moving bed chromatography, thereby obtaining the enantioenriched compound of formula I;
wherein
formula F is

formula I is

R is alkyl;
(iii)

wherein R is alkyl;
(iv)
selectively hydrolyzing with a first enzyme the 2S-enantiomer of a compound of formula D, thereby forming a fourteenth product mixture;
separating from the fourteenth product mixture an enantioenriched amount of the 2R-enantiomer of a compound of formula D, thereby forming a fifteenth product mixture comprising an enantioenriched compound of formula G;
regioselectively hydrolyzing with a second enzyme the compound of formula G, thereby forming a sixteenth product mixture comprising a compound of formula H,
wherein
formula D is

formula G is

formula H is

or a salt thereof; and
R is alkyl;
(v)

wherein R is alkyl; or
(vi)
heating a compound of formula C and trimethylsulfoxonium iodide in the presence of a second base and a second solvent at a fourth temperature for a fourth period of time, thereby forming a third product mixture comprising a compound of formula D,
wherein
formula C is

formula D is

R is ethyl or n-propyl.

9. A compound, or a salt thereof, having a structure

wherein, independently for each occurrence,
R is alkyl; and
R′ is alkyl.

10. The compound of claim 9 , wherein R is lower alkyl.

11. The compound of claim 9 , wherein R is ethyl.

12. The compound of claim 9 , wherein R is propyl.

13. The compound of claim 9 , wherein R is isopropyl.

14. The compound of claim 9 , wherein R′ is ethyl, propyl, or isopropyl.

15. The compound of claim 9 , wherein the compound is selected from

Assignees

• Abbvie Inc

Inventors

• Lukin Kirill A
• Mei Jianzhang
• Hill David R
• Abrahamson Michael J

Classifications

• C07C69/708

  Ethers · CPC title

• C07C69/08

  of dihydroxylic compounds · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title

• C07C67/31

  by introduction of functional groups containing oxygen only in singly bound form · CPC title

• C12P41/005

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