Chiral synthesis of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamides

Patent metadata

Field	Value
Publication number	US-9328066-B2
Application number	US-201214122568-A
Country	US
Kind code	B2
Filing date	May 24, 2012
Priority date	May 27, 2011
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present invention relates to a novel enantioselective method of preparing (S)- and (R)-enantiomers of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-5 methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamide, to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said (S)- and (R)-enantiomers of N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[2,3-dihydroxy-propyl]cyclopropanesulfonamide.

First claim

The invention claimed is:

1. The compound
1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonyl bromide (S)-10-Br:

2. A method of preparing a compound of formula (S)-14:

comprising:
i) reacting a compound of formula (S)-10:

with a compound of formula (12):

in the presence of a bromide, optionally in the presence of a base, and optionally in a solvent,
thereby providing a reaction mixture containing a compound of formula (S)-13:

and, then,
ii) adding an aqueous mineral acid to said reaction mixture containing a compound of formula (S)-13,
thereby providing a compound of formula (S)-14.

3. A method of preparing a compound of formula (S)-14:

comprising:
i) reacting a compound of formula (S)-10-Br:

with a compound of formula (12):

optionally in the presence of a base, and optionally in a solvent,
thereby providing a reaction mixture containing a compound of formula (S)-13:

and, then,
ii) adding an aqueous mineral acid to said reaction mixture containing a compound of formula (S)-13,
thereby providing a compound of formula (S)-14.

4. The method according to claim 2 , wherein said compound of formula (S)-10:

is prepared by reacting a compound of formula (S)-7:

with a chlorinating agent, optionally in a solvent, thereby providing a compound of formula (S)-10.

5. The method according to claim 3 , wherein said compound of formula (S)-10-Br:

is prepared by reacting a compound of formula (S)-7:

with a brominating agent, optionally in a solvent, thereby providing a compound of formula (S)-10-Br.

6. The method of claim 4 , wherein said compound of formula (S)-7:

is prepared by reacting a compound of formula (S)-6:

with a sodium alkoxide, optionally in a solvent, thereby providing a compound of formula (S)-7.

7. The method of claim 6 , wherein said compound of formula (S)-6:

is prepared by reacting a compound of formula (S)-4:

with either:
a) boron trifluoride, optionally in the form of a complex, optionally in a solvent, or
b) phosphomolybdic acid hydrate, optionally in a solvent,
thereby providing a compound of formula (S)-6.

8. The method of claim 7 , wherein said compound of formula (S)-4:

is prepared by reacting a compound of formula (S)-3:

with a base, optionally in a solvent,
thereby providing a compound of formula (S)-4.

9. The method of claim 8 , wherein said compound of formula (S)-3:

is prepared by:
a) reacting a compound of formula 2:

with a base to form a deprotonated compound of formula 2, optionally in a solvent,
b) adding a compound of formula (S)-1 and boron trifluoride, optionally in the form of a complex; and
c) allowing the deprotonated compound of formula 2 to react with the compound of formula (S)-1:

thereby providing a compound of formula (S)-3.

10. The method of claim 6 , wherein said compound of formula (S)-6:

is prepared by reacting a compound of formula (S)-5:

with 2,2-dimethoxypropane, optionally in a solvent, and optionally in the presence of a catalyst,
thereby providing a compound of formula (S)-6.

11. The method of claim 10 , wherein said compound of formula (S)-5:

is prepared by reacting a compound of formula (S)-9:

wherein PG represents a protecting group, with an acid, optionally in a solvent,
thereby providing a compound of formula (S)-5.

12. The method of claim 11 , wherein said compound of formula (S)-9:

wherein PG represents a t-butyldimethylsilyl- group or a tetrahydropyranyl group, is prepared by:
a) reacting a compound of formula 2:

with a base to form a deprotonated compound of formula 2, optionally in a solvent,
b) adding a compound of formula (S)-8 and boron trifluoride, optionally in the form of a complex; and
c) allowing the deprotonated compound of formula 2 to react with the compound of formula (S)-8:

wherein PG represents a t-butyldimethylsilyl- group or a tetrahydropyranyl group thereby providing a compound of formula (S)-9.

13. The method of claim 5 , wherein said compound of formula (S)-7:

is prepared by reacting a compound of formula (S)-6:

with a sodium alkoxide, optionally in a solvent,

Assignees

• Fey Peter
• Mayer Agathe Christine
• Bayer Ip Gmbh

Inventors

• Fey Peter
• Mayer Agathe Christine

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07D309/12

  only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers · CPC title

• C07D317/24

  esterified · CPC title

• C07C309/71

  having sulfur atoms of esterified sulfo groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07C2601/02

  with a three-membered ring · CPC title