Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction

Patent metadata

Field	Value
Publication number	US-10385010-B1
Application number	US-201815970478-A
Country	US
Kind code	B1
Filing date	May 3, 2018
Priority date	Mar 28, 2018
Publication date	Aug 20, 2019
Grant date	Aug 20, 2019

Abstract

Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.

First claim

What is claimed is:

1. A method of stereoselectively diazidating a cyclohexene compound of Formula (I):

wherein R 1 comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;
wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs;
R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl,
comprising contacting the compound of Formula (I) with:
a) an iron compound;
b) an azide source;
c) an activator, wherein the activator is selected from an iodine (III) compound or a peroxy compound;
d) a polydentate ligand;
to give a diazido compound of Formula (II):

wherein R 1′ is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;
wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h and R 2 together form a double bond.

2. The method according to claim 1 , wherein the polydentate ligand has the formula:

wherein m is selected from the group consisting of 0, 1, 2, and 3, and in each case R LA , R LB , R LC , and R LD are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R LA , R LB , R LC , R LD , and R may together form a ring.

3. The method according to claim 2 , wherein the polydentate ligand has the formula:

wherein each of R 7a , R 7b , R 8a , and R 8b are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R 7a , R 7b , R 8a , R 8b , R LD , and R may together form a ring.

4. The method according to claim 2 , wherein the polydentate ligand has the formula:

5. The method of claim 1 , further comprising converting the compound of Formula (II) to oseltamivir or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , further comprising converting the compound of Formula (II) to a compound of Formula (III):

wherein R 1″ is selected from R 1a″ , C(O)R 1a″ , C(O)OR 1a″ , C(O)N(R 1a″ ) 2 , Si(R 1a″ ) 3 , wherein R 1a″ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, and heteroaryl, C 3-8 cycloalkyl.

7. The method of claim 6 , further comprising converting the compound of Formula (III) into oseltamivir or a pharmaceutically acceptable salt thereof.

8. The method of claim 6 , further comprising converting the compound of Formula (III) to a compound of Formula (IV):

wherein R 4 , R 4′ , R 5 , and R 5′ are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;
R 1′″ is selected from R 1a′″ , C(O)R 1a′″ , C(O)OR 1a′″ , C(O)N(R 1a′″ ) 2 , Si(R 1a′″ ) 3 , wherein R 1a′″ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl.

9. The method of claim 8 , further comprising converting the compound of Formula (IV) into oseltamivir, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , further comprising reducing the compound of Formula (II) into the compound of Formula (V):

wherein R 4 , R 4′ , R 5 , and R 5′ are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl.

11. The method of claim 10 , comprising further converting the compound of Formula (V) into oseltamivir, or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , comprising preparing the compound of Formula (I) by cycloaddition between a compound of Formula (VI):

and a compound of Formula (VII):

to give the compound of Formula (I).

13. The method of claim 10 , wherein the compound of Formula (VII) is prepared from a compound of Formula (VIII):

wherein R LG represents a leaving group.

14. A method comprising
a) conducting a cycloaddition reaction to give a cycloaddition product:

wherein R 1 comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;
wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs;
R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; and
b) diazidating the cycloaddition product to give a compound of Formula (II):

wherein R 1′ is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl;
wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or O

Assignees

• Univ Georgia State Res Found

Inventors

• Xu Hao
• Li Hongze
• Shen Shoujie
• Zhu Chengliang

Classifications

• C07C227/04

  Formation of amino groups in compounds containing carboxyl groups · CPC title

• C12P13/008

  containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO) · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C247/14 Primary

  with azido groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07C231/10 Primary

  from compounds not provided for in groups C07C231/02 - C07C231/08 · CPC title