Granted Patent B2

US 9,464,043 · App. 14/511,725 · Granted Oct 11, 2016

Inventors: Jacques Roberge (Princeton, NJ); Carine Vaxelaire (Shanghai, CN); Baohu Liu (Shanghai, CN); Ge Xu (Shanghai, CN); Jian Zhang (Shanghai, CN); Xinxing Tang (Shanghai, CN); Baihua Xu (Malden, MA)

Assignee: THERACOS SUB, LLC

C07C309/75C07C37/50C07C41/09C07C303/28C07C309/73C07B2200/05C07B2200/13C07C2101/02

Abstract

Claims (58)

1. A method for preparing the compound of Formula I:

the method comprising:

forming a reaction mixture comprising a compound of Formula II:

a silane reducing agent,

a catalyst which is present in an amount of less than about 0.1 eq. (mol/mol) to the compound of Formula II, and

a solvent, under conditions suitable to prepare the compound of Formula I,

wherein

X is bromo or iodo,

R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, C 3 -C 6 cycloalkyl, and —CN,

each R 2 and R 3 is independently selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl-hydroxy, C 3 -C 6 cycloalkyl, (C 1 -C 3 alkoxy)C 1 -C 3 alkyl, (C 1 -C 3 haloalkoxy)C 1 -C 3 alkyl, (C 2 -C 4 alkenyloxy)C 1 -C 3 alkyl, (C 2 -C 4 alkynyloxy)C 1 -C 3 alkyl, (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy, (C 1 -C 3 alkoxy)C 1 -C 3 alkoxy, (C 1 -C 3 haloalkoxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkenyloxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkynyloxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 heterocycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 2 -C 4 alkenyloxy, (C 3 -C 6 cycloalkyl)C 2 -C 4 alkynyloxy, —C(O)H, —C(O)OH, and —C(O)O—C 1 -C 3 alkyl,

wherein at least one R 3 is selected from the group consisting of C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy, (C 1 -C 3 alkoxy)C 1 -C 3 alkoxy, (C 1 -C 3 haloalkoxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkenyloxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkynyloxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 heterocycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 2 -C 4 alkenyloxy and (C 3 -C 6 cycloalkyl)C 2 -C 4 alkynyloxy;

each R 4 is independently selected from the group consisting of hydrogen, halo, —OR 4a , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl-hydroxy, C 3 -C 6 cycloalkyl, (C 1 -C 3 alkoxy)C 1 -C 3 alkyl, (C 1 -C 3 haloalkoxy)C 1 -C 3 alkyl, (C 2 -C 4 alkenyloxy)C 1 -C 3 alkyl, (C 2 -C 4 alkynyloxy)C 1 -C 3 alkyl, (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy, (C 1 -C 3 alkoxy)C 1 -C 3 alkoxy, (C 1 -C 3 haloalkoxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkenyloxy)C 1 -C 3 alkoxy, (C 2 -C 4 alkynyloxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 heterocycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 2 -C 4 alkenyloxy, (C 3 -C 6 cycloalkyl)C 2 -C 4 alkynyloxy, —C(O)H, —C(O)OH, and —C(O)O—C 1 -C 3 alkyl, wherein R 4a is selected from the group consisting of hydrogen and a silyl group;

wherein at least one R 4 is —OR 4a ;

ring C is selected from the group consisting of an aryl and a heteroaryl,

ring D is absent or selected from the group consisting of an aryl and a heteroaryl,

subscript n is an integer from 1 to 4,

wherein the alkyl, alkoxy, cycloalkyl, alkenyloxy, alkynyloxy, cycloalkoxy, hydroxyalkoxy, and heterocycloalkoxy groups or portions thereof may optionally be partially or completely fluorinated, and

one or more hydrogen atoms optionally may be replaced with deuterium.

2. The method of claim 1 , wherein the compound of Formula I has the structure of Formula Ia:

and the compound of Formula II has the structure of Formula IIa:

3. The method of claim 1 , wherein the compound of Formula Ia has the structure:

and the compound of Formula Ha has the structure:

4. The method of claim 1 , wherein R 1 is halogen.

5. The method of claim 1 , wherein R 3 is selected from the group consisting of C 1 -C 3 alkoxy, and C 3 -C 6 cycloalkoxy.

6. The method of claim 1 , wherein

R 1 is chloro;

R 2 is H;

R 3 is C 1 -C 3 alkoxy; and

R 4 is —OR 4a .

7. The method of claim 1 , wherein R 3 is methoxy.

8. The method of claim 1 , wherein the silane reducing agent is selected from the group consisting of tetramethyldisiloxane (TMDS), pentamethyldisiloxane (PMDS), polymethylhydrosiloxane (PMHS), and Et 3 SiH.

9. The method of claim 1 , wherein the silane reducing agent is tetramethyldisiloxane (TMDS).

10. The method of claim 1 , wherein the silane reducing agent is present in an amount of from about 1.0 to about 5.0 eq. (mol/mol) to the compound of Formula II.

11. The method of claim 1 , wherein the silane reducing agent is present in an amount of from about 1.0 to about 2.0 eq. (mol/mol) to the compound of Formula II.

12. The method of claim 1 , wherein the catalyst is selected from the group consisting of B(C 6 F 5 ) 3 , —BF 3 -THF, BF 3 —Bu 2 O, BF 3 -MeCN, BF 3 AcOH, BF 3 H 3 PO 4 , BF 3 , and trimethylsilyl trifluoromethanesulfonate (TMSOTf).

13. The method of claim 1 , wherein the catalyst is selected from the group consisting of B(C 6 F 5 ) 3 , —BF 3 -THF, BF 3 —Bu 2 O, BF 3 -MeCN, BF 3 AcOH, BF 3 H 3 PO 4 , and BF 3 .

14. The method of claim 1 , wherein the catalyst is B(C 6 F 5 ) 3 .

15. The method of claim 1 , wherein the catalyst is present in an amount of less than about 0.01 eq. (mol/mol) to the compound of Formula II.

16. The method of claim 1 , wherein the solvent comprises at least one member selected from the group consisting of pentanes, hexanes, heptanes, cyclopentanes, cyclohexanes, benzene, toluene, xylene, trifluoromethylbenzene and chlorobenzene, or combinations thereof.

17. The method of claim 1 , wherein the solvent comprises toluene.

18. The method of claim 1 , wherein the reaction mixture is at a temperature of from about −25° C. to about 50° C.

19. The method of claim 1 , wherein the reaction mixture is at a temperature of from about −10° C. to about 25° C.

20. The method of claim 1 , wherein the reaction mixture is at a temperature of from about 0° C. to about 20° C.

21. The method of claim 1 , wherein the compound of Formula I is prepared in at least 75% yield.

22. The method of claim 1 , wherein the compound of Formula I is prepared in at least 90% yield.

23. The method of claim 1 , wherein the compound of Formula I is prepared in at least 95% yield.

24. The method of claim 1 , wherein the compound of Formula I is prepared in at least 95% purity.

25. The method of claim 1 , wherein the compound of Formula I is prepared in at least 98% purity.

26. The method of claim 1 , wherein R 4a is the silyl group, and wherein the method further comprises:

adding an acid to the reaction mixture, under conditions sufficient to prepare the compound of Formula I wherein R 4 is —OH.

27. The method of claim 26 , wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.

28. The method of claim 27 , wherein the acid is hydrochloric acid.

29. The method of claim 26 , further comprising heating the reaction mixture, thereby preparing the compound of Formula I wherein R 4 is —OH.

30. The method of claim 1 , wherein the compound of Formula I has the structure:

the method comprising:

forming the reaction mixture comprising the compound of Formula II having the structure:

tetramethyldisiloxane (TMDS), a catalytic amount of B(C 6 F 5 ) 3 , and toluene; and

adding hydrochloric acid to the reaction mixture, under conditions suitable to prepare the compound of Formula I.

Assignments (8)

Continuity (1)