Process for the preparation of benzylbenzene SGLT2 inhibitors

1. A method of preparing a compound of Formula Ia:

the method comprising:

(a) forming a first reaction mixture comprising a compound of Formula IIa:

 an alkyl-magnesium complex selected from the group consisting of C 1 -C 4 alkylmagnesium chloride, C 1 -C 4 alkylmagnesium bromide, di(C 1 -C 4 alkyl)magnesium, C 3 -C 7 cycloalkylmagnesium chloride, C 3 -C 7 cycloalkylmagnesium bromide, and di(C 3 -C 7 cycloalkyl)magnesium, and

a first organic solvent,

wherein the ratio of the alkyl-magnesium complex to the compound of Formula IIa is less than or equal to 1.0 (mol/mol), and

 wherein the first reaction mixture is at a temperature of less than about −50° C., to afford an intermediate compound;

(b) forming a second reaction mixture comprising the intermediate compound, a second organic solvent, and a compound of Formula IIIa:

 to afford the compound of Formula Ia wherein R 4 is OH and each R a is R b ;

(c) forming a third reaction mixture comprising a C 1 -C 3 alkylhydroxy, a strong acid and the compound of Formula Ia wherein R 4 is OH, thereby forming the compound of Formula Ia wherein R 4 is C 1 -C 3 alkoxy, and each R a is independently selected from the group consisting of H and R b ; and

(d) forming a fourth reaction mixture comprising a reducing agent and the compound of Formula Ia wherein R 4 is C 1 -C 3 alkoxy, thereby preparing the compound of Formula Ia wherein R 4 is H and each R a is H,

wherein

X is iodo,

R 1 is chloro,

R 2 is H,

R 3 is (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy,

R 4 is selected from the group consisting of H, OH and C 1 -C 3 alkoxy,

each R a is independently selected from the group consisting of H and R b , and

R b is a protecting group,

wherein the alkyl, alkoxy, cycloalkyl, and cycloalkoxy 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 R 3 is 2-cyclopropoxyethoxy.

3. The method of claim 1 , wherein the ratio of the alkyl-magnesium complex in step (a) to the compound of Formula IIa is from about 0.95 up to 1.0 (mol/mol).

4. The method of claim 1 , wherein the first reaction mixture further comprises an accelerating agent selected from the group consisting of LiCl, ZnCl 2 , diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, tri-methylsilyl chloride, and 2,2′-oxybis(N,N-dimethylethanamine).

5. The method of claim 4 , wherein the first reaction mixture further comprises LiCl.

6. The method of claim 4 , wherein the ratio of the accelerating agent to the alkyl-magnesium complex is about 1.0 (mol/mol).

7. The method of claim 1 , wherein the first reaction mixture is at a temperature of from about −60 to about −50° C.

8. The method of claim 1 , wherein the second reaction mixture further comprises additional alkyl-magnesium complex.

9. The method of claim 8 , wherein the ratio of additional alkyl magnesium complex in the second reaction mixture to the compound of Formula IIa is from about 0.01 to about 0.1 (mol/mol).

10. The method of claim 1 , wherein the second reaction mixture is at a temperature of from about −60 to about 25° C.

11. The method of claim 1 , wherein the second reaction mixture is at a temperature of from about −60 to about −10° C.

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

the method comprising:

(a) forming the first reaction mixture comprising the compound of Formula IIa having the structure:

 isopropylmagnesium chloride, lithium chloride, tetrahydrofuran and heptane, wherein the ratio of the isopropylmagnesium chloride to the compound of Formula IIa is from about 0.95 up to 1.0 (mol/mol), the ratio of the isopropylmagnesium chloride to the LiCl is about 1.0 (mol/mol), wherein the first reaction mixture is at a temperature of less than about −50° C., to afford the intermediate; and

(b) forming the second reaction mixture comprising the intermediate, the second organic solvent, and the compound of Formula IIIa having the structure:

 thereby preparing the compound of Formula Ia.

13. The method of claim 12 , wherein the second reaction mixture further comprises additional isopropylmagnesium chloride and lithium chloride, where the ratio of the additional isopropylmagnesium chloride to the compound of Formula IIa is from about 0.01 to about 0.1 (mol/mol), and the ratio of the additional isopropylmagnesium chloride to the additional LiCl is 1.0 (mol/mol).

14. The method of claim 1 , wherein the first and second reaction mixtures are formed in the same reaction vessel.

15. The method of claim 1 , wherein each R b of the compound of Formula Ia in the third reaction mixture is an acid-labile protecting group, thereby removing the acid-labile protecting groups such that each R a is H.

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

17. The method of claim 1 , wherein the third reaction mixture is at a temperature of about 0° C.

18. The method of claim 1 , wherein the fourth reaction mixture is at a temperature from about −40 to about −10° C.

19. The method of claim 1 , wherein the fourth reaction mixture is at a temperature from about −25 to about −22° C.

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

21. A method of preparing a compound of Formula IIa:

the method comprising forming a first reaction mixture comprising a compound of Formula IV:

and a compound of Formula V:

under conditions suitable to prepare the compound of Formula IIa,

wherein

R 1 is selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 3 alkyl and C 1 -C 3 alkoxy,

R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, 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 and (C 3 -C 6 cycloalkyl)C 2 -C 4 alkynyloxy,

R 3a is OH,

R 6 is selected from the group consisting of OH and Br,

X is bromo or iodo,

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 substituted with deuterium.

22. The method of claim 21 , wherein the first reaction mixture further comprises a Lewis acid.

23. The method of claim 22 , wherein the Lewis acid is selected from the group consisting of BF 3 .Et 2 O, BCl 3 , BBr 3 , B(C 6 F 5 ) 3 , SnCl 4 , I 2 , FeCl 3 , FeBr 3 , TMSOTf-AgClO 4 , AgOTf, Cu(OTf) 2 , Bi(OTf) 3 , In(OTf) 3 , Zn(NTf 2 ) 2 , AuCl 3 , HgCl 2 , HgSO 4 , Hg(OCOCF 3 ) 2 , PdCl 2 , Pd(OAc) 2 , ZnCl 2 , ZnBr 2 , ZnI 2 , Polyphosphoric acid trimethylsilylester, AlCl 3 , AlBr 3 , AlI 3 , Al(OiPr) 3 , Al(OPh) 3 , TiCl 4 , TiCl 2 (OiPr) 2 , Ti(OiPr) 4 , PBr 3 , BeCl 2 , CdCl 2 , CeCl 3 , DyCl 3 , EuCl 3 , Eu(OTf) 3 , ErCl 3 , Er(OTf) 3 , GaCl 3 , GdCl 3 , Gd(OTf) 3 , HoCl 3 , LaCl 3 , La(OTf) 3 , LuCl 3 , Lu(OTf) 3 , Mg(ClO 4 ) 2 , MgCl 2 , MgBr 2 , MgI 2 , NdCl 3 , Nd(OTf) 3 , PCl 3 , PBr 3 , PrCl 3 , Pr(OTf) 3 , PmCl 3 , Pm(OTf) 3 , Sc(OTf) 3 , SnCl 4 , SbCl 5 , SmCl 3 , Sm(OTf) 3 , Tf 2 O, TbCl 3 , Tb(OTf) 3 , TmCl 3 , Tm(OTf) 3 , YbCl 3 , Yb(OTf) 3 , ZrCl 4 , and Cp 2 ZrCl 2 .

24. The method of claim 22 , wherein the Lewis acid is ZnCl 2 .

25. The method of claim 21 , wherein

R 1 is chloro;

R 2 is H; and

X is iodo.

26. The method of claim 21 , wherein R 3 is hydroxy.

27. The method of claim 21 , wherein the compound of Formula IIa has the structure:

28. The method of claim 21 , wherein the method comprises forming the first reaction mixture comprising the compound of Formula IV having the structure:

the compound of Formula V having the structure:

gaseous hydrobromic acid and ZnCl 2 , to prepare the compound of Formula IIa having the structure:

29. The method of claim 21 , wherein the method further comprises forming a second reaction mixture of the compound of Formula IIa having the structure:

and a compound of formula VI:

LG-R 3b   VI

wherein

R 3b is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, (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 hydroxyalkyl, (C 3 -C 6 heterocycloalkoxy)C 1 -C 3 alkyl, (C 3 -C 6 cycloalkyl)C 3 -C 4 alkenyl and (C 3 -C 6 cycloalkyl)C 3 -C 4 alkynyl, and

LG is a leaving group,

thereby forming the compound of Formula IIa:

wherein

R 3 is selected from the group consisting of C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy, 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 1 -C 3 hydroxyalkoxy, (C 3 -C 6 heterocycloalkoxy)C 1 -C 3 alkoxy, (C 3 -C 6 cycloalkyl)C 3 -C 4 alkenyloxy and (C 3 -C 6 cycloalkyl)C 3 -C 4 alkynyloxy.

30. The method of claim 29 , wherein

R 1 is halo;

R 2 is H; and

R 3 is selected from the group consisting of C 1 -C 3 alkoxy and (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy.

31. The method of claim 29 , wherein

R 1 is chloro;

R 2 is H; and

R 3 is selected from the group consisting of ethoxy and 2-cyclopropoxyethoxy.

32. The method of claim 29 , wherein

LG is selected from the group consisting of chloride, bromide, iodide, hydroxy, tosylate and mesylate; and

R 3 is selected from the group consisting of C 1 -C 3 alkyl and (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkyl.

33. The method of claim 29 , wherein

LG is selected from the group consisting of chloride, bromide, and tosylate; and

R 3 is selected from the group consisting of ethyl and 2-cyclopropoxyethyl.

34. The method of claim 29 , wherein the compound of Formula VI has the structure:

35. The method of claim 29 , forming a second reaction mixture comprising a compound of Formula VI having the structure:

and the compound of Formula IIa having the structure:

thereby forming the compound of Formula IIa having the structure:

36. The method of claim 1 , further comprising

forming a fifth reaction mixture comprising a compound of Formula IV:

 and a compound of Formula V:

 under conditions suitable to prepare the compound of Formula IIa,

wherein

R 3a is OH, and

R 6 is selected from the group consisting of OH and Br.