Preparation of hydroxy-benzylbenzene derivatives
Methods for preparing intermediates of SGLT2 inhibitors are provided, including crystalline forms and methods of crystallizing intermediates.
1. A method of preparing a compound of Formula III:
the method comprising:
(a) forming a first reaction mixture comprising Mg and a compound having the structure:
in tetrahydrofuran solvent, under conditions suitable to form an intermediate compound having the structure:
(b) contacting the first reaction mixture with water and 2-methyl-tetrahydrofuran such that the intermediate of step (a) is substantially dissolved in the 2-methyl-tetrahydrofuran; and
(c) forming a second reaction mixture comprising 4-methylbenzene-1-sulfonyl chloride (Tosyl-Cl) and the 2-methyl-tetrahydrofuran of step (b) containing the intermediate of step (a), under conditions suitable to form the compound of Formula III,
wherein the 2-methyl-tetrahydrofuran containing the intermediate of step (a) is used in step (c) without removing the 2-methyl-tetrahydrofuran to form a concentrated intermediate.
2. The method of claim 1 , wherein the compound of step (a) is
3. The method of claim 1 , wherein the first reaction mixture in step (a) further comprises I 2 .
4. The method of claim 1 , wherein the first reaction mixture in step (a) further comprises BrCH 2 CH 2 Br.
5. The method of claim 1 , wherein the first reaction mixture in step (a) further comprises BrCH 2 CH 2 Br and 12.
6. The method of claim 1 , wherein step (b) comprises contacting the first reaction mixture with water, an acid, and 2-methyl-tetrahydrofuran such that the intermediate of step (a) is substantially dissolved in the 2-methyl-tetrahydrofuran.
7. The method of claim 6 , wherein step (b) comprises contacting the first reaction mixture with water, an acid, sodium chloride and 2-methyl-tetrahydrofuran such that the intermediate of step (a) is substantially dissolved in the 2-methyl-tetrahydrofuran.
8. The method of claim 7 , wherein the acid is selected from the group consisting of hydrochloric acid, formic acid, acetic acid, citric acid, lactic acid, oxalic acid, and glycolic acid.
9. The method of claim 8 , wherein the acid is hydrochloric acid.
10. The method of claim 8 , wherein the acid is glycolic acid.
11. The method of claim 1 , wherein the second reaction mixture of step (c) further comprises tetrahydrofuran (THF).
12. The method of claim 1 , wherein the compound of Formula III is prepared in at least 50% yield.
13. The method of claim 12 , wherein the compound of Formula III is prepared in at least 65% yield.
14. The method of 1 , wherein at least about 75% of the intermediate of step (a) is dissolved in the 2-methyl-tetrahydrofuran in step (b).
15. The method of 1 , wherein at least about 90% of the intermediate of step (a) is dissolved in the 2-methyl-tetrahydrofuran in step (b).