PREPARATION OF HYDROXY-BENZYLBENZENE DERIVATIVES

• US 20160355471A1
• Filed: 08/16/2016
• Published: 12/08/2016
• Est. Priority Date: 10/12/2013
• Status: Active Grant

• Current Assignee: Theracosbio LLC
• Original Assignee: Theracos Sub, LLC
• Inventors: ROBERGE, Jacques, VAXELAIRE, Carine, LIU, Baohu, XU, Ge, TANG, Xinxing, XU, Baihua, ZHANG, Jian
• Granted Patent: US 10,093,616 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 303/28 by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
• CPC Class Codes: C07C 309/73 to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 309/75 containing singly-bound oxygen atoms bound to the carbon skeleton
• CPC Class Codes: C07C 37/055 the substituted group being bound to oxygen, e.g. ether group
• CPC Class Codes: C07C 37/50 by reactions decreasing the number of carbon atoms C07C37/04, C07C37/045, C07C37/055, C07C37/08 take precedence
• CPC Class Codes: C07C 39/367 polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
• CPC Class Codes: C07C 41/09 by dehydration of compounds containing hydroxy groups
• CPC Class Codes: C07C 41/16 by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
• CPC Class Codes: C07C 41/24 by elimination of halogens, e.g. elimination of HCl
• CPC Class Codes: C07C 41/26 by introduction of hydroxy or O-metal groups
• CPC Class Codes: C07C 41/40 by change of physical state, e.g. by crystallisation
• CPC Class Codes: C07C 43/196 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 43/225 containing halogen

Abstract

Methods for preparing intermediates of SGLT2 inhibitors are provided, including crystalline forms and methods of crystallizing intermediates.

Claims

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

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 I₂.

4. The method of claim 1, wherein the first reaction mixture in step (a) further comprises BrCH₂CH₂Br.

5. The method of claim 1, wherein the first reaction mixture in step (a) further comprises BrCH₂CH₂Br and I₂.

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 claim 1, 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.

15. The method of claim 1, wherein the 2-methyl-tetrahydrofuran mixture of step (b) containing the intermediate of step (a), can be used in step (c) without forming a concentrated intermediate.

16. A method for preparing a crystalline form of a compound having the structure:

17. A crystalline form of the compound having the structure: