Process for the preparation of compounds useful as inhibitors of SGLT

Patent metadata

Field	Value
Publication number	US-9056850-B2
Application number	US-57893409-A
Country	US
Kind code	B2
Filing date	Oct 14, 2009
Priority date	Oct 17, 2008
Publication date	Jun 16, 2015
Grant date	Jun 16, 2015

Abstract

The present invention is directed to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT) being present in the intestine or kidney.

First claim

We claim:

1. A process for the preparation of compounds of formula (I)

wherein Ring A and Ring B are one of the following:
(1) Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; or
(2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring wherein Y is linked to the heterocyclic ring of the fused heterobicyclic ring; or
(3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, wherein the sugar moiety X-(sugar) and the moiety —Y-(Ring B) are both on the same heterocyclic ring of the fused heterobicyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring;
X is a carbon atom;
Y is —(CH 2 ) n —; wherein n is 1 or 2;
provided that in Ring A, X is part of an unsaturated bond;
or a pharmaceutically acceptable salt or solvate thereof; comprising

reacting a compound of formula (X) wherein Q 0 is bromo or iodo with a complex of di(C 1-4 alkyl)magnesium with lithium chloride or a complex of C 1-4 alkyl magnesium chloride with lithium chloride or a complex of C 1-4 alkyl magnesium bromide with lithium chloride; in an organic solvent or mixture thereof; at a temperature in the range of from about ambient temperature to about −78° C.; to yield the corresponding compound of formula (XI), wherein Q 1 is the corresponding MgCl or MgBr;

reacting the compound of formula (XI) with a compound of formula (XII), wherein Z is an oxygen protecting group selected from the group consisting of acetyl and pivaloyl; in an organic solvent or mixture thereof; at a temperature in the range of from about ambient temperature to about −78° C.; to yield the corresponding compound of formula (XIII);

reacting the compound of formula (XIII), to yield the corresponding compound of formula (I).

2. A process as in claim 1 , further comprising

reacting the compound of formula (XIII) with a Lewis acid; in the presence of a trialkylsilane; in an organic solvent or mixture thereof; at a temperature in the range of from about 0° C. to about reflux; to yield the corresponding compound of formula (XIV);

de-protecting the compound of formula (XIV); to yield the corresponding compound of formula (I).

3. A process as in claim 1 , wherein
X is a carbon atom;
Ring A is selected from the group consisting of 4-methylphenyl and 4-chlorophenyl;
Y is —CH 2 — and is bound at the 3-position of Ring A; and
Ring B is selected from the group consisting of 2-(5-(4-fluorophenyl)-thienyl) and 2-(5-(6-fluoro-pyrid-3-yl)thienyl).

4. A process as in claim 1 , wherein the compound of formula (X) is reacted with a complex of di(C 1-4 alkyl)magnesium with lithium chloride; and wherein the complex of di(C 1-4 alkyl)magnesium with lithium chloride is a complex of di(sec-butyl)magnesium with lithium chloride; to yield the corresponding compound of formula (XI) wherein Q 1 is MgCl.

5. A process for the preparation of a compound of formula (I-S)

or solvate thereof; comprising

reacting a compound of formula (X-S) wherein Q 0 is bromo or iodo with a complex of di(C 1-4 alkyl)magnesium with lithium chloride or complex of C 1-4 alkyl magnesium chloride with lithium chloride or a complex of C 1-4 alkyl magnesium bromide with lithium chloride; in an organic solvent or mixture thereof; at a temperature in the range of from about ambient temperature to about −78° C.; to yield the corresponding compound of formula (XI-S), wherein Q 1 is the corresponding MgCl or MgBr;

reacting the compound of formula (XI-S) with a compound of formula (XII-S), wherein Z is an oxygen protecting group selected from the group consisting of acetyl and pivaloyl; in an organic solvent or mixture thereof; at a temperature in the range of from about ambient temperature to about −78° C.; to yield the corresponding compound of formula (XIII-S);

reacting the compound of formula (XIII-S), to yield the corresponding compound of formula (I-S).

6. A process as in claim 5 , further comprising

reacting the compound of formula (XIII-S) with a Lewis acid; in the presence of a silane reagent; in an organic solvent or mixture thereof; at a temperature in the range of from about 0° C. to about reflux; to yield the corresponding compound of formula (XIV-S);

de-protecting the compound of formula (XIV-S); to yield the corresponding compound of formula (I-S).

7. A process as in claim 5 , wherein the complex of di(C 1-4 alkyl)magnesium with lithium chloride or the complex of C 1-4 alkyl magnesium chloride with lithium chloride or the complex of C 1-4 alkyl magnesium bromide with lithium chloride is present in an amount in the range of from about 1.0 to about 1.5 molar equivalents.

8. A process as in claim 5 , wherein the compound of formula (X-S) is reacted with a complex of di(C 1-4 alkyl)magnesium with lithium chloride; and wherein the complex of di(C 1-4 alkyl)magnesium with lithium chloride is a complex of di(sec-butyl)magnesium with lithium chloride; to yield the corresponding compound of formula (XI-S) wherein Q 1 is MgCl.

9. A process as in claim 8 , wherein the complex of di(sec-butyl)magnesium with lithium chloride is present in an amount in the range of from about 1.0 to about 1.5 molar equivalents.

10. A process as in claim 5 , wherein Z is acetyl.

11. A process as in claim 5 , wherein the compound of formula (XII-S) is present in an amount in the range of from about 1.0 to about 2.0 molar equivalents.

12. A process as in claim 5 , wherein, when the compound of formula (XI-S) is reacted with the compound of formula (XII-S), the compound of formula (XI-S) is added to a mixture of the compound of formula (XII-S) in an organic solvent or mixture thereof.

13. A process as in claim 6 , wherein the Lewis acid is selected from the group consisting of BF 3 •OEt 2 , BF 3 •THF, aluminum chloride, zinc chloride and iron chloride; and wherein the silane is selected from the grou

Assignees

• Filliers Walter Ferdinand Maria
• Broeckx Rudy Laurent Maria
• Nieste Patrick Hubert J
• Hatsuda Masanori
• Yoshinaga Masahiko
• Yada Mitsuhiro
• Teleha Christopher
• Janssen Pharmaceutica Nv
• Mitsubishi Tanabe Pharma Corp

Inventors

• Filliers Walter Ferdinand Maria
• Broeckx Rudy Laurent Maria
• Nieste Patrick Hubert J
• Hatsuda Masanori
• Yoshinaga Masahiko
• Yada Mitsuhiro
• Teleha Christopher

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title

• C07D333/12 Primary

  Radicals substituted by halogen atoms or nitro or nitroso radicals · CPC title

• C07D409/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07H7/04

  Carbocyclic radicals · CPC title