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US 9,174,971 B2Granted
Process for the preparation of compounds useful as inhibitors of SGLT2
AssigneeJanssen Pharmaceutica NV
InventorsVittorio Farina, Sebastien François Emmanuel Lemaire, Ioannis N. Houpis
Life of this patent
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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.
Claims35
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 —(CH2)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 (VII), wherein M2 is a zinc species, with a compound of formula (VIII), wherein each Z is pivaloyl and wherein LG2 is bromo;
- in a mixture of an ether solvent and a hydrocarbon solvent;
- wherein the ether solvent is selected from the group consisting of di-n-butyl ether and cyclopentylmethyl ether;
- at a temperature in the range of from about 60° C. to about 95° C.;
- to yield the corresponding compound of formula (IX);
- de-protecting the compound of formula (IX);
- to yield the corresponding compound of formula (I).
16 more elements
A process for the preparation of a compound of formula (I-S)
- or solvate thereof;
- comprising
- reacting a compound of formula (VII-S), wherein M2 is a zinc species, with a compound of formula (VIII-S), wherein each Z is pivaloyl and wherein LG2 is bromo;
- in a mixture of an ether solvent and a hydrocarbon solvent;
- wherein the ether solvent is selected from the group consisting of di-n-butyl ether and cyclopentylmethyl ether;
- at a temperature in the range of from about 60° C. to about 95° C.;
- to yield the corresponding compound of formula (IX-S);
- de-protecting the compound of formula (IX-S);
- to yield the corresponding compound of formula (I-S).
6 more elements
A process for the preparation of a compound of formula (X-P)
- wherein both Q1 groups are the same and are
- and 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 —(CH2)n—;
- wherein n is 1 or 2;
- provided that in Ring A, X is part of an unsaturated bond;
- reacting a compound of the formula (Z1), wherein Ha2 is a halogen, with a lithium trialkyl magnesate, a compound of formula (Z2);
- in a suitably selected anhydrous organic solvent or mixture or anhydrous organic solvents;
- to yield the corresponding compound of formula (Z3);
- reacting the compound of formula (Z3) with a zinc halide.lithium halide complex, a compound of formula (Z4), wherein Ha1 is a halogen;
- in a suitably selected anhydrous organic solvent or mixture or anhydrous organic solvents;
- to yield the corresponding compound of formula (X-P).
14 more elements
Dependencies are inferred from the claim text.