Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors
AssigneeLexicon Pharmaceuticals, Inc.
InventorsNicole Cathleen Goodwin, Bryce Alden Harrison, Shinya Iimura, Ross Mabon, Qiuling Song, Wenxue Wu, Jie Yan, Haiming Zhang, Matthew Mangzhu Zhao
Life of this patent
Estimating the term…
Abstract
Methods of synthesizing sodium glucose co-transporter 2 inhibitors, as well as compounds useful therein, are disclosed. Particular inhibitors are compounds of formula I:
Claims42
A method of preparing a compound of formula I:
- or a salt thereof, which comprises contacting a compound of formula II:
- with a base under conditions sufficient to provide the compound of formula I, wherein:
- Y is O, S, NR4, or C(R4)2;
- Z1 is O, S, SO, or SO2;
- each P1 is independently a hydroxyl protecting group stable under acidic conditions;
- each R1 is independently hydrogen, halogen, cyano, OR1A, SR1A, or optionally substituted alkyl;
- each R1A is independently hydrogen or optionally substituted alkyl or aryl;
- each R2 is independently hydrogen, halogen, cyano, OR2A, SR2A, or optionally substituted alkyl;
- each R2A is independently hydrogen or optionally substituted alkyl or aryl;
- R3 is optionally substituted alkyl, aryl or heterocycle;
- each R4 is independently hydrogen or optionally substituted alkyl or aryl;
- n is 1-3;
- and
- m is 1-3.
A method of preparing a compound of formula II(b):
- or a salt thereof, which comprises contacting a compound of formula II(c):
- with a compound of the formula R3X under conditions sufficient to provide the compound of formula II(b), wherein:
- X is bromine, iodine, alkanesulfoxy, or alkoxysulfoxy;
- Y is O, S, NR4, or C(R4)2;
- each P1 is independently a hydroxyl protecting group stable under acidic conditions;
- each R1 is independently hydrogen, halogen, cyano, OR4, SR4, or optionally substituted alkyl;
- each R2 is independently hydrogen, halogen, cyano, OR4, SR4, or optionally substituted alkyl;
- R3 is optionally substituted alkyl, aryl or heterocycle;
- each R4 is independently hydrogen or optionally substituted alkyl;
- n is 1-2;
- and
- m is 1-2.
A method of preparing a compound of formula II(d):
- or a salt thereof, which comprises contacting a compound of formula II(e):
- with a salt of P1X′″ under conditions sufficient for the formation of the compound of formula II(d), wherein:
- X′″ is chlorine, bromine, iodine, alkylcarboxy, alkanesulfoxy, or alkoxysulfoxy;
- Y is O, S, NR4, or C(R4)2;
- each P1 is independently a hydroxyl protecting group stable under acidic conditions;
- each R1 is independently hydrogen, halogen, cyano, OR4, SR4, or optionally substituted alkyl;
- each R2 is independently hydrogen, halogen, cyano, OR4, SR4, or optionally substituted alkyl;
- each R4 is independently hydrogen or optionally substituted alkyl;
- n is 1-2;
- and
- m is 1-2.
A method of preparing ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone:
- which comprises contacting (3a8,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid with morpholine under conditions sufficient to provide ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone.
A crystalline compound of the formula:
A compound of the formula:
- or a salt thereof.
A compound of the formula:
- or a salt thereof.
A compound of the formula:
- or a salt thereof.
A compound of the formula:
- or a salt thereof.
A compound of the formula:
- or a salt thereof.
A compound of the formula:
A compound of the formula:
A compound of the formula:
- or a salt thereof.
Dependencies are inferred from the claim text.