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US 2013/0211102 A1Published application
Chemical processes for the manufacture of substituted benzofurans
AssigneeBionomics Limited
InventorBernard Luke Flynn
Life of this patent
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Abstract
The present invention relates to the scaled-up synthesis of biologically active compounds which display useful therapeutic activity in treating proliferative disorders. In particular the invention relates to process methods for the kilogram scale synthesis of a particular class of substituted benzofuran tubulin polymerisation inhibitors.
Claims21
A method of preparing kilogram quantities of a compound of formula (1)
- or a C-7 disodium phosphate ester thereof,
- wherein R1 is an optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C5 alkynyl;
- said method comprising the steps of:
- a) coupling a compound of formula (2) with an alkyne of formula (3) in the presence of a palladium catalyst
- wherein Hal is I or Br, and
- P is a hydroxy protecting group;
- b) reacting in situ the resultant coupled product of step a) with a compound of formula (4)
- wherein R2 is Br, I or CF3SO3,
- in the presence of CO at a temperature below 50° C.;
- and
- c) removing the C-7 hydroxy protecting group to obtain a compound of formula (1) and optionally converting the C-7 hydroxy group into the disodium phosphate ester thereof.
8 more elements
A method of preparing kilogram scale quantities of a compound of formula (1a),
- said method comprising the steps of:
- a) coupling a compound of formula (2) with an alkyne of formula (3) in the presence of a palladium catalyst
- wherein Hal is I or Br,
- P is a hydroxy protecting group;
- and
- R1 is an optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C5 alkynyl;
- b) reacting in situ the resultant coupled product with a compound of formula (4)
- wherein R2 is Br, I, or CF3SO3,
- in the presence of CO at a temperature below 50° C.;
- c) treating the resultant compound with tributylphosphine to enable the substantial removal of the palladium catalyst;
- and
- d) optionally removing the C-7 hydroxy protecting group to obtain a compound of formula (1);
- and,
- e) optionally converting the C-7 hydroxyl group into the disodium phosphate ester to obtain a compound of formula (1a).
11 more elements
A method of preparing kilogram quantities of a compound of formula (2)
- wherein P represents a protecting group,
- including the steps of:
- (a) protecting the 2-hydroxy group of o-vanillin to form (2a);
- (b) oxidizing (2a) followed by saponification to form (2b);
- and
- (c) halogenating (2b) to form (2).
3 more elements
A method of preparing kilogram quantities of a compound of formula (1)
- or a C-7 disodium phosphate ester thereof,
- wherein R1 is an optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C5 alkynyl;
- said method comprising the steps of:
- (a) protecting the 2-hydroxy group of o-vanillin to form a compound of formula (2a);
- (b) oxidizing (2a) with m-CPBA followed by saponification with an inorganic base to form a compound of formula (2b);
- (c) halogenating (2b) to form a compound of formula (2);
- (d) coupling a compound of formula (2) with an alkyne of formula (3) in the presence of a palladium catalyst
- wherein Hal is I or Br, and
- P is a hydroxy protecting group;
- (e) reacting in situ the resultant coupled product of step (d) with a compound of formula (4)
- wherein R2 is Br, I or CF3SO3,
- in the presence of CO at a temperature below 50° C.;
- and
- (f) removing the C-7 hydroxy protecting group to obtain a compound of formula (1) and optionally converting the C-7 hydroxy group into the disodium phosphate ester thereof.
11 more elements
A method of preparing kilogram scale quantities of a compound of formula (1a),
- said method comprising the steps of:
- (a) protecting the 2-hydroxy group of o-vanillin to form a compound of formula (2a);
- (b) oxidizing (2a) with m-CPBA followed by saponification with an inorganic base to form a compound of formula (2b);
- (c) halogenating (2b) to form a compound of formula (2);
- (d) coupling a compound of formula (2) with an alkyne of formula (3) in the presence of a palladium catalyst
- wherein Hal is I or Br,
- P is a hydroxy protecting group;
- and
- R1 is an optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C5 alkynyl;
- (e) reacting in situ the resultant coupled product with a compound of formula (4)
- wherein R2 is Br, I, or CF3SO3,
- in the presence of CO at a temperature below 50° C.;
- (f) treating the resultant compound with tributylphosphine to enable the substantial removal of the palladium catalyst;
- and
- (g) removing the C-7 hydroxy protecting group to obtain a compound of formula (1);
- and,
- (h) converting the C-7 hydroxyl group into the disodium phosphate ester to obtain a compound of formula (1a).
14 more elements
Dependencies are inferred from the claim text.