Process for the stereoselective preparation of (−)-halofenate and derivatives thereof
The present invention provides a compounds the formula (IV): and methods for producing an α-(phenoxy)phenylacetic acid compound of the formula: wherein R 1 is a member selected from the group consisting of: each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro; the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d); the subscript m is an integer of from 0 to 3; * indicates a carbon which is enriched in one stereoisomeric configuration; and the wavy line indicates the point of attachment of R 1 ; and compounds.
1. A method for preparing a compound of formula (I):
wherein
R 1 is a member selected from the group consisting of:
each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro;
the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d);
the subscript m is an integer of from 0 to 3;
* indicates a carbon which is enriched in one stereoisomeric configuration; and
the wavy line indicates the point of attachment of R 1 ;
the method comprising:
(a) contacting a compound of formula (II):
with a carboxylic acid activating reagent selected from the group consisting of thionyl halides, anhydrides and thioester generating reagents; in a compatible solvent;
(b) brominating the product of step (a) with bromine in a compatible solvent;
(c) esterifying the product of step (b) with a chiral alcohol selected from the group consisting of:
in a compatible solvent to stereoselectively produce a compound of formula (I).
2. The method of claim 1 , wherein R 1 is
3. The method of claim 1 , wherein the compound of formula (II) is 4-chlorophenylacetic acid.
4. The method of claim 1 , wherein the carboxylic acid activating reagent is thionyl halide.
5. The method of claim 1 , wherein the carboxylic acid activating reagent is thionyl chloride.
6. The method of claim 1 , wherein bromine is present in a concentration of about at least 1 molar equivalent to the amount of the compound of formula (II).
7. The method of claim 1 , wherein the solvent is a halogenated alkane solvent.
8. The method of claim 1 , wherein the solvent is 1,2-dichloroethane.
9. The method of claim 1 , wherein said brominating is carried out at a temperature of at least about 70° C.
10. The method of claim 1 , further comprising removing excess bromine under reduced pressure before said step (c).
11. The method of claim 1 , wherein the method is conducted in one reaction vessel.
12. The method of claim 1 , wherein only the compound of Formula (I) is isolated.
13. A method for preparing a compound of formula (I):
wherein
R 1 is a member selected from the group consisting of:
each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro;
the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d);
the subscript m is an integer of from 0 to 3;
* indicates a carbon which is enriched in one stereoisomeric configuration; and
the wavy line indicates the point of attachment of R 1 ;
the method comprising esterifying a compound of the formula:
wherein R is a halide, or when combined with the carbonyl to which it is attached is an anhydride or thioester group; in a compatible solvent with a chiral alcohol selected from the group consisting of:
in a compatible solvent to stereoselectively produce a compound of formula (I).
14. A method for preparing (−)-halofenate comprising i) preparing a compound of formula (I):
wherein
R 1 is a member selected from the group consisting of:
each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro;
the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d);
the subscript m is an integer of from 0 to 3;
* indicates a carbon which is enriched in one stereoisomeric configuration; and
the wavy line indicates the point of attachment of R 1 ;
the method comprising:
(a) contacting a compound of formula (II):
with a carboxylic acid activating reagent selected from the group consisting of thionyl halides, anhydrides and thioester generating reagents; in a compatible solvent;
(b) brominating the product of step (a) with bromine in a compatible solvent;
(c) esterifying the product of step (b) with a chiral alcohol selected from the group consisting of:
in a compatible solvent to stereoselectively produce a compound of formula (I); and further converting the product of said step(s) to (−)-halofenate.
15. A method for preparing (−)-halofenate comprising i) preparing a compound of formula (I):
wherein
R 1 is a member selected from the group consisting of:
each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro;
the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d);
the subscript m is an integer of from 0 to 3;
* indicates a carbon which is enriched in one stereoisomeric configuration; and
the wavy line indicates the point of attachment of R 1 ;
the method comprising:
(a) contacting a compound of formula (II):
with a carboxylic acid activating reagent selected from the group consisting of thionyl halides, anhydrides and thioester generating reagents; in a compatible solvent;
(b) brominating the product of step (a) with bromine in a compatible solvent; and further converting the product of said step(s) to (−)-halofenate.
16. A method for preparing (−)-halofenate comprising i) preparing a compound of formula (I):
wherein
R 1 is a member selected from the group consisting of:
each R 2 is a member independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )haloalkyl, amino, (C 1 -C 4 )aminoalkyl, amido, (C 1 -C 4 )amidoalkyl, (C 1 -C 4 )sulfonylalkyl, (C 1 -C 4 )sulfamylalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )heteroalkyl, carboxy and nitro;
the subscript n is 1 when R 1 has the formula (a) or (b) and 2 when R 1 has the formula (c) or (d);
the subscript m is an integer of from 0 to 3;
* indicates a carbon which is enriched in one stereoisomeric configuration; and
the wavy line indicates the point of attachment of R 1 ;
the method comprising esterifying a compound of the formula:
wherein R is a halide, or when combined with the carbonyl to which it is attached is an anhydride or thioester group; in a compatible solvent with a chiral alcohol selected from the group consisting of:
in a compatible solvent to stereoselectively produce a compound of formula (I); and further converting the product of said step(s) to (−)-halofenate.