Process for the preparation of anastrozole and intermediates thereof
A process for the preparation of anastrozole is provided, the process comprising: (a) reacting 3,5-bis(1-cyano-1-methylethyl)benzyl halide with a 4-Z-1,2,4-triazole compound of the formula wherein Z is a protecting group to produce 2,2′-[5-(4-Z-1,2,4-triazolium-1-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile) halide; and (b) deprotecting the 2,2′-[5-(4-Z-1,2,4-triazolium-1-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile)halide to produce anastrozole. Also provided is anastrozole substantially free of its isomers.
1 . A process for the preparation of a compound of Formula III:
wherein X is a halide and Z is a protecting group, the process comprising reacting a 3,5-bis(1-cyano -1-methylethyl)benzyl halide with a 4-Z-1 ,2,4-triazole compound of the formula
wherein Z has the aforementioned meaning.
2 . The process of claim 1 , wherein Z is an amine.
3 . The process of claim 1 , wherein Z is —NH 2 .
4 . The process of claim 1 , wherein the reaction is carried out in a solvent selected from the group consisting of an alcohol, ketone, nitrile, water and mixtures thereof.
5 . The process of claim 1 , wherein the compound of Formula III is thereafter converted to anastrozole or a pharmaceutically acceptable salt thereof.
6 . A compound of Formula III:
wherein X is a halide and Z is a protecting group.
7 . The compound of claim 6 , which is a 2,2′-[5-(4-amino-1,2,4-triazolium-1-ylmethyl) -1,3-phenylene]di(2-methylpropionitrile)halide of the general formula:
wherein X has the aforestated meaning.
8 . The compound of claim 7 , wherein X is bromide.
9 . A process for the preparation of anastrozole comprising:
(a) reacting a 3,5-bis(1-cyano-1-methylethyl)benzyl halide with a 4-Z-1,2,4-triazole compound of the formula
wherein Z is a protecting group to produce a compound of Formula III:
wherein X is a halide and Z has the aforementioned meaning; and
(b) deprotecting the compound of Formula III to produce anastrozole.
10 . The process of claim 9 , wherein Z is an amine and wherein step (b) comprises deaminating the compound of Formula III.
11 . The process of claim 10 , wherein the deaminating step comprises removing the protecting group with a deaminating agent.
12 . The process of claim 11 , wherein the deaminating agent is selected from the group consisting of an inorganic nitrite, organic nitrite, nitrous acid and mixtures thereof.
13 . The process of claim 12 , wherein the inorganic nitrite is selected from the group consisting of sodium nitrite, potassium nitrite and mixtures thereof.
14 . The process of claim 12 , wherein the organic nitrite is a C 1 -C 6 alkyl nitrite.
15 . The process of claim 9 , wherein Z is —NH 2 and the step of deprotecting comprises deaminating the compound of Formula III.
16 . The process of claim 15 , wherein the deaminating step comprises removing the protecting group with a deaminating agent.
17 . The process of claim 16 , wherein the deaminating agent is selected from the group consisting of an inorganic nitrite, organic nitrite, nitrous acid and mixtures thereof.
18 . The process of claim 15 , wherein the deaminating step comprises adding an inorganic nitrite with a mineral acid to produce nitrous acid in situ.
19 . The process of claim 18 , wherein the inorganic nitrite is sodium nitrite and the mineral acid is hydrochloric acid in an aqueous medium.
20 . The process of claim 9 , further comprising the step of recovering the anastrozole.
21 . The process of claim 20 , wherein the recovering step comprises basifying with an inorganic base.
22 . The process of claim 21 , wherein the inorganic base is an aqueous ammonia solution.
23 . The process of claim 22 , wherein the basification is with an inorganic base to a pH greater than about 8.
24 . The process of claim 9 , wherein the 3,5-bis(1-cyano-1-methylethyl)benzyl halide of step (a) is prepared by
reacting mesitylene with a N-halosuccinimide to produce a 3,5-bis(halomethyl)toluene;
reacting the 3,5-bis(halomethyl)toluene with a cyanide-containing radical to produce 3,5-bis(cyanomethyl)toluene;
reacting the 3,5-bis(cyanomethyl)toluene with a methyl halide to produce 3,5-bis(1-cyano -1-methylethyl)toluene; and
reacting the 3,5-bis(1-cyano-1-methylethyl)toluene with a N-halosuccinimide to produce 3,5-bis(1-cyano-1-methylethyl)benzyl halide.
25 . The process of claim 9 , wherein the product anastrozole is substantially free of its isomers.
26 . The process of claim 9 , further comprising purifying the product anastrozole.
27 . Substantially pure anastrozole.
28 . The substantially pure anastrozole of claim 27 , wherein the anastrozole is substantially free of its isomers.
29 . The anastrozole of claim 27 , which is substantially free of its 2,2′-[5-(1,2,4-triazol -4-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile) isomer of Formula II.
30 . The anastrozole of claim 28 , having less than one weight percent of isomer impurity.
31 . Anastrozole prepared by the process of claim 9 .
32 . A pharmaceutical composition comprising a therapeutically effective amount of the anastrozole of claim 28 or a pharmaceutically acceptable salt thereof.
33 . The pharmaceutical composition of claim 32 , wherein the anastrozole is micronized anastrozole or a pharmaceutically acceptable salt thereof having a particle size of less than about 400 microns.
34 . The pharmaceutical composition of claim 32 , wherein the anastrozole is micronized anastrozole or a pharmaceutically acceptable salt thereof having a particle size of less than about 15 microns.