Processes for the preparation of zuclomiphene intermediates
The present invention provides continuous flow processes for the preparation of the compound of Formula (2-A), an intermediate used in the preparation of zuclomiphene or a salt thereof.
1. A continuous flow process for the preparation of a compound of Formula (2-A):
comprising contacting a continuous flow (F1) of the compound of Formula (X):
in a solvent (S1), with a continuous flow (F2) of a chlorinating agent in a solvent (S2), to provide continuous flow (F3) containing the compound of Formula (2-A),
wherein
G is OPG or X 1 ;
PG is an alcohol protecting group;
M is zinc or magnesium; and
X and X 1 are independent halide groups.
2. The continuous flow process of claim 1 , wherein the continuous flow (F1) of the compound of Formula (X) comprises a reaction mixture resulting from reacting diphenylacetylene, in the presence of a nickel(II) catalyst and solvent (S1), with a compound of Formula (3-A):
wherein
G is OPG or X 1 ;
PG is an alcohol protecting group;
M is zinc or magnesium; and
X and X 1 are independent halide groups.
3. The continuous flow process of claim 2 , wherein the nickel(II) catalyst is selected from the group consisting of nickel(II) chloride, nickel(II) chloride hexahydrate, nickel(II) bromide, nickel(II) chloride ethylene glycol dimethyl ether complex, nickel(II) bromide ethylene glycol dimethyl ether complex, nickel(II) acetylacetonate, and nickel(II) acetate tetrahydrate.
4. The continuous flow process of claim 3 , wherein the nickel(II) catalyst is nickel(II) chloride hexahydrate.
5. The continuous flow process of claim 3 , wherein solvent (S1) is selected from the group consisting of methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and mixtures thereof.
6. The continuous flow process of claim 1 , wherein M is magnesium and X is bromide.
7. The continuous flow process of claim 6 , wherein G is fluoride.
8. The continuous flow process of claim 7 , wherein the chlorinating agent is selected from the group consisting of chlorine, N-chlorosuccinimide, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, hexachloroethane, and 1,3-dichloro-5,5-dimethylhydantoin.
9. The continuous flow process of claim 8 , wherein the chlorinating agent is 1,3-dichloro-5,5-dimethylhydantoin.
10. The continuous flow process of claim 9 , wherein solvent (S2) is selected from the group consisting of methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and mixtures thereof.
11. The continuous flow process of claim 10 , wherein the solvent (S2) is toluene.
12. The continuous flow process of claim 7 , wherein continuous flow (F1) and continuous flow (F2) are maintained at a temperature in the range of about 50° C. to about 70° C.
13. The continuous flow process of claim 1 , wherein continuous flow (F1) and continuous flow (F2) are combined at an intersection to provide continuous flow (F3) that passes through a plug flow reactor downstream of the intersection.
14. The continuous flow process of claim 1 , wherein the compound of Formula (2-A) is further converted to the compound of Formula (1-A):
or a salt thereof.
15. The continuous flow process of claim 14 , wherein the compound of Formula (1-A) is provided as an oxalate salt.
16. The continuous flow process of claim 14 , wherein the compound of Formula (1-A) is provided as a citrate salt.