Process for making zilpaterol
This invention generally relates to processes for making zilpaterol and salts thereof, as well as processes for making intermediates that, interalia, may be used to make zilpaterol and salts thereof.
1. A method of preparing a compound of Formula I or a salt thereof
comprising:
a. reacting a compound of Formula II
with a halogenating agent to produce a compound of Formula III
wherein X is CI, Br, or I;
b. reacting compound III with a compound of Formula A
to produce a compound of Formula IV;
and
c. reacting compound IV with a reducing agent to produce a compound of Formula I wherein:
R 1 is selected from hydrogen, amino, alkyl, alkenyl, alkynyl, aryl, or benzyl, and wherein for each alkyl, alkenyl, alkynyl, aryl, and benzyl may be substituted or unsubstituted;
R 2a and R 2b are the same or different and are each independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, aryl, benzyl, alkoxy, alkylthioxy, alkyl sulfonyl, alkyl sulfoxy, or alkyl thio, and wherein for each alkyl, alkenyl, alkynyl, aryl, benzyl, alkoxy, alkylthioxy, alkyl sulfonyl, alkyl sulfoxy, and alkyl thio may be substituted or unsubstituted;
R 3 is selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, aryl, benzyl, alkoxy, alkylthioxy, alkyl sulfonyl, alkyl sulfoxy, or alkyl thio, and wherein for each alkyl, alkenyl, alkynyl, aryl, benzyl, alkoxy, alkylthioxy, alkyl sulfonyl, alkyl sulfoxy, and alkyl thio may be substituted or unsubstituted; and
R 4 and R 5 are independently selected from hydrogen, amino, alkyl, alkenyl, alkynyl, aryl, or benzyl, and wherein for each alkyl, alkenyl, alkynyl, aryl, and benzyl, may be substituted or unsubstituted; or R 4 and R 5 may be taken together to form a cyclic substituent, wherein the cyclic substituent may be aromatic or non aromatic and may further include one or more additional hetero atoms selected from O, S and N.
2. The method of claim 1 , wherein the reaction of part b and the reaction of part c are conducted in situ and compound IV is not isolated.
3. The method of claim 1 , wherein R 1 , R 2a , R 2b , R 3 and R 5 are hydrogen.
4. The method of claim 1 , wherein R 4 is isopropyl.
5. A method of preparing a compound of Formula I or a salt thereof
comprising reacting a compound of Formula III
wherein X is CI, Br, or I;
with a compound of Formula A
to produce a compound of Formula IV;
and
reacting compound IV with a reducing agent to produce a compound of Formula I;
wherein R 1 , R 2a , R 2b , R 3 , R 4 and R 5 are defined as in claim 1 .
6. A method of preparing a compound of Formula I or a salt thereof
comprising reacting a compound of Formula IV
with a reducing agent to produce a compound of Formula I, wherein R 1 , R 2a , R 2b , R 3 , R 4 and R 5 are defined as in claim 1 .
7. The method of claim 1 , wherein the reducing agent is selected from sodium borohydride, potassium borohydride, lithium aluminum hydride and borane-tetrahydrofuran complex.
8. The method of claim 7 wherein the reducing agent is NaBH 4 .
9. The method of claim 1 , wherein the halogenating agent is selected from N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine and iodine.
10. The method of claim 9 , wherein the halogenating agent is N-bromosuccinimide (NBS).
11. The method of claim 9 , wherein the halogenating agent is bromine.
12. The method of claim 9 , wherein the halogenating agent is N-chlorosuccinimide (NCS).
13. The method of claim 9 , wherein the halogenating agent is iodine.