Methods and compositions for the synthesis of multimerizing agents
The invention features methods and compositions for the synthesis of multimerizing agents. An exemplary method for producing AP20187 may comprise: (a) coupling 2-N,Ndimethylaminomethyl-1,3-diaminopropane with AP20792 to produce the dimeric alcohol, AP20793; and (b) coupling the AP20793 so produced with API7362 to yield AP20187. In particular embodiments, the method further includes the step of producing API7362 by coupling API7360 with methyl-L-pipecolic acid, or a salt thereof.
1. A method for producing AP20793:
the method comprising: (a) dissolving a composition comprising the carboxylic acid, AP20792, of the formula:
in a solvent; (b) treating the resulting solution with a carboxyl activating agent to form activated AP20792;
and (c) reacting the activated AP20792 with a composition comprising 2-N,N-dimethylaminomethyl-1,3-diaminopropane to form a mixture comprising AP20793.
2. The method of claim 1 which further comprises the step of producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane by the following method:
(a) reacting compound 4 with HBr to form 3-bromo-2-bromomethyl-N,N-dimethylpropylamine; and
(b) reacting the 3-bromo-2-bromomethyl-N,N-dimethylpropylamine with diformylamine to produce 2-N,N-dimethylaminomethyl-1,3-diaminopropane (compound 6).
3. The method of claim 1 which further comprises the step of producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane by the following method:
providing the quaternary salt:
and reacting it with diformylamine to produce 2-N,N-dimethylaminomethyl-1,3-diaminopropane.
4. A method for producing AP20187, having the formula:
the method comprising coupling the dimeric alcohol, AP20793, having the formula:
with the carboxylic acid, AP20792, having the formula:
to yield AP20187.
5. A method for producing AP20187, having the formula
by:
(a) coupling 2-N,N-dimethylaminomethyl-1,3-diaminopropane with AP20792, having the formula
to produce the dimeric alcohol, AP20793, having the formula
and
(b) coupling the AP20793 so produced with AP 17362, having the formula
to yield AP20187.
6. A method for producing AP20187, having the formula
by:
(a) reacting 3-bromo-2-bromomethyl-N,N-dimethylpropylamine or the quaternary salt thereof with diformylamine to produce 2-N,N-dimethylaminomethyl-1,3-diaminopropane;
(b) coupling 2-N,N-dimethylaminomethyl-1,3-diaminopropane with AP20792, having the formula
to produce the dimeric alcohol, AP20793, having the formula
and
(c) coupling the AP20793 so produced with AP17362, having the formula
to yield AP20187.
7. The method of claim 5 which further includes the step of producing AP 7362, having the formula
by coupling AP17360, having the formula
with methyl-L-pipecolic acid, or a salt thereof.
8. The method of claim 6 which further includes the step of producing AP 17362, having the formula
by coupling AP17360, having the formula
with methyl-L-pipecolic acid, or a salt thereof.
9. The method of any of claims 1 - 8 which further comprises recovering the compound so produced, or a salt thereof, from the reaction mixture.