Methods and compositions for the synthesis of multimerizing agents

1. The compound

2. The compound

or a salt thereof.

3. The quaternary salt of 3-bromo-2-bromomethyl-N,N-dimethylpropylamine in solid form and described by the formula:

4. The compound AP22895, having the formula:

5. A method for the chiral synthesis of the compound, AP17360, the method comprising: (a) reacting the compound AP22895 with ethyl iodide in the presence of a base to form compound X:

and (b) cleaving the compound X under acidic conditions to produce AP17360:

6. The method of claim 5 wherein the base is lithium bis(trimethylsilyl)amide.

7. A method for producing dimethyl amide 3 by treating the corresponding ethyl ester with dimethylamine in the presence of base:

to form the desired dimethyl amide.

8. A method for producing compound 4 by providing the corresponding amide 3 and treating it with a reducing agent to produce compound 4:

9. The method of claim 8 in which the reducing agent is LiAlH 4 .

10. A method for producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane (compound 6), the method comprising:

11. A method for producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane (compound 6), the method comprising providing the quaternary salt:

and reacting it with diformylamine to produce 2-N,N-dimethylaminomethyl-1,3-diaminopropane.

12. 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.

13. The method of claim 12 which further comprises the step of producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane by the method of claim 10 .

14. The method of claim 12 which further comprises the step of producing 2-N,N-dimethylaminomethyl-1,3-diaminopropane by the method of claim 11 .

15. A method for producing AP20187, having the formula:

the method comprising coupling the dimeric alcohol, AP20793, with the carboxylic acid, AP20792, having the formula:

to yield AP20187.

16. A method for producing AP20187 by:

(a) coupling 2-N,N-dimethylaminomethyl-1,3-diaminopropane with AP20792 to produce the dimeric alcohol, AP20793; and

(b) coupling the AP20793 so produced with AP17362 to yield AP20187.

17. A method for producing AP20187 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 to produce the dimeric alcohol, AP20793; and

(c) coupling the AP20793 so produced with AP17362 to yield AP20187.

18. The method of claim 16 which further includes the step of producing AP17362 by coupling AP17360 with methyl-L-pipecolic acid, or a salt thereof.

19. The method of claim 17 which further includes the step of producing AP17362 by coupling AP17360 with methyl-L-pipecolic acid, or a salt thereof.

20. The method of any of claims 5 - 19 which further comprises recovering the compound so produced, or a salt thereof, from the reaction mixture.