Synthesis of 1,4-diazaspiro[5.5]undecan-3-one
This invention provides a process for preparing 1,4-diazaspiro[5.5]undecan-3-one and analogues thereof that are useful in the preparation of pharmaceutical compound, including for the treatment of disorders involving abnormal cellular proliferation. Chemical intermediates in the process are also provided.
1. A process to prepare a spirocyclic compound comprising:
a. reacting a cyclic ketone with a nitroalkane to afford a cycloalkyl group substituted with nitroalkylene;
b. reacting the compound of step (a) with a glycinate to afford a compound of Formula III;
c. reducing the compound of Formula III with a reducing agent;
d. cyclizing the compound of step (c);
wherein the cyclic ketone is of Formula:
wherein the nitroalkane is of Formula:
wherein the glycinate is of Formula:
wherein Formula III is:
wherein the spirocyclic compound is of Formula:
wherein
y is 0;
n is 0 or 1;
R 1 is hydrogen;
R 2 is hydrogen, substituted heteroaryl, or
R 3 is hydrogen;
R 4 is NR 8 R 9 or OR 10 ;
R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, aryl, -alkyl-aryl, and —C(O)R 11 ;
R 7 is alkyl, aryl, or -alkyl-aryl;
R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, aryl, and -alkyl-aryl;
R 10 is alkyl, aryl, or -alkyl-aryl;
R 11 is alkyl or aryl;
R 12 is alkyl, aryl, or -alkyl-aryl;
R 13 is —S-alkyl or Cl.
2. The process of claim 1 , wherein the nitroalkane is also a solvent.
3. The process of claim 1 , wherein a base is used in step (a).
4. The process of claim 3 , wherein the base is an organic base.
5. The process of claim 3 , wherein the base is an inorganic base.
6. The process of claim 1 , wherein oxalic acid is added after step (b) to precipitate and remove byproducts.
7. The process of claim 1 , wherein an acid is added after step (b) to isolate the compound of Formula I as a salt.
8. The process of claim 7 , wherein the acid is hydrobromic acid.
9. The process of claim 1 , wherein n is 1.
10. The process of claim 1 , wherein R 4 is —OMe or —OEt.
11. The process of claim 1 , wherein the spirocyclic compound is:
and wherein the compound of Formula III is:
12. A compound of Formula
or an acceptable salt thereof;
wherein
y is 0, 1, 2, 3, or 4;
n is 0 or 1;
R 1 is hydrogen, alkyl, or aryl;
R 2 is hydrogen, substituted heteroaryl, or
R 3 is hydrogen, NR 5 R 6 , OR 7 , SR 7 , or halogen;
R 4 is NR 8 R 9 or OR 10 ;
R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, aryl, -alkyl-aryl, and —C(O)R 11 ;
R 7 is alkyl, aryl, or -alkyl-aryl;
R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, aryl, and -alkyl-aryl;
R 10 is alkyl, aryl, or -alkyl-aryl;
R 11 is alkyl or aryl;
R 12 is alkyl, aryl, or -alkyl-aryl; and
R 13 is —S-alkyl or Cl;
each instance of R 50 is independently selected from the group consisting of hydrogen, halogen, and alkyl.
13. The compound of claim 12 , wherein y is 1.
14. The compound of claim 13 , wherein R 50 is halogen.
15. The compound of claim 13 , wherein R 50 is alkyl.
16. The compound of claim 12 , wherein R 1 is hydrogen.
17. The compound of claim 16 , wherein n is 1.
18. The compound of claim 17 , wherein y is 0.
19. The compound of claim 18 , wherein R 2 is hydrogen.
20. The compound of claim 19 , wherein R 3 is hydrogen.
21. The compound of claim 20 , wherein R 4 is —OMe or —OEt.
22. The compound of claim 12 , wherein the compound is of Formula:
23. The compound of claim 12 , wherein the compound is of Formula:
24. The compound of claim 12 , wherein the compound is of structure:
25. The compound of claim 12 , wherein the compound is of structure:
26. A process to prepare a compound of Formula III comprising:
a. reacting a cyclic ketone with a nitroalkane to afford a cycloalkyl group substituted with nitroalkylene;
b. reacting the compound of step (a) with a glycinate;
wherein the cyclic ketone is of Formula:
wherein the nitroalkane is of Formula:
wherein the glycinate is of Formula:
wherein Formula III is:
wherein
y is 0;
n is 0 or 1;
R 1 is hydrogen;
R 2 is hydrogen, substituted heteroaryl, or
R 3 is hydrogen;
R 4 is NR 8 R 9 or OR 10 ;
R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, aryl, -alkyl-aryl, and —C(O)R 11 ;
R 7 is alkyl, aryl, or -alkyl-aryl;
R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, aryl, and -alkyl-aryl;
R 10 is alkyl, aryl, or -alkyl-aryl;
R 11 is alkyl or aryl;
R 12 is alkyl, aryl, or -alkyl-aryl;
R 13 is —S-alkyl or Cl.