Oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-{N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds
View Patent ↗The present application relates to a process for preparing a compound of formula I: wherein R 1 is alkyl; R 2 is alkyl; and R 3 is optionally substituted cycloalklylalkyl which comprises oxidizing a compound of the formula wherein R 1 , R 2 and R 3 are defined above to yield a compound of formula I.
1. A process for preparing a compound of formula I:
wherein
R 1 is alkyl;
R 2 is alkyl; and
R 3 is optionally substituted cycloalklylalkyl
which comprises oxidizing the compound of Formula II,
wherein R 1 , R 2 and R 3 are defined above
with an oxidizing agent selected from the group consisting of NaClO, Ca(OCl) 2 , and NaBrO 3 to yield a compound of formula I.
2. The process of claim 1 , wherein from about 1 to about 2 equivalents of the oxidizing reagent is used.
3. The process of claim 1 , wherein said oxidation reaction additionally employs a catalyst.
4. The process of claim 3 , wherein the catalyst is present in the reaction in an amount of from about 0.1 to about 3 equivalents based on the compound of Formula II.
5. The process of claim 3 , wherein the catalyst is selected from the group consisting of TEMPO, 4-methoxyIEMPO, and 4-aminoTEMPO.
6. The process of claim 3 , wherein said oxidation reaction additionally employs a co-catalyst.
7. The process of claim 6 , wherein the co-catalyst is potassium bromide or sodium bromide.
8. The process of claim 6 , which comprises a second co-catalyst.
9. The process of claim 6 , wherein the co-catalyst is potassium acetate or sodium acetate.
10. The process of claim 9 , wherein the amount of co-catalyst is from about 0.1 to about 3 equivalents.
11. The process of claim 1 , wherein said oxidation reaction additionally employs an acid.
12. The process of claim 11 , wherein the amount of acid ranges from about 0.1 to about 3 equivalents.
13. The process of claim 11 , wherein the acid is selected from the group consisting of acetic acid, ClCH 2 COOH, Cl 2 CHCOOH, Cl 3 CCOOH, and CF 3 COOH.
14. The process of claim 1 , wherein the oxidation reaction temperature ranges from about 0° C. to about 80° C.
15. The process of claim 1 , wherein the reaction temperature ranges from about 10° C. to about 50° C.
16. The process according to claim 7 wherein the oxidizing agent is NaOCl, the catalyst is TEMPO and the co-catalyst is KBr.
17. The process of claim 1 , wherein said oxidation reaction temperature ranges from about 15° C. to about 30° C.
18. The process of claim 16 , wherein R 1 and R 2 are tert-butyl and R 3 is cyclobutylmethyl.
19. The process of claim 3 , which further comprises the step of adding a catalyst removing reagent following the oxidation reaction step.
20. The process of claim 19 , wherein the catalyst removing reagent is selected from the group consisting of acorbic acid, a mineral acid, and a mixture thereof.
21. The process of claim 20 , wherein the catalyst removing reagent is ascorbic acid, and is added in an amount from about 0.1 to about 3 equivalents.
22. The process according to claim 19 , wherein the catalyst removing reagent is HCl at a concentration from about 3N to about 5N and is added in an amount of from about 1 to about 10 times by volume based on the weight of a compound of formula II.
23. A process preparing a compound of formula IA
wherein
R 1 is alkyl;
R 2 is alkyl; and
R 3 is optionally substituted cycloalklylalkyl
which comprises oxidizing the compound of Formula IIA
wherein R 1 , R 2 and R 3 are defined above,
with an oxidizing agent selected from the group consisting of NaClO, Ca(OCl) 2 , and NaBrO 3 to yield a compound of formula IA.
24. The process according to claim 23 , wherein R 1 and R 2 are tert-butyl and R 3 is cyclobutylalkyl.
25. A process for the preparation of a compound of formula IB
wherein
R 1 is alkyl;
R 2 is alkyl; and
R 3 optionally substituted cycloalklylalkyl
which comprises oxidizing the compound of Formula IIB
wherein R 1 , R 2 and R 3 are defined above,
with an oxidizing agent selected from the group consisting of NaClO, Ca(OCl) 2 , and NaBrO 3 to yield a compound of formula IIB.
26. The process according to claim 25 , wherein R 1 and R 2 are tert-butyl and R 3 is cyclobutylalkyl.
27. A process for the preparation of a compound of formula IC
wherein
R 1 is alkyl;
R 2 is alkyl; and
R 3 is optionally substituted cycloalklylalkyl,
which comprises oxidizing the compound of Formula IIC
wherein R 1 , R 2 and R 3 are defined above
with an oxidizing agent selected from the group consisting of NaClO, Ca(OCl) 2 , and NaBrO 3 to yield a compound of formula IC.
28. The process according to claim 27 , wherein R 1 and R 2 are tert-butyl and R 3 is cyclobutylalkyl.
29. A process for the preparation of a compound of formula ID comprising:
wherein
R 1 is alkyl;
R 2 is alkyl; and
R 3 is optionally substituted cycloalklylalkyl
which comprises oxidizing the compound of Formula IID
wherein R 1 , R 2 and R 3 are defined above,
with an oxidizing agent selected from the group consisting of NaClO, Ca(OCl) 2 , and NaBrO 3 to yield a compound of formula ID.
30. The process according to claim 29 , wherein R 1 and R 2 are tert-butyl and R 3 is cyclobutylalkyl.
31. The process of claim 13 , wherein the acid selected is acetic acid.
32. The process of claim 31 , wherein the water is added to the acetic acid.