N-carboxyanhydride-based-scale synthesis of elamipretide
Disclosed are methods of making elamipretide (MTP-131), a peptide compound with therapeutic potential for treating various mitochondrial myopathies. The synthesis of the peptide can be achieved via the use of N-carboxyanhydride-modified amino acid residues, which increases the efficiency of the synthetic process and the purity of the peptide product generated.
1. A method of preparing compound 1, or a salt thereof, comprising:
combining compound 1a and compound 1b under conditions sufficient to produce compound 1, wherein:
compound 1 is represented by:
compound 1a is represented by:
compound 1b is represented by:
PG 1 represents alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl;
PG 2 represents H or an amino protecting group; and
R 1 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
2. The method of claim 1 , further comprising combining compound 1 with an amino protecting reagent represented by PG 3 -X, thereby forming compound 1c, wherein:
compound 1c is represented by:
PG 3 represents an amino protecting group; and
X represents a leaving group.
3. The method of claim 2 , further comprising combining compound 1c and a deprotection reagent under conditions sufficient to form compound 1d, wherein:
compound 1d is represented by:
4. The method of claim 3 , further comprising combining compound 1d and compound 2 under conditions sufficient to produce compound 10, wherein:
compound 10 is represented by:
compound 2 is represented by:
and
PG 4 represents an amino protecting group.
5. The method of claim 4 , wherein the conditions sufficient to produce compound 10 comprise a peptide coupling reagent.
6. The method of claim 1 , further comprising combining compound 1e and a phosgene equivalent reagent under conditions sufficient to produce compound 1b, wherein:
compound 1e is represented by:
7. The method of claim 4 , further comprising combining compound 2a and compound 2b under conditions sufficient to produce compound 2, wherein:
compound 2a is represented by:
compound 2b is represented by:
and
R 2 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
8. The method of 7 , further comprising combining compound 2c and a phosgene equivalent reagent under conditions sufficient to produce compound 2b, wherein:
compound 2c is represented by:
9. The method of claim 4 , wherein compound 10 has the following structure:
10. A method of preparing compound 2, or a salt thereof, comprising:
combining compound 2a and compound 2b under conditions sufficient to produce compound 2, wherein:
compound 2 is represented by:
compound 2a is represented by:
compound 2b is represented by:
PG 4 represents an amino protecting group; and
R 2 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
11. The method of claim 10 , further comprising combining compound 2c and a phosgene equivalent reagent under conditions sufficient to produce compound 2b, wherein:
compound 2c is represented by:
12. The method of claim 10 , further comprising combining compound 2 and compound 1d under conditions sufficient to produce compound 10, wherein:
compound 10 is represented by:
compound 1d is represented by:
PG 2 represents H or an amino protecting group; and
PG 3 represents an amino protecting group.
13. The method of claim 10 , further comprising combining compound 2 and compound 3a under conditions sufficient to produce compound 3, wherein:
compound 3 is represented by:
compound 3a is represented by:
and
R 3 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
14. The method of claim 13 , further comprising combining compound 3b and a phosgene equivalent reagent under conditions sufficient to produce compound 3a, wherein:
compound 3b is represented by:
15. The method of claim 13 , further comprising combining compound 3 and compound 4a under conditions sufficient to produce compound 4, wherein:
compound 4 is represented by:
compound 4a is represented by:
R 4 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl; and
PG 2 represents H or an amino protecting group.
16. The method of claim 15 , further comprising combining compound 4b and a phosgene equivalent reagent under conditions sufficient to produce compound 4a, wherein:
compound 4b is represented by:
17. A method of preparing compound 5, or a salt thereof, comprising:
combining compound 5a and compound 3a under conditions sufficient to produce compound 5, wherein:
compound 5 is represented by:
compound 5a is represented by:
compound 3a is represented by:
PG 4 represents an amino protecting group;
PG 5 represents alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; and
R 3 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
18. The method of claim 17 , further comprising combining compound 3b and a phosgene equivalent reagent under conditions sufficient to produce compound 3a, wherein:
compound 3b is represented by:
19. The method of claim 17 , further comprising combining compound 5 and compound 1b under conditions sufficient to produce compound 6, wherein:
compound 6 is represented by:
compound 1b is represented by:
PG 2 represents H or an amino protecting group; and
R 1 represents H, alkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-aralkyl, —C(O)O-heteroaryl, —C(O)O— heteroaralkyl, or aralkyl.
20. The method of claim 19 , further comprising combining compound 1e and a phosgene equivalent reagent under conditions sufficient to produce compound 1b, wherein:
compound 1e is represented by: