Methods of synthesizing
View Patent ↗The present disclosure relates to methods of synthesizing N-hydroxysuccinimidyl-carbonate intermediates from the corresponding sulfones useful in the preparation of 1-(acyloxy)-alkyl carbamate prodrugs.
1. A method of synthesizing a 1-(acyloxy)alkyl N-hydroxysuccinimidyl carbonate compound of Formula (I) or a salt thereof comprising:
reacting a compound of Formula (V) or a salt thereof with an N-hydroxysuccinimidyl compound of Formula (VII) or a salt thereof to provide the corresponding compound of Formula (I) or a salt thereof:
wherein:
R 1 is chosen from C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, phenyl, substituted phenyl, and C 7-9 phenylalkyl;
R 2 and R 3 are independently chosen from hydrogen, C 1-4 alkyl, substituted C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxycarbonyl, phenyl, substituted phenyl, and C 7-9 phenylalkyl; or R 2 and R 3 together with the carbon atom to which they are bonded form a ring chosen from a cyclobutyl, cyclopentyl, and cyclohexyl ring;
R 4 is chosen from C 1-4 alkyl and substituted C 1-4 alkyl wherein each of the one or more substituent groups is independently chosen from halogen, halo-C 1-3 alkyl, hydroxyl, and cyano;
each of R 5 , R 6 , R 7 , and R 8 is independently chosen from hydrogen, halogen, C 1-3 alkyl, and halo-C 1-3 alkyl; and
R 11 and R 12 are independently chosen from hydrogen, C 1-16 acylamino, C 1-16 acyloxy, C 1-6 alkoxycarbonylamino, C 1-6 alkoxycarbonyloxy, C 1-4 alkyl, substituted C 1-4 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, C 6-12 aryl, substituted C 6-12 aryl, C 7-16 arylalkyl, C 1-6 carbamoyl, C 1-6 dialkylamino, C 5-12 heteroaryl, hydroxyl, and sulfonamide; or R 11 and R 12 together with the atoms to which they are bonded form a ring chosen from a substituted C 3-12 cycloalkyl, substituted C 3-12 heterocycloalkyl, and substituted C 6-12 aryl ring.
2. The method of claim 1 , wherein the method comprises:
reacting the compound of Formula (I) or a salt thereof with a primary or secondary amine-containing drug of the formula HNR 9 R 10 or a salt thereof to provide a corresponding 1-(acyloxy)-alkyl carbamate compound of Formula (VI):
wherein —NR 9 R 10 is a moiety of a primary or secondary amine-containing drug.
3. The method of claim 1 , wherein R 1 is chosen from methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1,diethoxyethyl, phenyl, and cyclohexyl.
4. The method of claim 1 , wherein one of R 2 and R 3 is hydrogen; and the other of R 2 and R 3 is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl.
5. The method of claim 1 , wherein R 1 is isopropyl; R 2 is methyl; and R 3 is hydrogen.
6. The method of claim 1 , wherein R 1 is isopropyl; R 2 is isopropyl; and R 3 is hydrogen.
7. The method of claim 1 , wherein R 4 is chosen from C 1-4 alkyl, phenyl, and C 5-6 cycloalkyl.
8. The method of claim 1 , wherein R 4 is C 1-4 alkyl.
9. The method of claim 1 , wherein R 4 is methyl.
10. The method of claim 1 , wherein each of R 5 , R 6 , R 7 , and R 8 is hydrogen.
11. The method of claim 1 , wherein each of R 11 and R 12 is hydrogen.
12. The method of claim 1 , wherein R 11 and R 12 are independently chosen from acetoxy, isobutyroyloxy, pivaloyloxy, benzoyloxy, C 1-4 alkyl-substituted benzoyloxy, methoxy, and benzyloxy.
13. The method of claim 12 , wherein R 11 and R 12 are the same and are chosen from isobutyroyloxy and benzoyloxy.
14. The method of claim 1 , wherein one of R 2 and R 3 is hydrogen; and the other of R 2 and R 3 is chosen from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl; R 4 is chosen from C 1-4 alkyl, phenyl, and C 5-6 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 is hydrogen; and R 11 and R 12 are the same and are chosen from hydrogen, isobutyroyloxy, and benzoyloxy.
15. The method of claim 2 , wherein HNR 9 R 10 is chosen from gabapentin, pregabalin, R-baclofen, and tranexamic acid.
16. The method of claim 15 , wherein the compound of Formula (VI) is {[(1-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid or a salt thereof.
17. The method of claim 15 , wherein the compound of Formula (VI) is (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or a salt thereof.
18. The method of claim 15 , wherein the compound of Formula (VI) is 1-(R)-3-({[1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl) (3S)-5-methylhexanoic acid or a salt thereof.
19. The method of claim 15 , wherein the compound of Formula (VI) is trans-4-({[(1R/S)-1-(2-methylpropanoyloxy)ethoxy]carbonylamino}methyl)-cyclohexanecarboxylic acid or a salt thereof.