Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
View Patent ↗Methods for synthesis of 1-(acyloxy)-alkyl carbamates, particularly, the synthesis of 1-(acyloxy)-alkyl carbamate prodrugs of primary or secondary amine-containing drugs are described. Also described are methods for synthesis of 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonates which are useful intermediates in the synthesis of 1-(acyloxy)-alkyl carbamates are also described.
1. A method of synthesizing a 1-(acyloxy)-alkyl carbamate compound of formula (XI) or a salt thereof, comprising contacting a compound of Formula (I) or a salt thereof with gabapentin or a salt thereof:
wherein:
R 1 is isopropyl;
R 2 is methyl;
R 3 is hydrogen; and
R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl or substituted aryl ring.
2. The method of claim 1 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl ring.
3. The method of claim 2 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted cyclohexyl ring.
4. The method of claim 1 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted aryl ring.
5. The method of claim 4 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted phenyl ring.
6. A method of synthesizing a 1-(acyloxy)-alkyl carbamate compound of Formula (XII) or a salt thereof, comprising contacting a compound of Formula (I) or a salt thereof with baclofen or a salt thereof:
wherein:
R 1 is isopropyl;
R 2 is isopropyl;
R 3 is hydrogen; and
R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl or substituted aryl ring.
7. The method of claim 6 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl ring.
8. The method of claim 7 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted cyclohexyl ring.
9. The method of claim 6 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted aryl ring.
10. The method of claim 9 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted phenyl ring.
11. A method of synthesizing a 1-(acyloxy)-alkyl carbamate compound of Formula (XIII) or salt thereof comprising contacting a compound of Formula (I) or salt thereof with R-(−)-baclofen or a salt thereof:
wherein:
R 1 is isopropyl;
R 2 is isopropyl;
R 3 is hydrogen; and
R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl or substituted aryl ring.
12. The method of claim 11 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl ring.
13. The method of claim 12 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted cyclohexyl ring.
14. The method of claim 11 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted aryl ring.
15. The method of claim 14 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted phenyl ring.
16. A method of synthesizing a 1-(acyloxy)-alkyl carbamate compound of the formula:
or salt thereof comprising contacting a compound of Formula (I) or salt thereof with tranexamic acid or a salt thereof:
wherein:
R 1 is isopropyl;
R 2 is methyl;
R 3 is hydrogen; and
R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl or substituted aryl ring.
17. The method of claim 16 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl ring.
18. The method of claim 17 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted cyclohexyl ring.
19. The method of claim 16 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted aryl ring.
20. The method of claim 19 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted phenyl ring.
21. A method of synthesizing a 1-(acyloxy)-alkyl carbamate compound of the formula:
or salt thereof comprising contacting a compound of Formula (I) or salt thereof with pregabalin or a salt thereof:
wherein:
R 1 is isopropyl;
R 2 is methyl;
R 3 is hydrogen; and
R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl or substituted aryl ring.
22. The method of claim 21 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl ring.
23. The method of claim 22 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted cyclohexyl ring.
24. The method of claim 21 , wherein R 5 and R 6 together with the atoms to which they are attached form a substituted aryl ring.
25. The method of claim 24 , wherein R 5 and R 6 together with the atoms to which they are attached form a 1,2-disubstituted phenyl ring.