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 are each hydrogen.
2. 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 are each hydrogen.
3. 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 are each hydrogen.
4. 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 are each hydrogen.
5. 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 are each hydrogen.
6. A compound of Formula (I) or a salt thereof;
wherein:
R 1 is isopropyl;
R 2 is selected from methyl and isopropyl;
R 3 is hydrogen; and
R 5 and R 6 are each hydrogen, acylamino, acyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, carbamoyloxy, dialkylamino, heteroaryl, hydroxy, sulfonamido, or optionally, R 5 and R 6 together with the atoms to which they are attached form a substituted cycloalkyl, substituted cycloheteroalkyl, or substituted aryl ring.
7. The compound of claim 6 , wherein R 5 and R 6 are each hydrogen.
8. The compound of claim 6 , wherein the stereochemistry of the carbon to which R 2 and R 3 are attached is of the S-onfiguration.
9. The compound of claim 6 , wherein the stereochemistry of the carbon to which R 2 and R 3 are attached is of the R-configuration.