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 N-hydroxysuccinimidyl carbonate compound of Formula (I):
comprising contacting a thiocarbonate compound of Formula (VIII) with an oxidant (IX), in the presence of an N-hydroxysuccinimide compound of Formula (X) to afford the compound of Formula (I);
wherein:
R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R 2 and R 3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;
R 4 is C 1-4 alkyl, phenyl, substituted phenyl or C 7-9 phenylalkyl; and
R 5 and R 6 are independently 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.
2. The method of claim 1 , wherein R 1 is selected from the group consisting of C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, substituted phenyl and C 7-9 phenylalkyl.
3. The method of claim 2 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl or cyclohexyl.
4. The method of claim 1 , wherein R 2 and R 3 are independently selected from the group consisting of 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.
5. The method of claim 4 , wherein R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R 3 is hydrogen or methyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring.
6. The method of claim 1 , wherein R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 4-methoxyphenyl, 4-methylphenyl or benzyl.
7. The method of claim 1 , wherein R 5 and R 6 are each hydrogen, acyloxy, alkoxycarbonyloxy, alkoxy, carbamoyloxy, hydroxyl, acetoxy, isobutyroyloxy, pivaloyloxy, benzoyloxy, C 1-4 alkyl-substituted benzoyloxy, methoxy, or benzyloxy.
8. The method of claim 1 , wherein R 1 is isopropyl, R 2 is methyl or isopropyl, R 3 is hydrogen, R 4 is methyl, ethyl or tert-butyl, and R 5 and R 6 are each hydrogen, benzoyloxy, isobutyroyloxy, pivaloyloxy or C 1-4 alkyl-substituted benzoyloxy.
9. The method of claim 1 , wherein R 2 and R 3 in the compound of Formula (I) are different, such that the carbon atom to which R 2 and R 3 are attached is a stereogenic center.
10. The method of claim 9 , wherein the compound of Formula (X) is chiral and non-racemic.
11. The method of claim 10 , wherein R 5 and R 6 in the compound of Formula Formula (X) are each isobutyryloxy or benzoyloxy, and the stereochemistry of the compound is either (1) the stereochemistry at the carbon to which R 5 is attached is of the R-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the R-configuration; and (2) the stereochemistry at the carbon to which R 5 is attached is of the S-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the S-configuration.
12. The method of claim 10 , wherein the compound of Formula (I) comprises substantially one diastereomer.
13. The method of claim 12 , wherein R 1 is isopropyl, R 2 is isopropyl, R 3 is hydrogen, R 4 is methyl, ethyl or tert-butyl, R 5 and R 6 are each benzoyloxy or isobutyroyloxy, and the stereochemistry of the compound is selected from:
(i) the stereochemistry at the carbon to which R 2 and R 3 are attached is of the S-configuration, the stereochemistry at the carbon to which R 5 is attached is of the R-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the R-configuration;
(ii) the stereochemistry at the carbon to which R 2 and R 3 are attached is of the R-configuration, the stereochemistry at the carbon to which R 5 is attached is of the S-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the S-configuration;
(iii) the stereochemistry at the carbon to which R 2 and R 3 are attached is of the R-configuration, the stereochemistry at the carbon to which R 5 is attached is of the R-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the R-configuration; and
(iv) the stereochemistry at the carbon to which R 2 and R 3 are attached is of the S-configuration, the stereochemistry at the carbon to which R 5 is attached is of the S-configuration, and the stereochemistry at the carbon to which R 6 is attached is of the S-configuration.
14. The method of claim 1 , wherein said contacting is carried out in the presence of a base.
15. The method of claim 1 , wherein the oxidant (IX) comprises a composition selected from the group consisting of a peroxy acid, a peroxide, ozone and oxygen.
16. The method of claim 15 , wherein the peroxy acid is selected from the group consisting of peroxyacetic acid, m-chloroperoxybenzoic acid, monoperoxy-o-phthalic acid, monoperoxymaleic acid, peroxytrifluoroacetic acid and salts thereof.
17. The method of claim 1 , wherein said contacting is carried out in the presence of a solvent selected from the group consisting of acetic acid, dichloromethane, dichloroethane, chloroform, ethyl acetate, toluene, chlorobenzene, xylene, acetonitrile, methyl tert-butyl ether, cyclohexane or combinations thereof.
18. The method of claim 17 , wherein said contacting is carried out at a temperature between about −20° C. and about 80° C.
19. The method of claim 1 , wherein said contacting is carried out in the absence of a base.
20. A compound of Formula (I),
and salts thereof, wherein:
R 1 is phenyl, substituted phenyl, or styryl;
R 2 is methyl or isopropyl;
R 3 hydrogen; and
R 5 and R 6 are each hydrogen, benzoyloxy or isobutyroyloxy.
21. The method of claim 1 , further comprising:
contacting the compound of Formula (I) with a primary or secondary amine-containing drug of Formula (II) to afford a compound of Formula (III) or a pharmaceutically acceptable salt, or hydrate thereof;
wherein:
HNR 7 R 8 is a primary or secondary amine-containing drug.
22. The method of claim 21 , wherein HNR 7 R 8 is gabapentin.
23. The method of claim 21 , wherein said contacting of the compound of Formula (I) with the primary or secondary amine-containing drug of Formula (II) is conducted in the presence of a solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, toluene, tetrahydrofuran, pyridine, methyl tert-butyl ether, methanol, ethanol, isopropanol, water, and combinations thereof.
24. The method of claim 21 , wherein said contacting of the compound of Formula (I) with the primary or secondary amine-containing drug of Formula (II) is carried out at a temperature between about −20° C. and about 40° C.
25. The method of claim 21 , wherein said contacting of the compound of Formula (I) with the primary or secondary amine-containing drug of Formula (II) is performed in the absence of a base.
26. The method of claim 21 , wherein said contacting of the compound of Formula (I) with the primary or secondary amine-containing drug of Formula (II) is performed in the presence of a base.
27. The method of claim 21 , wherein the base is an alkali metal bicarbonate, an alkali metal carbonate salt or an organic base selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine.
28. The method of claim 21 , wherein HNR 7 R 8 is pregabalin.
29. The method of claim 21 , wherein HNR 7 R 8 is tranexamic acid.
30. A method of synthesizing a 1-(acyloxy)-alkyl carbamate prodrug of pregabalin or a salt or hydrate thereof, comprising contacting a compound of Formula (I) with pregabalin or a salt, thereof:
wherein R 1 , R 2 , R 3 , R 5 and R 6 are as defined in claim 1 .
31. A method of synthesizing a 1-(acyloxy)-alkyl carbamate prodrug of tranexamic acid or a salt or hydrate thereof, comprising contacting a compound of Formula (I) with tranexamic acid or a salt thereof:
wherein R 1 , R 2 , R 3 , R 5 and R 6 are as defined in claim 1 .
32. The method of claim 21 , wherein HNR 7 R 8 is R-baclofen.