Methods for the synthesis of pyridoxamine
The invention provides non-oxidative methods for the large scale manufacture of pyridoxamine (I) (4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine): and salts thereof. The invention also provides intermediate compounds for the synthesis of pyridoxamine, as well as compositions and methods for the treatment and/or prevention of conditions associated with the formation of post-Amadori advanced glycation end-products.
1. A method for preparing pyridoxamine, or salt thereof, the method comprising the steps of:
(a) protecting the hydroxyls of a compound of formula (II), or salt thereof, to form a compound of formula (III), or salt thereof:
wherein R at each occurrence is a hydroxyl protecting group, wherein R is selected from the group consisting of alkanoyl, arylcarbonyl, lower alkoxycarbonyl; lower alkenyloxycarbonyl; and aryl lower alkoxycarbonyl;
(b) converting the compound of formula (III), or salt thereof, to a compound of formula (IV), or salt thereof:
and
wherein
represents a cyclic imide substituent;
(c) converting the compound of formula (IV), or salt thereof, to a compound of formula (V)
wherein R 1 is H or is R,
wherein when R 1 is R, step (c) is followed by (d), wherein step (d) comprises:
(d) converting the compound of formula (V), or salt thereof, to a compound of formula (I), or a salt thereof:
2. A method of claim 1 wherein step (a) comprises treating the compound of formula (II) with a hydroxyl protecting reagent.
3. A method according to claim 1 wherein step (b) comprises treating the compound of formula (II) with a cyclic imide.
4. A method according to claim 1 wherein step (c) comprises treating the compound of formula (IV) with a deprotecting agent to form the compound of formula (V).
5. A method according to claim 1 wherein step (d) comprises treating the compound of formula (V) with a deprotecting agent.
6. A method according to claim 1 wherein R is an arylcarbonyl.
7. A method according to claim 1 wherein the cyclic imide substituent is selected from the group consisting of phthalimidyl, and succinimidyl.
8. A method according to claim 1 wherein the product of step (c) is isolated prior to carrying out step (d).
9. A method according to claim 1 wherein the product of step (c) is not isolated prior to carrying out step (d).
10. The method of claim 1 , wherein:
step (a) comprises acylating the hydroxyls of pyridoxine, to form an triester, or salt thereof, of the formula:
step (b) comprises treating the triester formed in step (a) with phthalimide, or salt thereof, to form an phthalimido compound, or salt thereof, of the formula:
step (c) comprises treating the phthalilimido compound formed in step (b) with a primary amine to form an amide compound, or salt thereof, of the formula:
and
step (d) comprises treating the amide formed in step (c) with a deprotecting agent to form pyridoxamine, or salt thereof.
11. A method according to claim 10 , wherein the product of step (c) is not isolated prior to carrying out step (d).
12. A method according to claim 10 , wherein the product of step (c) is isolated prior to carrying out step (d).
13. The method of claim 1 , wherein:
step (a) comprises acylating the hydroxyls of pyridoxine, to form an triester, or salt thereof, of the formula:
step (b) comprises treating the triester formed in step (a) with phthalimide, or salt thereof, to form an phthalimido compound, or salt thereof, of the formula:
step (c) comprises treating the phthalilimido compound formed in step (b) with a primary amine to form an amide compound, or salt thereof, of the formula:
and
step (d) comprises treating the amide formed in step (c) with a deprotecting agent to form pyridoxamine, or salt thereof.
14. A method according to claim 13 , wherein the product of step (c) is not isolated prior to carrying out step (d).
15. A method according to claim 13 , wherein the product of step (c) is isolated prior to carrying out step (d).