Methods of producing cancer targeting compounds
Provided herein are methods of making the compound of Formula I: and certain intermediates involved in such process.
1. A method of producing 12-ADT, having Formula 6
the method comprising
(a) reacting thapsigargin, having Formula 2
to produce 8-O-debutanoyl-thapsigargin, having Formula 3
(b) reacting 8-O-debutanoyl-thapsigargin (3) with Boc-12-AD, having Formula 4
to produce Boc-12ADT, having Formula 5
and
(c) deprotecting Boc-12ADT (5) to produce 12-ADT (6).
2. The method of claim 1 , wherein, in (a), thapsigargin (2) is reacted with sodium ethoxide in ethanol.
3. The method of claim 2 , wherein the reaction in (a) is at a temperature of −15±5° C.
4. The method of claim 1 , wherein, in (b), 8-O-debutanoyl-thapsigargin (3) is reacted with Boc-12-AD (4) in the presence of 4-dimethylaminopyridine and dichloromethane until a homogeneous solution is obtained, after which diisopropylcarbodiimide is added.
5. The method of claim 1 , wherein, in (c), Boc-12ADT (5) is dissolved in dichloromethane and deprotected with trifluoroacetic acid.
6. The method of claim 1 , wherein
in (a), thapsigargin (2) is reacted with sodium ethoxide in ethanol at a temperature of −15±5° C.;
in (b), 8-O-debutanoyl-thapsigargin (3) is reacted with Boc-12-AD (4) in the presence of 4-dimethylaminopyridine and dichloromethane until a homogeneous solution is obtained, after which diisopropylcarbodiimide is added; and
in (c), Boc-12ADT (5) is dissolved in dichloromethane and deprotected with trifluoroacetic acid.
7. The method of claim 1 , wherein Boc-12-AD (4) is produced by a method comprising
esterify, by acid catalysis in methanol, 12-AD, having Formula 10
to form the compound of Formula 11
react the compound of formula 11 with Boc 2 O to form the compound of Formula
and
hydrolyze the compound of Formula 12 to form the compound of Formula 4.
8. The method of claim 7 , wherein the acid catalysis of the compound of Formula 10 is with acetyl chloride.
9. The method of claim 7 , wherein the reaction with Boc 2 O with the compound of Formula 11 is in CH 2 Cl 2 in the presence of dimethylaminopyridine and triethylamine.
10. The method of claim 7 , wherein the compound of Formula 12 is hydrolyzed with NaOH.
11. The method of claim 7 , wherein
the acid catalysis of the compound of Formula 10 is with acetyl chloride;
the reaction with Boc 2 O with the compound of Formula 11 is in CH 2 Cl 2 in the presence of dimethylaminopyridine and triethylamine; and
the compound of Formula 12 is hydrolyzed with NaOH.