Processes for the convergent synthesis of calicheamicin derivatives
This invention describes processes for the convergent synthesis of calicheamicin derivatives, and similar analogs using bifunctional and trifunctional linker intermediates.
1. A method of preparing compounds of the following formula:
wherein Z is selected from the group consisting of
and wherein W′ is
R 5 ′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms;
X is an iodine or bromine atom;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the following formula:
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimdyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula:
d. reacting the trilinker-activated ester formed in step c in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent to generate an activated ester of the formula below and the temperature of the reaction is ≦5° C. and wherein the methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ comprises N-acetyl-LL-E33288 γ 1 I :
e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of the formula:
2. The method of claim 1 , wherein the carboxylic acid and mercapto compound are present in a ratio of about 1.2:1.
3. The method of claim 1 , wherein the alcohol solvent is methanol.
4. The method of claim 1 , wherein the alkyl carboxylic acid is acetic acid.
5. The method of claim 1 , wherein the isolated bilinker-carboxylic acid is reacted with N-hydroxysuccinimide in step (c).
6. The method of claim 5 , wherein at least a 3 fold molar excess of N-hydroxysuccinimide is used.
7. The method of claim 1 , wherein the isolated bilinker-carboxylic acid is reacted in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in step (c).
8. The method of claim 1 , wherein the inert solvent is acetonitrile or dioxane.
9. The method of claim 1 , wherein the trilinker-activated ester and CH 3 —S—S—S—W′ in step (d) are in a ratio of 3.3:1.
10. The method of claim 1 , wherein the inert organic solvent is acetonitrile.
11. The method of claim 1 wherein the purifying of step (e) comprises the use of reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed by normal phase chromatography.
12. A method of preparing compounds of the following formula:
wherein Z is selected from the group consisting of
and wherein W′ is
R 5 ′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms;
X is an iodine or bromine atom;
comprising the steps of:
a. reacting a carboxylic acid of the formula:
with a mercapto compound of the formula:
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the formula:
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in the presence of a base or an organic base in an inert organic solvent wherein CH 3 —S—S—S—W′ comprises N-acetyl-LL-E33288 γ 1 I ;
d. reacting the compound of step (c) with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) and purifying to yield antitumor antibiotics of the following formula:
13. The method of claim 12 , wherein the carboxylic acid and mercapto compound are present in a ratio of about 1.2:1.
14. The method of claim 12 , wherein the alcohol solvent is methanol.
15. The method of claim 12 , wherein the alkyl carboxylic acid is acetic acid.
16. The method of claim 12 , wherein the bilinker-carboxylic acid and CH 3 —S—S—S—W′ in step (c) are in a ratio of 3.3:1.
17. The method of claim 12 , wherein the inert organic solvent is acetonitrile.
18. The method of claim 12 , wherein the compound of step (c) is reacted with N-hydroxysuccinimide in step (d).
19. The method of claim 18 , wherein at least a 3 fold molar excess of N-hydroxysuccinimide is used.
20. The method of claim 12 , wherein the compound of step (c) is reacted in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in step (d).
21. The method of claim 12 , wherein the inert solvent is acetonitrile or dioxane.
22. The method of claim 12 , wherein the purifying comprises the use of reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed by normal phase chromatography.
23. A method of preparing compounds of the following formula:
wherein W′ is
R 5 ′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms;
X is an iodine or bromine atom;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the following formula:
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with at least a 3 fold molar excess of N-hydroxysuccinimide, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula:
d. reacting the trilinker-activated ester formed in step c in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent to generate an activated ester of the formula below and the temperature of the reaction is ≦5° C. and wherein the methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ comprises N-acetyl-LL-E33288 γ 1 I :
e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of the formula:
24. The method of claim 23 , wherein the carboxylic acid and mercapto compound are present in a ratio of about 1.2:1.
25. The method of claim 23 , wherein the alcohol solvent is methanol.
26. The method of claim 23 , wherein the alkyl carboxylic acid is acetic acid.
27. The method of claim 23 , wherein the inert solvent is acetonitrile or dioxane.
28. The method of claim 23 , wherein the trilinker-activated ester and CH 3 —S—S—S—W′ in step (d) are in a ratio of 3.3:1.
29. The method of claim 23 , wherein the inert organic solvent is acetonitrile.
30. The method of claim 23 wherein the purifying of step (e) comprises the use of reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed by normal phase chromatography.
31. A method of preparing compounds of the following formula:
wherein W′ is
R 5 ′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms;
X is an iodine or bromine atom;
comprising the steps of:
a. reacting a carboxylic acid of the formula:
with a mercapto compound of the formula:
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the formula:
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in the presence of a base or an organic base in an inert organic solvent wherein CH 3 —S—S—S—W′ comprises N-acetyl-LL-E3328γ 1 I to give a compound of formula:
d. reacting the compound of step (c) with at least a 3 fold molar excess of N-hydroxysuccinimide in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) and purifying to yield antitumor antibiotics of the following formula:
32. The method of claim 31 , wherein the carboxylic acid and mercapto compound are present in a ratio of about 1.2:1.
33. The method of claim 31 , wherein the alcohol solvent is methanol.
34. The method of claim 31 , wherein the alkyl carboxylic acid is acetic acid.
35. The method of claim 31 , wherein the bilinker-carboxylic acid and CH 3 —S—S—S—W′ in step (c) are in a ratio of 3.3:1.
36. The method of claim 31 , wherein the inert organic solvent is acetonitrile.
37. The method of claim 31 , wherein the inert solvent is acetonitrile or dioxane.
38. The method of claim 31 , wherein the purifying comprises the use of reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed by normal phase chromatography.
39. A method of preparing trifunctional linker intermediates of the following formula:
comprising the steps of:
a. reacting a carboxylic acid of the formula:
with a mercapto compound of the formula:
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the formula:
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker of step (b) with N-hydroxysuccinimide in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate trifunctional linker intermediates of the formula: