Patent EA-004331-B1 (EA)
Title: Regioselective synthesis of rapamycin derivatives
Inventor: SHAW CHIA-CHENG
IPC: C07D498/18
Filed: 2000-09-27
Abstract: 1. A process for preparing rapamycin 31-silyl ether, which comprises: (a) reacting rapamycin with a silylating agent to form rapamycin 31, 42-bis-silyl ether; and (b) hydrolysing the 31, 42-bis-silyl ether with cold dilute acid to provide rapamycin 31-silyl ether. 2. A process for preparing a 42-ester or ether of rapamycin having the structure wherein R is an ester or ether, which comprises: (a) reacting rapamycin with a silylating agent to form rapamycin 31, 42-bis-silyl ether; (b) hydrolysing the 31, 42-bis-silyl ether in cold dilute acid to provide rapamycin 31-silyl ether; (c) reacting the rapamycin 31-silyl ether with a suitable esterifying or etherifying reagent to form rapamycin 31-silyl ether 42-ester or ether; and (d) hydrolysing the 31-silyl ether in cold dilute acid to provide the desired rapamycin 42-ester or ether; if desired sequentially or simultaneously removing any other protecting group present. 3. A process as claimed in claim 2 in which R in the compound of formula (I) is selected from: either (i) -O-C=CR7R<8>R<9>; (ie., esters) wherein: R<7> is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, -(CR<3>R<4>)fOR<10>, -CF3, -F, or -CO2R<11>; R<8> and R<9> are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or -(CR<3>R<4>)fOR<10>; or R<8> and R<9> may be taken together to form X; R<10> is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, chloroethyl, or tetrahydropyranyl; X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2-spiro(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]-dioxanyl, 4-(2-spiro(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2-spiro(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; R<3> and R<4> are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or -F; and f = 0-6; with the proviso that R contains at least one -(-(CR<3>R<4>)fOR<10>or X group; or (ii) -OR<1> (ie., ethers) where R<1> is alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acyl-aminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl and dioxolanylallyl, carbalkoxyalkyl; wherein "alk-" or "alkyl" refers to C1-6alkyl, branched or linear, preferably C1-3 alkyl, in which the carbon chain may be optionally interrupted by an ether (-O-) linkage; "acyl" represents alkylcarbonyl and "aryl" has 6-10 carbon atoms. 4. A process as claimed in claim 3 in which R<1> is selected from hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl, and aminoalkyl. 5. A process as claimed in claim 4 in which R<1> is selected from 2-hydroxyethyl; 3-hydroxypropyl; 2-[(2-hydroxy)ethoxy]ethyl and 2-acetaminoethyl. 6. A process as claimed in claim 2 in which R in the compound of formula (I) is 2,2-bis (hydroxymethyl)propionyloxy or 2,2,5-trimethyl[1.3-dioxane]-5-carbonyloxy. 7. A process as claimed in claim 6 in which the esterification step (c) is carried out using 2,2,5-trimethyl[1,3-dioxane]-5-carboxylic acid chloride or the 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1,3-dioxane]-5-carboxylic acid. 8. A process as claimed in claim 7 which is carried out in a solvent comprising methylene chloride. 9. A process as claimed in claim 7 or claim 8 which is carried out at a temperature of from about -50 degree C to about 25 degree C. 10. A process as claimed in any one of claims 2 to 9 wherein the acid in step (d) is a dilute inorganic acid. 11. A process according to claim 10 wherein the acid is sulphuric, hydrochloric or phosphoric acid. 12. A process according to any one of claims 2 to 11 wherein the acid used in step (d) is from about 0.1N to about 3N. 13. A process according to any one of claims 2 to 11 wherein the acid used in step (d) is from about 0.2N to about 2N. 14. A process according to any one of claims 2 to 11 wherein the acid used in step (d) is about 0.5N. 15. A process according to any one of claims 2 to 14 wherein step (d) is carried out in a single phase aqueous acid/organic solvent system. 16. A process according to claim 15 wherein the organic solvent is acetone. 17. A process according to any one of claims 2 to 16 wherein step (d) is carried out at a temperature from about 25 degree C or below. 18. A process according to any one of claims 2 to 16, wherein step (d) is carried out at a temperature from about -5 degree C to about 10 degree C. 19. A process according to any one of claims 2 to 16 wherein step (d) is carried out at a temperature from about 0 degree C to about 5 degree C. 20. A process according to any one of claims 1 to 19 in which the 31-silyl ether prepared in step (b) has the formula IA: wherein R', R" and R'" are the same or different selected from alkyl of 1-6 carbon atoms, phenyl and benzyl. 21. A process according to any one of claims 1 to 20 wherein the silylating agent in step (a) is a tri-(C1-C6)alkylsilyl halide. 22. A process according to claim 21 wherein the silylating agent in step (a) is trimethylsilyl chloride. 23. A process as claimed in any one of claims 1 to 22 in which the silylation step (a) is carried out in an inert solvent in the presence of a suitable base. 24. A process according to claim 23 wherein the base is imidazole, 1-methylimidazole, triethylamine, or N, N-diisopropylethylamine. 25. A process according to any one of claims 1 to 24 wherein the acid in step (b) is a dilute inorganic acid. 26. A process according to claim 25 wherein the acid is sulfuric, hydrochloric or phosphoric acid. 27. A process according to any one of claims 1 to 26 wherein the acid used in step (b) is from about 0.08N to about 2.5N. 28. A process according to any one of claims 1 to 26 wherein the acid strength in step (b) is from about 0.1N to about 1N. 29. A process according to any one of claims 1 to 26, wherein the acid used in step (b) is about 0.5N. 30. A process according to any one of claims 1 to 29, wherein step (b) is carried out in a two phase aqueous acid/water-immiscible organic solvent system. 31. A process according to claim 30 wherein the water-immiscible organic solvent is ethyl acetate. 32. A process according to any one of claims 1 to 31 wherein step (b) is carried out at a temperature from about 25 degree C or below. 33. A process according to any one of claims 1 to 31 wherein step (b) is carried out at a temperature from about -5 degree C to about 10 degree C. 34. A process according to any one of claims 1 to 31 wherein step (b) is carried out at a temperature from about 0 degree C to about 5 degree C. 35. A process for preparing rapamycin 42-ester with 2,2-bis-(hydroxy-methyl)propionic acid, which comprises: (a) reacting rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether; (b) selectively hydrolyzing the 42-silyl ether in cold dilute acid to provide rapamycin 31-silyl ether; (c) acylating the rapamycin 31-silyl ether with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride or the 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid to give rapamycin 31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid; and (d) either (i) selectively hydrolyzing the 31-silyl ether in cold dilute acid to provide rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid; followed by treating the rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid with dilute acid to provide 42-ester with 2,2-bis-(hydroxymethyl)propionic acid; or (ii) treating the rapamycin 31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid with dilute acid to provide 42-ester with 2,2-bis-(hydroxymethyl)propionic acid; 36. The process according to claim 35 wherein the acylation step (c) is carried out at a temperature less than 0 degree C. 37. A process for preparing 42-O-(2-hydroxy)ethyl-rapamycin which comprises: (a) reacting rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether; (b) selectively hydrolyzing the 42-silyl ether in cold dilute acid to provide rapamycin 31-silyl ether; (c) reacting the rapamycin 31-silyl ether with an ethylene glycol equivalent containing an acid labile hydroxyl protecting group protected on one terminus of the ethylene glycol equivalent and a leaving group suitable for alkylating a hydroxyl group as the other terminus of the ethylene glycol equivalent. (d) hydrolysing the protecting groups on the 31-position and on the 42-hydroxy ethyl position under mildly acidic conditions. 38. The process according to claim 37 wherein the silylating agent is a trialkylsilyl halide. 39. The process according to claim 38 wherein the silylating agent is chlorotrimethylsilane. 40. The process according to any one of claims 37 to 39 wherein the ethylene glycol equivalent is 2-(t-butyldimethylsilyl)oxyethyl triflate). 41. The process according to claim 40 wherein the acid used in steps (b) and (d) is sulfuric acid. 42. A compound which is a rapamycin 31-O-silyl ether. 43. A compound according to claim 42, which has the formula IA or IB: or in which formulae, R is an ester or ether group, and R', R" and R'" are the same or different selected from alkyl of 1-6 carbon atoms, phenyl and benzyl. 44. A compound of claim 42 wherein R is as defined in claim 3. 45. A compound of claim 42 or claim 43 in which the 31-O-silyl ether is a tri-(C1-C6)alkylsilyl ether. 46. A compound of claim 42, which is rapamycin 31-O-trimethylsilyl ether. 47. A compound of claim 42, which has formula (D) wherein R', R" and R'" are the same or different selected from alkyl of 1-6 carbon atoms, phenyl and benzyl. 48. A compound of claim 42 which is rapamycin 31-O-trimethylsilyl e