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US 6,555,677 B2Granted
Phase transfer catalyzed glycosidation of an indolocarbazole
AssigneeMerck & Co., Inc.
InventorsDaniel E. Petrillo, Steven A. Weissman, Shouichi Hiraga, Nobuya Satake, Kai Rossen
Life of this patent
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Abstract
The present invention relates to a novel glycosidation process to make intermediates useful in the preparation of indolopyrrolocarbazole derivatives which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals, and the like.
Claims13
A process for the preparation of a compound of Formula I,
- wherein
- Q is O, N—R, S, or CH2;
- X1 and X2 are independently selected from:
- 1) H,
- 2) halogen,
- 3) OH,
- 4) CN,
- 5) NC,
- 6) CF3,
- 7) (C═O)NO2,
- 8) (C═O)C1-C6 alkyl,
- 9) (C═O)OC1-C6 alkyl,
- 10) OCH2OCH2CH2Si(CH3)3,
- 11) NO2,
- 12) 9-fluorenylmethylcarbonyl,
- 13) NR5R6,
- 14) OC1-C6 alkyl,
- 15) C1-C6 alkyl,
- 16) C1-C6 alkylenearyl, and
- 17) OC1-C6 alkylenearyl;
- R and R1 are independently:
- 1) H,
- 2) (C═O)C1-C6 alkyl,
- 3) (C═O)CF3,
- 4) (C═O)OC1-C6 alkyl,
- 5) 9-fluorenylmethylcarbonyl,
- 6) a furanose group, or
- 7) a pyranose group,
- so long as one of R and R1 is a furanose group or a pyranose group;
- R2 and R3 are independently OH or H, or
- R2 and R3 are taken together to form an oxo group;
- R4 is:
- 1) H,
- 2) C1-C10 alkyl,
- 3) CHO,
- 4) (C═O)C1-C10 alkyl,
- 5) (C═O)OC1-C10 alkyl,
- 6) C0-C10 alkylenearyl, or
- 7) C0-C10 alkylene-NR5R6;
- R5 and R6 are independently:
- 1) H,
- 2) (C1-C8 alkyl)—(R7)2,
- 3) (C═O)O(C1-C8 alkyl),
- 4) 9-fluorenylmethylcarbonyl,
- 5) OCH2OCH2CH2Si(CH3)3,
- 6) (C═O)(C1-C8 alkyl),
- 7) (C═O)CF3, or
- 8) (C2-C8 alkenyl)—(R7)2, or
- R5 and R6 are taken together with the nitrogen to which they are attached to form N-phthalimido;
- R7 is:
- 1) H,
- 2) OH,
- 3) OC1-C6 alkyl, or
- 4) aryl, said aryl optionally substituted with up to two groups selected from OH, O(C1-C6 alkyl), and (C1-C3 alkylene)—OH;
- which comprises the steps of:
- (a) reacting a furanose or a pyranose with an activating reagent to produce an activated sugar;
- and
- (b) coupling the activated sugar with a compound of Formula IV
- wherein R1a is H if Q is O, S, CH2, or N—R and R is not H, otherwise R1a is selected from R1;
- in the presence of an aqueous solution of alkali hydroxide and a phase transfer catalyst in a biphasic system to produce the compound of Formula I.
57 more elements
A process for the preparation of a compound of Formula V,
- wherein
- R4 is:
- 1) H,
- 2) C1-C10 alkyl,
- 3) CHO
- 4) (C═O)C1-C10 alkyl,
- 5) (C═O)OC1-C10 alkyl,
- 6) CO-C10 alkylenearyl, or
- 7) C0-C10 alkylene-NR5R6;
- R5 and R6 are independently:
- 1) H,
- 2) (C1-C8 alkyl)—(R7)2,
- 3) (C═O)O(C1-C8 alkyl),
- 4) 9-fluorenylmethylcarbonyl,
- 5) OCH2OCH2CH2Si(CH3)3,
- 6) (C═O)(C1-C8 alkyl),
- 7) (C═O)CF3, or
- 8) (C2-C8 alkenyl)—(R7)2, or
- R5 and R6 are taken together with the nitrogen to which they are attached to form N-phthalimido;
- R7 is:
- 1) H,
- 2) OH,
- 3) OC1-C6 alkyl, or
- 4) aryl, said aryl optionally substituted with up to two groups selected from OH, O(C1-C6 alkyl), and (C1-C3 alkylene)—OH;
- R9 is:
- 1) H,
- 2) C1-C6 alkyl,
- 3) (C1-C6 alkylene)-aryl,
- 4) SO2(C1-C6 alkyl),
- 5) SO2aryl,
- 6) CH2OCH2CH2Si(CH3)3,
- 7) (C═O)(C1-C6 alkyl), or
- 8) (C═O)CF3;
- which comprises the steps of:
- (a) reacting a sugar derivative of Formula VI with an acid chloride to produce the activated sugar;
- and
- (b) coupling the activated sugar with a compound of Formula VII
- in the presence of an aqueous solution of an alkali hydroxide and tricaprylmethyl ammonium chloride in t-butyl methyl ether to produce the compound of Formula V.
35 more elements
A process for the preparation of a compound of Formula VIII,
- which comprises the steps of;
- (a) reacting a sugar derivative of Formula IX with thionyl chloride to produce the activated sugar;
- (b) coupling the activated sugar with a compound of Formula X
- in the presence of an aqueous solution of potassium hydroxide or sodium hydroxide and tricaprylmethyl ammonium chloride in t-butyl methyl ether to form the glycosidated compound XI;
- (c) deprotecting the glycosidated product XI by reacting it with catalytic palladium in the presence of hydrogen gas to form the deprotected glycosidated product XII;
- (d) reacting the deprotected glycosidated product XII with an aqueous solution of alkali hydroxide to form anhydride XIII;
- and
- (e) reacting anhydride XIII with 2-hydrazino-1,3-propanediol to produce the compound of Formula VIII.
5 more elements
Dependencies are inferred from the claim text.