Phase transfer catalyzed glycosidation of an indolocarbazole
First Claim
Patent Images
1. A process for the preparation of a compound of Formula I, whereinQ 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.
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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.
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Citations
13 Claims
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1. 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, or8) (C2-C8 alkenyl)—
(R7)2, orR5 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.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
R and R1 are independently selected from a furanose group of Formula IIA or a pyranose group of Formula IIB, when R or R1 is defined as a furanose group or a pyranose group, respectively; R8 is independently selected from;
1) hydrogen, 2) C1-C6 alkyl, 3) OH, 4) halogen, 5) O(C1-C6 alkyl), 6) O(C1-C6 alkylene)-aryl, 7) OSO2(C1-C6 alkyl), 8) OSO2aryl, 9) OCH2OCH2CH2Si(CH3)3, 10) O(C═
O)(C1-C6 alkyl),11) O(C═
O)CF3,12) azido, or 13) NR5R6, or two R8'"'"'s on the same carbon are taken together to be oxo, ═
N—
R5, or ═
N—
R7; and
the furanose or pyranose in Step (a) is a furanose of Formula IIIA or a pyranose of Formula IIIB, respectively;
- R, S, or CH2;
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3. The process according to claim 2 wherein the activating reagent in Step (a) is selected from an acid halide and the biphasic system in Step (b) is comprised of an organic solvent selected from a hydrocarbon, a nitrile, an ether, a halogenated hydrocarbon, a ketone, or an apolar aprotic solvent.
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4. The process according to claim 3 wherein the activating reagent is selected from SOCl2 or oxalyl chloride.
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5. The process according to claim 3 wherein the biphasic system is comprised of methyl-t-butyl ether, dichloromethane, or trifluorotoluene.
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6. The process according to claim 3 wherein the phase transfer catalyst in Step (b) is (Ra)4M+A−
- ;
Ra is independently H or C1-C18 aliphatic hydrocarbon;
M is N or P; and
A is OH, F, Br, Cl, I, HSO4, CN, MeSO3, or PhCH2CO2.
- ;
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7. The process according to claim 6, wherein the phase transfer catalyst is tricaprylmethyl ammonium chloride.
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8. The process according to claim 3, wherein the aqueous solution of alkali hydroxide in Step (b) has a concentration of about 5% to about 95% w/w and the alkali hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.
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9. The process of claim 8 wherein the aqueous solution of alkali hydroxide has a concentration of about 45% to about 50% w/w and the alkali hydroxide is potassium hydroxide or sodium hydroxide.
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10. 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, or8) (C2-C8 alkenyl)—
(R7)2, orR5 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), or8) (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.- View Dependent Claims (12, 13)
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11. 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.
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Specification
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Current AssigneeBanyu Pharmaceutical Company Limited (Merck & Co., Inc.), Merck & Co., Inc.
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Original AssigneeMerck & Co., Inc.
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InventorsWeissman, Steven A., Petrillo, Daniel E., Rossen, Kai, Satake, Nobuya, Hiraga, Shouichi
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Primary Examiner(s)Wilson, James O.
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Assistant Examiner(s)MCINTOSH III, TRAVISS C
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Application NumberUS10/002,061Publication NumberTime in Patent Office554 DaysField of Search536/27.1, 536/27.11, 536/27.12, 536/17.7, 536/18.7, 536/29.1US Class Current536/27.1CPC Class CodesA61P 35/00 Antineoplastic agentsC07H 17/02 Heterocyclic radicals conta...C07H 19/23 Heterocyclic radicals conta...
