Phase transfer catalyzed glycosidation of an indolocarbazole

Details Phase transfer catalyzed glycosidation of an indolocarbazole Phase transfer catalyzed glycosidation of an indolocarbazole

2001-10-22

2003-04-29

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S027110, C536S027120, C536S017700, C536S018700, C536S029100

Reexamination Certificate

active

06555677

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
In the field of cancer chemotherapy, a large number of compounds have already been put to practical use as antitumor agents. However, a need continues for the development of more efficacious compounds that work against a variety of tumors (see the Proceedings of the 47th General Meeting of the Japan Cancer Society, pp. 12-15 (1988)). This need has led to the development of indolocarbazole derivatives. (See U.S. Pat. Nos. 4,487,925; 4,552,842; 4,785,085; 5,591,842 and 5,922,860; Japanese Patent No. 20277/91; Journal of Antibiotics, Vol. 44, pp. 723-728 (1991); WO91/18003; WO 98/07433; and EP0545195 A1.) These compounds have been shown to act as topoisomerase inhibitors and therefore useful in the treatment of cancer (Cancer Chemother. Pharmacol. 34 (suppl): S41-S45 (1994)).
The success of these compounds in treating numerous cancers has necessitated the development of improved methods for their syntheses. (See Bioorg. & Med. Chem. Letters 2000, 10, 419; Tetrahedron 1997, 53, 5937; Tetrahedron 1997, 53, 585; and Synthesis 1976, 414.) The previously known methods, however, suffer from numerous problems, including the use of undesirable solvents, mercury or silver salts, low yields and formation of unwanted side-products necessitating tedious or protracted purification steps.
An object of this invention therefore is to provide a novel route to intermediates useful in the preparation of indolopyrrolocarbazole-derived antitumor substances while overcoming the problems inherent in the previously known syntheses.
SUMMARY OF THE INVENTION
The present invention is 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, such as those of Formula I below.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is illustrated by a process for the preparation of a compound of Formula I,
wherein
Q is O, N—R, S, or CH
2
;
X
1
and X
2
are independently selected from:
1) H,
2) halogen,
3) OH,
4) CN,
5) NC,
6) CF
3
,
7) (C═O)NO
2
,
8) (C═O)C
1
-C
6
alkyl,
9) (C═O)OC
1
-C
6
alkyl,
10) OCH
2
OCH
2
CH
2
Si(CH
3
)
3
,
11) NO
2
,
12) 9-fluorenylmethylcarbonyl,
13) NR
5
R
6
,
14) OC
1
-C
6
alkyl,
15) C
1
-C
6
alkyl,
16) C
1
-C
6
alkylenearyl, and
17) OC
1
-C
6
alkylenearyl;
R and R
1
are independently:
1) H,
2) (C═O)C
1
-C
6
alkyl,
3) (C═O)CF
3
,
4) (C═O)OC
1
-C
6
alkyl,
5) 9-fluorenylmethylcarbonyl,
6) a furanose group, or
7) a pyranose group,
so long as one of R and R
1
is a furanose group or a pyranose group;
R
2
and R
3
are independently OH or H, or
R
2
and R
3
are taken together to form an oxo group;
R
4
is:
1) H,
2) C
1
-C
10
alkyl,
3) CHO
4) (C═O)C
1
-C
10
alkyl,
5) (C═O)OC
1
-C
10
alkyl,
6) C
0
-C
10
alkylenearyl, or
7) C
0
-C
10
alkylene-NR
5
R
6
;
R
5
and R
6
are independently:
1) H,
2) (C
1
-C
8
alkyl)—(R
7
)
2
,
3) (C═O)O(C
1
-C
8
alkyl),
4) 9-fluorenylmethylcarbonyl,
5) OCH
2
OCH
2
CH
2
Si(CH
3
)
3
,
6) (C═O)(C
1
-C
8
alkyl),
7) (C⊚O)CF
3
, or
8) (C
2
-C
8
alkenyl)—(R
7
)
2
, or
R
5
and R
6
are taken together with the nitrogen to which they are attached to form N-phthalimido;
R
7
is:
1) H,
2) OH,
3) OC
1
-C
6
alkyl, or
4) aryl, said aryl optionally substituted with up to two groups selected from OH, O(C
1
-C
6
alkyl), and (C
1
-C
3
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 R
1a
is H if Q is O, S, CH
2
, or N—R and R is not H, otherwise R
1a
is selected from R
1
;
 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.
Another embodiment is the process described above, wherein
R and R
1
are independently selected from a furanose group of Formula IIA or a pyranose group of Formula IIB, when R or R
1
is defined as a furanose group or a pyranose group, respectively;
R
8
is independently selected from:
1) hydrogen,
2) C
1
-C
6
alkyl,
3) OH,
4) halogen,
5) O(C
1
-C
6
alkyl),
6) O(C
1
-C
6
alkylene)-aryl,
7) OSO
2
(C
1
-C
6
alkyl),
8) OSO
2
aryl,
9) OCH
2
OCH
2
CH
2
Si(CH
3
)
3
,
10) O(C═O)(C
1
-C
6
alkyl),
11) O(C═O)CF
3
,
12) azido, or
13) NR
5
R
6
, or
two R
8
's on the same carbon are taken together to be oxo, ═N—R
5
, or ═N═R
7
; and
the furanose or pyranose in Step (a) is a furanose of Formula IIIA or a pyranose of Formula IIIB, respectively;
In another embodiment, the activating reagent in Step (a) is selected from an acid halide, a sulfonate, a phosphate, a sulfate, a borate, or an acetate 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.
Yet another embodiment is the process described above wherein the activating reagent is selected from SOCl
2
or oxalyl chloride.
A further embodiment is the process described above wherein the biphasic system is comprised of methyl-t-butyl ether, dichloromethane, or trifluorotoluene.
In still another embodiment the phase transfer catalyst in Step (b) is (R
a
)
4
M+A
−
;
R
a
is independently H or C
1
-C
18
aliphatic hydrocarbon;
M is N or P; and
A is OH, F, Br, Cl, I, HSO
4
, CN, MeSO
3
, or PhCH
2
CO
2
.
A preferred embodiment is the process described above wherein the phase transfer catalyst is tricaprylmethyl ammonium chloride.
Another preferred embodiment is the process according to the description above, 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.
Also favored is the process wherein the aqueous solution of alkali hydroxide has a concentration of about 45% to about 50% w/v and the alkali hydroxide is potassium hydroxide or sodium hydroxide.
A more preferred embodiment is a process for the preparation of a compound of Formula V,
wherein
R
4
is:
1) H,
2) C
1
-C
10
alkyl,
3) CHO
4) (C═O)C
1
-C
10
alkyl,
5) (C═O)OC
1
-C
10
alkyl,
6) C
0
-C
10
alkylenearyl, or
7) C
0
-C
10
alkylene-NR
5
R
6
;
R
5
and R
6
are independently:
1) H,
2) (C
1
-C
8
alkyl)—(R
7
)
2
,
3) (C═O)O(C
1
-C
8
alkyl),
4) 9-fluorenylmethylcarbonyl,
5) OCH
2
OCH
2
CH
2
Si(CH
3
)
3
,
6) (C═O)(C
1
-C
8
alkyl),
7) (C═O)CF
3
, or
8) (C
2
-C
8
alkenyl)—(R
7
)2, or
R
5
and R
6
are taken together with the nitrogen to which they are attached to form N-phthalimido;
R
7
is:
1) H,
2) OH,
3) OC
1
-C
6
alkyl, or
4) aryl, said aryl optionally substituted with up to two groups selected from OH, O(C
1
-C
6
alkyl), and (C
1
-C
3
alkylene)—OH;
R
9
is:
1) H,
2) C
1
-C
6
alkyl,
3) (C
1
-C
6
alkylene)-aryl,
4) SO
2
(C
1
-C
6
alkyl),
5) SO
2
aryl,
6) CH
2
OCH
2
CH
2
Si(CH
3
)
3
,
7) (C═O)(C
1
-C
6
alkyl), or
8) (C═O)CF
3
;
 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.
And yet another preferred embodiment is 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) coupl

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