Linker binding carriers for organic synthesis, their...

Details Linker binding carriers for organic synthesis, their... Linker binding carriers for organic synthesis, their...

1999-08-30

2002-05-14

Raymond, Richard L. (Department: 1624)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C544S398000, C544S399000, C546S236000, C546S237000, C558S046000, C558S052000, C562S828000, C562S831000

Reexamination Certificate

active

06388022

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel carriers extremely useful in synthesis of organic compounds (particularly in the field of combinatorial chemistry), as well as the production method and uses thereof.
BACKGROUND ART
In the field of combinatorial chemistry, compounds to be synthesized are linked via covalent bonds to carriers (e.g. resin, etc.) for organic synthesis on the carriers. For this linkage mode, various chemical structures are known and described in detail for example by G. Jung et al. (Angew. Chem. Int. Ed. Engl., Vol. 35, p. 17 (1996)). This covalent bond moiety for linking a synthetic compound to a carrier is usually called a linker in this field.
In the case of the conventional linkage mode, functional groups derived from the chemical structure of the linker moiety will usually remain in a product upon cleaving the synthetic compound off from the carriers. Such known functional groups include e.g. carboxyl groups, their derivatives, hydroxy groups, amino groups, etc. These functional groups are not necessarily required for exhibiting the action of a functional substance in the synthetic compound, or the presence of these functional groups interferes often with the action of the functional substance, and these remaining functional groups constitute one major factor limiting the type of compounds which can be synthesized by a synthesis method using carriers.
However, a method of permitting no functional group derived from a linker to remain on a product, that is, a synthesis method of using a traceless linker, has been recently reported. For example, traceless linkers making use of the binding properties of aryl-silane are reported by A. Ellman et al. (J. Org. Chem., Vol. 60, p. 6006 (1995)) and D. F. Veber et al. (J. Am. Chem. Soc., Vol. 117, p. 11999 (1995)). In any of these methods, however, formation of aryl-silane bonds requires lithiation of aryl groups with a strong base, so in this step, functional groups unstable to the base cannot be present at the side of the aryl group. Further, there is also the case where the aryl-silane bonds are hardly cleaved owing to the properties of substituent groups on the aryl group. For this reason, the type of compounds to which the aryl-silane-type traceless linker can be applied has been limited.
Meanwhile, D. J. Wustrow et al. (Tetrahedron Lett., Vol. 39, p. 3651 (1998)) have reported a method of reacting a phenol derivative bound to sulfonate resin with a palladium catalyst and formic acid salt to obtain its corresponding benzene derivative. However, this method of using the linker-bound carrier derived from the sulfonate type ion-exchange resin is applicable only to synthesis of benzene derivatives substituted with electron attractive groups such as carboxyl group, carbamoyl group etc., so this is not a synthesis method that is universally applicable to the preparation of a wide variety of aromatics.
The present invention provides linker-bound carriers for organic synthesis, which carry a novel traceless linker universally applicable to synthesis of various synthetic compounds resulting desired synthetic compounds, free of any functional group derived from the linker, as well as a process for producing the same and uses thereof.
As a result of their studies, the present inventors first synthesized carriers to which linkers represented by the formula:
 Y—Z—W—(SO
2
X)m
wherein each symbol has the same meaning as defined below, have been bound, and they unexpectedly found that these carriers, owing to the special chemical structure of their linker moiety, achieved such excellent characteristics that various compounds, particularly synthetic compounds having aromatic hydroxy groups as substrate, are easily carried onto the carriers, the synthetic compounds can be carried on the carriers stably even under various organic synthesis reaction conditions, the desired synthetic compounds can be easily cleaved therefrom, and the resulting synthetic compounds do not have any functional group derived from the linker moiety, and on the basis of these findings, the present invention was completed.
DISCLOSURE OF INVENTION
The present invention provides:
(1) A linker binding carrier for organic synthesis represented by the formula:
—Y—Z—W—(SO
2
X)m  (I)
 wherein
 is a carrier, X is a leaving group, Y is a bond or spacer, Z is a bivalent group, when Z is a bivalent electron attractive group, W is an aromatic ring which may be substituted and when Z is a bivalent non-electron attractive group, W is an aromatic ring which is substituted by an electron attractive group and may be further substituted and m is 1 or 2, or a salt thereof,
(2) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein X is (i) a halogen atom or (ii) a sulfonyloxy group which may be substituted by alkyl or aryl,
(3) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein X is (i) a halogen atom or (ii) a sulfonyloxy group which may be substituted by C
1-6
alkyl or C
6-14
aryl,
(4) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein X is a halogen atom,
(5) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein X is a chlorine atom,
(6) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the spacer represented by Y is an optionally substituted chained bivalent group composed of 1 to 20 atoms selected from the group consisting of carbon, nitrogen, hydrogen, oxygen and sulfur,
(7) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the spacer represented by Y is
—(CH
2
)p—,  (i)
—(CH
2
)q—NR
1
—(CH
2
)r—,  (ii)
—(CH
2
)q—O—(CH
2
)r—.  (iii)
—(CH
2
)q—S—(CH
2
)r—,  (iv)
—(CH
2
)q—SO—(CH
2
)r—,  (v)
—(CH
2
)q—SO
2
—(CH
2
)r—,  (vi)
 wherein p is an integer of 1 to 6, q is an integer of 1 to 3, r is an integer of 1 to 3 and R
1
is a C
1-6
alkyl group,
(8) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the spacer represented by Y is
—(CH
2
)q—NR
1
—(CH
2
)r—, or  (i)
 wherein q is an integer of 1 to 3, r is an integer of 1 to 3 and R
1
is a C
1-6
alkyl group,
(9) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein Y is a bond, —CH
2
NH— or a group represented by
(10) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent electron attractive group represented by Z is a substituent group wherein the Hammet's substituent constant &sgr; has a positive value,
(11) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent electron attractive group represented by Z is a carbonyl group, a thiocarbonyl group, a sulfonyl group, a sulfinyl group, a carbamoyl group, a thiocarbamoyl group, a halogeno-methene group or a halogeno-ethene group,
(12) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent electron attractive group represented by Z is a carbonyl group, a thiocarbonyl group, a sulfonyl group or a sulfinyl group,
(13) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent electron attractive group represented by Z is a carbonyl group or a sulfonyl group,
(14) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent non-electron attractive group represented by Z is a C
1-6
alkylene group, C
2-6
alkenylene group or C
2-6
alkynylene group, which is substituted by hydroxy, amino, carboxyl, nitro, (mono- or di-C
1-6
alkyl)amino, C
1-6
alkoxy, (C
1-6
alkyl)carbonyloxy or a halogen atom
(15) A linker binding carrier for organic synthesis or a salt thereof as defined in (1), wherein the bivalent non-electron attractive group represented by Z is a methylene group or an ethylene group,
(16) A linker

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