Chemistry: analytical and immunological testing – Tracers or tags
Reexamination Certificate
2000-05-05
2004-11-30
Ponnaluri, Padmashri (Department: 1627)
Chemistry: analytical and immunological testing
Tracers or tags
C436S124000, C570S142000, C570S171000, C570S177000
Reexamination Certificate
active
06825043
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to fluorous tagging compounds and to methods of increasing the fluorous nature of compounds.
BACKGROUND OF THE INVENTION
Organic chemists are typically trained that organic compounds have to be synthesized, as pure substances through well-planned reactions and scrupulous separation. In fields such as drug discovery, catalyst design and new material development, however, tens of thousands of organic compounds must be synthesized and tested to discover a few active ones. In the pharmaceutical industry, for example, synthesizing such a large number of compounds in the traditional way is too slow compared to the rapid emergence of new biological targets. A major factor limiting the productivity of orthodox solution (liquid) phase organic synthesis is the tedious separation process for the purification of products. High throughput organic synthesis, therefore, preferably integrates organic reactions with rapid purification/separation procedures.
Recently, fluorous synthetic and separation techniques have attracted the interest of organic chemists. In fluorous synthetic techniques, reaction components are typically attached to fluorous groups such as perfluoroalkyl groups to facilitate the separation of products. In general, fluorous-tagged molecules partition preferentially into a fluorous phase while non-tagged ones partition into an organic phase. Although fluorous synthetic and/or separation techniques are promising, such techniques are currently limited by a lack of availability of suitable fluorous tags.
It is thus very desirable to develop fluorous tagging compounds and methods of increasing the fluorous nature of compounds.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method of increasing the fluorous nature of a compound. The method includes the step of reacting the compound with at least one second compound having the formula:
wherein Rf is a fluorous group (for example, a fluoroalkyl group, a fluorinated ether or another highly fluorinated group), Rs is a spacer group, d is 1 or 0 (that is, Rs may be present or absent), m is 1, 2 or 3, Ra is an alkyl group and X is a suitable leaving group. Suitable leaving groups include, but are not limited to, a halide (F, Cl, Br or I), —N
3
, CN, RO—, NH
2
O—, NHRO—, NR
2
O—, RCO
2
—, ROCO
2
—, RNCO
2
—, RS—, RC(S)O—, RCS
2
—, RSC(O)S—, RSCS
2
— RSCO
2
—, ROC(S)O—, ROCS
2
—, RSO
2
—, RSO
3
—, ROSO
2
—, ROSO
3
—, RPO
3
—, ROPO
3
—, an N-imidazolyl group, an N-triazolyl group, an N-benzotriazolyl group, a benzotriazolyloxy group, an imidazolyloxy group, an N-imidazolinone group, an N-imidazolone group, an N-imidazolinethione group, an N-imidazolinthione group, an N-succinimidyl group, an N-phthalimidyl group, an N-succinimidyloxy group, an N-phthalimidyloxy group, —ON═C(CN)R, or a 2-pyridyloxy group. R is preferably an alkyl group or an aryl group.
The terms “alkyl”, “aryl” and other groups refer generally to both unsubstituted and substituted groups unless specified to the contrary. Unless otherwise specified, alkyl groups are hydrocarbon groups and are preferably C
1
-C
15
(that is, having 1 to 15 carbon atoms) alkyl groups, and more preferably C
1
-C
10
alkyl groups, and can be branched or unbranched, acyclic or cyclic. The above definition of an alkyl group and other definitions apply also when the group is a substituent on another group. The term “aryl” refers to phenyl (Ph) or napthyl, substituted or unsubstituted. The terms “alkylene” refers to bivalent forms of alkyl.
The groups set forth above, can be substituted with a wide variety of substituents. For example, alkyl groups may preferably be substituted with a group or groups including, but not limited to, halide(s). Preferably, halide constituents are F and/or Cl. Aryl groups may preferably be substituted with a group or groups including, but not limited to, halide(s), alkyl group(s), a cyano group(s) and nitro group(s). As used herein, the terms “halide” or “halo” refer to fluoro, chloro, bromo and iodo. Preferred halide substituents are F and Cl.
The resulting fluorous “tagged” compound can be used in a variety of fluorous reaction and/or separation techniques. Such fluorous reaction and separation techniques are disclosed, for example, in U.S. Pat. Nos. 5,859,247 and 5,777,121 and U.S. patent application Ser. No. 09/506,779, assigned to the assignee of the present invention, the disclosures of which are incorporated herein by reference.
Preferably, the molecular weight of the fluorous tag of the present invention does not exceed about 2,500. More preferably, the molecular weight does not exceed about 2,000. Even more preferably the molecular weight does not exceed about 1,750. Compounds may bear more than one fluorous tag of the present invention.
In another aspect, the present invention provides a compound (a fluorous tagging compound) having the formula:
wherein Rf is a fluorous group (for example, a fluoroalkyl group, a fluorinated ether or another highly fluorinated group), n is an integer between 0 and 6, m is 1, 2 or 3, Ra is an alkyl group and X is a leaving group. Ra is preferably C
1
-C
6
alkyl group.
As used herein, the term “fluorous”, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons or perfluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinated amines). The term “fluorous compound,” thus refers generally to a compound comprising a portion rich in carbon-fluorine bonds. As used herein, the term “perfluorocarbons” refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms “fluorohydrocarbons” and “hydrofluorocarbons” include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. A few examples of suitable fluorous groups Rf for use in the present invention include, but are not limited to, —C
4
F
9
, —C
6
F
13
, —C
8
F
17
, —C
10
,F
21
, —C(CF
3
)
2
C
3
F
7
, —C
4
F
8
CF(CF
3
)
2
, and —CF
2
CF
2
OCF
2
CF
2
OCF
3
.
As used herein, the term “tagging” refers generally to attaching a fluorous moiety or group (referred to as a “fluorous tagging moiety” or “tagging group”) to a compound to create a “fluorous tagged compound”. Separation of the tagged compounds of the present invention is achieved by using fluorous separation techniques that are based upon differences between/among the fluorous nature of a mixture of compounds. As used herein, the term “fluorous separation technique” refers generally to a method that is used to separate mixtures containing fluorous molecules or organic molecules bearing fluorous domains or tags from each other and/or from non-fluorous compounds based predominantly on differences in the fluorous nature of molecules (for example, size and/or structure of a fluorous molecule or domain or the absence thereof). Fluorous separation techniques include but are not limited chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., “Fluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,”
J. Chromat.,
544, 187-199 (1991). Examples of suitable fluorocarbon bonded phases include commercial Fluofix® and Fluophase™ columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), and FluoroSep™-RP-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include liquid-liquid based separation methods such as liquid-liquid extraction or countercurrent distribution with a fluorous solvent and an organic solvent.
REFERENCES:
patent: 3627799 (1971-12-01), Anderson
patent: 3732274 (1973-05-01), Fox
patent: 4454233 (1984-06-01), Wang
patent: 5401847 (1995-03-01), Glazer
patent: 5463082 (1995-10-01), Horvath
patent: 5777121 (1998-07-01), Curran
patent: 5798032 (1998-08-01), Khan
patent:
Curran Dennis P.
Luo Zhiyong
Read Roger
Bartony & Hare, LLP
Ponnaluri Padmashri
Tran My Chau T
University of Pittsburgh
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