Fluorophenyl resin compounds

Details Fluorophenyl resin compounds Fluorophenyl resin compounds

2000-01-19

2003-10-28

Lipman, Bernard (Department: 1713)

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

Synthetic resins

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

C525S333300, C525S333600, C525S343000

Reexamination Certificate

active

06639023

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to a fluorophenyl resin compound and its derivatives, to methods of its preparation and to its use in the solid phase synthesis of amides, peptides, hydroxamic acids, amines, urethanes, carbonates, carbamates, sulfonamides and a-substituted carbonyl compounds.
BACKGROUND OF THE INVENTION
Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools for preparing amides and peptides as well as for effecting various functional group transformations. For solid phase peptide synthesis, a summary of the many techniques may be found in J. M. Stewart and J. D. Young,
Solid Phase Peptide Synthesis
, 2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984); J. Meienhofer,
Hormonal Proteins and Peptides
, vol. 2, p. 46, Academic Press (New York), 1973; and E. Atherton and R. C. Sheppard,
Solid Phase Peptide Synthesis: A Practical Approach, IRL
Press at Oxford University Press (Oxford, 1989). For the use of solid phase methodology in the preparation of non-peptide molecules see Leznoff, C. C.,
Acc. Chem. Res
., 11, 327-333 (1978). For the use of polymeric reagents in functional group transformations see A. Akelah and D. C. Sherrington, Application of Functionalized Polymers in Organic Synthesis,
Chem Rev
., 81, 557-587 (1981) and W. T. Ford and E. C. Blossey,
Polymer Supported Reagents, Polymer supported Catalysts, and Polymer Supported Coupling Reactions, in Preparative Chemistry using Supported Reagents
, Pierre Laszlo, ed., Academic Press, Inc., 193-212 (1987). For the use of polymeric reagents in oxidation reactions see J. M. J. Frechet et al.,
J. Org. Chem
., 43, 2618 (1978) and G. Cainelli et al.,
J. Am. Chem. Soc
., 98, 6737 (1976). For the use of polymeric reagents in halogenation reactions see J. M. J. Frechet et al.,
J. Macromol. Sci. Chem
., A-11, 507 (1977) and D. C. Sherrington et al.,
Eur. Polym. J
., 13, 73, (1977). For the use of polymeric reagents in epoxidation reactions see J. M. J. Frechet et al.,
Macromolecules
, 8, 130 (1975) and C. R. Harrison et al.,
J. Chem. Soc. Chem. Commun
., 1009 (1974). For the use of polymeric reagents in acylation reactions see M. B. Shambhu et al.,
Tet. Lett
., 1627 (1973) and M. B., Shambhu et al.,
J. Chem. Soc. Chem. Commun
., 619 (1974). For the use of polymeric reagents in Wittig reactions see S. V. McKinley et al.,
J. Chem. Soc. Chem. Commun
., 134 (1972).
Polymeric reagents also have found widespread use in combinatorial synthesis and for preparing combinatorial libraries. See F. Balkenhohl et al.,
Angew. Chem. Int. Ed. Engl
., 35, 2288-2337 (1996) and L. A. Thompson et al.,
Chem Rev
., 96, 555-600 (1996).
A 4-hydroxy-tetrafluorophenoxy resin compound of formula
is disclosed by H. Shao et al., in Abstract No.: 072
, Development of TFP Resin for Combinatorial Library Synthesis
, Division of Organic Chemistry, 213th ACS National Meeting, Apr. 13-17, 1997.
SUMMARY OF THE INVENTION
This invention is directed to a fluorophenyl resin compound of formula I
wherein
is a solid support;
A is selected from
L is a chemical bond,
m is 1 to 5;
p is 0, 1 or 2;
B is F, OW or SO
2
Z;
D is CH or N;
W is hydrogen, tripyrrolidinophosphonium, C(O)V, C(O)R
a
, C(O)NR
b
R
c
, C(O)OR
a
, SO
2
R
a
or
V is Cl or imidazol-1-yl;
Y is O or NR
3
;
Z is Cl, —OH, OR
a
or NR
a
R
i
;
R
a
and R
f
are independently aliphatic or aromatic;
R
b
and R
c
are independently H, aliphatic or aromatic, or R
b
and R
c
, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl;
R
i
is CH
2
R
f
;
R
0
, R
1
and R
2
are independently a ring system substituent, or R
0
and R
1
taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl;
R
3
is H or lower alkyl;
R
4
, R
5
, R
6
and R
7
are independently ring system substituents, or R
4
and R
5
taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and.
R
11
, and R
12
are independently alkyl, heteroaryl, or aryl.
The fluorophenyl resin compounds of this invention possess a unique advantage over other solid-phase synthesis reagents in that the fluorine atom ortho to the B substituent permit the absolute loading of the resin to be determined using
19
F NMR. The large chemical shift differences seen in the spectrum due to the different environments of the ortho fluoro atoms depending whether the chemical species is a phenolate anion, a phenol or a phenolate ester, is extremely useful to monitor the extent of loading of reagents on the tetrafluoro polymer (TFP) resin. The progress of reactions performed on the fluorophenyl resin compounds of this invention may also be monitored by
19
F NMR, providing a useful analytical method for reaction optimization. This is especially useful in the case of the activated sulfonate esters where there is not a simple diagnostic IR signal to monitor the-reaction.
In another aspect, this invention is directed to a fluorophenyl activated ester resin compound of formula
wherein
R
a
is aliphatic or aromatic;
is a solid support;
A is selected from
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR
3
or O;
R
0
, R
1
and R
2
are independently a ring system substituent, or R
0
and R
1
taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R
4
, R
5
, R
6
and R
7
are independently ring system substituents, or R
4
and R
5
taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.
In another aspect, this invention is directed to a process for preparing an amide of formula
wherein
R
a
is aliphatic or aromatic; and
R
b
and R
c
are independently H, aliphatic or aromatic, or R
b
and R
c
, taken together with the N atom through which they are attached, form an azaheterocyclyl or azaheterocyclenyl,
comprising reacting a fluorophenyl activated ester resin compound of formula
wherein
R
a
is aliphatic or aromatic;
is a solid support;
A is selected from
L is a chemical bond,
D is CH or N;
m is 1 to 5;
Y is NR
3
or O;
R
0
, R
1
and R
2
are independently a ring system substituent, or R
0
and R
1
taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R
4
, R
5
, R
6
and R
7
are independently ring system substituents, or R
4
and R
5
taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl
with a compound of formula HNR
b
R
c
.
In another aspect, this invention is directed to a process for preparing a fluorophenyl activated ester resin compound of formula
wherein
R
a
is aliphatic or aromatic;
is a solid support;
A is selected from
L is a chemical bond,
m is 1 to 5;
D is CH or N;
Y is NR
3
or O;
R
0
, R
1
and R
2
are independently a ring system substituent, or R
0
and R
1
taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; and
R
4
, R
5
, R
6
and R
7
are independently ring system substituents, or R
4
and R
5
taken together with the carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl, comprising coupling a 4-hydroxyfluorophenyl resin compound of formula
wherein
A, R
0
, R
1
and R
2
are defined above,
with a carboxylic acid compound of formula R
a
CO
2
H, wherein R
a
is defined above, optionally in the presence of an activating agent selected from the group consisting of diisopropylcarbodiimide in the presence of 4-dimethylaminopyridine, and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP™) in the presence of triethylamine (TEA).
In another aspect, this invention is directed to a process for preparing an amine compound of formula
whe

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