Process for the solid phase synthesis of aldehyde, ketone,...

Details Process for the solid phase synthesis of aldehyde, ketone,... Process for the solid phase synthesis of aldehyde, ketone,...

1999-12-22

2002-05-21

Davis, Brian J. (Department: 1621)

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

Synthetic resins

Treating polymer containing material or treating a solid...

C528S492000, C528S493000, C528S494000, C528S495000, C528S497000, C528S498000

Reexamination Certificate

active

06392010

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to processes for the solid-phase synthesis of aldehyde, ketone, oxime, amine, and hydroxamic acid and &agr;,&bgr;-unsaturated carboxylic acid and aldehyde compounds and to polymeric hydroxylamine resin compounds useful therefor.
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, peptides and hydroxamic acids. 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).
A number of polymeric reagents have found synthetic use in simple 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 polymeric reagent has the advantage of ease of separation from low molecular weight reactants or products by filtration or selective precipitation. The polymeric reagent also can be used in excess to effect fast and quantitative reactions, such as in the case of acylations, or a large excess of reactants may be used to drive the equilibrium of the reaction towards product formation to provide essentially quantitative conversion to product, as in solid phase peptide synthesis. A further advantage of supported reagents and catalysts is the fact that they are recyclable and that they lend easily to automated processes. In addition, supported analogs of toxic and odorous reagents are safer to use.
PCT application publication no. WO96/26223 discloses the synthesis of hydroxamic acid compounds using a solid phase hydroxylamine substrate.
Prasad et al. disclose a O-methylhydroxylamine-polystyrene resin compound in J. Steroid Biochem., 18, 257-261 (1983).
Resin-bound Weinreb-like amides are disclosed by Fehrentz et al., Tet. Lett., 1995, 36, 7871-7874 and Dinh et al., Tet. Lett., 1996, 37, 1161-1164.
Polymeric Horner-Wadsworth-Emmons reagents are disclosed by Wipf et al., J. Org. Chem., 1997, 62, 1586 and Johnson et al., Tetrahedron Lett., 1995, 36, 9253.
SUMMARY OF THE INVENTION
This invention is directed to a process for the preparation of a ketone compound of formula
wherein R
c
and R
a
are independently aliphatic or aromatic, this process comprising
(a) reacting an N-alkylated polymeric hydroxamic acid resin compound of formula
wherein
is a solid support, L is absent or a linking group and R
b
is aliphatic or aryl with an organometallic reagent of formula R
c
M wherein R
c
is an aliphatic or aryl anion and M is a metal cation; and
(b) liberating the ketone compound from the resin.
In another aspect, this invention is directed to a process for the preparation of an aldehyde compound of formula R
a
CHO wherein R
a
is defined above, comprising
(a) reacting an N-alkylated polymeric hydroxamic acid resin compound of formula
wherein
L and R
a
and R
b
are defined above;
with a reducing agent; and
(b) liberating the aldehyde compound from the resin.
In another aspect, this invention is directed to a process for the preparation of an N-alkylated polymeric hydroxamic acid resin compound of formula
wherein
L and R
a
and R
b
are defined above, comprising
(a) coupling a carboxylic acid compound of formula R
a
CO
2
H with a polymeric hydroxylamine resin compound formula
 to form a polymeric hydroxamic acid resin compound of formula
(b) reacting the polymeric hydroxamic acid resin compound with an alkylating agent of formula R
b
LG wherein LG is a leaving group.
In another aspect, this invention is directed to a process for the preparation of an N-alkylated polymeric hydroxamic acid resin compound of formula
wherein
L and R
a
and R
b
are defined above, comprising
(a) reacting an N-protected polymeric hydroxamic acid resin compound of formula
wherein P is an amine protecting group, with an alkylating agent of formula R
b
LG wherein LG is defined above, to form a polymeric N-protected N-alkylated hydroxylamine resin compound of formula
(b) removing the amine protecting group to form a polymeric N-alkylated hydroxylamine resin compound of formula
(c) coupling the polymeric N-alkylated hydroxylamine resin compound with a carboxylic acid compound of formula R
a
CO
2
H.
In another aspect, this invention is directed to a process for preparing a hydroxamic acid compound of formula
wherein
A
2
is a direct bond, alkylene, or NR
13
;
R
13
is hydrogen or alkyl;
R
9
is —L
1
—R
14
or —L
2
—R
15
;
L
1
is a direct bond or alkylene;
R
14
is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidylalkyl, heterocyclyl, heteroaryl, —NH—C(═O)—NH
2
, (N-carbamoyl)cyclic amine, —C═N—O—C(═O)—NH
2
, —C(═O)—NY
1
Y
2
, —NY
1
SO
2
aryl, —NHR
13
, —SR
13
or —OR
13
;
L
2
is alkenylene or alkynylene;
R
15
is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, heterocyclylalkyl or heteroaryl;
R
10
and R
12
are independently hydrogen oralkyl; or R
10
and R
12
together form a bond, or R
10
and R
9
taken together with the carbon atom through which R
10
and R
9
are attached form spirocycloalkyl;
R
11
is a group —L
3
—R
16
, or R
11
and R
9
taken together with the carbon atoms through which R
11
and R
9
are attached form cycloalkylene; or R
11
and R
12
taken together with the carbon atom through which R
11
and R
12
are attached form spirocycloalkyl;
L
3
is a direct bond, alkylene, alkenylene or alkynylene;
R
16
is hydrogen, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, —NH—C(═O)—NH
2
, —C═N—O—C(═O)—NH
2
, —C(═O)—NY
1
Y
2
; —NY
1
SO
2
aryl, —NR
13
, —SR
13
, or —OR
13
Y
1
and Y
2
are independently selected from hydrogen, a

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