Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2003-01-01
2004-02-24
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S169000, C564S199000, C564S163000, C564S193000
Reexamination Certificate
active
06696605
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of resin-bound &agr;-hydroxyamides and &agr;-ketoamides which is adaptable for the preparation of Combinatorial Chemical Libraries.
BACKGROUND OF THE INVENTION
Polymer resin-bound substrates have been used for peptide synthesis since R. B. Merrifield first described his methodology for chemical synthesis on a solid matrix. In fact, resin-bound reactions have become ubiquitous toward the application of Combinatorial Libraries.
Isocyanides are reagents which are useful for the preparation of many nitrogen containing cyclic and acyclic compounds. I. Ugi et al., have used these reagents to prepare compounds under multicomponent reaction (MCR) conditions, for example, in the 4 component Ugi Reaction first described in 1959 (I. Ugi et al.,
Angew. Chem
., 1959, 71, 386). However, the simple use of isocyanide as a means for converting aldehydes to &agr;-hydroxyamides and &agr;-ketoamides on a solid phase resin has heretofore not been described.
There is a long felt need for a means for preparing &agr;-hydroxy-amides and &agr;-ketoamides in a manner which is adaptable to solid state synthetic procedures, as well as Combinatorial Libraries.
SUMMARY OF THE INVENTION
The present invention meets the aforementioned need in that it has been surprisingly discovered that the isocyanide functional group can be used as a reagent for a carbon-nitrogen two-atom homologation reaction which produces &agr;-hydroxyamides. In addition, this reaction can be extended to accomplish the solid phase preparation of &agr;-ketoamides.
The first aspect of the present invention relates to a process for preparing a &agr;-hydroxyamide, said process comprising the steps of:
a) reacting a resin which comprises a polymer-supported isocyanide having the formula:
with an aldehyde having the formula:
in the presence of a catalyst, to form a resin-bound &agr;-hydroxyamide having the formula:
b) reacting said resin-bound &agr;-hydroxyamide with a reagent which cleaves the nitrogen-resin bond to form a &agr;-hydroxyamide having the formula:
wherein J is a compatible organic radical which is not capable of reacting with said resin which comprises a polymer-supported isocyanide in step (a).
The second aspect of the present invention relates to a process for preparing a &agr;-ketoamide, said process comprising the steps of:
a) reacting a resin which comprises a polymer-supported isocyanide having the formula:
with an aldehyde having the formula:
in the presence of a catalyst, to form a resin-bound &agr;-hydroxyamide having the formula:
b) oxidizing said resin-bound &agr;-hydroxyamide to a &agr;-ketoamide having the formula:
c) reacting said resin-bound &agr;-ketoamide with a reagent which cleaves the nitrogen-resin bond to form a &agr;-ketoamide having the formula:
wherein J is a compatible organic radical which is not capable of reacting with said resin which comprises a polymer-supported isocyanide in step (a).
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing &agr;-hydroxyamides and &agr;-ketoamides. The process of the present invention can be adapted to the preparation of any &agr;-hydroxyamides or &agr;-ketoamides, including amino acids and other nitrogen atom containing synthetic intermediates. The process of the present invention is especially useful for introducing a &agr;-hydroxy amido or &agr;-keto amido functionality into molecules having base sensitive protecting groups.
For the purposes of the present invention the term “hydrocarbyl” is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]heptan-1-yl, and naphth-2-yl.
Included within the definition of “hydrocarbyl” are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
The term “heterocycle” includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, pyrrolyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted. A non-limiting example of a C
1
heterocycle is tetrazole
The term “substituted” is used throughout the specification. The term “substituted” is defined herein as “encompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also the term “substituted” can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit.” For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two-hydrogen atom replacement includes carbonyl, oximino, and the like. A two-hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Threehydrogen replacement includes cyano, and the like. The term “substituted” is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a hydrocarbyl unit is described as “substituted” any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”, (N,N-dimethyl-5-amino)octanyl is a “substituted C
8
alkyl unit, 3-guanidinopropyl is a “substituted C
3
alkyl unit,” and 2-carboxypyridinyl is a “substituted heteroaryl unit.” There may also be substitutions at more than one carbon atom in a hydrocarbyl moiety, for example, 3,5-difluorobenzene, and 2,3-dihydroxy butane. The following are non-limiting examples of units which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as “substituted.”
i) —[C(R
4
)
2
]
p
(CH═CH)
q
R
4
; wherein p is from 0 to 12; q is from 0 to 12;
ii) —C(X)R
4
;
iii) —C(X)
2
R
4
;
iv) —C(X)CH═CH
2
;
v) —C(X)N(R
4
)
2
;
vi) —C(X)NR
4
N(R
4
)
2
;
vii) —CN;
viii) —CNO;
ix) —CF
3
, —CCl
3
, —CBr
3
;
x) —N(R
4
)
2
;
xi) —NR
4
CN;
xii) —NR
4
C(X)R
4
;
xiii) —NR
4
C(X)N(R
4
)
2
;
xiv) —NHN(R
4
)
2
;
xv) —NHOR
4
;
xvi) ═NOR
4
;
xvii) —NCS;
xviii) —NO
2
;
xix) —OR
4
;
xx) —OCN;
xxi) —OCF
3
, —OCCl
3
, —OCBr
3
;
xxii) —F,
Echler Sr. Richard S.
Kumar Shailendra
The Procter & Gamble & Company
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