Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1999-11-08
2002-05-07
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S615000, C549S336000, C560S174000, C568S309000, C568S312000, C568S317000
Reexamination Certificate
active
06384251
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the allylic oxidation of organic compounds.
BACKGROUND
Allylic oxidation is a fundamental organic reaction of significant interest to organic chemists practicing in a variety of fields from agricultural products to pharmaceuticals. A variety of procedures are known for oxidizing various organic compounds that possess allylically activated hydrogen(s), but such procedures typically suffer from unsatisfactory yields, tedious workups and/or require the use of expensive reagents.
Allylic oxidation reactions have traditionally been performed with chromium reagents, such as chromium trioxide and sodium/potassium dichromate. While generally effective, such reactions usually require a large excess of the reagent under harsh conditions (e.g., a large volume of aqueous acetic acid, anhydrous acetic acid (Fieser's Reagent) or concentrated or dilute sulfuric acid). Chromium trioxide pyridine complex allows the oxidation to be carried out at ambient temperature, but requires the use of a large excess of the reagent (~20 equiv.) and is highly hygroscopic, making the reagent unattractive for large scale production.
Pyridinium chlorochromate (PCC) and pyridinium dichromate have more or less become ubiquitous for chromate based oxidations as they are generally effective and can be prepared by a procedure significantly less hazardous than that required to prepare the chromium trioxide-pyridine complex. However, these reagents also tend to require a large excess (~20 equiv.) of the reagent. The use of tert-butyl hydroperoxide in combination with a chromium reagent affords allylic oxidation under relatively mild processing conditions, but often requires the use of an undesirable organic solvent such as benzene.
A further drawback associated with the aforementioned procedures is the incomplete nature of the conversion, requiring the implementation of expensive techniques, such as chromatography, to remove unreacted starting material and obtain a product of sufficient purity.
Hence, a continuing need exists for a simple, efficient, safe and cost effective procedure for selectively effecting the allylic oxidation of organic compounds, particularly &Dgr;5-steroids, suitable for use on a commercial scale.
SUMMARY OF THE INVENTION
We have discovered a simple, efficient, safe, and cost effective procedure for oxidizing organic compounds having allylic hydrogen atom(s). The procedure involves reactively contacting an organic compound having an allylic hydrogen atom(s) with a combination of a chromium compound and an N-hydroxy dicarboxylic acid imide under conditions sufficient to effect oxidation of the allylic hydrogen(s) on the organic compound.
The successful incorporation of an N-hydroxy imide of a suitable dicarboxylic acid with a chromium oxidant allows the reaction to be conveniently conducted at ambient or near ambient temperature and normal pressure using conventional, relatively safe organic solvents.
DETAILED DESCRIPTION OF THE INVENTION INCLUDING A BEST MODE
Definitions
As utilized herein, including the claims, the term “allylic compound” references an organic compound having at least one allylic hydrogen atom.
As utilized herein, including the claims, the term “allylic oxidation ” means oxidation of an allylic compound by replacing at least one allylic hydrogen(s) with oxygen or an oxygen-containing group.
As utilized herein, including the claims, the term “reactants” collectively references allylic substrates, N-hydroxy dicarboxylic acid imides and chromium-containing compounds. Solvents, including both aqueous and organic solvents, are specifically excluded from the definition of reactants.
Process
The present process is extremely useful both in terms of yield and operational simplicity. This is particularly true for the allylic substrates of &Dgr;5-steroids and benzylic compounds. Excellent yields are obtained with low molar ratios of the reactants under ambient or near ambient conditions. Of particular interest is the discovery that the process achieves the desired allylic oxidation with a near total absence of any competitive side reactions.
The process involves reactively contacting an allylic compound with a combination of N-hydroxy dicarboxylic acid imide and a chromium-containing oxidant(s), under conditions sufficient to effect oxidation of the allylic hydrogen atom(s) on the organic compound. For example, an allylic compound can be dissolved in a suitable organic solvent and a mixture of the N-hydroxy dicarboxylic acid imide and chromium-containing oxidant(s) added. Water may optionally be incorporated into the reaction mixture in a suitable amount.
Constituents
Allylic Compounds
Allylic compounds are any organic compound incorporating the structure —RC
1
═C
2
H—C
3
H
n
— within the molecule, wherein n is 1, 2 or 3. Hydrogen atoms attached to the C
1
and C
2
carbon atoms are referenced as vinylic hydrogen. Hydrogen atoms attached to the C
3
carbon atom are referenced as allylic hydrogen. The process of this invention selectively oxidizes allylic hydrogen atoms over vinylic hydrogen atoms. Exemplary allylic compounds include specifically, but not exclusively, (i) aliphatic vinylic compound such as methyl oleate, (ii) aromatic benzylic compounds such as fluorene and diphenyl methane, (iii) isoprenoids, such as carotenoids, terpenes, sesquiterpenes and vitamins, and (iv) steroids and sterols, such as androstenes, cholesterol, estraenes, pregnenes and derivatives thereof such as esters, esters, and ketals of these compounds.
Of particular commercial interest is the allylic oxidation of steroids, particularly &Dgr;5 steroids such as dehydroepiandrosterone and derivatives of dehydroepiandrosterone, because such steroids possess pharmacological activity and can be conveniently and effectively allylically oxidized in excellent yields by the process of this invention.
Cooxidants
The procedure utilizes a cooxidant system of N-hydroxy dicarboxylic acid imide and a chromium-containing oxidant.
A cooxidant system of a N-hydroxy dicarboxylic acid imide and chromium-containing oxidant is used to allylically oxidize the allylic compound. Experimentation has shown the specific combination of N-hydroxy dicarboxylic acid imide and chromium-containing oxidant generally provides a superior yield and/or superior quality of allylically oxidized product under mild reaction conditions.
N-hydroxy Dicarboxylic Acid Imide
The N-hydroxy dicarboxylic acid imide includes those formed from dicarboxylic acids which can form cyclic imides in accordance with the general formula:
wherein X-Y stands for saturated or unsaturated aliphatic hydrocarbon residue, aromatic hydrocarbon residue or a group derived from one of the groups.
Preferred examples of the imide include N-hydroxy succinimide, N-hydroxy-phthalimide, N-hydroxy imides of naphthalene dicarboxylic acids, and derivatives thereof.
Chromium-containing Oxidants
A number of chromium-containing oxidants are known in the art. Preferred examples of chromium-containing oxidants include sodium dichromate monohydrate (SDC), chromium trioxide (CTO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and chromium perchlorate hexahydrate (CPC).
Both the N-hydroxy dicarboxylic acid imide and chromium-containing oxidants are available from a number of chemical suppliers as an aqueous solution. Since the reaction mixture may include small amounts of water, the oxidants can generally be used as obtained.
Generally, the concentrations of N-hydroxy dicarboxylic acid imide (Imide) and chromium-containing oxidant (Chromium) set forth in Table One below are effective for allylically oxidizing an allylic compound.
TABLE ONE
CONCENTRATION
GENERALLY
PREFERRED
MOST PREFERRED
OXIDANT
(Mole/Eq)
(Mole/Eq)
(Mole/Eq)
Imide
0.5-1.5
0.7-1.2
1
Chromium
0.5-3
0.7-2.5
1-2
Concentrations of less than about 0.5 mole equivalent of chromium-containing oxidant and less than about 0.5 mole equivalents of N-hydroxy dicarboxylic acid imide significantly slows the reaction, while greater than about 3 mole equivalents of chromium-
Lardy Henry A.
Marwah Padma
Badio Barbara P.
Humanetics Corporation
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