Reexamination Certificate
2001-04-27
2002-08-27
Carr, Deborah D. (Department: 1621)
Reexamination Certificate
active
06440056
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention pertains to a process for preparing diacetylenics, to diacetylenic compounds and to reduced diacetylenic compounds.
2. Description of Related Art
Diacetylenic acids are a major precursor for making diacetylenic phospholipids, which are basic building materials for making and stabilizing technologically useful structures called “tubules”. The high cost of the diacetylenic acids pushes the cost of phospholipids up thus making them less attractive in the development of technologies such as electronic devices; controlled release of substances, particularly drugs; drug delivery systems; nano composites; and the like. Diacetylenic phospholipids consisting of diacetylenic acids with keto functional groups, and a combination of keto and aryl or cyclic groups, constitutes useful molecular probes for studying bilayer membrane structures and dynamics.
The prior art process of making the isomeric diacetylenic acids, disclosed in U.S. Pat. No. 4,867,917, involves a heterocoupling reaction between a starting acetylenic acid and an omega haloalkyne. While the synthetic scheme provides an easy way to prepare any combination of diacetylenic acids, the cost of the starting diacetylenic acid is high enough to prevent commercial use of the product diacetylenic acids.
The patented prior art preparation of the diacetylenic acids noted above, is further complicated by the fact that it is disadvantageous from commercial as well as product purity points of view. Preparation of the haloalkyne requires three steps, starting with an alkene, such as dodecene, progressing to an alkyne by the use of bromine and a basic ethanol, and finally arriving at the haloalkyne with the aid of the Grignard reagent and iodine. Similarly, it takes two steps to prepare an alkanoic acid, such as dodecanoic acid, starting either with an alkylenic acid, such as dodecylenic acid, or from a reaction of lithium acetylide/ethylene diamine complex with a bromoalkenoic acid, such as 9-bromododecanoic acid.
The overall yields for making a haloalkyne and an acetylenic acid are in the range of 60% and the reactions involve expensive and air sensitive reagents. Moreover, coupling a haloalkyne and an acetylenic acid is not only a low yield reaction of about 25% but also provides a mixture of three products. Though the separation of individual products is easy, additional reaction steps add to the product cost. The cost of the diacetylenics of interest herein is on the order $4,000/kg when prepared by the prior art process. There is a clear need for a new procedure which should be more cost effective and which minimizes the use of hazardous chemicals.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of this invention to prepare diacetylenics using a procedure that is more cost-effective and which minimizes the use of hazardous chemicals.
Another object of this invention is new compounds of diacetylenics containing at least one keto group.
Another object of this invention is new diacetylenic compounds containing at least one saturated or unsaturated cyclic group.
Another object of this invention is the preparation of diacetylenics which contain adjoining acetylene groups and carbon chains of varying length on either side thereof.
Another object of this invention is the ability to vary chain length on the sides of the adjoining acetylene groups in the diacetylenics described herein.
These and other objects of this invention are accomplished by oxidative coupling reaction involving an acetylenic acid to produce a diacetylenic diacid which is subsequently converted to a novel diacetylenic keto compound, which in turn is reduced to a reduced diacetylenic compound.
DETAILED DESCRIPTION OF THE INVENTION
This invention pertains to a high yield synthesis process, to diacetylenic compounds and to reduced diacetylenic compounds. More specifically, this invention pertains to a coupling process for making diacetylenics starting with an omega monoacetylenic acid, to diacetylenic compounds containing two adjacent acetylenic groups and to reduced diacetylenic compounds containing an alkyl or cyclic group at one or both ends thereof.
The versatile general procedure for making unsymmetric diacetylenics includes the steps of coupling an acetylenic acid using oxidative coupling involving cuprous chloride (CuCl), ethylamine (EtNH
2
) and hydroxylamine hydrochloride (NH
2
OH.HCl) to form a diacetylenic diacid followed by reaction of one of the carboxyl moieties on the diacetylenic diacid with a lithium reagent RLi wherein R is alkyl, phenyl or the like group to generate a keto derivative to form the diacetylenic keto acid. In the next reaction step, the keto group at one end of the diacetylenic keto acid is reduced using either hydrogenation with Raney nickel W-7 as catalyst or alkaline hydrazine hydrate or triethylsilane/trifluoroacetic acid reagent or some other keto reducing agent. The general procedure can be illustrated as follows:
where m is 1-35, more typically 2-8 carbon atoms; and R is selected from alkyl groups of 1-10, more typically 1-6 carbon atoms, and cyclic groups containing 3-35 carbon atoms, more typically aromatic monocyclic and multicyclic groups containing 6-15 carbon atoms; and X is a halogen, typically chloride.
In the general procedure given above, if the acetylenic acid is solid, it is dissolved in water and then converted to a salt, typically a sodium or potassium salt. The acetylenic acid is then coupled to itself in the presence of cuprous chloride catalyst, which is unstable and facilitates the coupling reaction. In place of cuprous chloride, one can use pyridine, tetramethylethylene diamine, an aliphatic amine of 1-6 carbon atoms or another suitable catalyst. The coupling reaction is also carried out in the presence of basic ethylamine (EtNH
2
), which dissolves and solubilizes cuprous chloride, and hydroxylamine hydrochloride (NH2 OH.HCl), which reduces any cupric chloride present as a result of conversion of cuprous chloride to cupric chloride (Cu
++
→Cu
+
). The coupling reaction is typically carried out at room temperature although it can be accelerated at elevated temperatures. Elevated temperatures that degrade reactants or products should be avoided. The coupling reaction can be carried out at 0-40° C. and its duration is typically a minimum of about 2 hours and its termination can be confirmed by thin liquid chromatography (TLC). The coupling reaction is the first step in the process and its product is a symmetric diacetylenic dicarboxylic acid. Conversion of the coupling reaction is about 85%.
When cuprous chloride in ethylamine is added to the salt of the acetylenic acid, the reaction medium turns dark blue and several drops of hydroxylamine hydrochloride are added to the reaction medium to turn it light yellow temporarily since the reaction medium again turns dark blue. Addition of hydroxylamine hydrochloride is thus continued until the reaction medium remains yellow, indicating endpoint of the reaction step. Thin layer chromatography is typically used to confirm conversion of all acetylenic acid to the diacetylenic dicarboxylic acid.
In the next or the second step of the reaction, one or both of the carboxyl groups on the diacetylenic diacid are converted to a ketone by the lithium compound RLi where the R group is selected from alkyl and cyclic groups. The alkyl groups contain at least 1 carbon atom and typically up to about 6 carbon atoms whereas the aromatic groups are at least monocyclic containing at least 3 carbon atoms. The cyclic group can be a multicyclic, saturated or unsaturated group and can contain up to about 35, more typically up to about 14 carbon atoms. Typical alkyl groups suitable herein include methyl, ethyl, propyl, butyl and pentyl whereas typical aromatic groups contemplated herein include phenyl, naphthyl and biphenyl.
The lithium compound reacts with the two carboxylic groups and converts them to a first lithium salt in the following manner:
the carbonyl oxygen of which is next converted to a seco
Schnur Joel M.
Schoen Paul
Singh Alok
Zabetakis Dan
Carr Deborah D.
Kap George A.
Karasek John J.
The United States of America as represented by the Secretary of
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