Due to the major importance of Amphetamine derivatives, numerous synthetic methods for their synthesis and their derivatisation have been developed e. A general problem which has to be overcome is the fact that Amphetamines include a stereodefined amine center which is potentially subject to racemisation. As a result, only methods which suppress racemisation can be applied. At the same time, these methods do need to fulfil the standard economic requirements of high yields, high selectivity and low process costs.
Typically such reactions involve a coupling agent. Due to the production application area, coupling reagents also need to be non-toxic to avoid any risk. For the synthesis and derivatisation of most Amphetamine derivatives, a variety of different coupling reagents has been tested but so far none has fulfilled all of the above requirements.
It was, therefore, an object of the present invention to provide for a method to manufacture amphetamine derivatives using an amphetamine coupling reaction which - avoids racemisation of the stereodefined amphetamine amine centre, i. More specifically it was an object of the present invention to provide for a process for the derivatisation of Amphetamines, Dexamphetamines and Methamphetamines in coupling reactions to acylated products in high yields and without racemisation, in easy processes.
The present invention achieves these objects. Surprisingly, it was found that the application of alkyl phosphonic acid anhydrides, especially cyclic anhydrides, e.
Accordingly, the present invention relates to a process for preparing acylated amphetamine, methamphetamine and dexamphetamine derivatives including their salts by reacting the parent amine with the optionally protected to be coupled acid or a salt of the to be coupled acid in the presence of an alkylphosphonic acid anhydride as coupling agent and, if required, the cleavage of the protecting group s , in a one- pot reaction or in two or more separate steps.
The reaction is illustrated in the following equation 1. The alkylphosphonic acid anhydride of the formula is either cyclic see formula I below or linear see formula Il below. If it is linear the open bonds are saturated by OH and H respectively see formula Il below. Boc with d-Amphetamine III , followed by deprotection equation 2. They can be cyclic or linear. In both cases the alkyl substituent can be the same or different per molecule.
The surprising advantages of T3P, and the other phosphonic acid anhydrides in the reaction according to the invention are their very high selectivities, leading to highest yields and product purities and to the lowest level of racemisation and epimerisation. These alkylphosphonic acid anhydrides are non-toxic and very easy to process, resulting in an overall reduction of process costs. Workup can be performed by a simple hydrolysis and phase separation, which results in a - surprisingly already very pure - product solution in an organic solvent and a phosphorous product in the aqueous phase.
The anhydride can be used as a pure material, but typically it is applied as a solution in an organic solvent for reasons of most economic processes. A solvent can be selected from those available materials which do not react with the phosphonic acid anhydride, especially aprotic organic solvents. Preferred solvents are Dichloromethane, Chloroform, Ethylacetate, Propylacetate, Butylacetate, Dimethylformamide, Diethylformamide, Dimethylacetamide, Diethylacetamide, Diisopropylether, tert.
Especially preferred solvents are Dichloromethane, Chloroform, Ethylacetate, Butylacetate, Dimethylformamide, Dimethylacetamide, tert. Different coupling strategies can be applied. A standard method comprises mixing the substrates Amphetamine derivative, acid, base and solvent and slowly adding a phosphonic acid anhydride solution to this mixture. After completion of the addition, the mixture is stirred for some time, e.
The coupling step can be conducted as a one- pot reaction. As bases, both organic amines or inorganic bases can be used hydrogen carbonates, carbonates, hydroxides, etc. Best results are typically achieved with using equivalents of base plus one additional equivalent for each acid equivalent present in the substrates e.
In the case of Lisdexamphetamine, the protection of the two amino groups of Lysine can be accomplished with Boc groups which result in high overall yields and very easy cleavage after the coupling to yield Lisdexamphetamine as a free base or as a salt.
Og, 3. The selectivity aspects of catalytic hydrogenation over heterogeneous catalysts will be discussed and documented with several examples. All three types of selectivity chemo-, regio- and stereoselectivity will be addressed with special emphasis on the applicability of the catalytic procedure. The scope of chemoselective hydrogenation will be demonstrated by selective hydrogenation of unsaturated nitriles.
Finally, an example will be given on stereoselective hydrogenation. It will include the synthesis of major bulk and fine chemicals, of petrochemicals, the researchers in depollution and in biomass uses and its derived chemicals. Case studies have been chosen to exemplify the different fields of interest. A high combinatorial therapeutic approach for catalyst preparation was given. References Heidari A. Brown C.
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In both cases the alkyl substituent can be the same or different per molecule. The coupling step can be conducted as a one- pot reaction. Optimized conditions of reaction were 0. Mass Spectrom Purif Tech.
The filter-cake was washed with 1 , 4-dioxane 3x1. The slurry was filtered through filter paper and the flask was rinsed with 1 8ml of 1 , 4-dioxane. Og, T3P solution in EtOAc, Cell Biol Henderson, NV.
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Nano Res Appl. Children 3—5 years of age: Dosage must be initiated and titrated with conventional tablets in this age group.