Synthetic route to scopolamine and/or atropine
Inventors
Blumberg, Shawn T. • MIGUEL, Paul W. • HINOJOSA, Daniel A.
Assignees
Southwest Research Institute SwRI
Publication Number
US-11739084-B2
Publication Date
2023-08-29
Expiration Date
2041-10-07
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Abstract
A synthetic route to scopolamine and/or atropine. In such context, the present invention identifies a method for preparing 6,7-dehydro atropine, which can be converted into either scopolamine and/or atropine, along with a method for converting a protected pyrrole into a tetrachlorobicylic compound, such as benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.
Core Innovation
The invention discloses a synthetic route to scopolamine and/or atropine. It presents a method for preparing 6,7-dehydro atropine from a protected pyrrole, which can then be converted into either scopolamine or atropine. The process involves converting a protected pyrrole into a tetrachlorobicyclic compound, specifically benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, through a defined sequence of reactions and subsequent functional group transformations.
The background section identifies that currently, scopolamine is primarily isolated from plants in the Solanaceae family, which must be farmed, harvested, and subjected to extensive purification, yielding only 2-4% (w/w) scopolamine and generating significant waste. This method is subject to the limitations of plant growth rates, fluctuating crop yields, and increasing global demand, making it difficult and expensive to procure scopolamine at scale. Other existing chemical synthesis routes rely on the use of toxic or expensive reagents, such as Fe2(CO)9 and tetrabromoacetone, and are not considered optimal.
The newly proposed method in this invention employs protected pyrrole as a starting material. It details a stepwise chemical pathway including reaction with pentachloroacetone to form tetrachloro-bicyclic intermediates, reductive dechlorination, reductive methylation, and strategic functionalization steps, ultimately yielding 6,7-dehydro atropine. This intermediate is subsequently converted through additional synthetic operations into scopolamine or atropine, by either oxidation or reduction, respectively.
Claims Coverage
There are three independent claims in this patent, each defining a method for synthesizing key intermediates or end products in the route to scopolamine and/or atropine.
Method for preparing 6,7-dehydro atropine from protected pyrrole
This inventive feature covers a method involving: 1. Providing a protected pyrrole where the protecting group R can be alkyl, phenyl, or benzyl. 2. Reacting this pyrrole with pentachloroacetone to form a tetrachloro-bicyclic compound. 3. Performing a reductive dechlorination to yield a bicyclic compound. 4. Reductive methylation of the bicyclic compound to produce 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol. 5. Converting this intermediate to 6,7-dehydro tropene tosylate. 6. Converting the tosylate to 6,7-dehydro atropine.
Method for preparing scopolamine from protected pyrrole
This inventive feature covers a method that comprises: 1. Providing a protected pyrrole (with R as alkyl, phenyl, or benzyl). 2. Conducting the same series of transformations as in the previous method to produce 6,7-dehydro atropine. 3. Further oxidizing 6,7-dehydro atropine to produce scopolamine.
Method for preparing atropine from protected pyrrole
This inventive feature covers a method in which: 1. A protected pyrrole (with R as alkyl, phenyl, or benzyl) is used as the starting material. 2. The synthetic sequence leads to 6,7-dehydro atropine. 3. 6,7-dehydro atropine is then subjected to a reduction step to form atropine.
The claims broadly cover methods for synthesizing 6,7-dehydro atropine, scopolamine, and atropine from protected pyrrole intermediates, specifying key steps for conversion and transformation, thereby providing alternate synthetic access to these medically relevant compounds.
Stated Advantages
The invention circumvents the need to rely on plant sources, such as Duboisia leichhardtii, for scopolamine, thereby overcoming limitations of crop yield, harvesting, and extraction inefficiency.
The synthetic route enables more efficient and scalable production of scopolamine and/or atropine from pyrrole, meeting expanding global demand for nerve agent remedies.
Documented Applications
The synthesized scopolamine and/or atropine are applicable as OPNA (organophosphorous nerve agent) antidotes.
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