Brotato
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Synthesis of Tacrine
Tacrine was used as a first line treatment for Alzheimer's disease before being discontinued for hepatotoxicity concerns. However, the alternative use
for tacrine also provides keen interest in this drug, which is its use as a treatment for anticholinergic induced delirium. Doses of 60 mg orally were
found to be quick acting and effective for up to 6-12 hrs in patients with this form of delirium. In comparison to other drugs used for this purpose
such as physostigmine, which lasts just 2 hrs and must be continually applied mostly through IV, tacrine finds increased efficacy due to its longer
duration of action and formulation as an oral tablet. These properties make tacrine a vital safety tool to those interested in the exploration of
ultra-potent delirium inducing compounds. Notably, this is the compound that Dr. James Moore (PhD in organic synthesis) used to treat his delirium
from accidental exposure to BZ (3 quinuclidinyl benzilate) during his time working at Edgewood arsenal.
So how can we make this compound ? Well there are many approaches to this class of compounds (of which tacrine is the simplest) due to their wide
application as a building block in larger drugs. The two main methods rely on either 2-aminobenzonitrile or anthranilic acid as starting materials.
While both are possible to obtain, 2-aminobenzonitrile is around 30$/10 grams whereas anthranilic acid can be made for far cheaper via hydrolysis of
methyl anthranilate. The approach relies on the reaction of cyclohexanone with anthranilic acid and POCl3 as a reagent and the solvent. This undergoes
a Niementowski reaction mediated by POCl3. After isolation, this intermediate can then undergo nucleophilic substitution with ammonia to yield
tacrine.
Step 1: Synthesis of Anthranilic acid
75 mLs of 3 M NaOH solution in water was added to 50 mLs of methyl anthranilate. The mixture was stirred thoroughly and refluxed for 1 hr. After 1 hr,
the solution was cooled to rt, neutralized w/ 1 M HCl solution and filtered. The filtrate was washed with cold water, dried on the vacuum filter, and
finally dried in an oven at ~100 C for 2 hrs.
Step 2: Synthesis of 9-chloro tetrahydroacridine
To a 250 mL flask was added 3 grams of 2 aminobenzoic acid, after which 2.7 grams of cyclohexanone was added. 30 mLs of POCl3 was added slowly
dropwise with thorough stirring in an ice bath. The ice bath was removed and this mixture was refluxed for 3.5 hrs. It was quenched with iced water
and sodium carbonate was added until the mixture was neutral (NOTE: A significant amount of CO2 is released so it is important to use a secondary
container and be patient with the additions). The resultant solution was extracted 3 x 100 mLs EtOAc, dried w/ anhydrous MgSO4, and rotary evaporated
to obtain a yellow waxy solid that solidifies quickly after removal from the rotovap. This solid was purified via silica gel column chromatography
(50/50 v/v EtOAc/ Pet Ether) to obtain 3.1 grams of a crystalline yellow solid (71%; lit: 88%).
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Note: This was lower than lit, this may be explained by the fact that this reaction was somewhat scaled up ~3x however it may also be simple deviance
in the yields with the authors performing several trials and only reporting the best of those.
Step 3: Synthesis of Tacrine from 9-chloro tetrahydroacridine
3.1 grams of 9-chloro tetrahydroacridine was dissolved in a minimal amount of 1- pentanol to which 18 mLs of 30% NH4OH was added dropwise. This
solution was stirred at 1200 rpm and refluxed for 15.2 hrs. The solution was cooled to RT and acidified slowly with 37% HCl to pH 2. Diethyl ether is
added as an antisolvent (just until a small amount of white precipitate is noted) and the whole solution is placed in the fridge at 0 C to crystalize.
The precipitate is redissolved in 75 mLs of water and basified to pH 10 with sat sodium carbonate (Note: This precipitates a white solid that is the
product, this solid should be extracted). This basified solution is extracted with 150 mLs of DCM, dried over sodium sulfate, the solvent is stripped
under reduced pressure.
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The white compound is purified via column chromatography, isolating Tacrine in a yield of 60% (lit:60%).
Overall, this is a simple synthesis of an interesting compound, please stay tuned for some more projects!
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Fery
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Well done and thx for sharing. Keep up good work.
You are right with the toxicity of tacrine. Today we use donepezil, rivastigmine, galantamine for treatment of patients suffering from Alzheimer's
disease.
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Maui3
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Good work Brotato!
Fery, yeah and don't forget Memantine! 
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