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Author: Subject: transesterification of hormones
jwarr
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[*] posted on 13-3-2021 at 15:55
transesterification of hormones


Many hormones contain a cyclic alcohol and are prepared for medicinal use by esterification of that alcohol. The length/size of the carbon chain on the ester determine the rate of metabolism by plasma esterases. So, for example, testosterone acetate has a half life measured in minutes, where are testosterone undecanoate has a half life measured in days.

My question is how one could perform a near-complete transesterifcation of a short chain hormone (ex) testosterone acetate to testosterone undecanoate?

Given that the longer chain alkoxide is likely going to be more stable, I'd imagine that the short chain ester is the more thermodynamically stable product in the equillibrium (R1)-O- + testosterone-O-CO-(R2) <=>(R2)-O- + testosterone-O-CO-(R1) when catalyzed by base or acid.

My first thought is that one could prepare the sodium oxide of the long chain alcohol in a high concentration solution of the alcohol in organic solution. That way you'd be pushing the equillibrium towards the longer ester. Is this dumb? Any thoughts/comments/critiques on my thought process?
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[*] posted on 13-3-2021 at 23:32


Hi, so do you have testosterone acetate and would you like to convert it to undecanoate? Like adding undecanoic acid and acid catalyst into the testosterone acetate and distilling out acetic acid?
Or are you interested how is testosterone undecanoate produced in pharma companies?
Esterification with fatty acids also occurs in human body:

Attachment: edrv0331.pdf (312kB)
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Another even more long term ester was developed - testosterone buciclate, but has never been marketed.

Testosterone undecanoate is an interesting substance, as it could be administered not only intramuscularly, but also orally. In the second case it is transported by intestinal lymphatic system bypassing liver first-pass metabolism. But efficacy of oral form is much poorer than intramuscular.
Another interesting form of application are dermal gels, transdermal patches of testosterone and mucoadhesive buccal testosterone tablets.




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jwarr
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[*] posted on 14-3-2021 at 12:34


I'm specifically interested in the conversion of testosterone acetate to testosterone undecanoate. That's an option I didn't even consider - distilling off the acetic acid. I'm assume giving the boiling point it would be best performed under vacuum ya?
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[*] posted on 14-3-2021 at 13:16


yes vacuum



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Dr.Bob
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[*] posted on 15-3-2021 at 15:34


It is possible, but not trivial to swap a small alkyl ester for a larger one, such as done with biodiesel production, where a methoixde displaces a glycerol (or partial ester of it) from a long chain acid. But swapping acids would require the alcohol (in this case a very sterically hindered one) to somehow lose the acetate and then react with a longer chain acid. This does not seem likely.

It would be much easier to try to cleave the acetate, perhaps by methonol and potassium carbonate, and then try to react the free alcohol with an acid chloride. But even that is tough for such a hindered alcohol.

Better to start with the parent alcohol and go from their. But making your own pharmaceuticals is a risky business and worse yet if you don't know what you are doing. This is not a trivial operation, and transesterifications are tough, especially going to a larger acid or alcohol from a small one.

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