Damn those solvents

[clubcard]

I have found a wonderfully elegant route to make a compound a friend asked for. The problem is that it takes 2500mL of methanol to dissolve 250g of the main precursor. The paper simply states that the methanol is distilled off which is going to be SLOW. Evidently the product is also soluble in methanol AND DCM. AFAIK the addition salt of the product is also soluble in methanol but I'm not sure if it's soluble in DCM (likely not). I wondered if anyone knew of a cunning method of producing an insoluble derivative.
Much as I hate crashing stuff out because it's such a waste so I have toyed with the idea of freezing out the product. The reaction is run at 30°C but before NaBH4, it's chilled to 0°C. Now the paper I based this on used methylamine hydrochloride (freebased by KOH that also removes water from the system) but in my case, BP is >30°C. The NaBH4 is added in 3 lots so I am wondering if that lower temperature is just to ensure that no amine escapes.
I wish I could be more specific but when the time comes, you will be the first to know. All I can tell you that it was the result of patent mining on a massive scale. This took >150 searches. AFAIK the product is legal everywhere.

 

[Gaffy]

PM me what it is, I'm so curious

 

[sekio]

The problem is that it takes 2500mL of methanol to dissolve 250g of the main precursor. The paper simply states that the methanol is distilled off which is going to be SLOW.

1. 1g product in 10ml solvent is pretty good by my reckoning, especially with a cheap solvent like methanol
2. methanol is not that difficult to distill off? apply an aspirator vacuum and it just flies off

AFAIK the addition salt of the product is also soluble in methanol but I'm not sure if it's soluble in DCM (likely not)

DCM can actually dissolve some amine salts, e.g. PCP hydrochloride can actually be extracted out of water into DCM. Chloroform is probably similar

[quote ]I wondered if anyone knew of a cunning method of producing an insoluble derivative.[/quote]
bind the product onto an ion exchange resin... oh wait that would require 2500kg of resin

I have toyed with the idea of freezing out the product

in my experience most things don't have a big enough solubility difference with temperature in methanol

also I have worked up reactions in methanol (and dmf) before by dilution with large amounts of water and then extracting your nonpolar product out with hexanes or ether, usually the methanol wants to stay in the water phase

consider too that you can run borohydride reductions in higher alcohols as well, perhaps ethanol or isopropanol would allow a more concentrated reaction mixture

it's a crazy idea too but maybe liquid methylamine would work? borohydride is stable in amine solvents as well

 

[clubcard]

It's a class of reduction in which the solvent is also part of the reaction. It's a simple reductive alkylation but the amine is added as an addition salt and then KOH both freebases the amine and then pushes the reaction to the right by removing water. Well, I was impressed!

 

[atara]

This would be so much easier if we were on SM but anyway

There are plenty of tricks to making insoluble salts but the problem is that you're using methanol and everything is soluble in methanol. You just have to boil it off, takes a while but probably not longer than 150 searches... sekio's technique can work but at your scale you use like eight liters of water and extract it three times with a liter of DCM each time, which probably isn't economical.

Also aren't these kinds of solvent-assisted CTH reactions usually run in isopropanol?

 

[clubcard]

This would be so much easier if we were on SM but anyway

There are plenty of tricks to making insoluble salts but the problem is that you're using methanol and everything is soluble in methanol. You just have to boil it off, takes a while but probably not longer than 150 searches... sekio's technique can work but at your scale you use like eight liters of water and extract it three times with a liter of DCM each time, which probably isn't economical.

Also aren't these kinds of solvent-assisted CTH reactions usually run in isopropanol?

Well Sekio is right when he states that methanol does distil off pretty fast and my solvent miscibility chart:

https://www.restek.com/images/pages/solvent-miscibility-chart.jpg

Suggests that if the media were made acidic (forming an addition salt of product) then copious amounts of DCM would see the product crash out. Of course, I really need to find the solubility values at given temperatures because it's very convenient to simply obtain a cryogenic chest freezer that can reach -104°C given that the freezing point of methanol is -97.6°C (and DCM is -97°C).

I loved this reaction because every single reagent performs multiple roles within the reduction which is satisfying, Chilling would conveniently remove the side-products and eventually the product.

 

[sekio]

just distill the methanol off, simplicity is best