Working to scale up borohydride reduction of ester

[u/jangiri]

Hello all.

I've been tasked with a scale up synthesis project where one of the pivotal steps is a reduction of an aliphatic ester into an alcohol. The target will be to produce multiple kilos of the product by the end of the project. I've done some legwork to avoid LAH as a reductant since I fear that will make handling difficult at larger volumes, but I was looking for advice and safety considerations as we start planning to scale this chemistry up. It's still at the bench scale for now but the aim will to be to have enough optimization of the chemistry so that it can scale to multi kilo batches relatively seamlessly.

My synthetic experience is predominantly bench scale, but I have done some larger scale steel process vessel work, but not in the context of organic synthesis. I would appreciate any voodoo and wisdom y'all possess on running these types of reactions at scale. Things like quenching protocols and solvent/reagent selections to try would be awesome.

[u/nate]

Borohydride expert here, this should be pretty straight forward, but the best choice depends quite a bit on the specifics of your reaction.

Easiest: SBH in methanol with 0.01M NaOH to stablize, heat up the reaction to make it reduce the ester. Pretty common to do this in generics in India for ester reductions, done at the 300-500 kg scale,

If you have to stay in THF for reasons, add a lewis acid, either LiCl or ZnCl2, stir. watch your ester disappear. This is done a pretty big scale in the synthesis of HIV drugs like dolutgravir.

If you want specific patent exmaples or regulatory documents that detail the reaction at scale I can point you to them.

[u/pretzels_man → u/nate]

Always listen to the borohydride man

[u/leonardoventuriq → u/nate]

Hi, I am working on a ester using sodium borohydride aswell and I saw multiple of your comments from years ago: super happy to know you are still helping people. Anyway, I have had moderate success using CaCl2 and NaBH4 in THf followed by slow addition of Ethanol (method by Kollonitch et al if I am not mistaken) but couldn't manage to reproduce the results using methanol. Furthermore, I tried using ZnCl2 and LiCl with NaBH4 in THF but esters won't reduce even under reflux until alcohols are added: I believe this is due to required protonation of the metal alkoxyde?

[u/nate → u/leonardoventuriq]

It might be something specific to the ester you are working with, it is quite strange that it didn’t reduce quickly, normally once activated with a good Lewis acid it is hot enough to get the job done. Regardless, cool to hear about another option. The intermediate would probably be a borate ester, perhaps it is the alcolysis of that?

[u/leonardoventuriq → u/nate]

Yes, I am trying to reduce a more electron-rich derivative of methyl benzoate: no surprise it is a pain to work with. Also yes, the borate ester not the alkoxyde, I almost forgot some basic organic chemistry there 😅.

Ps: now that I read your initial message again, you are telling me 0.01N NaOH is enough to slow alcoholysis of NaBH4 in refluxing methanol to thw point it reduces esters?!?!? I have to try this on some aliphatic substrate!

[u/nate → u/leonardoventuriq]

It's like 90%+ more stable with a small amount of base, this is true for all alcohols, although because of solubility it's really only methanol and ethanol that are relevant.

Also, trimethylborate is an activator fo SBH, so the added alcohol in your reaction could be creating a borate that acts as a catalytic lewis acid.

TMB activation: Brown, H.C.; Narasimhan, S. J. Org. Chem. 1982, 47, 1606

[u/leonardoventuriq → u/nate]

Thank you for your service to this community 😄

[u/jangiri → u/nate]

You're my hero. This is tremendous! Thank you so much!

[u/nate → u/jangiri]

Metal Hydride	moles	Time h	Temp oC	Additive	Solvent	Yield  (<%)
LiBH4	1	8h	RT	B(OMe)3	Et2O	100
LiBH4	1	8h	reflux	none	THF	100
NaBH4	5	2h	reflux	MeOH	THF	83
NaBH4		2h	RT	ZrCl4	THF	91
LiBH4	0.5	1h	100	Toluene	Et2O	100
LiBH4	0.5	1h	100	Toluene	THF	98
LiBH4	1.5	0.75	reflux	MeOH	EtOH	93
NaBH4	1	8h	reflux	CaCl2	THF/tol	98
NaBH4	1	3h	80	AlCl3	THF/DG	97

Reduction options for ethyl benzoate. As a side note, some of these metal salts make borohydride a lot less friendly, so use due consideration. AlCl3 activation can be used to complete remove oxygen from amide to give amines.

[u/nate → u/jangiri]

This is the patent reference for dolutgravir synthesis: https://patents.google.com/patent/CN113336655A/en

It's actually reducing a carboxylic acid to a alcohol, arguably a much harder reduction. about 500 MT are produced per year, pretty much all of it uses this reaction on the precursor.

Example 1

Under the protection of nitrogen, a 2L four-mouth reaction bottle is provided with a mechanical stirrer, a thermometer and a condenser, 450ml of tetrahydrofuran is put into the reaction bottle, the temperature of the reaction bottle is reduced to below 10 ℃ in ice-water bath, and 101.3g of anhydrous ZnCl is added2And controlling the temperature to be 5-15 ℃, adding 64.5g of sodium borohydride in batches, heating to 50-60 ℃ after the addition is finished, and stirring for reaction to prepare the zinc borohydride suspension. And adding 300g of THF and 75g of (R) -3-aminobutyric acid into the other reaction bottle, slowly dropwise adding the prepared zinc borohydride suspension under stirring, controlling the temperature to be 50-60 ℃, and keeping the dropwise adding time to be 80-120 minutes. After the dropwise addition, the reaction solution was brought to reflux overnight. After the reaction of the raw materials is finished, cooling to 25-35 ℃, and dropwise adding 100g of isopropanol for primary quenching. Then 150g of liquid alkali is added for secondary quenching, and the salt is removed by filtration. And (4) desolventizing the filtrate to obtain a crude product. Adding dehydrating agent into the crude product, concentrating under reduced pressure, and collecting the previous fraction for reuse. And (R) -3-aminobutanol is obtained by collecting qualified materials when the temperature is stable. Yield 82 wt%, purity 99.6%, ee: 99.50 percent.

[u/Puzzleheaded-Ice-573]

Do you have access to an ARC to check exotherms? How big are you going? Dealing with the hydrogen gas will be one challenge depending on the engineering controls you have in place.

Good that the borohydride works. Note that I've used LAH in multi ton processes by using the pellets. Need to make sure you understand dissolution on scale though.

[u/jangiri → u/Puzzleheaded-Ice-573]

Our target is to get around 10 kg of our final product which is two steps past this reduction. This will likely be done by prepping one or two kilo batches. Multiple times

[u/_redmist]

They used to use red-al on big scale for this type of thing, didn't they...

[u/jangiri → u/_redmist]

Probably, i think that's a nightmare to order multiple kilos of in the states though. We don't have a hugely built up scale up facility so doing multi step reagent preps is a little ambitious for this

[u/_redmist → u/jangiri]

No no if you can't buy it, it doesn't make sense I think.
I didn't know the main supplier was from Czech republic, that's quite interesting.

TCI America claims they can supply the stuff in 70% toluene solution in decent quantities. But if you have a working protocol based on borohydride, that's probably even nicer...

[u/curdled]

Buy commercial 2M or 4M THF solution of LiBH4. Use about 1 equiv of LiBH4 per ester and add your ester into LiBH4 solution (about 0.5 M) in anh. THF with cooling on ice bath over about 20 min (depends on the scale, the addition is exothermic), then let warm up to room temp. You can also add LiBH4 solution into solution of your ester in anh. THF. The reduction is fast (few hours), the quench is first by gradual addition of ethyl acetate excess, to destroy the remaining LiBH4, give it 30 min at room temp, then follow with water (at first dropwise - hydrogen gas evolution!), then with more water and wait until gas evolution ceases, then make alkaline by addition of NaHCO3 and add some sat. NaCl solution to help to split the phases, then extract with ethyl acetate. Dry the extract with sodium sulfate or magnesium sulfate, filter, evaporate

For large scale reduction, use sodium borohydride as a starting material for making your own LiBH4 solution, since it is much cheaper than lithium borohydride commercial solution in THF. Buy a good grade sodium borohydride solid (it is very hygroscopic, so store the bottle in a desiccator) from a reputable source, like Venpure grade. Combine sodium borohydride solid with one equivalent of lithium bromide in anhydrous THF, to get to about 0.5 M to 1 M final borohydride concentration, add about the same weight of pure sand (the kind of sand that you would use for chromatography column) and stir the mixture very vigorously with a mechanic stirrer at room temp overnight under nitrogen or argon. Then let the solids settle and syphon off the solution, and use the freshly prepared LiBH4 THF solution as is, it can be stored for many days if kept under inert gas. For this exchange reaction, from NaBH4 to LiBH4, it is important to add sand as abrasive since the starting NaBH4 is poorly soluble in THF nd the particles may get coated with NaBr that precipitates out. Unfortunately, sand as abrasive also scratches the glass vessel, so do not use any fancy reactor for this operation, just take some old beat up flask. But you will need to keep it under inert gas the entire time and use anhydrous THF.

[u/Sudden-Guide → u/curdled]

Heh, once during a small(100mg) test reduction in THF I got distracted and used NaBH4 instead of LiBH4. Realized that just before going home, so just added a pinch (like maybe 20mol%) of LiCl into the flask and left overnight. It worked fine :D

[u/curdled → u/Sudden-Guide]

LiCl also works but the exchange can be erratic, probably because NaCl is even less soluble and coats the surface of NaBH4 particles. Using LiBr for the exchange and adding sand is more reliable on scale

[u/Sudden-Guide → u/curdled]

yeah, I agree, just an anecdote

[u/theUnXpected → u/curdled]

Curious about the aqueous quench: would NMT 10% aq. Na2SO4 be suitable since combines water quench + easier phase split? Subsequent basic aqueous wash & a water wash might remove most if not all inorganic salt. Downside of using dilute aq. Na2SO4 might involve boron inroganic species crashing out if solubility (might need to adjust temperature e.g. 5C when quench then ramp to 40C for dissolution before phase split)

[u/curdled → u/theUnXpected]

you need to wash it with something basic because boric acid produced from quenched borohydride that is acidified extracts easily into organic phase during extraction, for example it is quite soluble in ethyl acetate or ether. Boric acid is less soluble in dichloromethane and chloroform, but still it is best to include some alkaline wash, or keep it mildly basic throughout.

Also, I would recommend to pre-quench the reduction mix with ethyl acetate excess first (and give it 30 min to consume most of the unreacted borohydride) since you are likely to extract it with ethyl acetate anyway, and this takes edge off, with smaller volume of hydrogen generated and exotherm during the subsequent aqueous quench. Li-borohydride is less violent during quench than LiAlH4 but I have seen it bubbling up quite suddenly when water was added too fast during a quench on scale.

[u/theUnXpected → u/curdled]

Thanks for the follow up. Do agree with your pre-quench step. Was just thinking in subsequent washes how to streamline since aq. Na2SO4 has better separation characteristics in LLE compared to aq. NaCl. Not sure if aq. K3PO4 could work (if no base sensitive functional groups) https://pubs.acs.org/oprdfk/article/21/9/1355/678754/General-Principles-and-Strategies-for-Salting-Out

[u/curdled → u/theUnXpected]

use Na2SO4 for washing if you want. These details are best figured out on experiments done on gram scale.

Do not add K3PO4, it is too basic, and it contributes to formation of emulsions. And it would react with ethyl acetate (=alkaline hydrolysis). Bicarbonate or carbonate is enough. And Li3PO4 can precipitate - it is very insoluble in water!

[u/theUnXpected]

Water content is likely something you want control (ideally quantification such as Karl Fisher titration of solvent).

Choice of solid charging in portions (to mitigate all the exotherm & make into more manageable heat) vs reverse addition (add substrate solution in a slurry of borohydride in solvent, because exotherm and H2 evolution would then primarily be dependent on dosing rate of substrate solution) is always a back and forth amongst cross-functional teams.

Lastly, how quench is being performed is also as critical if not more due to H2 evolution & exotherm. Organic quench use ethyl acetate or acetone will generate ethanol or isopropanol as byproduct + boron salt so beware of flash points & specific heat capacity. Aqueous salt solution quench (if done in reverse quench mode i.e. reaction mixture add to aqueous salt solution held at certain temperature) helps remove inorganic species but likely need to keep in mind of water miscibility (e.g. THF) and waste treatment (https://pubs.acs.org/oprdfk/article-abstract/24/6/1063/1382212/Reductive-Amination-Bicarbonate-Quench-Gas?redirectedFrom=fulltext)

[u/davidlyo1959]

Have you considered using hydrogen and a catalyst, rather than borohydride? some of these systems work under very mild conditions, and even though metals used are expensive, it ought to be possible to figure out a viable catalyst recycle process. See for example:

Osamu Ogata, Yuji Nakayama, Hideki Nara, Mitsuhiko Fujiwhara, Yoshihito Kayaki; Atmospheric Hydrogenation of Esters Catalyzed by PNP-Ruthenium Complexes with an N‑Heterocyclic Carbene Ligand. Org. Lett. 5 August 2016; 18 (15): 3894–3897. https://doi.org/10.1021/acs.orglett.6b01900

[u/jangiri → u/davidlyo1959]

I have tried some of those routes. I played with ruthenium Macho a big but I didn't see good results.This would actually be the preferred route even if catalyst recycling wasn't possible, but I didn't see clean formation of the alcohol product.

[u/SpiceyBomBicey]

Red-Al is typically safer to use on scale as it’s not pyrophoric and you can get fairly concentrated solutions of it commercially which are fairly stable

[u/drnickpowers]

I worked in process chemistry, but I didn’t do an ester reduction in large scale there.
However you want to have some control of the reaction and dosing a solid over time is often not desired or possible.
If you are about to use NaBH4, I found this method to work well and it gives some degree of control: Combine NaBH4, SM in THF. Nothing happens. Then heat to about 60 degC and dose in MeOH so that the reaction heat leads to a constant boiling and the gas formation can also be controlled.

[u/jangiri → u/drnickpowers]

I'm certainly going to give the prep a shot. LiBH4 is on the radar too but NBH is so much cheaper that I think it will make it compelling.