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Method for synthesis of NR

nicotinamide riboside

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#1 wolfeye

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Posted 25 December 2017 - 08:59 AM


 

Synthesis of β-Nicotinamide Riboside Using an Efficient Two-Step Methodology.

A two-step chemical method for the synthesis of β-nicotinamide riboside (NR) is described. NR has achieved wide use as an NAD+ precursor (vitamin B3) and can significantly increase central metabolite NAD+ concentrations in mammalian cells. β-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). 1 H NMR showed that the product was formed with complete stereoselectivity to produce only the β-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly β-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar.

PMID:29275540
 

 

 

 

 

 
 

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#2 stefan_001

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Posted 25 December 2017 - 09:53 AM

I think they filed some IPR on this.This is pure NR, so needs to be stored in the freezer. You probably noticed that one of the two authors is Anthony Sauve, looks like defensive move or potental improvement in efficiency for NR production in the future.

 

You can also find this mentioned in the paper:

Conflict of Interest:

Cornell University and Anthony Sauve receive
royalties on commercial sales of nicotinamide
riboside by Chromadex Inc. Anthony
Sauve has intellectual property related to uses
and derivatives of nicotinamide riboside. Anthony
Sauve is a co-founder and equity holder
in Metro MidAtlantic Biotech LLC.


Edited by stefan_001, 25 December 2017 - 09:54 AM.


#3 Michael

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Posted 25 December 2017 - 11:52 PM

I think they filed some IPR on this.This is pure NR, so needs to be stored in the freezer. You probably noticed that one of the two authors is Anthony Sauve, looks like defensive move or potental improvement in efficiency for NR production in the future.

 

You can also find this mentioned in the paper:

Conflict of Interest:

Cornell University and Anthony Sauve receive
royalties on commercial sales of nicotinamide
riboside by Chromadex Inc. Anthony
Sauve has intellectual property related to uses
and derivatives of nicotinamide riboside. Anthony
Sauve is a co-founder and equity holder
in Metro MidAtlantic Biotech LLC.

 

To be clear, this is the inventor of Cornell synthesis method licenced by CDXC.

 

https://www.prnewswi...-125478993.html

https://chromadex.com/patents/

 

Purifying it is separate from synthesis.

 

Interestingly, he also has a patent on an NMN synthetic route.

 

https://patentscope....Id=WO2016160524


Edited by Michael, 25 December 2017 - 11:58 PM.

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#4 MikeDC

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Posted 02 January 2018 - 01:40 AM

I think they filed some IPR on this.This is pure NR, so needs to be stored in the freezer. You probably noticed that one of the two authors is Anthony Sauve, looks like defensive move or potental improvement in efficiency for NR production in the future.

You can also find this mentioned in the paper:
Conflict of Interest:
Cornell University and Anthony Sauve receive
royalties on commercial sales of nicotinamide
riboside by Chromadex Inc. Anthony
Sauve has intellectual property related to uses
and derivatives of nicotinamide riboside. Anthony
Sauve is a co-founder and equity holder
in Metro MidAtlantic Biotech LLC.


To be clear, this is the inventor of Cornell synthesis method licenced by CDXC.

https://www.prnewswi...-125478993.html
https://chromadex.com/patents/

Purifying it is separate from synthesis.

Interestingly, he also has a patent on an NMN synthetic route.

https://patentscope....Id=WO2016160524

The method to synthesize NR could be used as starting step to synthesize NMN. Eventually ChromaDex will sell both.
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#5 Chris Pollyanna

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Posted 03 January 2018 - 06:18 PM

Hiya,

 

Just noticed this on Pubmed: 

Synthesis of β-Nicotinamide Riboside Using an Efficient Two-Step Methodology.

https://www.ncbi.nlm...pubmed/29275540

 

Now the abstract is all gobbledygook to me, but it might mean that cheaper NR could be on the horizon?  :)  (or maybe how Basis is getting their new supply??)

 

Chris


Edited by Chris Pollyanna, 03 January 2018 - 06:19 PM.

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#6 Oakman

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Posted 03 January 2018 - 06:31 PM

Verly interesting..... another piece in the puzzle?


Edited by Oakman, 03 January 2018 - 06:32 PM.


#7 Supierce

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Posted 03 January 2018 - 07:39 PM

And they aren't alone. Here's another one from Proctor and Gamble:

 

Method For Preparing Nicotinamide Riboside 
US 20170121746 A1
 

Edited by Supierce, 03 January 2018 - 07:40 PM.


#8 smithx

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Posted 03 January 2018 - 08:24 PM

The difficulty is not in producing NR. The difficulty is in producing NR-Cl.

NR-Cl (what Chromadex calls "Niagen") is an easy-to-work-with powder which stays a powder. NR is extremely hygroscopic, and absorbs moisture from the air, quickly becoming a sludge.

So if you see another method to produce NR-Cl, then Chromadex could be in trouble (if it's a cheaper, more efficient method).
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#9 Daniel Cooper

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Posted 03 January 2018 - 10:56 PM

Excellent.

 

 

 

 

 

 



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#10 Daniel Cooper

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Posted 03 January 2018 - 11:24 PM

The difficulty is not in producing NR. The difficulty is in producing NR-Cl.

NR-Cl (what Chromadex calls "Niagen") is an easy-to-work-with powder which stays a powder. NR is extremely hygroscopic, and absorbs moisture from the air, quickly becoming a sludge.

So if you see another method to produce NR-Cl, then Chromadex could be in trouble (if it's a cheaper, more efficient method).

 

 

Once you get NR is it really that difficult to form it into a salt?


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#11 smithx

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Posted 04 January 2018 - 01:24 AM

Once you get NR is it really that difficult to form it into a salt?


I think the difficulty is doing it in a way that doesn't violate their patents.

#12 Michael

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Posted 04 January 2018 - 09:18 PM

As explained here, this is not likely a new way to synthesize NR, and it's almost certainly no threat to CDXC. Chris, with your permission, I'll merge this thread into the existing one on this subject.
 

The difficulty is not in producing NR. The difficulty is in producing NR-Cl.

NR-Cl (what Chromadex calls "Niagen") is an easy-to-work-with powder which stays a powder. NR is extremely hygroscopic, and absorbs moisture from the air, quickly becoming a sludge.

So if you see another method to produce NR-Cl, then Chromadex could be in trouble (if it's a cheaper, more efficient method).


What you say all seems to be widely believed here, and almost none of it is true ;) . The trick is is, in some part, the synthesis of NR: CDXC appears to have licensed both Sauve's method through Cornell and a fermentative method. There are at least two other patented methods, and so if you want to play in th eNR space you're going to have to either license one, or come up with a novel route — or wait for the patents to expire.

 

And the trick is not in producing NR-Cl per se: plenty of unstable, hygroscopic NR-Cl salts have been produced for 50 years, but none are patented because they're useless. The trick is to make a stable, crystalline, pharmaceutically-acceptable salt. As explained in this GSK patent:
 

The first chemical synthesis was accomplished by Todd and coworkers in 1957 … [who] produced NR chloride as a mixture of α- and β-anomers about the glycosidic linkage in an approximately 1 : 4 ratio. The product was described as a hygroscopic oil that could not be crystallized. Other investigators who isolated NR chloride from biochemical sources also described it as a hygroscopic oil … Significantly, biochemical syntheses should have produced only the natural β-anomer, though the exact stereochemical arrangement was not determined. Later reports confirmed the hygroscopic, amorphous nature of NR chloride ...
 
Other groups investigated alternative NR anions. One synthesis described the anomerically pure NR bromide salt as crystalline, but the product was not adequately described to ascertain whether the material was truly crystalline or merely an amorphous solid. … Subsequently, other NR salts were prepared and solids were obtained, though they were never described as crystalline ...

Previously described NR salt preparations are amorphous NR and extremely hygroscopic, becoming sticky solids within seconds or minutes and collapsing to oils within hours at ambient temperature and humidity. Maintaining the amorphous salts as solids required storing them under a dry atmosphere, or keeping them frozen at approximately -20°C. Importantly, the oily mixtures decomposed significantly over the course of one day at ambient temperature. This property presents a major challenge for isolating and handling NR salts. It also makes it difficult to specify the purity of an NR preparation, because some handling under ambient conditions is inevitable during analysis or use. Ease of handling and purity are important parameters for a substance that might be manufactured for human consumption. These are also important considerations for a substance that will be used for any subsequent purpose, for example as a synthetic intermediate for another chemical transformation, as a biochemical reagent, as an analytical standard, or for any other use where chemical purity and stability are desired. …

 

Furthermore, while several of the previously described preparations of anomerically pure NR salt crystals have been bromide rather than chloride salts, bromide salts may be unnecessarily toxic or otherwise undesireable as a pharmaceutical salt form compared to corresponding chloride salts. ...

The present invention describes the preparation and characterization of two distinct crystalline forms of nicotinamide riboside chloride.



#13 Daniel Cooper

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Posted 04 January 2018 - 09:35 PM

Is NR Sulfate or some other salt an option and has any investigated it?

 

 


Edited by Daniel Cooper, 04 January 2018 - 10:09 PM.


#14 Michael

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Posted 05 January 2018 - 10:26 PM

Is NR Sulfate or some other salt an option and has any investigated it?

 

Read the patent quote ;) .



#15 Dharmaless Dharma

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Posted 20 January 2018 - 02:19 AM

Why is the discussion always about NR when you can take NAD+ itself?


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#16 stefan_001

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Posted 20 January 2018 - 11:45 AM

Why is the discussion always about NR when you can take NAD+ itself?

 

for starters where do you buy NAD+ supplements? And note the pharmacokinetics.

 

For the reasons discussed
below, we believe the evaluation criteria
weigh against
placing NAD on the list of bulk drug
substances that can be used to compound drug pr
oducts in accordance with section 503A of the
FD&C Act (503A Bulks List)

 

NAD is a dinucleotide coenzyme found endogenously in animals and humans. 
The bulk substance substantially degrades when
exposed to light, moisture, alkaline pH, or
standard room temperatures; therefore, it will not
be stable under ordinary storage conditions.

 

Gross and Henderson (1983) assesse
d intestinal contents (fluid and tissue) following oral dosing
of
14
C labeled-NAD using a vascularly perfused rat
intestine model and a whole in vivo rat
model (unspecified dose and number of animals).
The decline of labeled-NAD in the intestinal
fluid and the increase in hydrolysis products in
intestinal tissue after dosing was interpreted to
mean that NAD was absorbed and converted to
nicotinamide riboside and nicotinamide.

 

Overall, the nonclinical
safety data for NAD are inadequate to evaluate
NAD, particularly for treatment of a chronic
condition.

 

https://www.fda.gov/...e/ucm553368.pdf



#17 Dharmaless Dharma

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Posted 21 January 2018 - 09:13 PM

Well, Im not sure everyone would agree with that conclusion.  I do appreciate you sending that link, it is interesting, as I wonder if the FDA is truly trying to limit bulk access to NAD?



#18 stefan_001

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Posted 21 January 2018 - 10:00 PM

Well, Im not sure everyone would agree with that conclusion.  I do appreciate you sending that link, it is interesting, as I wonder if the FDA is truly trying to limit bulk access to NAD?

 

Well its an FDA decision, so end of story.
 


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#19 Dharmaless Dharma

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Posted 22 January 2018 - 12:16 AM

I didnt realize that difficulty on compounding could make it be limited as a bulk agent?  It does seem to be all over the internet at this time.   NR does seem to be the way to go at this point in time.  Although I did see sirtuins available as research chemicals...



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#20 Michael

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Posted 23 January 2018 - 08:27 PM

Well, Im not sure everyone would agree with that conclusion.  I do appreciate you sending that link, it is interesting, as I wonder if the FDA is truly trying to limit bulk access to NAD?

 

They're not generically "trying to limit access," but clearly saying (correctly) that there's no reason to authorize its use in compounding, since it's likely useless — certainly as an oral supplement, and there's little evidence yet (and none human, beyond the anecdotal from interested parties) for a benefit of IV.







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