July 20, 2019, 04:11:49 PM
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Topic: How is this reaction done?  (Read 379 times)

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Offline sharbeldam

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How is this reaction done?
« on: June 11, 2019, 02:42:55 PM »
There is this drug called Selexipag which gets active by this reaction in the liver, can someone direct me to what this reaction called (Converting NHSO2R to OH) ? and what is the mechanism of it?

Offline jeffmoonchop

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Re: How is this reaction done?
« Reply #1 on: June 11, 2019, 02:53:46 PM »
Just a guess, is it hydrolysis?

Offline sharbeldam

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Re: How is this reaction done?
« Reply #2 on: June 11, 2019, 03:01:16 PM »
I honestly knew someone was going to say that, but I want a deeper answer, like I know the mechanism of ester hydrolysis, but this is different I guess, No?

Offline Borek

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Re: How is this reaction done?
« Reply #3 on: June 11, 2019, 03:30:10 PM »
If it is vitro most likely some enzyme is responsible.
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Offline sharbeldam

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Re: How is this reaction done?
« Reply #4 on: June 11, 2019, 04:40:13 PM »
the enzyme is carboxylesterase 1 but do you think the mechanism is the same as the ester/amide hydrolysis? as in the nitrogen will be protonated and then the NH2+SO2R become a leaving group just like the OR in ester?

Offline clarkstill

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Re: How is this reaction done?
« Reply #5 on: June 11, 2019, 04:44:01 PM »
I think more likely the latter - the pKa of methanesulfonamide is 17.5 according to Bordwell (https://www.chem.wisc.edu/areas/reich/pkatable/), only 2 units or so higher than an alcohol so you'd expect a similar leaving group ability. I don't think it's plausible that the N becomes protonated - that nitrogen is a terrible base (at least not by specific acid catalysis, i guess a general acid catalysis mechanism is plausible).

Offline David Tan

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Re: How is this reaction done?
« Reply #6 on: June 14, 2019, 04:46:53 PM »
Treat it as an amide and don't let the "sulfoxide" distract you. Just perform an acidic hydrolysis on an amide and you would get the carboxylic acid group. Do the same for this molecule. Hope it helps.
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Offline hollytara

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Re: How is this reaction done?
« Reply #7 on: June 15, 2019, 02:02:36 PM »
This is a mixed imide: one side is a carboxylic acid, the other side a sulfonic acid.  The sulfonamide is the better leaving group.  Bordwell lists pKa of methanesulfonamide in DMSO as 17.5, but other references have pKas that are more acidic (in the range of 4-10).  The phenylsulfonamides can be deprotonated and solubilized in water. 

I could see either ester or amide hydrolysis enzymes working on this.

Offline rolnor

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Re: How is this reaction done?
« Reply #8 on: June 15, 2019, 03:56:31 PM »
Hollytara, I sent you a PM about something, can you please respond, its important.
Thanx.

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