[williamrobinson57]

I no little beyond what I learned in high school regarding chemistry.  I am a person that MUST understand how everything works, and how it was made.  Curiosity has brought me to a page with this process.  I am unfamiliar with some terms such as "stirred suspension", concentrated in "vacuo".  Also, was article describing three seperate methods for the same chemical? 

I'm looking for any type of breakdown, be it partial, or full analysis of my post.  Thank you.




*****8-chloro-1-mehtyl-6-pheny-4H-s-triazolo-[4,3-a][1,4]benzodiazepine

   A stirred suspension of 5-chloro-2[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391mg., 0.001 mole) in tetrahydrofuran (15 ml.) was cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.).  The resulting solution was allowed to warm to ambient temperature and stand for 24  hours.  It was then concentrated in vacuo.  The residue was suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride.  The extract was washed with brine, dried with anhydrous potassium carbonate and concentrated.  The residue was crystallized from methylene chloride-ethyl acetate to give 0.220 g. of crude product of melting point 227-228.5º C. of 8-chloro-1-methyl-6-phenyl-4H-s-triazol[4,3-a][1,4]benzodiazepine.

   Reaction of the 5-chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone with ammonia in methanol also gave 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, but the reaction was slower.  It required more than 2 days to go to completion.

   In like manner, 782mg. (0.002 mole) of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone in methylene chloride cooled in a Dry Ice-methanol bath gave with anhydrous ammonia 515mg. of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 226-227º C.*****

[Arkcon]

It would be hard for us to teach you years of chemistry, a few messages at a time, but I'll define your two terms:

"stirred suspension" means the substance doesn't dissolve, but they continue to do something, while stirring.  Surely you can relate, in some way to this procedure -- not everything you stir dissolves, but you still use it, for example, salad dressing.

"concentrated in vacuo" means they sealed it in a heavy glass container and pumped out the air and evaporating solvent, I'm guessing because heating it to drive off excess solvent would be detrimental, in some way.

Yes, it does look like three different ways to make the same thing.  Patents do that, it lets the patent office know the author really knows their stuff, and prevents others from making it one of those ways and patenting that method.  There may be other, better methods too, those the company keeps secret, and doesn't even patent, so as not to tip their hand.

Like I told you in your other thread http://www.chemicalforums.com/index.php?topic=24534.msg92699#msg92699 patents are not written to be easily understood, or useful for manufacture.

I can relate to the urge to find out everything there is to know about the world around us.  Once, when I was a kid, I jumped out of bed at midnight, and ran to the encyclopedias, (no internet in those days.) I had just realized that I didn't know how TV worked, and that couldn't wait 'til morning.

However, we do kinda have a policy, on these boards, of not giving a layman specific procedures for the manufacture of pharmaceuticals, particularly psychoactive, or addictive ones. http://en.wikipedia.org/wiki/Alprazolam

[williamrobinson57]

Thank you for your response.  My curiousity has driven me to the point of spending $300 on "Encyclopedia of pharmaceutical manufacturing" in order to get a better understanding of what is taking place.  I understand there might be easier ways to make it, but my intention is to understand processes.  Even if I were to have a company develope a method of synthesis, it would cost an arm and a leg for them to divulge information to me.

The policies are understandable, but I must object with the fact that if one were going to try and manufacture alprazolam, they must first aquire an intermediate that would require custom synthesis (due to the fact that it doesn't have a CAS# designated to it).  Custom synthesis can easily hit the $100,000 price range.  I must say that I can figure out a thousand things I can do with 100 grand.  Also, there would have to be extensive planning to enable one to acquire all the chemicals (chloroform, anhydrous ammonia, etc.) and equipment needed to create the intermediate on their own (not to mention a degree in advanced chemistry).  Not to mention that dosing would be almost in possible as well (2mg) without putting it into the form of a pill.  If one were considering starting from scratch, the price tag would seem very discouraging.  Long story short, I'm not asking anybody to teach me to make drugs, but to translate what it actually being said.  I don't seek alternative methods, because this method is publicly available.

Back to the subject at hand... So, from what I read, I suspect that process 2 & 3 are just alternates for the first phase of process 1.  In other words, 2 & 3 will be allowed to cool to ambient temperature, and then concentrated in vacuo.  And so on...  Also, would a higher melting point indicate that a "better' reaction took place?

[macman104]

Long story short, I'm not asking anybody to teach me to make drugs, but to translate what it actually being said.  I don't seek alternative methods, because this method is publicly available.

I think Arkcon's point was that if you want a step-by-step procedure for the synthesis, you won't get it here.  However, if you want an explanation of the chemistry, or the like then you're in the right place.

Back to the subject at hand... So, from what I read, I suspect that process 2 & 3 are just alternates for the first phase of process 1.  In other words, 2 & 3 will be allowed to cool to ambient temperature, and then concentrated in vacuo.  And so on...  Also, would a higher melting point indicate that a "better' reaction took place?

Yes, it is just for the first part.  That is the chemistry part.  The procedure afterwards is fairly common for most organci reactions (dry under vacuum, separation/extraction, purification) and is really more about isolation of only the pure compound without side products and such.  If it had a lower melting point, it may have been from another impurity.  Impurities will lower your melting point.

[DrCMS]

Also, was article describing three seperate methods for the same chemical? 

If you look you see the following:

bromo intermediate in THF is the best
chloro intermediate in THF is slower
bromo intermediate in DCM did not give as clean a reaction

[williamrobinson57]

I noticed that in process one that it says to cool in an ice bath, which to me is distilled water frozen into cubes with excess water creating the bath.  Than you add a saturated solution of ammonia in methanol.  Now, I googled "ammonia in methanol" to get some information on the properties of it and was unable to find anything.  So, how would water, or ice, react with ammonia and methanol.

I believe that the role of the ice isn't to react with the ammonia and methanol, but just to cool THF+intermediate.  I know that anhydrous ammonia has a very low boiling point, and when it reacts with water...  well, i don't know, but I wouldn't want to be the guy to figure it out. 

I don't know much about methanol, but I know that the intermediate is almost entirely soluble in methanol.  So, from my understanding, intermediate reacts with THF, then is cooled, then is absorbed into ammonia/methanol and further reaction as it warms to room temperature.  So, I assume they use water because it allows for a cleaner reaction over dry ice?

[Arkcon]

Most of what you've said in you last posting is incorrect, or misguided.  The ice bath is a bunch of ice, from an industrial ice maker, not DI water, because it's not a reactant -- see, the ice is put into an ordinary hotel ice bucket, then the flask with the reactants is nestled into the crushed ice.  Then methanol saturated with dry ammonia gas (not the soapy cleaning fluid called household ammonia) is added to the THF containing the reactant.

This sort of thing is quite typical in synthetic organic chemistry.  Eventually, the product will be water soluble, but in the process of getting there, intermediates may be too "oily" to mix with water, as you'd expect.  Ultimately, the source chemicals for many pharmaceuticals is petroleum stock chemicals, and you know petroleum products and water don't mix.

Nor should they be mixed -- to be honest, it's been so long since I took organic chemistry I don't really understand the reaction, others may jump in, we have no shortage of bright organic chemistry people on this board.  However, I do know that reactions that involve ammonia and organics often must be scrupulously dry -- that's our jargon for "water free", I do mean the reaction remains "fluid", just that the ether (that's what THF is) and the methanol must not introduce water to the reaction, or it will "soak up" the ammonia with side reactions or react with the organic molecule we're trying to activate.

Your $300 investment in an advanced chemistry text is kinda wasted, for the moment, because you lack the very basics, which took us several years of daily dialog to absorb, and you're not going to glean enough context from a twice a day posting to learn it in this thread.  A further investment, in some basic organic chemistry texts is what you need.

Failing that, lots of basic, and intermediate organic chemistry questions are asked on this boards.  They're a great way to get started, on the path to figuring out these science behind your questions.

[DrCMS]

I noticed that in process one that it says to cool in an ice bath, which to me is distilled water frozen into cubes with excess water creating the bath. 

Yes it's just ice/water to get 0ºC

Than you add a saturated solution of ammonia in methanol.  Now, I googled "ammonia in methanol" to get some information on the properties of it and was unable to find anything.  So, how would water, or ice, react with ammonia and methanol.

No you dissolve bromo intermediate in THF inside a reaction flask.  The reaction flask is lowered into an ice bath to reduce the temperature of the THF solution.  Then ammonia in methanol is added to the reaction flask.  The ice bath is removed and  the reaction mixture warms up to room temperature.

I don't know much about methanol, but I know that the intermediate is almost entirely soluble in methanol.  So, from my understanding, intermediate reacts with THF, then is cooled, then is absorbed into ammonia/methanol and further reaction as it warms to room temperature.  So, I assume they use water because it allows for a cleaner reaction over dry ice?

No see above.

If you thinking of trying this don't bother.  If you can not understand the process as written you will not have the skills needed to do this or other reactions safely.

[williamrobinson57]

If you thinking of trying this don't bother.  If you can not understand the process as written you will not have the skills needed to do this or other reactions safely.

If THF is ether, than I would have a hard time finding necessary supplies to facilitate reaction.  Not to mention bromo intermediate (which requires 7-9 steps, no CAS# = custom synthesis), reaction flask, vaccum dryer, anhydrous ammonia, anhydrous potassium carbonate, methylene chloride.  None of which are readily available to the public.  If I could afford the required items, I could afford to hire a chemist to synthesize for me.

What books would you reccomend for organic chemistry, to get a basic understanding?  It's one thing to develope something new, it's much easier to try and understand something that already exists.  Keep that in mind with reccomendation. 

[williamrobinson57]

This might be old news, but has anybody here tried the virtual chemlab for organic chemistry http://chemlab.byu.edu/faq.php?  Interesting idea.  Anybody no of anything similar to this that would allow you to upload your own chemicals?  This would be a great way for me to trying to synthesize this, while minimizing risk to myself and others.

Maybe uploading my own chemicals is wishful thinking, but I'm sure I can learn something there.  I just want to know if this is worth trying out, or would I be just wasting my time. 

I just realized it was an educational tool intended for educational institutions.  I'm sure it's expensive...  Well, so much for that idea. 

[Arkcon]

If THF is ether, than I would have a hard time finding necessary supplies to facilitate reaction. 

THF is an ether, but it's not ether.   What's commonly called, even by chemists, ether is actually a common member of the class of chemicals called ether, and it's diethyl ether -- that would be CH₃CH₂OCH₂CH₃,  THF is a cyclic aromatic ether, C₄H₈O, which makes it great stuff for synthetic chemistry, being both an ether (that isolated oxygen atom makes it polar, as organics go) and aromatic (and I don't mean it smells nice, I mean chemical aromaticity) *[EDIT]* incorrect, oops.

Not to mention bromo intermediate (which requires 7-9 steps, no CAS# = custom synthesis), reaction flask, vaccum dryer, anhydrous ammonia, anhydrous potassium carbonate, methylene chloride.  None of which are readily available to the public. 

Actually, the lack of a CAS# doesn't mean that at all.  There's no reason a compound lacks a CAS#, except that the company didn't ask for one to be assigned.  We've been talking about this over here:  http://www.chemicalforums.com/index.php?topic=25307.msg95603#msg95603

What books would you reccomend for organic chemistry, to get a basic understanding?  It's one thing to develope something new, it's much easier to try and understand something that already exists.  Keep that in mind with reccomendation. 

We've got some favorites, over here:  http://www.chemicalforums.com/index.php?topic=2414.0  If I were you I'd jump right in with Mitch's first suggestion, he says it's advanced, but you seem to have more drive than the average Junior College burnout I went to school with.  Once you have a book, be sure to check this forum, for questions of others, and see if you can figure them out.

Now, you seem to be concentrating on techniques.  Try and get your hand on The Organic Chem Lab Survival Manual, by James W. Zubrick.  I recently picked this up at a library book sale, wish I had it back in the day.  Lots of good explanations for techniques.

*[EDIT]*
Opps, furan is the aromatic cyclic ether, not THF

[macman104]

THF is an ether, but it's not ether.   What's commonly called, even by chemists, ether is actually a common member of the class of chemicals called ether, and it's diethyl ether -- that would be CH₃CH₂OCH₂CH₃,  THF is a cyclic aromatic ether, C₄H₈O, which makes it great stuff for synthetic chemistry, being both an ether (that isolated oxygen atom makes it polar, as organics go) and aromatic (and I don't mean it smells nice, I mean chemical aromaticity)

One quick note, THF is not aromatic.  It is a completely saturated cyclic compound.

[williamrobinson57]

Great book suggestions.  Your explanation of CAS#'s were right on target.  I guess what I was trying to say is that if you look at the chemical that is the subject of debate, 5-chloro-2[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, is rather complex and I would guarantee that ALL chemical manufacturers won't have that item readily available because of it's limited use.  Also, there are many other simple techniques that I have read about producing alprazolam, 8-chloro-1-mehtyl-6-pheny-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, that don't require this chemical at all.  Sort of renders it useless.  The problem is, you can't find literature on the other processes.  Here is an example of the most detailed explanation that I have been able to find. http://hetchem.blogspot.com/2007/06/synthesis-of-alprazolam.html  For the average Joe, thats nothing but Chineese.

Now, I have done some reading on THF.  That's some dangerous stuff (http://hazmat.dot.gov/pubs/erg/g127.pdf).  At the same websites that give information on it also mention 2-Methyltetrahydrofuran as a green alternative.  Based on what I have read, there wouldn't be an issue substituting this for THF, based on the fact that process 2 omitted THF altogether.  Do green alternatives typically result in higher/lower quality end product, at the cost of an environmentally friendly production method?

[DrCMS]

Also, there are many other simple techniques that I have read about producing alprazolam, 8-chloro-1-mehtyl-6-pheny-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, that don't require this chemical at all.  Sort of renders it useless.  The problem is, you can't find literature on the other processes.  Here is an example of the most detailed explanation that I have been able to find. http://hetchem.blogspot.com/2007/06/synthesis-of-alprazolam.html  For the average Joe, thats nothing but Chineese.

The very last reaction step in this link is the same reaction as you originally asked about.

Now, I have done some reading on THF.  That's some dangerous stuff (http://hazmat.dot.gov/pubs/erg/g127.pdf).

Yeah THF is not good for you, it also smells horrible i detest the smell after using it most days during my Ph.D.

At the same websites that give information on it also mention 2-Methyltetrahydrofuran as a green alternative.  Based on what I have read, there wouldn't be an issue substituting this for THF, based on the fact that process 2 omitted THF altogether.  Do green alternatives typically result in higher/lower quality end product, at the cost of an environmentally friendly production method?

Never tried MeTHF but it might work in this?