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| | From:  MikeKL5 (Original Message) | Sent: 12/30/2004 10:49 PM |
Hey Steve,
The semester is over, and I made it out of Advanced Synthesis with both an "A" and an opportunity to do research in one of the professors labs. So all in all, things went well. :-)
I am currently working on said research, and I've run into a reaction that I can't figure out. We're working on improving the synthesis of a radioactive compound (18FMAU) that is already in use in PET imaging of cancer. Basically what we're trying to do is to figure out some way of getting the radioactive fluorine onto a the thymidine nucleoside at C2'. Currently, the radioactive fluorine must be added to the sugar ring before the nitrogen base. During the time it takes to add on the nitrogen base to the sugar ring, and purify the product so that it can be injected into somone, much the radioactive fluorine (which only has a half-life of 110 min) decays. If the radioactive fluorine could be added on to the competed nucleotide then there would not be all this wasted compound.
Anyway, I am trying to understand the existing technology in use which is used to make 18FMAU. The synthesis of it is detailed in the article "Synthesis of 2'-deoxy-2'-[18F]fluoro-beta-D-arabinofuranosyl nucleosides FAU, FMAU, FBAU, and FIAU as Potential PET Agents for Imaging Cellular Proliferation.", published in the journal called Nuclear Medicine and Biology, 2003, 30: 215-224. The first step of the synthesis, described on page 18, is described as follows:
"The target [18O] water containing the [18F]fluoride (~300 microliters) was collected directly into a 1.7 mL v-vail containing 50 microliters of butanediol (sic) and 10 microliters K2CO3 (6.5mg/mL). To this mixture was added 1 mL of anhydrous MeCN and the water was removed by azeotropic distillation at 120 C aided with a stream of argon gas. Two additional 0.8 mL aliquots of MeCN were added and also removed at 120 C with Ar flow to assure complete azeotropic removal of water. To the resulting oily residue was added 10 mg of 2-O-(imidazolylsulfonyl)-1,3,5-tri-O-benzoyl-alpha-D-ribofuranose,
in 60 microliters of MeCN and KHF2 in 10 microliters of 1% AcOH" The paper goes on to say that the mixture was refluxed, and eventually 2'-deoxy-2'[18F]fluoro-1,3,5-O-benzoyl-alpha-D-arabinofuranose.
Basically, this whole hoo-ha describes the replacement of the of the hydroxyl group at C2' by a radioactive fluorine atom. However, I have no idea what reaction is going on here that replaces that hydroxyl with the fluorine atom. And what is the deal with the KHF2, and its non-radioactive fluorines? Is this reaction giving a mixture of products, and if so, what are they?
Any and all help is deeply appreciated! I'm sorry that this letter is so long, but I couldn't see how to explain the problem in less space. :-) Hope you're having a nice holiday.
Sincerely,
MikeKL5 |
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| | | From: ·Steve· | Sent: 1/3/2005 12:59 AM |
Hi Mike, Happy New Year! I'm gradually getting back into "chemistry mode" after the holidays. I'm not sure at the moment about the details of the reaction of alcohol groups with KHF2, but I would assume that the mechanism is essentially that of the reaction of ROH with HX, where KHF2 is preferred as a safer form of HF. Is the reaction of KHF2 with the C-2' OH group of ribose stereospecific? Or do you start with an arabinose ring and get inversion at C-2' ? I am also curious to know what happens when the completed oxy-nucleoside is reacted with KHF2, although I understand that this unfortunately does not give the desired product.
In your quote, [18O]water was mentioned: "The target [18O]water containing the [18F]fluoride..." Is this [18O]water a "leftover" from the synthesis of [18F]fluoride ion? Perhaps the [18F]fluoride ion exchanges with fluoride from the added KHF2, in which case the isotopic abundance of 18F in the KHF2 would be less that 100% unless the [18F]fluoride is in large excess relative to KHF2.
From this paper it looks like an O-imidazolylsulfonyl group, not an OH group, gets replaced by the fluorine, presumably in SN2 fashion, because they start with a ribose ring and wind up with an arabinose ring, if I read that right. Which takes me back to square one about the reaction of alcohols with KHF2, perhaps that does not work after all! From your studies, you probably know more about this than I do.
So far I'm not much help on this one! But please do keep me posted; maybe I can make sense out of some of it, or at least be a good sounding board!
Steve
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| | | From: MikeKL5 | Sent: 1/4/2005 10:59 PM |
Hey Steve,
Thanks for your help, and I thank you for offering to help me out in
the future. The 18-O in the 18-O water is the target for whatever particle
it's hit with (I honestly don't know) that it turns it into 18-F. I do know
that 18-F has a half life of ~110 min, and decays by positron emission,
which I assume is why it's used in PET scans. So this 18-O water is
eventually transformed into 18-F hydrogen fluoride via a nuclear reaction.
Also, I was told by my professor yesterday that the fluorine atom
bonded to the 2' carbon must be in the arabino configuration, and that if
the fluorine is placed in the ribo position then it has the potential to
inhibit rNDP Reductase. This enzyme converts ribonucleotides to
deoxynucleotides for DNA synthesis, so inhibiting this enzyme would probably
be bad. :-) My professor didn't cite the research that showed that
2'-fluoro-ribonucleotide analogs inhibit rNDP Reductase, but it makes sense
that they should.
The problem that has been given to me to solve is that currently it
takes approximately three hours to make the particular compound used in the
PET imaging of cancers. These cancers have been injected with something
(probably a plasmid, the papers that I've read aren't very specific about
it) that causes them to express high amounts of Herpes Simplex Virus Type 1
Thymidine Kinase. The compound used in the PET imaging is
1-(2'-deoxy-2'-18fluoro-beta-D-arabinofuranosyl)-5-methyluracil (18-FMAU).
The HSV-1-tk phosphorylates the 18-FMAU, and traps it in the malignant cell.
Thus the tumor shows up in the PET scan. Anyway, since the half life of 18-F
is only 110 min more than half the 18-FMAU has been converted to inert FMAU
by the time it's injected into the patient. If a faster way can be found to
make 18-FMAU starting from H18-F then more patients can be treated than can
be presently done. The modern method takes three hours to make enough
18-FMAU to image two patients sequentially.
The problem is that fluorinating any nucleoside at C2' such that the
fluorine ends up in the arabino configuration is damn near impossible, yet
we're going to investigate whether or not it can be made to happen. What
we're going to try to do is to take 5'-DMT-2'-tBDMS-ribouridine, protect C3'
with a benzoyl group, remove the 2'-tBDMS with (n-Bu)4NF, and then add a
triflate group to C2'. We expect to get
3'-O-benzoyl-5'-DMT-2'-trifluoromethylsulfonyl-ribouridine in decent yield.
Once we have this compound we're going to attempt to fluorinate the 2'
carbon by bimolecular nucleophilic substitution using essentially the same
reagents and strategy used in the current synthesis: KF, and Cryptand 2.2.2
in DMF solvent at ~ 100 deg C. (BTW, the source for most of this information
can be found in Nuclear Medicine and Biology, 2003, 30: 215-224)
I honestly don't think that we're going to get high yields out of the
current protocol. I don't think that we can jack up the reaction conditions
to favor Sn2 more than we already plan to...at least, I don't how we could.
Polar aprotic solvent, cation ligand, and one of the best leaving groups
known to modern chemistry...I don't know how to make it better than that.
I'll be sure to let you know the eventual yield of FMAU that we get. If you
know any Sn2 or fluorination tricks that I don't, please let me know! lol!
I'll keep you posted. Thanks in advance for any suggestions, comments,
criticisms, etc that you may have. Any input is good. :-)
MikeKL5
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| | | From: Chris | Sent: 1/7/2005 3:05 PM |
phoe.. sounds quite complicated there :) although re-reading it.. not directly knowing about what kinda compounds ure discussing.. i can get the big picture though.. that looks like an interesting research subject.. hope ure team reaches the goal of trying to reduce the synthesis time of such radiactive F compound for PET scans. |
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