DOB, DOET, etc. from Methoxamine sans LAH or EtNO2

[neuromodulator]

Methoxamine is an injectable prescription drug available in the U.S., the U.K., Australia, Spain and maybe a few other countries to increase blood pressure.  It is quite expensive, but it is not a controlled substance.  (My Physician's Desk Reference makes no mention of its being scheduled in any way in the U.S. at least.) 

Chemically, methoxamine can be described as 1-(2,5-dimethoxyphenyl)propanol-2-amine. 

Here's my idea: 

(1) oxidize methoxamine to 2,5-dimethoxycathinone using Na2Cr2O7 or H2SO4 and CrO3 in acetone or with bleach (NaOCl).

(2) reduce the product with Zn(Hg) and HCl or with NH2NH2 and KOH to yield 2,5-DMA.

(3) react the 2,5-DMA with FeBr3 and Br2 to yield DOB, or with EtCl and AlCl3 to yield DOET, or with HNO3 and H2SO4 to yield DON, etc.

Steps one and two could be combined if red P and iodine were used, but I think that might cleave the methoxy groups.  The other thing I'm not sure about is how to best extract the drug from its aqueous environment or if that is even necessary before beginning step one. 

Also, I have never done this, nor do I ever intend to.  If I had, I obviously would have been able to include a lot more details.

[jim]

You could do a Birch reduction of methoxamine to yield the amphetamine. 

Or you could hydrogenate with a Pd catalyst.

By the way, using chemfinder.com I found methoxamine listed as "1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-4H-carbazol-4-one"

CAS # [390-28-3]

What are you referring to?

[neuromodulator]

I found the drug in a 1996 Physician's Desk Reference.  It is the generic name for Vasoxyl (U.S.) or Vasoxine (U.K.).  The chemical name given in the PDR is alpha-(1-aminoethyl)-2,5-dimethoxybenzenemethanol HCl.  Perhaps chemfinder would give better results using that name of the compound.

[sunlight]

From Merck:

6067. Methoxamine. .alpha.-(1-Aminoethyl)-2,5-dimethoxybenzenemethanol; .alpha.-(1-aminoethyl)-2,5-dimethoxybenzyl alcohol; 2-amino-1-(2,5- dimethoxyphenyl)-1-propanol; .beta.-hydroxy-.beta.-(2,5-dimethoxyphenyl)isopropylamine; .beta.-(2,5-dimethoxyphenyl)-.beta.- hydroxyisopropylamine; 2,5-dimethoxynorephedrine; C11H17NO3; mol wt 211.26. C 62.54%, H 8.11%, N 6.63%, O 22.72%.  .alpha.1-Adrenergic agonist. Prepn: Baltzly et al., U.S. pat. 2,359,707 (1944 to Burroughs Wellcome). Metabolism: A. Klutch, M. Bordun, J. Med. Chem. 10, 860 (1967). Clinical pharmacology: N. T. Smith, C. Whitcher, Anesthesiology 28, 735 (1967); P. D. Snashall et al., Clin. Sci. Mol. Med. 54, 283 (1978). HPLC determn in plasma: I. A. Al-Meshal et al., J. Liq. Chromatog. 12, 1589 (1989). Therapeutic use: P. M. C. Wright et al., Anesth. Analg. 75, 56 (1992); L. Cabanes et al., N. Engl. J. Med. 326, 1661 (1992). Comprehensive description: A. M. Al-Obaid, M. M. El-Domiaty, Anal. Profiles Drug Subs. 20, 399-431 (1991).

Hydrochloride, C11H17NO3.HCl, Vasoxine (Burroughs Wellcome), Vasoxyl (Burroughs Wellcome), Vasylox (Burroughs Wellcome). Crystals, mp 212-216 deg. pKa (25 degC) 9.2. Very sol in water: One gram dissolves in 2.5 ml water, in 12 ml ethanol. Practically insol in ether, benzene, chloroform. pH of a 2% aq soln between 4.5 and 5.5.

THERAP CAT: Antihypotensive.

Yes, you're right, it is interesting.

[PrimoPyro]

Neuromodulator: I tried to PM you about a spinoff topic of this thread, that I don't want to get off topic with here, but you are not accepting Private Messages.

                                                   PrimoPyro
Vivent Longtemps la Ruche!

[neuromodulator]

PrimoPyro:  It should work now.

[Rhodium]

Would the birch reduction really go as planned with those two electron-donating methoxies present on the ring? I'm afraid they would split off (at least one of them), or that they would prevent the ordinary expulsion of the hydroxyl group.

I think a better way would be to halogenate the OH, and then reduce it off using NaBH4/Diglyme or any other reagent known to reduce aliphaic halides to hydrocarbons.

The clemmensen reduction would not work, as the amino-ketone would probably cyclize to a pyrazine (or worse), and that the aromatic methoxies would not survive treatment with refluxing Zn/HCl. Perhaps if the nitrogen was protected and the OH oxidized to the ketone, the Wolff-Kishner reduction would work. Deprotection of the nitrogen would then afford 2,5-DMA.

[neuromodulator]

If reducing the alcohol proves to be problematic, perhaps one could methoxylate it with dimethylsulfate and then brominate to yield BOB DOB.

[Rhodium]

THat could be an interesting avenue to explore, but what about the nitrogen? How do you methylate the alcohol without dimethylating the amine?

[neuromodulator]

Supposedly there is a new, eco-friendly, highly-selective methylating agent called dimethylcarbonate (DMC) that will make methylethers of aliphatic alcohols under the right conditions.  The article says that aromatic amines (anilines) are mono-methylated, but makes no mention of aliphatic amines.  It's probably worth digging up the article, anyway.  I should be near a research university library sometime next week, if this sounds interesting.  For more information, see the link below.

http://cires.colorado.edu/env_prog/chemrawn/abstracts/Memoli.html

Even if DMC does N-mono-methylate BOB DOB, one would in all likelihood still end up with a very potent compound, right? 

[Rhodium]

According to Pihkal, N-methyl DOB is not that interesting even if it is still active.

[neuromodulator]

I'm going to do some more research on DMC and try to find out what it does, if anything, to primary aliphatic amines under the same reaction conditions necessary for the formation of methyl ethers from aliphatic alcohols.