Original
synthesis procedure and route
Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives,
Arava Veerareddy, Gogireddy Surendrareddy
& P. K. Dubey,
Volume 43, Issue 16, August 2013, pages
2236-2241
Details of the publication is here: http://newdrugapprovals.org/2015/08/19/gamendazole-a-novel-drug-candidate-for-male-contraception/The synthesis presents few drawbacks:
- - Solvent diversity
- - Use of dihydrogen implying a specific reactor
- - Manganese oxide and Wittig reagent which complicate the isolation
- - Use of an hydride
Optimization
700$/kg cheaper based on kilogram scale (reaction assumed quantitative to facilitate the comparison – see costing) with a shorter route from 9 to 6 steps, reducing the reagent diversity (and probably solvent), avoiding the use of H2, DIBAL-H, MnO2 and Wittig reagent, adopt the Fisher base strategy with 3-methyl Indazole.
But instead of have the precursor of the 3-methyl which involve some reduction / oxidation steps, i have chosen to have it directly with the starting material. It is more expensive, but by reducing the total synthesis from 9 to 6 steps and 3 one pot 2in1, the starting material cost difference should be absorbed. By this way, i can use the “fisher base like behavior” to add the side chain by adding an acetyl on the 2-N. I don’t know the solubility in DME, the solvent process must be modified if it is inadequate. I have take it as reference, since it is used in the first step in the literature, is polar and miscible with water.
The part where i am a little dubitative is
the 5th step with the elimination of the acetanilide. A varia could be the use
of the ethyl glyoxylate directly without a pre-activation by an imine if the
methylene derivative is sufficiently nucleophile, and activate the alpha
hydroxy by a tosylation to afford an E1 type elimination, or make the coupling
(imine-ene reaction) with a Lewis acid.
Lastly, a “step 0” could be added by using the
4-bromo-2-fluoro-(trifluoromethyl)benzene (5.5 cheaper) to obtain the starting
material by an acylation through an organocuprate (obtained by a organozinc).
But since the acetophenone derivative is liquid, an oxime should be prepared
(hoping it is solid) to isolate the compound, which also make simpler the step
of cyclization, by avoiding the 3-amino by product.
References:
Efficient Synthesis of FunctionalizedOrganozinc Compounds by the Direct Insertion of Zinc into Organic Iodides andBromides; A. Krasovski, V. Malakhov, A. Gavryushin, P.Knochel, Angew. Chem. Int. Ed., 2006, 45, 6040-6044.
NewPractical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes andTheir O-Methyloximes with Hydrazine. LUKIN*, K.; HSU, M. C.; FERNANDO, D.;LEANNA, M. R.; J. Org. Chem. 71 (2006) 21, 8166-8172).
References:
Efficient Synthesis of FunctionalizedOrganozinc Compounds by the Direct Insertion of Zinc into Organic Iodides andBromides; A. Krasovski, V. Malakhov, A. Gavryushin, P.Knochel, Angew. Chem. Int. Ed., 2006, 45, 6040-6044.
NewPractical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes andTheir O-Methyloximes with Hydrazine. LUKIN*, K.; HSU, M. C.; FERNANDO, D.;LEANNA, M. R.; J. Org. Chem. 71 (2006) 21, 8166-8172).
Synthetic route
Details:
I think this step could be done in a mix
water/DME in presence of a very weak base like sodium acetate to keep a pH near
5 and below to avoid a hydrazone or make an equilibrium displacement to the
hydrolysis of the hydrazone if there is some in the mixture (see hydrolytic
stability of hydrazones and oximes). A reaction temperature and kinetic study
should be done to ensure an aromatic SN without a cyclization with the
hydrazone.
References:
New Practical Synthesis ofIndazoles via Condensation of o-Fluorobenzaldehydes and Their O-Methyloximeswith Hydrazine. LUKIN*, K.; HSU, M. C.; FERNANDO, D.; LEANNA, M. R.; J. Org.Chem. 71 (2006) 21, 8166-8172.
New Practical Synthesis ofIndazoles via Condensation of o-Fluorobenzaldehydes and Their O-Methyloximeswith Hydrazine. LUKIN*, K.; HSU, M. C.; FERNANDO, D.; LEANNA, M. R.; J. Org.Chem. 71 (2006) 21, 8166-8172.
Naturally 1-N alkylation is the predominant
isomer, but 2-N alkylation occurs at nearly 15 %. This step could probably be chained
with the previous one, and a purification here or later, to eliminate the 2-N
isomer.
Reference:
Synthesis of Novel N1 andN2 Indazole Derivatives ; E-Journal of Chemistry 2012, 9(4),1676-1682.
Synthesis of Novel N1 andN2 Indazole Derivatives ; E-Journal of Chemistry 2012, 9(4),1676-1682.
To ensure a good deprotonation of the
3-methyl, 2-N must be acylated. The resulting salt is probably soluble in DME, depending
the stability and behavior, use AcOCl or Ac2O. My preference would
be Ac2O if sufficiently stable, because the counter ion AcO-
could play the role of base. If the indazolium salt is not soluble, an appropriate
solvent should be found to make it soluble, and this solvent should be also
used for the step 4.
Step
4: Preparation of the imine (13) (optional if the tosylate way is used)
To activate the glyoxylate for the coupling,
preparation of an imine with aniline in DME with azeotropic distillation to
remove the water in presence of sodium acetate and a PTC like aliquat 336.
Reference:
Inspired from personal experience.
Inspired from personal experience.
The imine is activated by addition of Ac2O onto the solution of step 4. Process the coupling by adding dropwise at a determined temperature the solution of step 3. The difficulty here is where will be the double bond: there is the presence of AcONa / AcOH in the mixture, formation of an uncharged molecule with no elimination of the anilide part or elimination of the anilide and the double bond in the good place. To displace the double bond if the anilide remains in place, the mixture could be acidified with AcOH and heated. Once the elimination occurred, make an aqueous basic treatment followed by an acidification to liberate the 2-N and the acid to obtain the targeted molecule.
Varia : If the methylene derivative is
sufficiently nucleophile, the ethyl glyoxylate could be added directly with
maybe LiCl, followed by an activation of the alpha hydroxy group by TsCl which
could lead to an elimination via an alpha carbocation (see reference).
Varia 2: Use a Lewis acid to make the
imine-ène coupling, but to afford the aniline elimination, make an acetylation.
References:
Inspired from personal experience
3-Methyl-2,1-benzisoxazolium, benzisothiazolium, and indazoliumsalts as new active-methyl compounds; Neil F. Haley, J. Org. Chem., 1978, 43(6), pp 1233–1237.
Inspired from personal experience
3-Methyl-2,1-benzisoxazolium, benzisothiazolium, and indazoliumsalts as new active-methyl compounds; Neil F. Haley, J. Org. Chem., 1978, 43(6), pp 1233–1237.
The conditions should be mild.
The product must be of course
recrystallized.
Costing (reaction considered as quantitative to facilitate the evaluation)
Disclaimer:
This is some personal works on paper only, i have no
responsibility in any way if somebody would try this route and has all
sort of troubles, including but not limited to: injuries and money loss.
This is for experienced chemists only, and tests must be conducted in a
suitable lab only.But if my work is used to synthesize the targeted molecule described here, please, send a word, even if it fails, chemistry is always an experimental science. This will make me pleased, thank you.
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