Alternate route proposal for VX-970 Part II
Sulfonyl oxime (19) preparation
Route proposal to (19)
Ways to obtain (14)
The choice of starting material is very prices dependent of the starting material itself conjugated with the process price. There are two available starting materials, (4-iodophenyl)-2-acetic acid at 619$/kg (162.2$/mol), and 4-bromo-N-methyl-benzylamine at 1075$/kg (215.09$/mol). Each route needs a α-arylation of diethylmalonate. The cheaper material needs an oxidative decarboxylation followed by a reductive amination, the other only an amine protection to reach the same stage before the α-arylation. To be competitive versus the bromo derivative, the phenyl acetic derivative must be treated in a one-pot procedure, which is possible.
The other solution would be the phenyl diethylmalonate which is really cheap: actually 9153$/ton, seen 60$/kg (14.18 $/mol) few months ago. A Friedel & Craft with an imidoyle chloride (prepared in situe) of N-methyl formamide give the imine, and make the reduction/N-formylation of the imine instead of a hydrolysis. But due to some uncertainty about solubility, i will only describe the reaction sequence without solvent indications but with an ideal process. The constraints are: “all solubles and compatible solvent with oxalyl chloride and Friedel on Zeolite”.
Method A1 (phenyl diethyl malonate)
Inspired from papers i have read, in the selected solvent, prepare the imidoyle chloride, pump the solution onto the suspension containing (E) and Zeolite to make the Friedel, add formic acid and ammonium formate to make the reduction/protection.
The key here is to find the suitable solvent for the Friedel i think. The shape of the imidoyle chloride is similar to the acetyl chloride shape except for the methyl which is at another place. It must be polar, unreactive versus oxalyl chloride and must have a sufficient high boiling point for the reduction/N-formylation.
References:
Preparation of imidoyle chloride
Friedel & Craft
Some hints on selectivity: Friedel-Crafts acylation of methyl ester of phenylacetic acid: a reinvestigation, Fulvio Uggeri, Claudio Giordano, Adriano Brambilla, Rita Annunziata, J. Org. Chem., 1986, 51 (1), pp 97–99.
Acylation of 2-Methoxynaphthalene over Ion-Exchanged Beta Zeolite, İsmail Cem Kantarli, Dissertation Msc, 2002.
Catalytic activity of the beta zeolite with enhanced textural properties in the Friedel-Crafts acylation of aromatic compounds, R.A. García*, D.P. Serrano, G. Vicente, D. Otero and M. Linares, Studies in Surface Science and Catalysis Volume 174, Part 2, 2008, Pages 1091-1094.
Zeolite coated structures for the acylation of aromatics, A.E.W Beers, T.A. Nijhuis, F. Kapteijn, J.A. Moulijin, Microporous and Mesoporous Materials, 48, 2001, 279-284.
Reduction/N-formylation
A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction, Michael O. Frederick, Douglas P. Kjell, Tetrahedron Letters, Volume 56, Issue 7, 11 February 2015, Pages 949–951.
A convenient method for the N-formylation of secondary amines and anilines using ammonium formate, P. Ganapati Reddy, G. D. Kishore Kumar and S. Baskaran*, Tetrahedron Letters 41 (2000) 9149–9151.
Method A2
There is also a shorter way, but i don’t know if the aromatic ring will be sufficiently reactive, it is probably more feasible in flow chemistry by irradiation with a cartridge (if exist) containing the catalyst and capable of to be irradiated by blue LEDs, or in a batch mode by heating, which is unfortunately less efficient:
Reference:
Method B ((4-iodophenyl)-2-acetic acid)
With this starting material, make a decarboxylative oxidation in aqueous DMF, it should work, this reaction is originally made in aqueous acetonitrile in presence of iodobenzene. Since there is an iodine, it is probably not necessary to add iodobenzene, except if it increases the yield, but if a way of chaining to (14) is found, the yield must be sacrificed. Since this is an oxidation which uses an iodonium specie, it would be prudent to check if the reaction is safe.
For the next step, water must be removed, so the amount of water must be studied. If a true Leuckart is used, which normally occur at elevated temperature, water could be removed by distillation, and without cooling the mixture add the N-methyl formamide and HCOOH.
At this stage, i am very dubitative to not isolate the product due to the use of a catalyst in the next step. If it is possible or if the product is liquid (which it could be the case), i would make a distillation to remove methanol, methyl formate, excess of trimethyl orthoformate if there is, formic acid, followed by a filtration to remove ammonium salt which is not dissolved. If the ammonium salt causes some troubles for the next step, an N-formylation with only HCOOH could be tried.
About the α-arylation, there are three methods i have noticed interesting. I have combined them into one since all, except one, uses Cesium carbonate which is expensive. Also, DMF could maybe be replaced by Acetonitrile.
References:
Decarboxylative oxidation: Novel Synthetic Methodologies for Bioactive Molecules, Part B: Using Reagents like Oxone and Iodobenzene, page 70A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction, Michael O. Frederick, Douglas P. Kjell, Tetrahedron Letters, Volume 56, Issue 7, 11 February 2015, Pages 949–951.
Copper Catalyzed Arylation/C-C Bond Activation: An Approach toward α-Aryl Ketones, C. He, S. Guo, L. Huang, A. Lei, J. Am. Chem. Soc., 2010, 132, 8273-8275.
CuI/L-Proline-Catalyzed Coupling Reactions of Aryl Halides with Activated Methylene Compounds, X. Xie, G. Cai, D. Ma, Org. Lett., 2005, 7, 4693-4695.
A General and Mild Copper-Catalyzed Arylation of Diethyl Malonate, E. J. Hennessy, S. L. Buchwald, Org. Lett., 2002, 4, 269-272.
Method C (4-bromo-N-methyl-benzylamine)
The N-formylation was discussed before, so i will make some precisions only about the α-arylation. I saw essentially this reaction with aryl iodide, with aryl bromide, a Pd catalyst is used. There is one reference where i saw a bromide derivative used with a Cu catalyst, which also use L-proline which give good yield.
References:
Same as above
Method A2 is obviously the cheapest, but involves the use of flow chemistry for better results, and i don’t known if a cartridge designed to contain a catalyst and capable of to be irradiated exist. Method A1 is also cheap, but need some solvent screening for the one-pot and zeolite activity (orientation and yield). Methods B and C must be evaluated, it is hard to say (C is most probably the less expensive), it depends mostly of fixed charges (site cost per time), salary, etc..., B has a distillation in step 1, and in step 2 the use of a methylamine solution, even if the reagents are cheap... If water could be consumed by the trimethyl orthoformate (if there is not a too large amount), it will maybe less expensive than a distillation (time and energy). There is only 50$/mol of difference between the two starting materials. C is the best; B if it is desired to try to scrape the bottom of the barrel.
Alkylation (15)
This is normally a series of reactions which could be chained, but the solvent must be determined by the oxidation (by Oxone®) conditions, again DMF or Acetonitrile. The crown ether has an additional role of side reaction inhibitor from the epichlorhydrin. Due to the presence of an alcoholate after the nucleophilic substitution, the carbonate ion is regenerated, it could be then in a catalytic amount. I think by adding slowly (14) on the mixture, a second alkylation by the Cl displacement could be avoided, or by limiting the reaction temperature to differentiate the reactivity of the epoxide versus Cl.
Reference:
Reactions of organic anions. 86. Sodium and potassium carbonates: efficient strong bases in solid-liquid two-phase systems, Michal Fedorynski, Krzysztof Wojciechowski, Zygmunt Matacz, Mieczyslaw Makosza, J. Org. Chem., 1978, 43 (24), pp 4682–4684.
Cyanation (16) (one-pot possible)
By adding KCN on the precedent mixture, most probably, the SN occurs without any problem, the potassium carbonate should not interfere, and it is also in a catalytic amount. Once the reaction is complete, all solids could be filtered to engage the next step.
KCN is of course not the best reagent, as alternative there is the acrylonitrile (epoxidation with oxone®), which is toxic too, and lastly the epicyanohydrine which is commercially available, but there is the need to find a supplier which could furnish the compound without back ordering.
KCN will most probably used in excess which add a problem of elimination of this reagent. Since there is an oxidation in the next step, a procedure could be elaborated to destruct the excess of KCN by Oxone®, the reagent used to oxidize the alcohol. This sequence must be separated from the alcohol oxidation by adding NaX only after the KCN oxidation and the cyanate hydrolysis are complete.
HCN/CN- has a pKa = 9.2 and HSO5-/SO52- has a pKa = 9. To avoids the presence of HCN in the mixture, the pH must be 10 and above. A solution of K2CO3 10% has a pH=11.6.
There is a need of 5eq of potassium monopersulfate per 2eq of cyanide following these equations:
Oxidation of cyanide ion (fast) |
| eq1 |
Hydrogenosulfate will be neutralized by CO32- (fast)
 |
| eq2 |
Oxidation of cyanate ion (slow)
 |
| eq3 |
 |
| eq4 |
 |
| eq5 |
Balance (2*eq1 + 2*eq2 + 3*eq3 + 2*eq4 + eq5)
There are two functional groups sensitive to basic hydrolysis, Ester and nitrile, they must be considered in the process design (that’s why i use carbonate instead of potassium or sodium hydroxide).
To prepare the mixture for the next step, it must be neutralized with a strong acid like aqueous HCl to a suitable pH for the best reaction condition, starting at pH=pKa of bicarbonate and lower, which also brings a halide ion.
Since Oxone® is not stable above pH=5.75 (Data here), the necessary oxidant quantity for the next step must be added after the neutralization.
About health and safety considerations for the oxidation, since potassium monopersulfate is unstable at pH=11 and starts slowly to decompose, the reactor must be under a continuous nitrogen flow instead of regulated pressure, to dilute all dioxygene produced to be out of the flammable region of the Acetonitrile at the operation temperature (see technical data about Acetonitrile here).
Reference:
Organic synthesis: Special Techniques p80-81 and reference thereinUS patent 8268960 B2 column 4 line 4 to 8 and cited reference: Reaction modes of fluorination of cyclic ethers by potassium fluoride-18-crown-6Y. KaWakami and Y. Yamashita, J. Org. Chem. (1980), 45(19), 3930-2]
Oxidation (17) (one pot possible)
There are plenty of conditions to oxidize an alcohol into ketone with Oxone®, but the key here is the solvent, moreover it will be better if this is in anhydrous conditions for the next step. Thankfully, there is a crown ether 18,6 in the mixture and the counter ion in Oxone® is potassium.
About the solvent, Acetonitrile or DMF should be the best for chaining reactions and limiting the solvent diversity, better yield for secondary alcohol oxidation is showed with toluene unfortunately. With water miscible solvent, water is added to increase the solubility of the oxidant. Also NaBr or TEMPO/nBu4NBr are used, other methods uses an in-situ generated periodinane derivative, which must stay in solution for health and safety considerations, and lastly “wet alumina”.
By reading the paper which describes the wet alumina preparation from super dried aluminium oxide (acidic) (reference1), i think (by reading some other publications) in place of this catalyst, probably a Zeolite or Boehmite could be tried.
Hydration over a long period of γ-alumina (acidic) leads to a transformation of the surface into Bayerite β-Al(OH)3 with a transient amorphous phase. Also, even if in this paper (reference2), the presence of pseudo-boehmite AlO(OH) was not studied (transient amorphous phase), i think a short hydration times conduct to this specie on some sites on the surface. The thermodynamic data of hydration reaction indicated in this paper also show this possibility.
Since in reference1 the hydration is done until the solid has a particular aspect, and obviously not during 1 day or 4 months, most probably this treatment affords aluminium oxy-hydroxide sites AlO(OH).
This specie has a pKa = 6.7, since Oxone® can be used with sodium bicarbonate (pKa=6.37), it probably plays the same role in the mixture (reference3 gives the pKa page H).
Also, “wet alumina” is only filtered, consequently there is water adsorbed on the alumina. Then the water plays a role of solubilization of Oxone® near the reactive sites of alumina, most probably, due to H-bonding as described in reference3, even if the solvent is water miscible, the water’s molecule stays on the alumina surface.
We can then postulate
that Oxone® reaches the surface of alumina through the adsorbed water, and then
there is proton exchange. The alcohol also reaches the surface by H-bonding to
be close to the Oxone®, and lastly, Aluminum atom probably plays a role of
Lewis acid which replaces the role of NaBr or TEMPO/nBu4NBr (C-O-Br
intermediate by HOBr) to activate the alcohol for the oxidation.
Consequently, i would change γ-alumina for pseudo-Boehmite, add a catalytic amount of water which will probably be adsorbed by the catalyst and use acetonitrile as solvent. The already present crown ether 18,6 in the mixture should probably help the reaction kinetic by a preliminary solubilization before Oxone® reaches the surface of the catalyst.
Maybe Zeolite Y after dealumination (USY), but not treated by acidic washes to remove Boehmite at the surface (reference4) could also replace “wet alumina”. Moreover, if it could be grafted by crown ether 18,6 with a linker (reference5 and 6), it could bring to the surface the Oxone® by solubilization (reference7). It will be interesting to see if the Boehmite located to the surface is sufficiently immobilized for near neutral conditions.
Lastly, there is two methods (Reference8, 9, and 10) involving NaCl/ACOEt/Water and NaBr/Acetonitrile/Water.
Conditions:
From reference 8, 9 and 10: Acetonitrile/Water/Oxone®/NaBr
From reference 1: Boehmite or pseudo-Boehmite/Water cat./Oxone®/Acetonitrile
For each, DMF could also be tried.
Since the oxidation could provide byproducts, (17) should be isolated.
If Boehmite or pseudo-Boehmite is used and the oxidation is clean, a simple filtration of the mixture before to engage the next step of oximation. Also, Boehmite could be reused by aqueous treatment to remove mineral salts arising from Oxone® and the oxidation reaction.
Conditions:
From reference 8, 9 and 10: Acetonitrile/Water/Oxone®/NaBr
From reference 1: Boehmite or pseudo-Boehmite/Water cat./Oxone®/Acetonitrile
For each, DMF could also be tried.
Since the oxidation could provide byproducts, (17) should be isolated.
If Boehmite or pseudo-Boehmite is used and the oxidation is clean, a simple filtration of the mixture before to engage the next step of oximation. Also, Boehmite could be reused by aqueous treatment to remove mineral salts arising from Oxone® and the oxidation reaction.
References:
Reference1: Hirano, M.; Oose, M.; Morimoto, T. Oxidation of s-Alcohols with Oxone in Aprotic Solvents in the Presence of Wet-Aluminium Oxide. Bull. Chem. Soc. Jpn. 1991, 64 (3), 1046–1047.
Reference2: Hydration ofγ-Alumina in Water and Its Effects on Surface Reactivity, Grégory Lefèvre, Myriam Duc, Patrick Lepeut, Renaud Caplain, and Michel Fédoroff, Langmuir 2002,18,7530-7537.
Reference3: Ab Initio Molecular Dynamics Study of the AlOOH Boehmite/Water Interface: Role of Steps in Interfacial Grotthus Proton Transfers, A. Motta, M-P. Gaigeot, and D. Costa, J. Phys. Chem. C, 2012, 116 (23), pp 12514–12524.
Reference4: Studies in surface science and catalysis #46, Zeolites as catalysts, sorbents and detergent builders page 103.
Reference5: Functional hybrids materials page 37
Reference6: Organo-lined alumina surface from covalent attachment of alkylphosphonate chains in aqueous solution, Stéphanie Lassiaz, Anne Galarneau, Philippe Trens, Dominique Labarre, Hubert Mutin and Daniel Brunel, New J. Chem., 2010,34, 1424-1435.
Reference7: Synthesis and application of new Schiff base Mn(III) complexes containing crown ether rings as catalysts for oxidation of cyclohexene and cyclooctene by Oxone, Seyed Mohammad Seyedi, Gholam Hossein Zohuri and Reza Sandaroos, Supramolecular Chemistry Vol. 23, No. 7, July 2011, 509–517.
Reference8: Recent advances in the use of oxone® in organic synthesis, Maria Carla Marcotullio, Francesco Epifano and Massimo Curini, Cheminform, June 2005.
Reference9: Oxone/Sodium Chloride: A Simple and Efficient Catalytic System for the Oxidation of Alcohols to Symmetric Esters and Ketones, Agnes Schulze, Georgia Pagona, and Athanassios Giannis, Synthetic Communications, 36, 1147–1156, 2006.
Reference10: Oxidation of benzyl alcohols with Oxone and sodium bromide, Bon-Suk Koo, Chang Keun Lee, andKee-Jung Lee, Synthetic Communications Vol. 32, No. 14, pp. 2115–2123, 2002.
Reference1: Hirano, M.; Oose, M.; Morimoto, T. Oxidation of s-Alcohols with Oxone in Aprotic Solvents in the Presence of Wet-Aluminium Oxide. Bull. Chem. Soc. Jpn. 1991, 64 (3), 1046–1047.
Reference2: Hydration ofγ-Alumina in Water and Its Effects on Surface Reactivity, Grégory Lefèvre, Myriam Duc, Patrick Lepeut, Renaud Caplain, and Michel Fédoroff, Langmuir 2002,18,7530-7537.
Reference3: Ab Initio Molecular Dynamics Study of the AlOOH Boehmite/Water Interface: Role of Steps in Interfacial Grotthus Proton Transfers, A. Motta, M-P. Gaigeot, and D. Costa, J. Phys. Chem. C, 2012, 116 (23), pp 12514–12524.
Reference4: Studies in surface science and catalysis #46, Zeolites as catalysts, sorbents and detergent builders page 103.
Reference5: Functional hybrids materials page 37
Reference6: Organo-lined alumina surface from covalent attachment of alkylphosphonate chains in aqueous solution, Stéphanie Lassiaz, Anne Galarneau, Philippe Trens, Dominique Labarre, Hubert Mutin and Daniel Brunel, New J. Chem., 2010,34, 1424-1435.
Reference7: Synthesis and application of new Schiff base Mn(III) complexes containing crown ether rings as catalysts for oxidation of cyclohexene and cyclooctene by Oxone, Seyed Mohammad Seyedi, Gholam Hossein Zohuri and Reza Sandaroos, Supramolecular Chemistry Vol. 23, No. 7, July 2011, 509–517.
Reference8: Recent advances in the use of oxone® in organic synthesis, Maria Carla Marcotullio, Francesco Epifano and Massimo Curini, Cheminform, June 2005.
Reference9: Oxone/Sodium Chloride: A Simple and Efficient Catalytic System for the Oxidation of Alcohols to Symmetric Esters and Ketones, Agnes Schulze, Georgia Pagona, and Athanassios Giannis, Synthetic Communications, 36, 1147–1156, 2006.
Reference10: Oxidation of benzyl alcohols with Oxone and sodium bromide, Bon-Suk Koo, Chang Keun Lee, andKee-Jung Lee, Synthetic Communications Vol. 32, No. 14, pp. 2115–2123, 2002.
Oximation – tosylation (18) (19)
Tosyloxime as mentioned earlier could represent some health and safety issues if isolated, so there is a chaining from (17). If the chaining reaction is too long from the ketone to the azirine and subsequent opening, the chaining could start from (18).
The oximation has a difficulty due to the nitrile group (amidoxime formation) but the reaction kinetic of oxime has a higher constant. This reaction could proceed in THF with KHCO3 and PTC at room temp. If the produced water is a problem for the reaction completion, a desiccant could be added like anhydrous Na2SO4.
About the tosylation, i think K2CO3 is sufficient to deprotonate the oxime, since there is an 8-ring by a H-bonding between H from the oxime and O from the ester carbonyl. This conformation is close to a hydroxamic acid conformation, and probably the H is consequently relatively acidic. A PTC could help, but probably not necessary.
H from OH has a calculated pKa = 7.78 and H from CH2 between CN and oxime has a calculated pKa = 11.68. Since the 8-ring conformer has a probability of existence, the pKa of OH is probably lower. To avoid a concurrent deprotonation of OH and CH2, and because K2CO3 has a stronger basicity in PTC conditions, i think it would be better to use KHCO3 to avoid the CH2 deprotonation. The produced water from H2CO3 will be trapped by Na2SO4 already present in the mixture. In this case, a PTC should probably be used, and the reaction temperature 0 to 5°C.
The better should be to find a process where K2CO3 is used as well as for the oximation, tosylation and Neber rearrangement, the difficulty here is to avoid a premature deprotonation of CH2 which has only a higher calculated pKa = 16.68 when the oxime is tosylated. A way could be to use a PTC only for the Neber rearrangement (only ion pair of K2CO3 in THF if a PTC is not used, the basicity is exalted -naked anion- with a crown ether).
The mixture of (19) should be used as is for the Neber Rearrangement.
Reference:
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.
© David Le Borgne, 2015, specialist in chemical process development and optimization.
Update: Added cyanide destruction treatment before oxidation of alcohol.
ReplyDeleteUpdate: Added optimization proposal for the sequence oximation-tosylation-Neber rearrangement.
ReplyDelete