Alternate route proposal for VX-970 an ATR inhibitor (for fun only)

Target

Presentation

The original route published by Vertex begins with the already synthesised pyrazine core (9 to 12 steps depending if the boronic acid is bought or synthesised) with 2 metal catalyzed cross-coupling. This route is obviously the shorter access to the target, but suffers of two drawbacks which are inevitable:
- 2 Pd Cross-coupling which sometimes could be capricious under scale up
- Use of boronic derivative recognized now as mutagen.

Considering these facts, i have chosen to first optimize the original route (process only) except the 2 cross-coupling, and secondly to propose an alternate route which avoids cross-coupling reactions with the construction of the Pyrazine core, which is very prospective.

This is a good chemistry exercise only, since the stability of intermediates is unknown, especially at the end of the synthesis starting at part III, and there are a larger number of steps, but i have some fun chemically speaking, even if this route is less efficient.

Also, it could give some ideas, which is the second role of this blog, like:

• In-situe oxidation of KCN to N2 as post-reaction treatment (inspired from mining industry) – part II
• Azirine opening by α-amino nitrile to give amino-pyrazine (inspired from α-amino ester/azirine reaction and hydroxyiminoketones/aminoacetonitriles reaction) – part III
• Oxone® as friendly oxidizing reagent for various oxidations types – part IV
• Friedel & Craft on Zeolite (avoiding the use of AlCl3) – part I and II
• Possible replacement of “wet-alumina” which needs a preparation by pseudo-Boehmite – part II

About Zeolite, i think this is a catalyst of choice for the flow chemistry (zeolite cartridge).

This proposal is divided in four parts because this is a very long report with nearly 20-21 steps (there are more than 20 chemicals transformations, but by using minerals reagents in many cases, and expected 9 isolations), and multiple proposals for the first step of the sulfonyloxime (19) synthesis, considering starting material prices and chemistry:

• Alternate route part I sulfonyloxime (13),
• Alternate route part II sulfonyloxime (19),
• Alternate route part III convergence: Azirine preparation and Pyrazine synthesis (two Neber rearrangement and convergence using azirine opening)
• Alternate route part IV VX-970 (trickier due to ketal fragility during the cascading oxidation)

Key words: Friedel and Craft, Acylation, Zeolite, reduction, oximation, Neber Rearrangement, azirine, imidoyle chloride, Oxone, oxidation, cyanation, pseudo-Boehmite, alpha-amino nitrile, alpha-amino ketone, alpha-amino ketal, decarboxylation, oxidative decarboxylation, isoxazole, amino pyrazine, malonic.

Original route published by Vertex

Alternate route proposal Part I: Sulfonyloxime (13) preparation

Alternate route proposal Part II: Sulfonyloxime (19) preparation

Alternate route proposal Part III: Pyrazine (23) preparation

Alternate route proposal Part IV: VX-970 (28)
Method A

Method B

Final stage

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.

© David Le Borgne, 2015, specialist in chemical process development and optimization.

Total Synthesis proposal (batch mode) of VX-661 a CFTR modulator against Cystic fibrosis disease, actually in Phase III

Target

Key words: oxidation, oxone, aromatic nucleophilic substitution, malonic synthesis, indolization, bromination, cross-coupling, lactonization,  decarboxylative cyclopropanation, decarboxylation, amidification, hydromethylation, fisher base, alkylation, Oppenauer, Vilsmeier, Haack, Wittig, Horner, Corey, Chaykovsky

Complete proposal here 

Route proposal

Introduction

 

Actually in Phase III, this molecule is planed to be manufactured commercially in a continuous flow chemistry type. More information here: Manufacturing Trends: In Continuous Mode

I didn’t find any publication about a synthetic route for this molecule, but i didn’t make a deep search. So i decided on paper to elaborate from scratch a total synthesis in a batch mode with the goal of industrial scale exploitation, with starting materials as cheap as possible, and the simpler chemistry as possible.

There is always numerous way which lead to the targeted molecule, this proposal is one among others.

I think the building block (5: indole) and (11: cyclopropyl phenyl carboxylic acid derivative) could be manufactured by a third party, and the convergence by flow chemistry with the constraint of absence of suspension (which is not the case in this proposal) to avoids a clogging of the installation.

Total steps: 15 with 10 isolations

Update (i have finally found a document describing the route)

I have finally found the patent (CA2796642A1), here the original route with 15 steps. I prefer my version about the indol part synthesis because it is not necessary to make a cross-coupling, or use a Grignard, perchlorate and dihydrogen. This is globally the same numbers of steps (7) and starting materials cost is similar.

About the cyclopropyl moiety, their starting materials for the two versions (only one showed) are expensive, it would be better to use the benzodioxole and make the bromination (2nd version not showed, 1 step shorter). My version is very explorative with the lactone opening, also the cross-coupling method must be tested (i have seen in a publication an analog of (8) without the Cl, cross-coupled by a Pd catalyst, so the cross-coupling is probably tolerated by (8)).

Update:
Added an optimized route for the alternate route access to the cyclopropyl moiety, shortening the synthesis by 2 steps.

Original route published by Vertex (15 steps)

Complete proposal here 

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.

© David Le Borgne, 2015, specialist in chemical process development and optimization. 

Alternate Synthetic route and process proposal of AZD 3264 an IKK2 Inhibitor

Target

Key words: Aromatic nucleophilic substitution, isoxazole, reduction, diazotation, amino-thiophene, chlorination, cross-coupling, hydrolysis

Complete report here

Original synthesis procedure and route (used for large scale synthesis)

Exploiting the Differential Reactivities of Halogen Atoms: Development of a Scalable Route to IKK2 Inhibitor AZD3264, Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Hebbal, OffBellary Road, Bangalore 560024, India, Org. Process Res. Dev.2014, 18, 646−651

Details of the publication here : http://newdrugapprovals.org/2015/05/15/azd-3264-an-ikk2-inhibitor-from-astra-zeneca/

The synthesis is already optimized (chosen route: scheme 4), but there are some drawbacks:

-        The use of boronic derivatives, which are now classified as mutagen, if avoided, should be better.

-        The isoxazole derivatives is expensive (1260 $/kg – molbase price)

-        Cryogenic conditions to prepare the unstable boronic derivative 3 with n-Hexyl lithium.

-        The process described in the patent for the compound 6 (an in house product) use a toxic reagent to prepare the 2-[(aminocarbonyl)amino] : chlorosulfonylisocyanate.

Alternate route proposal:

Cheaper starting materials (1336 $/kg less) but with 2 more steps (thiophene moiety excluded since this is an in-house product). This route avoids a cryogenic stage with n-Hexyl lithium (health and safety and plant capabilities considerations), and optionally avoids the use of boronic derivatives which are now classified as mutagenic.

Sum-up of the modifications:

Modification of the starting material with three possibilities, essentially to introduce the isoxazole moiety: According to some lectures about the VNS of H (reference mentioned later), it maybe possible to use 1-halo-2-nitrobenzene which is cheaper (27$/kg (Cl) 101$/kg (F) – molbase) and 3-chloropentane-2,4-dione (358$/kg), to take advantage of the nitro EWG behavior. It will be reduced later, followed by a diazotation and CuBr/KBr or KI dependently of the method, which will avoid a cryogenic step. Also, to go back to the original route, the diazonium salt could be reacted with B₂(OH­)₄ which afford the boronic derivative (see reference later)

If doesn’t work, 1-chloro-5-fluoro-2-nitrobenzene probably do, which is unfortunately more expensive than the trihalobenzene (675$/kg – molbase), but the exceeding price of 480$/kg should be absorbed by other starting materials, pentane-2,4-dione (110$/kg - molbase) and hydroxylamine sulfate (25$/kg - molbase).

6 is an in-house product, but to avoid the use of the toxic reagent, i will use in this proposal, the 2-amino-3-cyano-thiophene (450 $/kg – mol base), which is commercially available and treat it with CDI/formamide to obtain the 2-[(aminocarbonyl)amino].

Also if the original compound 6 is used, an exchange could be made with i-PrMgClBis[2-(N,N-dimethylamino)ethyl] Ether Complexes, followed by a treatment with trimethylborate which lead to the boronic acid derivatives (see reference), instead of using the unstable aryl boronic derivative.

Complete report here 

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.

© David Le Borgne, 2015, specialist in chemical process development and optimization.

Synthetic route and process optimization proposal of Rucaparib a PARP inhibitor (PF-01367338 or AG-014699)

Target

Key words: zeolite, acetalization, cross-coupling, acylation, nucleophilic aromatic substitution, indolization, hydrolysis, alkylation, reductive amination. leuckart

Complete report here

Original synthesis procedure and route

Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor

Chemical Research and Development, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom,

Organic Process Research and Development 2012, Vol 16, 1897−1904

http://pubs.acs.org/doi/abs/10.1021%2Fop200238p

Details of the publication is here: http://newdrugapprovals.org/2015/06/09/ag-014699-rucaparib/

Optimized route and process (starting material cheaper, 9 steps instead of 12, 5 isolations)

Optimization

The publication indicate a poor global yield (2.9%) even if the process is optimized, also the chosen indolization method seems to be difficult, metal catalyzed reaction employing boronic acids which are now recognized as mutagenic, reduction with cyanoborohydride and numerous steps.

The “ideal” route i have chosen involves a Fisher indolization. Few steps are tricky due to some functional group fragility, but by designing the process correctly, some side reactions could be avoided. Even if undesirable reaction occurs significantly, i have indicated some alternatives which, unfortunately, involve a cost.

The key point of this route is the indolization, i have evaluated the feasibility by some lectures and by using the software Hulis (Huckel theory), to roughly make a comparison between the hydrazone intermediate and intermediates seen in the literature, especially the trifluoroacetyl one. Starting at 4, it is really more an exploration, that’s why i have indicated some alternatives.

Complete report here

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 fail, chemistry is always an experimental science. This will make me pleased, thank you.

© David Le Borgne, 2015, specialist in chemical process development and optimization.

Synthetic route optimization proposal of Gamendazole - Experimental male oral contraceptive

Target

Key words: Fisher indolization, alkylation, imine, Fisher base, acylation, saponification

Complete report here

Original synthesis procedure and route

 

Total Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives,

Arava Veerareddy, Gogireddy Surendrareddy & P. K. Dubey,

Synthetic Communications

http://www.tandfonline.com/doi/full/10.1080/00397911.2012.696306

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

Optimized route

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.

Complete report here

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.

© David Le Borgne, 2015, specialist in chemical process development and optimization.