Synthesis of Cyclohexanoyl Chloride from Cyclohexane Carboxylic Acid

Published by Michael Wolfle on 5 January 2010 - 9:18am
1H NMR Cyclohexanoyl chloride.pdf88.3 KB



An early step in the Reissert approach to PZQ is the synthesis of cyclohexanoyl chloride (InChI=1/C7H11ClO/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2) from cyclohexane carboxylic acid, (InChI=1/C7H12O2/c8-7(9)6-4-2-1-3-5-6/h6H,1-5H2,(H,8,9)). This step is needed if it is found that the acid chloride is prohibitively more expensive than the acid.
Cyclohexanoyl chloride was prepared by refluxing cyclohexanecarboxylic acid (390 mmol, 50.0 g) and SOCl2 (770 mmol, 56.0 mL, 1.95 eq.) for 4 h with exclusion of moisture. The mixture was allowed to cool. Gas bubbles continued to evolve from the solution and hence the mixture was allowed to stir overnight at rt.
The residue was purified by fractional distillation (1 atm, bp 186°C) to give the acid chloride as a light yellow liquid (47.0 g, 321 mmol, 82%).
 1H NMR Cyclohexanoyl chloride
 1H NMR Cyclohexanoyl chloride



ndt228's picture

I work in the contracting side of the pharma industry, so know something about pricing of raw materials and operating the processes that use them.
1) You must not judge the economics of one route or another based on lab-scale prices
2) You must not waste time/effort on things other people can do/have already done.  ie don't concern yourselves with "better routes to C6H11COCl" ; use the time/effort for research on your molecule.
3)  You'll get the best price for a kg when you actually want to buy a kg.  It will change when you want 10 kg, 100 kg, 1000kg.  However it all a negotiation around how much, when, where, quality etc.  Caveat Emptor applies !  You must shop around !  The fact that you do actually want to buy some is what gives you leverage with a supplier - and you can always ask for indicative pricing of larger quantities. For more modest quantities it is always worth asking the catalog companies to quote you prices for (say) 10x their largest pack size.  It will usually be discounted, and once you have the price from them, see if you can get them to do half that qty for the same might work !  This all takes time and you'll have to weigh up what it costs in your time against what you may save in cash.
For C6H11COCl at large scale you are unlikely to do any better than a price from a Chinese company, and you certainly won't be able to make it cheaper from the acid, once you have bought the SOCl2 you'll need, plus the plant time, labour, analysis etc.  In miniature, the same even applies in the lab - even student time has value, and its better spent researching your molecule than making starting materials (unless that is part of the training process of course). 
4)  If your lab operations are hampered because you haven't a budget to pay lab chemical prices for even modest quantities of key raw materials, then I think you need to make that clear to the community and trawl for donations !     C6H11COCl is £31.20 per 100g from Aldrich (in the UK), which is not that bad.  I have to wince on behalf of my clients when I buy raw materials for them at 900 euros for 10 grams - or chiral ligands at £55 per 100mg (yes that is £0.55 million per kg).
5)  It would help if you could give some idea of the scale at which you are already working, and what your time/quantity targets are with respect to scale-up.  Do you actually have any proven routes to the chiral API yet ? 
 best regards

ndt228's picture

Since writing the above I have read more around the existing supply of racemic PZQ.  Since this uses the above acid chloride, this raw material must already be available at a price which allows the present overall cost of goods for racemate to be as low as it is.  The acid chloride will ultimately therefore be available at essentially the same price for use in synthesis of (R)-PZQ.  Obviously there is an interim period in which the limited scale of research purchases means you don't enjoy bulk prices, but the same goes for just about evry chemical and solvent we buy.
regards, Nick