Case Studies
Target Molecule: L10295, (R)-(-)-3-Fluoropyrrolidine hydrochloride
Original Route:
Initially made from (S)-3-Hydroxypyrrolidine hydrochloride using 3 stage route; Protection, fluorination with DAST followed by deprotection.
Challenges:
- 3 stage route, previously performed on <1kg scale with low overall yield ~20%
- Expensive fluorinating reagent
- Not economically viable at plant scale, new requirement was for 100kg
- No developed chiral hplc method. Optical rotation previously used as basis for chiral purity
Solutions:
- A new one-pot process was developed from the same raw material
- DAST was replaced with SF4, so much lower cost
- Yield increased to ~50%
- Formation of new impurity (3-chlropyrrolidine.HCl) was seen at ~0.2%
- Recrystallisation method developed to remove this impurity
- 100kg produced at competitive price. 1/3rd price of original route, scale for scale.
- Improved chiral hplc method developed. 98% e.e
- New one-pot route now allows scale-up to multi-tonne quantities
100kg delivered on time in full and within specification
Target Molecule: S10275, 2(S)-2-Trifluoromethylpyrrolidine
Original Route:
We had previously made this product on ~100g scale from (L)-Proline in 1 step using SF4 with retention of stereochemistry. Route works on gram scale but degradation and handling problems were seen on scale-up.
Challenges:
- To produce 250kg in 12 weeks. 98% ee requirement
Solutions:
New route was required from low cost, readily available raw materials:
The fluorination of the above substrate could be performed at a much lower temperature, since the raw material is activated towards fluorination (compared with the fluorination of (L)-Proline). Therefore , degradation was avoided and yields were >80%. We quickly screened several reducing agents for the second stage and managed to obtain >85% yield.
250kg product was delivered within 12 weeks. >98% ee
Target Molecule: Trans Trifluoromethylcyclohexane Compound
Original Route:
2 Stage synthesis involving high pressure reduction of aromatic ring followed by epimerisation from predominantly cis to trans. Material had previously been prepared at ~10kg level with pricing of ~$6000/kg. Specification had been set at 98%, 98% trans isomer and had contained up to 1% cis isomer and also ~1% olefin below.
Challenges:
- To provide customer with 150kg of material within 10 weeks
- To reduce price to be in region of $1000/kg
- Customer wanted tighter specification with <0.1% cis isomer and <0.25% olefin impurity
Solutions:
- Located lower cost source of the KSM, and also quickly developed an improved synthesis by lowering the catalyst loading, recycling the catalyst and adjusting the reaction conditions to improve the yield.
- Epimerisation conditions were improved to give better conversion to the trans isomer
- Formation of the olefin could not be avoided due to the harsh conditions of the epimerisation. New purification method successfully developed to fully remove the cis isomer and reduce the olefin to <0.25%
150kg was delivered early, within budget and to the new specifications
Next requirement expected to be ~500kg