2-MeTHF a cost saving alternative to THF

Migration of technologies from tetrahydrofuran (THF) to 2-methyltetrahydrofuran (2-MeTHF) can generate important cost savings : from higher extraction and reaction yields.

MeTHF versus Toluene

An experimental program was designed to look at the solvent/water partition for a series of alcohols of different polarities ranging from isopropanol to n-octanol. The alcohol partition between the organic and aqueous phase can be easily monitored by GC methods. These alcohols mimicked the wide range of polarities found in active pharmaceutical ingredients (API) and intermediates. The THF reactions often call for addition of toluene to THF as a means to achieve phase separation. We compared there fore the use of toluene as co-solvent against 2-MeTHF² to get the API partition trend.

It was expected that 2-MeTHF would a better extraction solvent than toluene based on its higher polarity. The limited solubility of water in 2-MeTHF should enhance the extraction capability particularly for polar compounds. This latter factor was invoked as a plausible explanation for the high reaction rates seen in the biphasic reactions where dichloromethane (DCM) had been replaced with 2-MeTHF³. Better extraction yield of the API or valuable intermediate should translate in important savings.

Figure 1 clearly shows that in fact these working hypotheses hold true. On the ternary mixture phase diagram for IPA / toluene / water the equilibrium lines are tilted to the left. This shows that the IPA prefers the aqueous phase over migration to the toluene phase. On the contrary, when 2-MeTHF is used instead of toluene, the equilibrium lines are tilted to the right, showing that the IPA prefers to migrate to the organic phase. The extraction in 2-MeTHF is very efficient.

The same behavior was found consistently for a alcohols covering a wide range of different polarities⁴.

This suggests that 2-MeTHF is a more efficient extraction solvent than toluene irrespective of the polarity of the alcohol. The differences diminish however when using less polar alcohols.

Cost saving

The vast superiority of 2-MeTHF as an extraction solvent is illustrated by the comparative back to back extractions illustrated in Figure 2⁵. A 80% yield in extracted IPA is achieved using 1.5 parts of 2-MeTHF, 0.2 parts IPA and 1 part water. By using 1.5 part toluene, 0.2 parts IPA, 1 part water and 1 part THF, the extraction yield drops at 56%⁶. The extraction yield difference is 24%. A second extraction step with 1.5 part toluene recovers the product in 68% combined yield for two steps. A second extraction step with 1.5 part 2-MeTHF recovers the product in 97% yield. The extraction yield difference increases to 29%.

Table 1 shows the calculated breakeven price of 2-MeTHF if one decides to switch the process from THF to 2-MeTHF. The calculations are based on experimental findings and commercial pricing for THF and toluene⁷.

For example, a buyer procuring 2-MeTHF at 8.67 Euros/kg will breakeven with 2-MeTHF compared to the classical THF / toluene work-up⁸ if the API price is 200 Euros/kg.

By using numerical analysis in an Excel spreadsheet similar to Table 1 one can calculate the breakeven price for MeTHF for any particular API price. Figure 3 captures these results for different API prices. For example, Figure 3 shows that the savings generated by the switch THF to 2-MeTHF amount to 3.20 Euros/kg API if the buyer pays 5.47 euros/kg of 2-MeTHF for a 200 euro/kg API⁹.

Switching from THF to 2-MeTHF technologies provide great savings opportunities based on improved extraction yields alone. These savings are going to be more important for polar compounds such as alcohols, amines, acids and aminoacids. The switch from THF to MeTHF can also be accompanied by other benefits such as shorter cycle times, less solvent degradation, improved reaction yields or easier recycling. Each of these advantages will translate into new saving opportunities above and beyond the extraction related savings discussed here. Ultimately, the savings will differ greatly on a case by case basis and have to be established experimentally.

The calculations provided in this article are therefore approximate and conservative in their nature; they provide merely a sense of the savings opportunities related to the switch from THF to 2-MeTHF processes.

1. B. Comanita, D. Aycock Industrie Pharma Magazine, 2005, 17, p. 54

2. Another common procedure calls for “salting out” the product by addition of a small quantity of saturated water solution to the THF solution; this procedure displays higher loss of product than extraction.

3. Ripin, D.; Vetellno, M., Synlett (2003), 15, 2353.

4. Supplementary experimental data available on request from the authors

5. Note that the ternary system shown for toluene/IPA/water do not apply directly; the presence of THF will modify ternary diagram however the general trend for extractions will be preserved.

6. Salting out experiments were not performed for cost comparison since they are generally lower yielding than the toluene work up.

7. Only the first step extraction results are considered.The second extraction step is ignored since the difference between THF and MeTHF yield increases from 24 to 29% making for a less conservative comparison.

8. The calculations are based on the experimental data detailed for the IPA in Figure 2.

9. Use of API market price should be preferred to the internal transfer price in order to capture real savings.