Newsletter Issue 10 May-Sep 2009

Reaction Optimization in Drug Discovery

The usual medicinal chemistry project involves preparing as many products as possible, specially at the beginning stages. Sometimes the yields and purities obtained in specific, critical reactions, are low and there is ample room for improvement. But medicinal chemistry is about new compounds, not perfect chemistry. In the last year we have approached our medicinal chemistry clients with a new idea: sometimes optimization can be carried out in parallel to the main work, and while med chemists prepare new compounds, another group can improve the chemistry, which in turn would be returned to them so the benefits can be applied to the synthesis in progress. The key is not diverting efforts, but adding an external resource which can add new value in a short period of time. One of our clients approached us with a request to optimize the preparation of an heterocyclic scaffold used as starting point for a drug discovery route. The product was obtained through the SNAr reaction of a chloroheterocycle with a high-value amine. Though the reaction worked, it was slow, conversion was low and a dimeric impurity was present in significative quantities. These problems translated into low yields (34% after 3 days) and difficult purifications.

Time was of paramount importance. A fast bibliographic search showed that similar reactions had been described using metal couplings, but not over our scaffold, so to avoid longer development times, metals were discarded. Though an obvious improvement was the application of microwave conditions this alternative was also discarded to avoid scaling-up issues. We concentrated our efforts in finding a new combination of solvent and base, so we designed a fast screening evaluating 9 different solvents and 2 bases, using as response factors the % of starting material and product obtained by LC-MS. Not the 18 possible combinations were considered, since some hints available in the bibliography lead us to expect bad results from some combinations. An initial set of six reactions was carried out in parallel in a Radley's carousel.

Entry Solvent Base Time Ratio 1:2 1 EtOH DIPEA 5 h 84 : 16 21 h 61 : 38 28 h 57 : 40 44 h 51 : 49 52 h 47 : 52 2 PrOH DIPEA 5 h 85 : 14 21 h 66 : 33 28 h 64 : 36 44 h 53 : 46 52 h 49 : 50 3 CH3CN DIPEA 5 h 89 : 11 21 h 75 : 22 28 h 76 : 23 44 h 72 : 27 52 h 71 : 27 4 BuOH DIPEA 5 h 66 : 32 21 h 79 : 18 28 h 64 : 8 44 h 73 : 7 5 DCE K2CO3 28 h 98 : 0.3 68 h 99 : 0.5 6 CH3CN K2CO3 20 h 75 : 24 28 h 68 : 31

Initially, all reactions were carried out at 86 °C with 1.5 eq of base. The reactions were monitored at different times, and soon it was clear that more base was needed, so 2 additional eq of the corresponding base were added to each reaction. Some conclusions were drawn: EtOH and PrOH with DIPEA (entries 1 and 2) gave similar results, with a 50% conversion after 52 h. No dimeric product was detected. CH3CN with DIPEA (entry 3) gives a mediocre result, with a 27% conversion after 52 h, but traces of dimeric product were detected. BuOH (entry 4) presented the worst results, with increasing quantities of the dimeric compound being detected in each sample. DCE with K2CO3 (entry 5) is a no-go, with no conversion. CH3CN with K2CO3 (entry 6) gives also acceptable results. Though the conversion is lower than using DIPEA, no dimeric product is detected. Results with EtOH and PrOH were promising. CH3CN had also potential, with a good conversion on a shorter reaction time. The next batch of experiments was set up to include other polar solvents with 3.5 eq of base from the beginning. Additionally, since conversion is quite similar at 44 and 52 h, a maximum time was established at 44 h.

Entry Solvent Base Temp. Time Ratio 1:2 7 DMA DIPEA 125 °C 45 h 98 : - 8 NMP DIPEA 125 °C 45 h 88 : - 9 EtOH DIPEA 86 °C 44 h 53 : 46 10 PrOH DIPEA 86 °C 44 h 87 : 13 11 CH3CN DIPEA 86 °C 44 h 79 : 19 12 CH3CN K2CO3 86 °C 42 h 13 : 87 13 Py neat 125 °C 18 h - 14 DMF K2CO3 86 °C 20 h 63 : 33

The results from the second set of experiments are much better: Entries 7, 8 and 14 show that other polar solvents do not improve the CH3CN result. The entries 9 and 10 reflect that a full quantity of base from the beginning gives no improvement with alcohols. The entry 11 reflect a similar behaviour for CH3CN with DIPEA: no improvement. Entry 12 show that for CH3CN with K2CO3, a full quantity of base from the beginning makes a difference. Entry 13 shows that pyridine, which is at the same time the solvent and the base, gives no product. Clearly the entry 12, 3.5 eq of K2CO3 in CH3CN for 42 h at 86 °C is the winner. But in fact, the reaction time can be shortened. A sample of the reaction monitored by LC-MS at 24 h showed a 16:83 ratio, not much worse than the final 13:87. So we decided that a 1-2% increase in conversion it's not worth of 24 additional hours. The reaction was finally reproduced at a larger scale with similar results: 12:87 ratio at 26 h.

Those were the conditions given to the client in a full experimental report including the results of each run. Note that in fact the reaction is not complete after 26 h; but no dimeric product is detected and purification is much easier than with the previous conditions.

GalChimia, S.L. Cebreiro s/n, 15823 O Pino (A Coruña) -  Spain Tel: +34 981 814 506 Fax: +34 981 814 507  www.galchimia.com