Article pubs.acs.org/OPRD
Development of Scalable Processes for the Preparation of N‑Methyl3-Bromo-5-Methyl Pyrazole Richard J. Fox,* Chester E. Markwalter, Michael Lawler, Keming Zhu, Jacob Albrecht, Joseph Payack, and Martin D. Eastgate Chemical & Synthetic Development, Bristol-Myers Squibb Company, P.O. Box 191 New Brunswick, New Jersey 08903-0191, United States S Supporting Information *
ABSTRACT: The development and optimization of two scalable routes to N-methyl-3-bromo-5-methyl pyrazole is described. The initial Sandmeyer route entailed a three-step sequence from crotonitrile and methyl hydrazine, proceeding through the 3amino pyrazole intermediate. Due to the GTI liability of the 3-amino pyrazole intermediate, a tedious steam-distillation, and 95% >95% 85% >95% >95% >95%
5:1 15:1 8:1 4:1 3:1 7−11:1 13:1
1 2 3 4 5 6 7 8 9
L/kg based on methyl hydrazine. bDetermined by HPLC.
a
demonstrated that the use of water or methanol led to the highest (i.e., 8−15:1) in-process (IP) regioselectivity, the high solubility (i.e., > 100 mg/mL) of 20·HBr, which was the ideal salt form to minimize halogen exchange in the subsequent bromination, in these solvents made a direct drop isolation challenging. On the other hand, while the low (i.e., < 5 mg/ mL) solubility of 20·HBr in IPA was attractive with respect to
10 10 10 10 10 10 10 10 6
Et3N equiv
additive (equiv)
temp. (°C)
LCAP 5a
0.7 0.9 1.1 2.2 0.9 0.9 0.9 0.9 0.9
none none none none DMF (0.1) NMM (0.1) DABCO (0.1) Et4NBr (0.3) Et4NBr (0.3)
20 20 20 20 20 20 20 20 30
56 71 63 2 55 73 69 81 95
After 7 h at 20 °C for entries 1−8 and 5 h at 30 °C for entry 9.
and (2) while catalytic DMF, N-methyl morpholine (NMM), and DABCO25 were not beneficial (entries 5−7), addition of 0.3 equiv of Et4NBr significantly increased the reaction rate (entry 8). This rate enhancement correlated well with FTIR data that supported 20·HBr rapidly converted to 22 upon the addition of POBr3, and the conversion of 22 to 5 was rate757
DOI: 10.1021/acs.oprd.7b00091 Org. Process Res. Dev. 2017, 21, 754−762
Organic Process Research & Development
Article
Table 5. Investigating POBr3 Workup Protocol entry
quench solution
addition mode
final pH
emulsion observed
Et3N in org layera
Et4NBr in org layera
IP yieldb
1 2 3
aq KOH aq NaOH aq NaOH
normal normal inverse
4−5 4−5 4−5
Y N N
N N N
N N N
NDc 74% 93%
Determined by 1H NMR. bDetermined by 1H NMR of final 5/DCM solution using 1,2-dichloroethane as an internal standard. cND = not determined.
a
determining.26 Final optimization of concentration and temperature decreased the time needed to reach >95% conversion from approximately 20 to 5 h (entry 9). For the aqueous workup,27 initial experimentation revealed the partitioning of 5 into aqueous solution was highly dependent on pH, with ∼15% yield loss observed at pH 1.5, but 4.5. As shown in Table 5, in order to remove both the residual Et3N and Et4NBr prior to the subsequent oxidation, our initial workup entailed addition of aqueous KOH to the reaction mixture to obtain a final pH of 4−5 (entry 1). Unfortunately, this led to a challenging emulsion. Based on the higher water solubility of NaH2PO4 vs KH2PO4, presumably the major phosphate salt present at pH 4−5 after quenching the excess POBr3,28 we replaced KOH with NaOH. This led to a clean phase split, the removal of both the Et3N and Et4NBr, and 5 in 74% in-process yield (entry 2). Switching to an inverse aqueous NaOH quench not only led to a more controlled exotherm but further improved the IP yield, presumably due to maintaining the pH > 4 throughout the quench (entry 3). Overall, the final workup protocol involved addition of the bromination reaction mixture into 4.5 equiv of NaOH in 19 L/kg water at 0 °C, followed by warming to 20 °C, and washing the resulting DCM layer sequentially with 5 L/kg 0.1 M Na2HPO4 and 5 L/kg water. Under these conditions, 5 was isolated in 93% solution yield with excellent purity on 30 g scale. This chemistry proved extremely robust, leading to 5 in 97% solution yield on 73 kg scale. Continuing with the proposed telescope, an extensive screen of oxidants supported that NaOCl, t-BuOOH/VO(acac)2, and MnO2 were most effective in converting 5 to 3.24 Due to the scale-up challenges of MnO2, and minimal purity profile differences between NaOCl and t-BuOOH/VO(acac)2,29 NaOCl was selected for further optimization. Our initial trials were conducted by adding 1 equiv of aqueous NaOCl to a biphasic solution of 5 in DCM and 1 equiv of K3PO4 in 5 L/kg water at 0−5 °C. Unexpectedly, we observed a significant induction period under these conditions (Figure 3). Based on the well-precedented impact of bromide additives in TEMPO/ bleach oxidations,30 we next charged 0.1 equiv of KBr at the start of the reaction. With the addition of KBr, we observed the expected near addition controlled kinetics. Taken together, these results supported that HOBr was the active oxidant, and the induction period observed in the absence of KBr was likely due to the time needed to induce some hydrolysis of 5 to release bromide into the reaction mixture. Further optimization led to our final oxidation conditions which entailed the slow addition of 1.75 equiv of aqueous NaOCl to a biphasic mixture of 5 in DCM and 2 equiv of K3PO4 and 0.5 equiv of KBr in 2 L/kg water at 0−5 °C (Table 6). The use of 2 equiv of K3PO4 was critical to maintain the pH > 12 and minimize the formation of dibromide 24. For example, subjecting 3 to the reaction conditions with pH 12 buffer led to
