Supporting Information Development of Scalable Processes for the Preparation of - Methyl-3-Bromo-5-Methyl Pyrazole Richard J. Fox,* Chester E. Markwalter, Michael Lawler, Keming Zhu, Jacob Albrecht, Joseph Payack and Martin D. Eastgate Initial screening of halogenation conditions to convert 20 HBr to 5 2 Initial screening of oxidation conditions to convert 5 to 3 2 Characterization of,-dimer (23) 3 Preparation of CD 3 containing compounds 5 Representative MR spectra 10
Initial screening of halogenation conditions to convert 20 HBr to 5. Representative screening studies for the conversion of 20 HBr to bromodihydroprazole 5 are shown in Table S1. This data supported: (1) POBr3 was uniquely effective for this transformation, (2) reaction rates were comparable in DCM and CH3C, (3) base was required, and (4) while Et3, DIPEA and 2,6-lutidine were all acceptable, K2CO3 led to low conversion. Table S1. Initial screening to prepare 5 Entry Reagent (eq) Solvent a Base (eq) LCAP 5 after 22 h 1 POBr 3 (2) DCM Et 3 (1.5) 64 2 oxalyl bromide (2) DCM Et 3 (1.5) 0 3 SOBr 2 (2) DCM Et 3 (1.5) 0 4 POBr 3 (1.5) DCM none 2 5 POBr 3 (1.5) DCM Et 3 (1.1) 95 6 POBr 3 (1.5) DCM DIPEA (1.1) 92 7 POBr 3 (1.5) DCM 2,6-lut (1.1) 96 8 POBr 3 (1.5) DCM K 2 CO 3 (1.1) 5 9 POBr 3 (1.5) CH 3 C none 1 10 POBr 3 (1.5) CH 3 C Et 3 (1.1) 97 11 POBr 3 (1.5) CH 3 C DIPEA (1.1) 97 12 POBr 3 (1.5) CH 3 C 2,6-lut (1.1) 97 13 POBr 3 (1.5) CH 3 C K 2 CO 3 (1.1) 21 a All reactions run using 10 L/kg solvent based on 20 HBr Initial screening of oxidation conditions to convert 5 to 3. Representative screening studies for the conversion of bromodihydropyrazole 5 to bromopyrazole 3 are shown in Table S2. The results of this screen supported that aocl, t-buooh/vo(acac)2 and MnO2 were the most effective conditions in converting 5 to 3.
Table S2. High-level summary of 96-well oxidant screening to prepare 3 Oxidants Catalysts/Activators Individual Conditions 35 % H2O2 TEMPO CA aocl (12%) MnO2 KMnO4 K- persulfate (or oxone) Mn(OAc)2 DDQ urea hydrogen peroxide ReIO2(PPh3)2 (CF3CO2)2IPh 77% mcpba MeReO3 aio4 with PTC peracetic acid Re2O7 H2O2 in F6-IPA cumene hydrogen peroxide oxalic acid a2wo4/ptc/phpo3h2/h2o2 70% t-buooh thiourea dioxide Chloramine-T Ca(OCl)2 VO(acac)2 trichlorocyanurate Bu4-oxone Bu4HSO4 trichloromelamine Sodium bromate Phthalic anhydride sodium perborate CuCl2 none sodium percarbonate benzoquinone Pd/C Characterization of,-dimer (23). Preparatory chromatography of a DCM solution containing 5 and 23 following the reaction and aqueous workup, but prior to the Et3 charge, was attempted. However, 23 proved volatile during lyophilization. Thus, the aqueous solution prior to lyophilization was extracted with CD2Cl2 to enable the characterization of 23 by MR and mass spectrometry (direct probe). While 23 was detected by HRMS, the data indicated that it readily oxidized to generate the mono and di-pyrazole dimers during purification. As a result of the isotopic overlap from the mixture of components present in
the sample, the mass accuracy for 23 and the mono pyrazole dimers was poor. The mass accuracy for the di-pyrazole dimer was excellent due to the absence of isotopic overlap. Br 23 Br Br Br Br Br Chemical Formula: C 8 H 12 Br 2 4 Exact Mass: 321.94 Chemical Formula: C 8 H 10 Br 2 4 Exact Mass: 319.9272 Chemical Formula: C 8 H 8 Br 2 4 Exact Mass: 317.9116 Accurate mass analysis: Calculated Mass (m/z) Measured mass (m/z) Elemental composition Deviation (ppm) 318.9194 318.9196 C8H94Br2 0.6 320.9350 320.9316 C8H114Br2-10.6 322.9507 322.9307 C8H134Br2-61.9 Due to the challenges in isolating 23, 1 H and COSY MR data was also collected on the concentrated DCM reaction solution following oxidation to support the assignment of 23. 1 H MR (600 MHz, CDCl3) 4.15 (m, 1 H), 3.60 (dd, J= 9.0, 18.3 Hz, 1H), 3.07 (dd, J=6.4, 18.3 Hz, 1 H), 1.78 (d, J= 6.8 Hz, 3 H).
Br H H H CH 3 23 Br H 1 or H 2 -H 3 H 1 or H 2 -H 3 H 3 - H 1 or H 2 H 3 -H 1 or H 2 H 3 -CH 3
Preparation of CD 3 containing compounds. Preparation of CD 3 HH 2 H 2 SO 4 (SI-1). Procedure adapted from Organic Syntheses, Coll. Vol. 2, p.395 (1943); Vol. 16, p.51 (1936) used to prepare CH 3 HH 2 H 2 SO 4. A 250 ml RBF equipped with a magnetic stir bar and condenser topped with a calcium sulfate drying tube was charged sequentially with benzaldehyde azine (14.00 g, 66.55 mmoles, 1.0 equiv), benzene (24 ml) and dimethylsulfate-d6 (9.88 g, 72.5 mmoles, 1.09 equiv). Warmed reaction to reflux to generate a homogeneous orange solution. After 5 h, reaction formed a biphasic solution, and upon cooling to 20-25 o C, formed a thick slurry that was difficult to stir. Charged water (42 ml) to fully dissolve solids and concentrated under vacuum (450 torr) until ~75 ml distillate (biphasic) was collected. Cooled reaction mixture to 20-25 o C, charged water (42 ml) and benzaldehyde (2.4 ml, 24 mmoles, 0.36 equiv), and let age overnight. Filtered mixture and washed solids with water (2 x 10 ml). Concentrated filtrate under vacuum (50 torr, jacket set to 110 o C) to ~50 ml to afford a yellow solution with some brown/orange droplets. Polish filtered hot solution and rinsed with water (2 x 10 ml). Concentrated filtrate under vacuum (50 torr, jacket set to 110 o C) to ~20 ml to afford a yellow solution with some additional brown/orange droplets. Polish filtered hot solution and rinsed with water (2 x 5 ml). Concentrated filtrate under vacuum (10 torr, jacket set to 60 o C) to dryness. Charged absolute ethanol (50 ml) and concentrated resulting slurry on rotovap (60 o C, 180 torr) to dryness. Repeated with additional absolute ethanol (3 x 50 ml). Charged slurry with absolute ethanol (20 ml) and aged at 20-25 o C for 2.5 h. Filtered slurry and washed sequentially with absolute ethanol (2 x 15 ml) and MTBE (2 x 15 ml). Dried in vacuum oven at 40 o C containing a crystallizing dish of calcium sulfate to afford 7.56 g (77% yield) of SI-1 as a white solid with characterization data identical to that previously reported in the literature (Lunn, G.; Sansone, E. B.; Keefer, l. K. J. Org Chem. 1984, 49, 3470 and Sucrow, W.; Lübbe, F.; Fehlauer, A. Chem. Ber. 1979, 112, 1712). mp = 141-143 o C; 1 H MR (500 MHz, d6-dmso) δ 7.95 (br s, 5 H); 13 C MR (125 MHz, D2O) δ 36.7 (sept, J= 22.5 Hz).
Preparation of SI-2. To a mixture of methanol (10 ml) and SI-1 (5.00 g, 34.0 mmoles, 1 equiv) was charged KOH (4.60 g, 69.7 mmoles, 2.05 equiv) at 20-25 C. Observed strong exotherm to 56 o C. Once internal temperature returned to 20-25 o C, charged additional methanol (10 ml) and methyl crotonate (4, 3.82 g, 37.4 mmoles, 1.1 equiv). After 23 h, reaction mixture was filtered, and the solids were washed with IPA (3 x 10 ml). Concentrated filtrate to dryness on rotovap (40 o C, 30 torr). Charged IPA (10 ml) and polish filtered solution, rinsing with IPA (10 ml). Concentrated filtrate to dryness and then charged IPA (3.7 ml). To a second vial was charged isopropanol (40 ml), cooled to 0-5 C and slowly charged acetyl bromide (4.64 g, 37.4 mmoles, 1.1 equiv) to maintain the internal temperature < 15 C. ote: strong exotherm observed. After an additional 5 min, charged HBr/IPA solution in 2 nd vial to 1 st vial via syringe pump over 1 h, maintaining the internal temperature in 1 st vial between 20 25 C. Rinsed 2 nd vial with IPA (1 ml) and transferred to 1 st vial. Aged resulting slurry @ 20 25 C for 3 h. Filtered slurry, sequentially washed cake with IPA (10 ml) and MTBE (2 x 10 ml) and dried under vacuum at 40 C to afford 4.72 g of SI-2 as a white solid in 70% yield; mp = 152-155 o C; 1 H MR (500 MHz, D2O, *represents minor rotamer) δ 4.57 * (m, 1 H), 4.22 (m, 1 H), 3.07 (dd, J= 10.0, 20.0 Hz, 1 H), 2.93 * (m, 1 H), 2.72 * (m, 1 H), 2.65 (dd, J= 10.0, 20.0 Hz, 1 H), 1.54 (d, J= 5.0 Hz, 3 H), 1.48 * (m, 3 H); 13 C MR (125 MHz, D2O, *represents minor rotamer) δ 174.28, 65.91, 61.75 *, 42.94 (sept, J = 22.5 Hz), 36.04, 34.62 *, 15.13, 13.36 * ; HRMS-ESI (m/z) calcd for C5H8D3O2 [M + H] + 118.1054, found 118.1051. CD 3 H Me O HBr SI-2 Br CD 3 Me 29
Preparation of 29. To a mixture of SI-2 (4.50 g, 22.7 mmoles, 1.0 equiv) and tetraethylammonium bromide (1.43 g, 6.80 mmoles, 0.3 equiv) in dichloromethane (13.5 ml) at 20 25 C was charged triethylamine (2.07 g, 20.5 mmoles, 0.90 equiv) over ~5 min maintaining the internal temperature <30 C. The resulting reaction mixture was then cooled to 0 5 C and charged with a solution of POBr3 in dichloromethane [prepared with 8.47 g (29.5 mmoles, 1.3 equiv) POBr3 and 9 ml dichloromethane] over 5-6 min, maintaining the internal temperature <20 C, followed by a dichloromethane rinse (4.5 ml). The reaction mixture was then warmed to 30 C and agitated for 4.5 h. The reaction mixture was then slowly added to a separate RBF containing a 0-5 C solution of water (86 ml) and aoh (4.09 g, 102 mmoles, 4.5 equiv) over ~10 min, maintaining the internal temperature <20 C, followed by a dichloromethane rinse (2.3 ml). The resulting biphasic mixture was then warmed to 20 25 C, agitated for 15 min, and the aqueous layer checked by ph. Target: 4 < ph < 5. If ph <4, adjusted with 2 aqueous aoh; if ph >5, adjusted with 2 aqueous H3PO4. Split layers, and washed lower product-rich organic layer sequentially with 0.1 M ah2po4 (22.5 ml) and water (22.5 ml). Isolated 48.91 g of final 29/DCM solution. Quantified wt% of DCM solution by 1 H QMR (d1 = 5 sec) using 1,2-dichloroethane as internal standard; 7.62 wt% and in process yield = 91%. 1 H MR (500 MHz, CDCl3) 3.16-3.08 (m, 1 H), 2.94 (dd, J= 9.3, 16.2 Hz, 1 H), 2.63 (dd, J= 14.3, 15.9 Hz, 1 H), 1.27 (d, J= 6.1 Hz, 3 H). Br CD 3 Me crude 28 in DCM Br CD 3 Me 30 Preparation of 30. To a 0 5 C solution of potassium phosphate tribasic (8.62 g, 40.6 mmoles, 2.0 equiv), potassium bromide (1.21 g, 10.2 mmoles, 0.5 equiv) and water (41 ml) was charged crude 29/DCM solution (48.0 g solution, 7.62 wt% 29 in DCM, 3.66 g 29, 20.3 mmoles, 1.0 equiv). Aqueous bleach (24.5 kg, 10.8 wt% in water, 35.5 mmoles, 1.75 equiv) was then added over 3 h, maintaining reaction mixture at 0 5 C. The reaction mixture was then agitated at 0-5 C for an additional 2 h, and charged
with water (7.5 ml). The layers were split, and the lower organic layer was charged into 0.1 M aqueous sodium thiosulfate (41 ml), followed by a dichloromethane rinse (5 ml), maintaining the internal temperature between 0-10 C. The layers were split, and the lower DCM layer was charged with triethylamine (1.04 g, 10.2 mmoles, 0.5 equiv), warmed to 30-35 C, and aged for 16 h. Cooled reaction mixture to 20 25 C, dried over MgSO4, filtered and concentrated on rotovap (30 o C, 50 torr). Purified on 80 g RediSep column (flow rate 60 ml/min; gradient: 100% hexanes for 1 CV, then to 20% EtOAc over 2 CV, 20% EtOAc for 4 CV then to 100% EtOAc over 9 CV. Collected 25 ml fractions. Combined fractions #32-47 (Rf = 0.35 in 2:1 hex:etoac) and concentrated on rotovap (30 o C, 20 torr) to afford 3.09 g (86% yield) of 30 as a colorless oil; 1 H MR (500 MHz, CDCl3) δ 5.98 (s, 1 H), 2.22 (s, 3 Η); 13 C MR (125 MHz, CDCl3) δ 140.8, 124.0, 107.6, 35.5 (sept, J= 21.3 Hz), 10.9; HRMS-ESI (m/z) calcd for C5H5D32Br [M + H] + 178.0053, found 178.0052.
Figure S1: 1 H MR spectrum of 20 HBr in D2O
Figure S2: 13 C MR spectrum of 20 HBr in D2O
Figure S3: 1 H MR spectrum of solution of crude 5 in DCM using 1,2-dichloroethane (DCE) as internal standard. Singlet at 3.71 ppm = DCE. Singlet at 5.28 ppm = DCM.
Figure S4: 1 H MR spectrum of 3 HCl in d6-dmso
Figure S5: 13 C MR spectrum of 3 HCl in d6-dmso
Figure S6: 1 H MR spectrum of 3 TfOH in d6-dmso
Figure S7: 13 C MR spectrum of 3 TfOH in d6-dmso
Figure S8: 1 H MR spectrum of S1-1 in d6-dmso
Figure S9: 13 C MR spectrum of S1-1 in d6-dmso
Figure S10: 1 H MR spectrum of S1-2 in d6-d2o
Figure S11: 13 C MR spectrum of S1-2 in d6-d2o
Br CD 3 Me 29 Figure S12: 1 H MR spectrum of solution of crude 29 in DCM using 1,2-dichloroethane (DCE) as internal standard. Singlet at 3.72 ppm = DCE. Singlet at 5.27 ppm = DCM.
Br CD 3 Me 30 Figure S13: 1 H MR spectrum of 30 in CDCl3
Br CD 3 Me 30 Figure S14: 13 C MR spectrum of 30 in CDCl3