| 80% |
With hydrogenchloride; water In methanol at 40 - 45℃; for 5h; Inert atmosphere; |
3.1
STEP 1: Synthesis of Hydroxyketone 2Materials: FW Grade Amount mmolesBromide 1 192.99 43.8 g 227THF 88 mL/-PrMgCl 102.85 2 M (THF) 113 mL 227(1 .0 eq)THF 20OmLCuCl 99.00 1.12g 11.351 [0 .05 eq)Acetoxyacetyl chloride 136.53 36.6 mL 340(1 .5 eq)MTBE 40OmLHCl 36.46 1.0 M 454 mL 454(2 .0 eq) Satd. aq. NaCl 227 mLSatd. aq. NaHCO3 227 mLThis process should be conducted under inert gas (N2) with exclusion of water/oxygen at all stages until aqueous workup (maintain exclusion of oxygen during workup).Charge THF (88 mL, KF = 50 ppm, 250 ppm BHT inhibitor is tolerated) to 0.5 L RBF equipped with overhead stirrer. Charge l-bromo-3,5-difluorobenzene (43.8 g, 0.227 mol, KF = 170 ppm). KF from resultant solution was 130 ppm. Heat the solution of 1 to 40 0C. Charge /-PrMgCl over 2 h (2 M in THF, 113 mL, 1 equiv), maintaining temperature 40-45 0C. Mg-Br Exchange is typically complete < 1 h after completion of /-PrMgCl charge to afford a homogenous solution. Monitor exchange via HPLC, quenching samples into MeOH and detect the 1,3-difluorobenzene.In a separate vessel, prepare mixture of CuCl (1.12 g, 0.05 equiv) in THF (200 mL) then add acetoxyacetyl chloride (37 mL, 1.5 equiv). Cool the CuCl/acid chloride mixture to -10 0C. Transfer (via dropping funnel) the solution of Grignard prepared above in THF - 10 0C over 4 h. No age is required after transfer of the Grignard. Proceed to next step upon complete addition.In a separate vessel, a two-phase mixture of IM HCl (227mL, 1.0 equiv) and MTBE (400 mL) is prepared and cooled to 0-10 0C. The reaction mixture is transferred into the aqueous workup mixture, maintaining < 10 0C. The resulting two-phase mixture can be allowed to warm to 20 0C for the phase cut. Wash the organic phase with a second portion of 1 M aqueous HCl (227 mL, 1.0 equiv). Wash the organic phase with saturated aqueous NaCl solution (227 mL). Wash the organic phase with saturated NaHCOβ solution (227 mL). Distill the organic phase and azeotrope with fresh MTBE until KF value was 483 ppm. Concentrate until solution is super-saturated and induce crystallization with seeding if necessary. Solvent switch to minimum 85% heptane and cool to 0-5 0C until supernatant concentration is < 3 g/L then filter. Rinse the cake with fresh heptane and then dry at 30 0C with N2 sweep. Acetoxyketone (1.1) was isolated as an off-white solid, 36 g, > 96 wt% purity for a corrected isolated yield of 70%.Charge 100.2 g of 93 wt% acetoxyketone to a 2 L flask with overhead stirring. Charge 300 mL MeOH. Charge 5 M aq. HCl (200 mL) and heat the thick slurry to 40-45 0C. After 5 h at 45 0C conversion is > 95:5 LCAP ratio of hydroxyketone: acetoxyketone. Color will change to light orange. Cool the batch to 20 0C and seed to induce crystallization if necessary. Add 1.2 L water over 1 h to cause further crystallization of 2 and then cool to 0-5 0C until supernatant concentration is < 4 g/L then filter. The hydroxyketone 2 is collected by filtration and rinsed with additional water. After 15 min suction drying the wet cake was 81 g. After 48 h under vacuum the mass was 62.5 g. The 62.5 g of off-white solid was 96 wt% purity for a corrected yield of 80% from the acetoxyketone. Overall yield from bromide 1 is 86% x 80% = 69%. This material is of sufficient quality for Step 2 but if necessary (e.g. wt% < 95%) the material can be recrystallized from EtO Ac/heptane as described below -After brief drying to remove bulk water, the hydroxyketone solid is re-dissolved in EtOAc and the resultant solution is subjected to azeotropic distillation until water content by KF titration is < 1000 ppm. The dry EtOAc solution is filtered and concentrated to approximately 5 volumes then switched with heptane at constant volume until the ratio is approx 3:1 heptane: EtOAc. The slurry of 2 is cooled to 0 0C and aged for 1 h, achieving < 10 mg/mL in the supernatant. The slurry is then filtered and rinsed with cold 3:1 heptane:EtOAc (1 bed volume) then heptane. The white solid is dried at 30-40 0C and approximately 20-25 in Hg (vacuum with N2 sweep). Isolated solid 2 has purity of > 98 LC wt% and > 98 NMR wt%. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
