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[ CAS No. 1146699-64-0 ]

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Chemical Structure| 1146699-64-0
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CAS No. :1146699-64-0 MDL No. :MFCD13181201
Formula : C9H6BrFN2O Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :257.06 g/mol Pubchem ID :57672367
Synonyms :

Safety of [ 1146699-64-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1146699-64-0 ]

  • Upstream synthesis route of [ 1146699-64-0 ]
  • Downstream synthetic route of [ 1146699-64-0 ]

[ 1146699-64-0 ] Synthesis Path-Upstream   1~4

  • 1
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  • [ 1146699-64-0 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.25 h;
Stage #2: With phosphonic acid diethyl ester In tetrahydrofuran at 20℃; for 1 h;
A 200 mL round bottom flask was charged with 3-(4-(dibromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (8.37 g, 25 mmol) and THF (60 mL).
The mixture was cooled to 0° C. and diisopropyl ethyl amine (3.48 g, 27 mmol) was added dropwise over 15 minutes, followed by diethyl phosphite (3.7 g, 26.8 mmol).
The mixture was stirred at room temperature for 60 minutes and quenched with 40 mL of water.
The aqueous layer was extracted with ether (2*80 mL).
The combined organic layer was washed with 20 mL of sat aq. NH4Cl and 20 mL of saturated sodium chloride solution.
The organic layer was dried over sodium sulfate, filtered and concentrated on a rotovap to give a crude solid which was purified by a short silica pad to afford 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (6.03 g, 94percent).
mp 87.3° C. 1H-NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 7.94 (dd, 1H), 7.87 (dd, 1H), 7.58 (t, 1H), 4.57 (s, 2H); 13C-NMR (CDCl3, 400 MHz) δ 166.97, 166.95, 165.45, 162.29, 159.73, 132.34, 132.30, 128.99, 128.90, 128.81, 124.04, 124.01, 115.56, 115.32, 25.22, 25.18; 19F-NMR (CDCl3, 400 MHz) δ -115.81, -115.84, -115.86. Anal. Calcd for C9H6BrFN2O: C, 42.05; H, 2.35; N, 10.90. Found: C, 42.17; H, 2.17; N, 10.63.
Reference: [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 6; 18
[2] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 18
[3] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 18
  • 2
  • [ 1146699-63-9 ]
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YieldReaction ConditionsOperation in experiment
51%
Stage #1: With sodium bromate In water; ethyl acetate at 20℃;
Stage #2: With sodium hydrogensulfite In water; ethyl acetate at 20℃; for 2 h;
Method C: Sodium bromate Bromination (Direct Isolation); Sodium bromate (2.54 g) was dissolved in water (8.4 mL). To this solution was added a solution of 3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazole (1.0 g) in EtOAc (12 mL) at rt. A solution of NaHSO3 (1.75 g) in water (17 mL) was added dropwise (CAUTION: EXOTHERMIC). The mixture was stirred at rt for 2 h, and then kept in a cold room overnight. The organic layer was separated, washed with 10percent Na2S2O3 and water, and then concentrated. The resulting solid was dissolved in EtOAc (6 mL). Heptane was added slowly (30 mL). The slurry was stirred at rt for 3 h, and then filtered. The solid was washed with heptane (15 mL), then dried giving 0.74 g (51percent) ofthe title compound: HPLC: 99.42AP. Second crop recovery: the filtrate was concentrated to a volume 30 mL and the resulting slurry was filtered to give the title compound as a white solid 0.23 (16percent) with HPLC 97.09 AP.
Reference: [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 18
  • 3
  • [ 1146699-63-9 ]
  • [ 1146699-64-0 ]
  • [ 1146699-65-1 ]
Reference: [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 18
[2] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 18
  • 4
  • [ 1146699-64-0 ]
  • [ 1146699-67-3 ]
  • [ 1146699-66-2 ]
YieldReaction ConditionsOperation in experiment
50% With hydroxylamine; tetra-(n-butyl)ammonium iodide; caesium carbonate In acetonitrile at 15 - 35℃; Step B, Procedure 2
To a suitable vessel was added (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (2.68 kg, 7.77 mol, 1 eq), 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (2.00 kg, 7.78 mol, 1 eq), cesium carbonate (1.65 kg, 5.06 mol, 0.65 eq), tetrabutylammonium iodide (0.29 kg, 0.78 mol, 0.1 eq) and acetonitrile (12.0 L 4.5 L/kg).
The reaction was heated to 35° C. until complete by HPLC (3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole <0.5 relative AP by HPLC).
The reaction was cooled to 15° C. and water (10.72 L, 4 L/kg) was added with stirring followed by glacial acetic acid (0.22 kg) to bring the pH of the reaction to <6.5.
The stirring was stopped and the phases were separated (the top layer contained the product).
To the product rich layer was added toluene (26.8 kg, 31 L, 10 kg/kg) followed by brine solution (20percent w/w, 6.39 kg, 2 L/kg) and the layers were separated (the top layer contained the product).
The mixture was distilled at ~50° C. under vacuum (200 mbar) until acetonitrile was removed.
The concentration was adjusted with additional toluene if needed after distillation to ensure total volume in the reactor was ~10 L/kg.
Isopropyl alcohol (0.48 kg, 0.2 L/kg) was charged and the batch was cooled to 15° C. to initiate crystallization.
The resulting slurry was filtered and washed with cold toluene (18.65 kg, 21.56 L, 8 L/kg).
The crude cake was tray dried under vacuum at 50° C. until loss on drying was <1.0percent.
The dry cake was added to a 100 L reactor along with isopropyl alcohol (27.34 kg, 34.8 L, 13 L/kg) and hydroxylamine (50percent aqueous solution, 0.05 kg, 1.51 mol, 0.2 eq).
The mixture was heated to 65° C. and monitored by HPLC until (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide was <0.4 AP.
The reaction was then distilled (pot temperature ~50° C., vacuum 300 mbar) until reaction volume was ~60percent of original.
Acetonitrile (5.36 kg, 2 L/kg) was charged and the reaction temperature was increased to 70° C. to achieve complete dissolution.
Water (11.26 L, 4.2 L/kg) was charged slowly while keeping the reaction temperature >65° C.
The reaction was cooled to 15° C. over 2 hours and crystallization occurred.
The slurry was filtered and washed with cold aqueous isopropyl alcohol (2:1 IPA:water by volume).
The cake was dried in a vacuum oven until loss on drying was <1percent.
The product was then recrystallized by dissolving in acetonitrile (2 L/kg based on weight of input of dried cake) and methanol (6 L/kg) and then heated to 50° C. Water (4 L/kg) was added slowly, keeping the reaction temperature >50° C.
The reaction was cooled to 15° C. over 2 hours.
The resulting slurry was filtered and washed with a solution of methanol:acetonitrile:water (6:2:4, 5 L/kg) to give (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (2.02 kg, 50percent yield) as a white solid.
Reference: [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 21-22
[2] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 20-21
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