Methanol → HCID 67053419, compound

HRID 2387341Notes

Reaction equation

HRID 2387341 reaction equation
[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15][C@@:16]([OH:45])([C:41]([F:44])([F:43])[F:42])[CH2:17][C:18]([C:21]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:22]=3[C:23]([NH:25][C@H]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)C)=[O:24])([CH3:20])[CH3:19])[NH:12][C:9]2=[CH:10][N:11]=1)(=[O:5])=[O:4])[CH3:2].C1(OC)C=CC=CC=1.OP(O)(O)=O.CO>CCC(C)=O.O>[C:31]1([O:34][CH3:35])[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1.[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15][C@@:16]([OH:45])([C:41]([F:42])([F:43])[F:44])[CH2:17][C:18]([C:21]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:22]=3[C:23]([NH2:25])=[O:24])([CH3:20])[CH3:19])[NH:12][C:9]2=[CH:10][N:11]=1)(=[O:5])=[O:4])[CH3:2]

Participants

7

Reactant 4

HCID 887MethanolHCID 1004Phosphoric AcidHCID 7519AnisoleHCID 67132116HCID 67132116, compound2×

Product 1

HCID 67053419HCID 67053419, compoundYield 92.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6569Methyl Ethyl KetoneSolvent

Procedure

2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide (50.0 g, 93.5 wt. %) and 200 mL of anisole are charged to a reactor and agitation at ˜150 rpm initiated to obtain an off-white slurry. 100 mL of 85% aqueous H3PO4 was added and the reaction mixture heated to 100° C.±5° C. After 1.0 hour, the reaction was checked by HPLC after preparing a sample by adding a ˜0.1 mL reaction mixture aliquot to 10 mL of MeOH. If the area % of 2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide is <0.5%, proceed; if it is not, age another 30 minutes at 100° C.±5° C. and repeat the HPLC check. The reaction mixture was cooled to 65° C.-70° C. and 200.0 mL of water was added while maintaining the reaction mixture at 65° C.-70° C. A rough slurry was obtained and 150 mL of MEK was added while maintaining the reaction mixture at 65° C.-70° C. The reaction mixture became a smooth slurry, which was held at 65° C.-70° C. for 30 minutes, then ramped to 20° C.-25° C. over no less than 3 hours. The reaction mixture was then held at 20° C.-25° C. for 3 to 4 hours. The solid was filtered, washed with 150 mL of water and then 150 mL of a mixture of MEK/heptane (1:2 v/v), and transferred to a vacuum oven and dried at 65° C.-70° C. with a nitrogen sweep until KF<0.5%. (R)-2-(4-((5-(Ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluorobenzamide anisole solvate was obtained as a white-yellow solid (44.1 g, 92.1% yield, HPLC: 98.0 area % (220 nm)).

Workup

  1. customto obtain an off-white slurry
  2. temperaturethe reaction mixture heated to 100° C.±5° C
  3. customafter preparing a sample
  4. additionby adding
  5. customanother 30 minutes
  6. customat 100° C.±5° C.
  7. temperatureThe reaction mixture was cooled to 65° C.-70° C.
  8. temperaturewhile maintaining the reaction mixture at 65° C.-70° C
  9. customA rough slurry was obtained
  10. temperaturewhile maintaining the reaction mixture at 65° C.-70° C
  11. waitwas held at 65° C.-70° C. for 30 minutes
  12. waitramped to 20° C.-25° C. over no less than 3 hours
  13. waitThe reaction mixture was then held at 20° C.-25° C. for 3 to 4 hours
  14. filtrationThe solid was filtered
  15. washwashed with 150 mL of water
  16. dry with materialdried at 65° C.-70° C. with a nitrogen sweep until KF<0.5%

Sources & evidence

ORD record
ord-8913f687a54e4e37a9f4720b87be7f99
Source dataset
uspto-grants-2012_09
Patent number
US08268859B2

Reaction notes

Loading…