Diisopropylethylamine → HCID 59272917, compound

HRID 1406591Notes

Reaction equation

HRID 1406591 reaction equation
[F:1][C:2]([F:39])([CH3:38])[C:3]([NH:5][C@@H:6]([CH3:37])[C@@H:7]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)[N:13]=[CH:12]2)=[O:4].Cl.[S:41]1(=[O:48])(=[O:47])[CH2:45][CH2:44][C@H:43]([NH2:46])[CH2:42]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCCC(C)C.CCOC(C)=O.O>[F:1][C:2]([F:39])([CH3:38])[C:3]([NH:5][C@@H:6]([CH3:37])[C@H:7]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:46][C@H:43]1[CH2:44][CH2:45][S:41](=[O:48])(=[O:47])[CH2:42]1)=[O:23])[N:13]=[CH:12]2)[C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=[O:4]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59272915HCID 59272915, compoundHCID 67205227HCID 67205227, compound

Product 1

HCID 59272917HCID 59272917, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 78922-MethylpentaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoic acid (I4) (106 mg, 0.20 mmol), (S)-(−)-tetrahydrothiophene-3-amine-1,1-dioxide hydrochloride (I6) (40 mg, 0.23 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (2 mL) was treated with DIEA (0.138 mL, 0.79 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes. Water (10 mL) was added, the formed suspension was stirred for 1 hour. The solid was collected by filtration, washed with water and further purified by HPLC using an Kromasil 100-10-C18, 50×250 mm column, an 30 min gradient from 50% to 90% MeCN in water with flow=40 mL/min and UV=254 nm to collect fractions. Fractions containing the product was freeze dried, the resulting solid was dissolved in MeOH and iso-Hexane was added. The biphasic mixture was evaporated to give an solid that was suspended in iso-Hexane containing a small volume of EtOAc, the suspension was stirred at ambient temperature for 18 hours. The crystalline solid was collected by filtration, washed with iso-Hexane and dried. Yield 77 mg (59%).

Workup

  1. stirringthe formed suspension was stirred for 1 hour
  2. filtrationThe solid was collected by filtration
  3. washwashed with water
  4. customfurther purified by HPLC
  5. customan 30 min gradient from 50% to 90% MeCN in water with flow=40 mL/min and UV=254 nm to collect fractions
  6. additionFractions containing the product
  7. customdried
  8. dissolutionthe resulting solid was dissolved in MeOH
  9. additioniso-Hexane was added
  10. customThe biphasic mixture was evaporated
  11. customto give an solid
  12. stirringthe suspension was stirred at ambient temperature for 18 hours
  13. filtrationThe crystalline solid was collected by filtration
  14. washwashed with iso-Hexane
  15. customdried

Sources & evidence

ORD record
ord-c9f58ee9381847f2869f6439d3585f7c
Source dataset
uspto-grants-2014_12
Patent number
US08916600B2

Reaction notes

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