Diisopropylethylamine → (S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate

HRID 596046Notes

Reaction equation

HRID 596046 reaction equation
[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([O:28][CH2:29][C@@H:30]([NH2:39])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)(=O)C>[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])([O:28][CH2:29][C@@H:30]([NH:39][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C@@H:8]3[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]3)[N:4]=2)=[CH:17][C:18]=1[F:25])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 118045308(S)-2-amino-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphateHCID 1180458424-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid

Product 1

HCID 118046009(S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphateYield 77%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (215 mg, 0.509 mmol) in NMP (Volume: 4 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (260 mg, 0.509 mmol), DIEA (0.534 mL, 3.06 mmol) and then HATU (290 mg, 0.764 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by LCMS. To the crude reaction was added 150 ml of ethyl acetate washed with saturated bicarbonate (2×), water (3×), saturated salt solution, dried sodium sulfate, filtered and dried to residue. The crude product was purified by silica gel chromatograph 24 g column (DCM loading) eluting with 0-80% (EtOAc with 10% MeOH)/heptane. The desired fractions were concentrated to constant mass to give 315 mg of desired product as free base. (77% yield). LCMS (m/z): 805.3 (MH+), 1.01 min.

Workup

  1. customTo the crude reaction
  2. washwashed with saturated bicarbonate (2×), water (3×), saturated salt solution, dried sodium sulfate
  3. filtrationfiltered
  4. customdried to residue
  5. customThe crude product was purified by silica gel chromatograph 24 g column (DCM loading)
  6. washeluting with 0-80% (EtOAc with 10% MeOH)/heptane
  7. concentrationThe desired fractions were concentrated to constant mass

Sources & evidence

ORD record
ord-f204cd990f7347f39232d49ba91f8b44
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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