Tetrahydrofuran → HCID 58920030, compound

HRID 1365549Notes

Reaction equation

HRID 1365549 reaction equation
CN(C)CCCN(CC)C([O:9][C:10](=O)[C:11]([F:48])([F:47])[CH:12]([NH:14][C:15]([NH:17][C@:18](C1C=CC(Cl)=CN=1)([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH3:13])=N.[CH3:53][NH2:54].[ClH:55].C[CH2:57][N:58](CC)CC.[CH2:63]1[CH2:67]O[CH2:65][CH2:64]1>>[Cl:55][C:64]1[CH:63]=[CH:67][C:53]([C@@:18]([NH:17][C:15](=[O:16])[NH:14][CH:12]([CH3:13])[C:11]([F:48])([F:47])[C:10]([NH:58][CH3:57])=[O:9])([C:26]2[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:54][CH:65]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 6364545Methylamine hydrochlorideHCID 87209568HCID 87209568, compound

Product 1

HCID 58920030HCID 58920030, compoundYield 32%

Conditions

Temperature
80 °C

Procedure

To a solution of 3-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-2,2-difluorobutanoic-(3-(dimethylamino)propyl)-N-ethylcarbamimidic anhydride (8 mg, 0.01 mmol) in THF (0.5 mL) was added CH3NH2HCl (7 mg, 0.10 mmol) and NEt3 (40 uL, 0.29 mmol). The reaction vessel was sealed and heated at 80° C. for 16 h, then allowed to cool to room temperature. The solvents were removed and the residue purified by preparative HPLC Phenomenex Luna AXIA 5u 21.2×100 mm eluting with 30-100% ACN (90% in H2O, 0.1% TFA) gradient over 10 min with UV detection at 220 nm to yield 3-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-2,2-difluoro-N-methylbutanamide as a white solid (2 mg, 32% yield). LCMS RT=1.97 min [M+H]=621.6 (LCMS Method 2). NMR: 500 MHz 1H (CDCl3) 8.25 ppm, 1H, m; 7.65 ppm, 1H, m; 7.36 ppm, 1H, m; 7.10 ppm, 5H, m; 6.89 ppm, 1H, m; 6.51 ppm, 3H, m; 5.86 ppm, 1H, J=65 Hz; 5.15 ppm, 1H, m; 4.48 ppm, 1H, m; 4.28 ppm, 1H, m; 3.50 ppm, 1H, m; 2.88 ppm, 3H, m; 1.20 ppm, 3H, m.

Workup

  1. customThe reaction vessel was sealed
  2. temperatureto cool to room temperature
  3. customThe solvents were removed
  4. customthe residue purified by preparative HPLC Phenomenex Luna AXIA 5u 21.2×100 mm
  5. washeluting with 30-100% ACN (90% in H2O, 0.1% TFA) gradient over 10 min with UV detection at 220 nm

Sources & evidence

ORD record
ord-4c7807f5c4354cada181fc2f69539dfc
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

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