Diisopropylethylamine → 6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide

HRID 1477772Notes

Reaction equation

HRID 1477772 reaction equation
[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]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.[NH2:54][C@@H:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:56]([NH:58][CH3:59])=[O:57]>CN(C=O)C>[CH3:61][C:60]([CH3:63])([CH3:62])[C@H:55]([NH:54][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:56](=[O:57])[NH:58][CH3:59]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 445856(2S)-2-Amino-N,3,3-trimethylbutanamideHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 866823246-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid

Product 1

HCID 715254026-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amideYield 10.39%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 0.1 g, 35 mmol) was suspended in DMF (3 mL). HBTU (266.14 mg, 0.7 mmol), DIEA (0.31 mL, 1.75 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 52.82 mg, 0.42 mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 10.39%) as white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6 (M+H).

Workup

  1. extractionThe mixture was extracted with ethyl acetate and water
  2. dry with materialthe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water)

Sources & evidence

ORD record
ord-9b1d412957744957beb614a38e0cefff
Source dataset
uspto-grants-2016_08
Patent number
US09403808B2

Reaction notes

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