Diisopropylethylamine → tert-Butyl{(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate

HRID 1842608Notes

Reaction equation

HRID 1842608 reaction equation
[F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:19](O)=[O:20])[S:16][C:17]=2[CH3:18])[CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:50][C@H:51]1[C:56]([F:58])([F:57])[CH2:55][CH2:54][CH2:53][C@H:52]1[NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:52]1[CH2:53][CH2:54][CH2:55][C:56]([F:58])([F:57])[C@@H:51]1[NH:50][C:19]([C:15]1[S:16][C:17]([CH3:18])=[C:13]([C:12]2[CH:11]=[N:10][N:8]3[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:22])[CH:5]=[N:6][C:7]=23)[CH:14]=1)=[O:20])([CH3:65])([CH3:63])[CH3:64]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 59603811tert-Butyl ((1R,2R)-2-amino-3,3-difluorocyclohexyl)carbamateHCID 683051734-[6-(Difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylic acid

Product 1

HCID 89750994tert-Butyl{(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamateYield 68.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

4-[6-(Difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylic acid (0.768 g, 2.36 mmol) and BOP (3.13 g, 7.08 mmol) were dissolved in DMF (15.7 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.650 g, 2.60 mmol) and diisopropylethyl amine (619, 3.54 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate twice and brine once. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc/Hex) to give the title compound (0.900 g, 1.61 mmol). LRMS (APCI) calc'd for (C24H27F4N5O4S) [M+H]+, 558.2; found 558.0.

Workup

  1. stirringthe reaction stirred at room temperature for 16 h
  2. washwashed with saturated sodium bicarbonate twice
  3. dry with materialThe organic layer was dried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by column chromatography (0-100% EtOAc/Hex)

Sources & evidence

ORD record
ord-2597a562c507424a87e94c6f68fd807e
Source dataset
uspto-grants-2015_02
Patent number
US08946237B2

Reaction notes

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