Diisopropylethylamine → (1S,3R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxycyclopentanecarboxamide

HRID 64032Notes

Reaction equation

HRID 64032 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C@H:27]3[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]3)=[O:31])=[C:16]2[N:15]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 45076184HCID 45076184, compoundHCID 58386314(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine

Product 1

HCID 46189280(1S,3R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxycyclopentanecarboxamideYield 30%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

A DMA (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), (1S,3R)-3-hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFID Therapeutics Inc.] and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (56 mg, 0.17 mmol) was first cooled in an ice-water bath, then DIEA (0.083 mL, 0.48 mmol) was added to reaction drop-wise. Ice bath was then removed and the reaction was stirred at ambient temperature for 1 hour to reach completion. The reaction mixture was diluted with water (10 mL) and vacuum-filtered, yielding the crude product as a beige solid. The crude was purified by reverse phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a solid (20 mg, 30% yield). MS (apci) m/z=428.2 (M+H).

Workup

  1. customIce bath was then removed
  2. additionThe reaction mixture was diluted with water (10 mL)
  3. filtrationvacuum-filtered
  4. customyielding the crude product as a beige solid
  5. customThe crude was purified by reverse phase column chromatography
  6. washeluting with 5 to 57% acetonitrile/water

Sources & evidence

ORD record
ord-d3c9cacfffde43b598fdb00d5c3c99ae
Source dataset
uspto-grants-2016_09
Patent number
US09447104B2

Reaction notes

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