Acetic Acid → 5-[(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)amino]-7-fluoro-1,3-dihydro-2H-indol-2-one

HRID 1039098Notes

Reaction equation

HRID 1039098 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5]2.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH:48]=O)[CH2:40][CH2:39]2)=[N:36][CH:37]=1>ClCCCl.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C@H:44]3[CH2:46][C@H:45]3[CH2:47][CH2:48][NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([F:11])[CH:10]=3)[NH:7][C:6](=[O:12])[CH2:5]4)[CH2:40][CH2:39]2)=[N:36][CH:37]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 669270705-Amino-7-fluoroindolin-2-oneHCID 86666140{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}acetaldehyde

Product 1

HCID 509402795-[(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)amino]-7-fluoro-1,3-dihydro-2H-indol-2-one

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

5-amino-7-fluoro-1,3-dihydro-2H-indol-2-one from step 2 of this example (33 mg, 0.20 mmol) was slurried in DCE (0.9 ml) and acetic acid (51 uL, 0.89 mmol) and NaBH(OAc)3 (76 mg, 0.36 mmol) added. {(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}acetaldehyde (50 mg, 0.18 mmol) from Example 3 was added and the mixture stirred at RT for 2 hours. The mixture was diluted with EtOAc (30 ml), and partitioned across 4:1 water:saturated sodium bicarbonate (50 ml). The layers were separated, the aqueous phase extracted with EtOAc (2×30 ml), the organic fractions combined, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 40% acetone:hexanes. This was followed by a second purification using chromatography on SiO2 eluting with 30% acetone:hexanes to give the titled compound. LRMS calc: 429.17; obs: 430.19 (M+1).

Workup

  1. custompartitioned across 4:1 water
  2. customThe layers were separated
  3. extractionthe aqueous phase extracted with EtOAc (2×30 ml)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customthe volatiles removed in vacuum
  7. customThe product was purified by chromatography on SiO2 eluting with 40% acetone
  8. customThis was followed by a second purification

Sources & evidence

ORD record
ord-f6617257414a4964a15b9771860554b1
Source dataset
uspto-grants-2013_10
Patent number
US08552022B2

Reaction notes

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