Sodium cyanoborohydride → 2-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

HRID 1866728Notes

Reaction equation

HRID 1866728 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[C:11](=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH3-]C#[N:43].[Na+]>CO.O.C([O-])(O)=O.[Na+]>[NH2:43][C@@H:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:14]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:34](=[CH:35][CH:36]=2)[CH2:33][C@:23]2([C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]2=[O:32])[CH2:22]3)=[O:17])[C:13](=[O:37])[C:12]1([CH3:38])[CH3:39]

Participants

6

Reactant 2

HCID 5003444Sodium cyanoborohydrideHCID 250207592-[(6S)-6-(3,5-Difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

Product 1

HCID 579776312-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (380 mg, 0.698 mmol, described in Example 7) and NH4OAc (571 mg, 7.41 mmol) in CH3OH (2 mL) was stirred at ambient temperature for 20 min. NaCNBH3 (498 mg, 7.92 mmol) was added and stirring was continued at ambient temperature for 12 h. The reaction mixture was diluted with H2O (40 mL) and aqueous NaHCO3 (70 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 80:20, to give 2-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted first, and 2-[(4S,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted second, the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.2287; calculated m/z=546.2311 for C30H30F2N5O3.

Workup

  1. stirringstirring
  2. waitwas continued at ambient temperature for 12 h
  3. extractionextracted with EtOAc (2×100 mL)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by silica gel chromatography
  8. washeluting with a gradient of CH2Cl2

Sources & evidence

ORD record
ord-21f903c1530b45aab7b5fe5a3b6b4f78
Source dataset
uspto-grants-2009_12
Patent number
US07629338B2

Reaction notes

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