Ethyl Acetate → HCID 86704075, compound

HRID 2206391Notes

Reaction equation

HRID 2206391 reaction equation
[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2OC)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH:43]([N:46](CC)C(C)C)([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1([O:68][C:69](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OCC)(=[O:78])C>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][CH:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](=[O:36])[NH:46][CH:43]([CH3:45])[CH2:44][OH:78])=[CH:33][C:32]=2[O:68][CH3:69])=[O:29])[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 53358942Idasanutlin

Product 1

HCID 86704075HCID 86704075, compoundYield 90.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

4-((2R,3S,4R,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 119.9 mg, 194 μmol) was suspended in methylene chloride (5 mL), then N,N-diisopropylethylamine (156 mg, 210 μL, 1.21 mmol) was added, followed by (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU, 120 mg, 316 μmol). After stirring at room temperature under argon for a few minutes, DL-alaminol (24.1 mg, 25 μL, 321 μmol) was added. The reaction progress was monitored by LC-MS. After its completion (˜2 h), the reaction mixture was taken in ethyl acetate (75 mL) and water (15 mL). The layers were separated, and the organic layers were washed with saturated solution of sodium bicarbonate (10 mL), water (15 mL), brine (15 mL), and dried over anhydrous sodium sulfate. The solids were filtered off, and the crude residue was purified by flash chromatography (8 g of silica gel, eluting with 0.5-5.0% ethanol in methylene chloride) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-(1-hydroxypropan-2-ylcarbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide (118.9 mg, 177 μmol, 90.8% yield) as white solids. MS (ES+) m/z calcd. for C34H37Cl2F2N4O4: [(M+H)+]: 673. found: 673.

Workup

  1. additionDL-alaminol (24.1 mg, 25 μL, 321 μmol) was added
  2. customAfter its completion (˜2 h)
  3. customThe layers were separated
  4. washthe organic layers were washed with saturated solution of sodium bicarbonate (10 mL), water (15 mL), brine (15 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationThe solids were filtered off
  7. customthe crude residue was purified by flash chromatography (8 g of silica gel, eluting with 0.5-5.0% ethanol in methylene chloride)

Sources & evidence

ORD record
ord-e3f64d01e1d5441f9f06989ea29dc91c
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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