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Water → (2s,3s,5r)-2-Benzyl-3-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1h-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester

HRID 409429
Notes
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Reaction equation

HRID 409429 reaction equation
[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([C:27]2[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[CH:17]=2)[C@@H:8]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[CH:17]=2)[C:27]2[N:32]=[CH:31][C:30]([C:45]3[CH:44]=[N:43][N:42]([CH3:41])[CH:46]=3)=[CH:29][N:28]=2)[C@@H:8]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])([CH3:3])[CH3:2]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 42633349(2S,3S,5R)-2-Benzyl-3-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester

Product 1

HCID 42633350
(2s,3s,5r)-2-Benzyl-3-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1h-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester
Yield 51%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

(2S,3S,5R)-2-Benzyl-3-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.042 mmol; 27 mg), tetrakis(triphenylphosphine) palladium (0.0042 mmol; 4.9 mg), 1-methylpyrazol-4-boronic acid pinacol ester (0.063 mmol; 13 mg) and sodium carbonate (0.084 mmol; 8.9 mg) are dissolved in 1,2-dimethoxyethane (0.8 mL) and water (0.08 mL) at room temperature. The mixture is stirred at 90° C. for 17 hours, and then cooled to ambient temperature. To the mixture is added brine and the solution is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-Benzyl-3-{(3-chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (13.6 mg, 51%); ESI-MS m/z: 641 [M+1]+, Retention time 2.62 min (condition A).

Workup

  1. customat room temperature
  2. temperaturecooled to ambient temperature
  3. extractionthe solution is extracted three times with EtOAc
  4. washThe combined organic layer is washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc)

Sources & evidence

ORD record
ord-b0775fece25f4f28a429dca19745adbc
Source dataset
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08759365B2

Reaction notes

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