Dichloromethane → (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

HRID 1043746Notes

Reaction equation

HRID 1043746 reaction equation
Br[C:2]1[N:3]=[C:4]([CH:33]2[CH2:35][CH2:34]2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[N:8]=1.[Cl:36][C:37]1[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=[CH:39][C:38]=1[NH:52][S:53]([CH2:56][CH2:57][CH3:58])(=[O:55])=[O:54].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:36][C:37]1[C:38]([NH:52][S:53]([CH2:56][CH2:57][CH3:58])(=[O:55])=[O:54])=[CH:39][CH:40]=[CH:41][C:42]=1[C:2]1[N:3]=[C:4]([CH:33]2[CH2:35][CH2:34]2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[N:8]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 58164515N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamideHCID 69811029(S)-tert-butyl 1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

Product 1

HCID 69811403(S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamateYield 31.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a mixture of (S)-tert-butyl 1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1a, 256 mg, 0.45 mmol), N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (SM-10, 292 mg, 0.81 mmol), aqueous 2.0 M Na2CO3 solution in DME (4 mL) was added PdCl2(dppf).DCM. The reaction vial was sealed and irradiated at 120° C. for 10 minutes in a microwave reactor. LCMS indicated complete conversion and the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated to furnish a dark red oil. Purification by flash chromatography (SiO2, 50-100% EtOAc in heptane) provided (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (4A-1: 116 mg, 0.14 mmol) as a yellow oil: LCMS (m/z) 720.3, (MH+), tR=1.03 minutes.

Workup

  1. customThe reaction
  2. customvial was sealed
  3. customirradiated at 120° C. for 10 minutes in a microwave reactor
  4. extractionextracted with EtOAc (2×)
  5. washThe combined organic portions were washed with water, brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customto furnish a dark red oil
  9. customPurification by flash chromatography (SiO2, 50-100% EtOAc in heptane)

Sources & evidence

ORD record
ord-0bb160bb3f4f456a8425cd3192a8bcba
Source dataset
uspto-grants-2013_10
Patent number
US08563553B2

Reaction notes

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