Cesium carbonate → 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 1670567Notes

Reaction equation

HRID 1670567 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[S:27][C:26]([NH:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[S:27][C:26]([NH:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[N:25][CH:24]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 598222763-tert-Butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 59822318N-(5-bromothiazol-2-yl)-cyclopropylmethylamine

Product 1

HCID 866237063-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 44%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.202 g, 0.617 mmol) and N-(5-bromothiazol-2-yl)-cyclopropylmethylamine (0.14 g, 0.62 mmol) in anhydrous DMF (6.2 mL) at room temperature add cesium carbonate (0.22 g, 0.68 mmol). Stir at room temperature overnight and partition the reaction mixture between saturated aqueous NaHCO3 (50 mL) and DCM (100 mL). Dry the organic extract over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to an Analogix® column (40 g) and purify the crude intermediate by preparative liquid chromatography (100:0 to 75:25 hexane/EtOAc over 30 min; 75:25 to 50:50 hexane/EtOAc over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.129 g, 44%). MS (ES+) m/z: 480.2 (M+H)+.

Workup

  1. custompartition the reaction mixture between saturated aqueous NaHCO3 (50 mL) and DCM (100 mL)
  2. customDry the
  3. extractionorganic extract over Na2SO4
  4. filtrationfilter
  5. concentrationconcentrate in vacuo
  6. dissolutionDissolve the residue in DCM
  7. customload the solution on to an Analogix® column (40 g) and purify the crude intermediate by preparative liquid chromatography (100:0 to 75:25 hexane/EtOAc over 30 min; 75:25 to 50:50 hexane/EtOAc over 33 min; 35 mL/min)

Sources & evidence

ORD record
ord-6e3cf61f8efa476d8c0144513a632a08
Source dataset
uspto-grants-2011_08
Patent number
US07994163B2

Reaction notes

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