Water → HCID 131731022, compound

HRID 876490Notes

Reaction equation

HRID 876490 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][C@H:22]5[C@H:28]([F:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl-].[CH3:38][Zn+].[NH4+].[Cl-].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C@H:28]1[C@H:22]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:6]4[CH:7]=[C:2]([CH3:38])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]1

Participants

7

Reactant 4

HCID 962WaterHCID 25517Ammonium ChlorideHCID 131731023HCID 131731023, compoundHCID 178477797HCID 178477797, compound

Product 1

HCID 131731022HCID 131731022, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of (trans)-tert-butyl 4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.125 g, 0.225 mmol) and Pd(PPh3)4 (0.0519 g, 0.0449 mmol) in 1.9 mL THF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) by syringe, and the reaction mixture was heated in an 80° C. reaction block. After 6 hours, the reaction mixture was cooled to ambient temperature and saturated NH4Cl and water were added, causing a precipitate to form. The solids were isolated by vacuum filtration through qualitative filter paper, rinsed with water, air dried, and dried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCM gradient) to give the racemic (trans)-product. The resulting mixture was separated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH in hexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid.

Workup

  1. customreaction block
  2. temperaturethe reaction mixture was cooled to ambient temperature
  3. customto form
  4. customThe solids were isolated by vacuum filtration through qualitative filter paper
  5. washrinsed with water, air
  6. customdried
  7. customdried in vacuo
  8. customThe crude was purified on silica gel (1-8% MeOH in DCM gradient)
  9. customto give the racemic (trans)-product
  10. customThe resulting mixture was separated by chiral HPLC
  11. customto give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid

Sources & evidence

ORD record
ord-bd1a6df08b724d56ad6c1629e2b3ae7f
Source dataset
uspto-grants-2015_03
Patent number
US08987251B2

Reaction notes

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