Lithium Chloride → Methyl (4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate

HRID 2402086Notes

Reaction equation

HRID 2402086 reaction equation
Br[C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1.[Cl-].[Li+]>O1CCOCC1.CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Br:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=2)[S:3][C:4]=1[C:10]1[N:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:11]=1

Participants

8

Reactant 3

HCID 433294Lithium ChlorideHCID 58095130Methyl[4-(trimethylstannyl)pyridin-2-yl]carbamateHCID 667492652,4-Dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

Product 1

HCID 68095977Methyl (4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamateYield 77.8%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (1.27 g, 3.05 mmol), methyl [4-(trimethylstannyl)pyridin-2-yl]carbamate (0.960 g, 3.05 mmol), lithium chloride (0.388 g, 9.14 mmol), copper(I) iodide (0.174 g, 0.914 mmol) and tetrakis(triphenylphosphine)platinum (0) (0.190 g, 0.152 mmol) in anhydrous 1,4-dioxane (45 mL) was degassed by evacuation in vacuum and backfilling with N2 4 times, then heated to 100° C. under N2 for 8 hours, then cooled to room temperature. The suspension was filtered and washed with dioxane. The solid was suspended in 20% MeOH in DCM (300 mL), and washed with water (2×). The organic suspension was concentrated in a rotavapor to give a solid residue. The residue was stirred in DMF/DCM (10 mL/10 mL) at room temperature for 20 min, filtered and washed with DCM to give a solid product (1.16 g, yield 77.8%). LC/MS: (FA) ES+ 489, 491. 1H NMR (400 MHz, d4-MeOH/d-chloroform) δ 8.26-8.35 (m, 3H), 7.34 (m, 1H), 5.48 (m, 1H), 4.00 (m, 1H), 3.73 (s, 3H), 3.64-3.69 (m, 1H), 1.97-2.14 (m, 3H), 1.58-1.68 (m, 3H).

Workup

  1. customwas degassed by evacuation in vacuum and backfilling with N2 4 times
  2. temperaturecooled to room temperature
  3. filtrationThe suspension was filtered
  4. washwashed with dioxane
  5. washwashed with water (2×)
  6. concentrationThe organic suspension was concentrated in a rotavapor
  7. customto give a solid residue
  8. filtrationfiltered
  9. washwashed with DCM

Sources & evidence

ORD record
ord-f0015ee23ca240ff992dde3d6fa22d7b
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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