3-Ethynyl-1-methyl-3-pyrrolidinol → 9-(3-Hydroxy-1-methyl-pyrrolidin-3-ylethynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide

HRID 575074Notes

Reaction equation

HRID 575074 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:27])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1)#[CH:20]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:27][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]4)[C:6]=3[CH:18]=2)[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1

Participants

7

Reactant 2

HCID 649161603-Ethynyl-1-methyl-3-pyrrolidinolHCID 6831288310-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Product 1

HCID 717147279-(3-Hydroxy-1-methyl-pyrrolidin-3-ylethynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amideYield 10%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6342AcetonitrileSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
100 °C

Procedure

This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.64 mmol) in acetonitrile (3 mL) and triethylamine (3 mL) were added, Pd(PPh3)2Cl2 (44 mg, 0.06 mmol), 3-Ethynyl-1-methyl-pyrrolidin-3-ol (160 mg, 1.3 mmol) and CuI (12 mg, 0.06 mmol). Then the solution was bubbled N2 for 5 min and heated by microwave for 1 h at 100° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column to afford crude product. The crude product was purified by Prep HPLC to afford the titled compound (22.3 mg, 10%). 1H NMR (DMSO-d6, 400 MHz): δ 8.52 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.48 (s, 4H), 2.95 (m, 1H), 2.77 (m, 2H), 2.67 (m, 1H), 2.31 (s, 3H), 2.28 (m, 1H), 2.08 (m, 1H). LCMS=353.1 [M+H]+.

Workup

  1. customThis compound was prepared
  2. customThen the solution was bubbled N2 for 5 min
  3. filtrationThe reaction mixture was filtered
  4. customthe filtrate was purified by column
  5. customto afford crude product
  6. customThe crude product was purified by Prep HPLC

Sources & evidence

ORD record
ord-26ea36cfdd2f4ea1a51d2c80e42a1bc2
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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