Formamidine → HCID 86693531, compound

HRID 575466Notes

Reaction equation

HRID 575466 reaction equation
I[C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3([C:11]4[N:12]([N:13]=[C:14]([C:16](OCC)=[O:17])[CH:15]=4)[C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.C(N)=[NH:24].C[O-].[Na+].[C:29]([C@:31]1([OH:38])[CH2:35][CH2:34][N:33]([CH3:36])[C:32]1=[O:37])#[CH:30]>CN(C=O)C.CO.[Cl-].[NH4+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:38][C@@:31]1([C:29]#[C:30][C:2]2[CH:22]=[CH:21][C:5]3[O:6][CH2:7][C:8]4([C:11]5[N:12]([N:13]=[C:14]([C:16]([NH2:24])=[O:17])[CH:15]=5)[C:4]=3[CH:3]=2)[CH2:10][CH2:9]4)[CH2:35][CH2:34][N:33]([CH3:36])[C:32]1=[O:37]

Participants

9

Reactant 4

HCID 68047FormamidineHCID 10942334Sodium MethoxideHCID 86693296(R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-oneHCID 86693528HCID 86693528, compound

Product 1

HCID 86693531HCID 86693531, compoundYield 27%

Reagents, catalysts & solvents 4

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Procedure

A solution of ethyl 9-iodo-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxylate (28 mg, 0.068 mmol) in 2 mL of DMF was treated sequentially with formamidine (0.2 mL) and 25 wt % sodium methoxide in methanol (0.1 mL). The mixture was stirred at room temperature overnight (complete conversion of starting material by LCMS). The mixture was diluted with ammonium chloride solution and extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated by rotoevaporation. Similar to as described elsewhere in the application the crude amide was dissolved in dissolved in DMF/TEA (0.75 mL/0.25 mL) and the mixture sparged with nitrogen. Solid bis(triphenylphosphine)palladium(II)dichloride (4.8 mg, 0.00068 mmol), cuprous iodide (1.3 mg, 0.0068 mmol) and (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one (24 mg. 0.17 mmol) was added and the MW vial was sealed. The mixture was heated at 80° C. (sand bath). Complete conversion at 30 min. Purification by reverse phase HPLC gave 7.2 mg of the titled compound as a colorless solid (27% yield).

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe combined organics were dried over sodium sulfate
  3. concentrationconcentrated by rotoevaporation
  4. dissolutionwas dissolved
  5. dissolutionin dissolved in DMF/TEA (0.75 mL/0.25 mL)
  6. customthe mixture sparged with nitrogen
  7. customthe MW vial was sealed
  8. temperatureThe mixture was heated at 80° C. (sand bath)
  9. waitComplete conversion at 30 min
  10. customPurification by reverse phase HPLC

Sources & evidence

ORD record
ord-b5a08b01c31449868925c4258ea78498
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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