2-Bromo-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one → 2-[8-(4-Morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin5-yl]-5,6-dihydro-furo[2,3-c]pyrrol-4-one

HRID 1921846Notes

Reaction equation

HRID 1921846 reaction equation
[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17](C4C=NNC=4C#N)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(=O)N(C1C=CC(N2CCOCC2)=CC=1)C1C2N(C=CN=2)C([Sn](CCCC)(CCCC)CCCC)=CN=1)(C)(C)C.Br[C:73]1[O:81][CH:76]2[CH2:77][NH:78][C:79](=[O:80])[CH:75]2[CH:74]=1>CN(C=O)C.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>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17]([C:73]4[O:81][C:76]5[CH2:77][NH:78][C:79](=[O:80])[C:75]=5[CH:74]=4)=[CH:18][N:19]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1

Participants

6

Reactant 3

HCID 590230212-Bromo-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-oneHCID 590230864-[8-(4-Morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin-5-yl]-2H-pyrazole-3-carbonitrileHCID 59023110(4-Morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester

Product 1

HCID 590229852-[8-(4-Morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin5-yl]-5,6-dihydro-furo[2,3-c]pyrrol-4-oneYield 64%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

In the same way as described for Compound 212, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (255 mg, 0.373 mmol), 2-bromo-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one (50 mg, 0.249 mmol) and Pd(PPh3)4 (29 mg, 0.0249 mmol) in DMF (3 mL). The reaction mixture is concentrated in vacuo and the residue dissolved in 1:1 DCM:TFA (drop of H2O) and stirred at room temperature for 3 hours. The mixture is partitioned between ethyl acetate and sat. NaHCO3 and the aqueous layer is extracted with ethyl acetate (3×). The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with DCM followed by a 97:3 mixture DCM:NH3 (7M in MeOH). The fractions containing the desired compound are concentrated in vacuo to give a solid which is triturated with diethyl ether to afford the title compound (66.3 mg, 64%). Conversion of the compound into the mesylate salt using 1M MsOH (0.16 mL) affords the title product as a solid (69.3 mg, 87%). LCMS: Rt 2.52 min (99%), m/z (APCI) 417 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.36 (3H, s, MsOH), 3.25 (4H, m), 3.84 (4H, m), 4.52 (2H, s), 7.18 (2H, br s), 7.40 (1H, s), 7.83 (1H, s), 7.90 (3H, m), 8.21 (1H, br s), 8.44 (1H, s), 10.25 (1H, br s).

Workup

  1. concentrationThe reaction mixture is concentrated in vacuo
  2. dissolutionthe residue dissolved in 1:1 DCM
  3. customThe mixture is partitioned between ethyl acetate and sat. NaHCO3
  4. extractionthe aqueous layer is extracted with ethyl acetate (3×)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue is purified by silica gel column chromatography
  9. washeluting with DCM
  10. additionThe fractions containing the desired compound
  11. concentrationare concentrated in vacuo
  12. customto give a solid which
  13. customis triturated with diethyl ether

Sources & evidence

ORD record
ord-637cc53768f345e5921620f2218cebf2
Source dataset
uspto-grants-2012_05
Patent number
US08173656B2

Reaction notes

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