Dimethylformamide → HCID 136595519, compound

HRID 601354Notes

Reaction equation

HRID 601354 reaction equation
[NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[OH2:32].[C:33]1([CH3:43])C=CC(S(O)(=O)=O)=C[CH:34]=1.CN(C)[CH:46]=[O:47]>>[OH:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:15](=[O:30])[C:14]=1[C:8]1[NH:7][C:6]2[CH:5]=[CH:4][C:3]3[O:31][C:43]([CH2:33][C:34]([O:47][CH3:46])=[O:32])=[N:1][C:2]=3[C:11]=2[S:10](=[O:12])(=[O:13])[N:9]=1

Participants

4

Reactant 3

HCID 6228DimethylformamideHCID 521998p-Toluenesulfonic acid monohydrateHCID 136358419HCID 136358419, compound

Product 1

HCID 136595519HCID 136595519, compoundYield 45%

Conditions

Temperature
50 °C

Procedure

A solution of the product of Example 354 (67.5 mg, 0.015 mmol) in N,N-dimethylformamide (2 mL) was treated with p-toluenesulfonic acid monohydrate (1 mg) and monoorthomalonic acid tetramethyl ester (272 mg, 1.52 mmol). The mixture was heated at 50° C. in an oil bath under a nitrogen atmosphere and the resulting yellow solution was stirred for 3 hrs. At this time, additional ortho ester was added (272 mg, 1.52 mmol) and heating continued for another 5 hrs. The reaction was cooled to room temperature and the solution was concentrated by rotary evaporation in vacuo. The residue was further dried on a vacuum pump, then dissolved in dichloromethane (100 mL) and washed with water (2×50 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol/dichloromethane. The resulting impure material was rechromatographed on silica gel, eluting with a gradient of 5% to 7% acetonitrile/dichloromethane to give the title compound (36 mg, 45%). MS (APCI+) m/z 526 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, J=6.62 Hz, 6 H) 1.91 (m, 1 H) 2.77 (br m, 2 H) 3.72 (s, 3 H) 4.40 (s, 2 H) 6.36 (br m, 1 H) 7.45 (t, J=7.35 Hz, 1 H) 7.70 (d, J=9.19 Hz, 1 H) 7.94 (m, 2 H) 8.20 (d, J=8.82 Hz, 2 H) 14.25 (br s, 1 H). A suspension of the product of Example 363 (6.0 mg, 0.0114 mmol) in anhydrous tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998 N aqueous sodium hydroxide (0.0114 mL, 0.0114 mmol) and the yellow solution mixed for 15 minutes. The solvent was removed under reduced pressure and the residue dried on a vacuum pump to afford the sodium salt of Example 363 (6.1 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=5.15 Hz, 6 H) 1.88 (m, 1 H) 2.75 (m, 1 H) 3.72 (s, 3 H) 4.31 (s, 2 H) 5.95 (m, 1 H) 7.08 (m, 1 H) 7.30 (m, 1 H) 7.58 (m, 2 H) 7.95 (m, 1 H) 8.09 (m, 1 H) 16.55 (s, 1 H).

Workup

  1. temperatureheating
  2. waitcontinued for another 5 hrs
  3. temperatureThe reaction was cooled to room temperature
  4. concentrationthe solution was concentrated by rotary evaporation in vacuo
  5. customThe residue was further dried on a vacuum pump
  6. dissolutiondissolved in dichloromethane (100 mL)
  7. washwashed with water (2×50 mL) and brine
  8. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was chromatographed on silica gel
  12. washeluting with 1% methanol/dichloromethane
  13. customThe resulting impure material was rechromatographed on silica gel
  14. washeluting with a gradient of 5% to 7% acetonitrile/dichloromethane

Sources & evidence

ORD record
ord-42621779ce72474aabcefeff5e081db2
Source dataset
uspto-grants-2011_03
Patent number
US07902203B2

Reaction notes

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