Trifluoroacetic acid → (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide

HRID 454998Notes

Reaction equation

HRID 454998 reaction equation
[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=O)[O:28]C(C)(C)C)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH:46]1[CH2:48][CH:47]1C(Cl)=O.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27]([C@H:47]1[CH2:48][C@@H:46]1[C:42]1[S:41][CH:45]=[CH:44][CH:43]=1)=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 852388192-Thiophen-2-yl-cyclopropane carbonylchlorideHCID 86658150tert-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate

Product 1

HCID 67430811(1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A precooled (0° C.) solution of tert-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (250 mg, 0.55 mmol) and dichloromethane (10 mL) was treated dropwise with trifluoroacetic acid (2 mL). The resulting solution was maintained at room temperature for 16 h, then concentrated to afford a yellow oil that was dissolved in dichloromethane (5 mL) and added to a room temperature solution of 2-thiophen-2-yl-cyclopropane carbonylchloride (100 mg, 0.60 mmol), triethylamine (0.20 mL, 1.4 mmol) and dichloromethane (4 mL). The resulting reaction was maintained overnight, then transferred to a separatory funnel and partitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (10%-50% ethyl acetate in hexanes) to afford (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J=5.6, 3.0 Hz, 2H), 7.76 (dd, J=5.6, 3.0 Hz, 2 H), 7.29-7.34 (m, 2H), 7.07 (dd, J=5.2, 1.1 Hz, 1H), 6.87-6.92 (m, 3H), 6.77 (d, J=3.0 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 5.29-5.37 (m, 1H), 4.03 (dd, J=14.1, 10.1 Hz, 1H), 3.97 (dd, J=14.1, 4.0 Hz, 1H), 3.81 (dd, J=8.8, 5.8 Hz, 1H), 3.73 (dd, J=9.1, 6.8 Hz, 1H), 2.57 (ddd, J=9.5, 5.9, 4.0 Hz, 1H), 1.86 (dq, J=13.1, 6.5 Hz, 1H), 1.66 (ddd, J=8.4, 5.1, 4.2 Hz, 1H), 1.52-1.63 (m, 2H), 1.23-1.36 (m, 2H), 1.14 (ddd, J=8.3, 6.3, 4.3 Hz, 1H), 1.02 (d, J=6.6 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).

Workup

  1. concentrationconcentrated
  2. customto afford a yellow oil that
  3. customThe resulting reaction
  4. temperaturewas maintained overnight
  5. customtransferred to a separatory funnel
  6. custompartitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL)
  7. customThe layers were separated
  8. extractionthe aqueous layer was extracted with ethyl acetate (15 mL)
  9. washThe combined organic layers were washed with water (15 mL) and brine (15 mL)
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customto afford a residue that
  14. customwas purified by column chromatography on silica gel (10%-50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-427d7500da70484da1785884a85cbcc3
Source dataset
uspto-grants-2013_07
Patent number
US08497271B2

Reaction notes

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