Diisopropylethylamine → Thiophene-2-carboxylic acid [3-(4-tert-butyl-benzenesulfonyl)-3-aza-bicyclo[3.1.0]hex-6yl-methyl]-(3-fluoro-4-morpholin-4-yl-phenyl)-amide

HRID 1452942Notes

Reaction equation

HRID 1452942 reaction equation
[CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>ClCCCl.CN(C1C=CN=CC=1)C>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:39])[CH3:40]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 1398824-t-Butylbenzenesulfonyl chlorideHCID 72401275HCID 72401275, compound

Product 1

HCID 86760807Thiophene-2-carboxylic acid [3-(4-tert-butyl-benzenesulfonyl)-3-aza-bicyclo[3.1.0]hex-6yl-methyl]-(3-fluoro-4-morpholin-4-yl-phenyl)-amideYield 78.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (60 mg, 0.15 mmol) in 3 mL of DCE was added DIEA (0.026 mL, 0.45 mmol), DMAP (cat.) and 4-tert-butylbenzene sulfonyl chloride (0.10 mL, 0.45 mmol). The resulting mixture was heated to 80° C. for 1.5 hours, cooled to room temperature and quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried and concentrated. The resulting crude material was purified via flash chromatography with 40% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 70 mg of a white foam. 400 MHz 1H NMR (CDCl3) δ 7.62-7.66 (m, 2H), 7.47-7.50 (m, 2H), 7.29-7.31 (m, 1H), 6.79-6.95 (m, 5H), 3.87-3.89 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.46 (d, J=9.13 Hz, 2H), 3.13-3.15 (m, 4H), 2.94-2.96 (m, 2H), 1.64 (s, 2H), 1.31 (s, 9H), 1.12-1.14 (m, 1H); MS (M+1) 598.2.

Workup

  1. temperaturecooled to room temperature
  2. customquenched with saturated NaHCO3
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with CH2Cl2
  5. customthe combined organic layers were dried
  6. concentrationconcentrated
  7. customThe resulting crude material was purified via flash chromatography with 40% EtOAc/hexanes
  8. additionThe product containing fractions
  9. customwere collected
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-a9e5ae71bd92467b87238d3ed4b33c86
Source dataset
uspto-grants-2009_01
Patent number
US07473787B2

Reaction notes

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