Triethylamine → HCID 135923075, compound

HRID 1751298Notes

Reaction equation

HRID 1751298 reaction equation
[Na].[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 66658077(1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl esterHCID 86638954HCID 86638954, compound

Product 1

HCID 135923075HCID 135923075, compoundYield 7.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

The crude sodium-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetate, (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 0.149 g, 0.51 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (0.194 g, 0.51 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (1 mL). The mixture was stirred at 25° C. for 1 h. Triethylamine (0.35 mL, 2.6 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% to 100% ethyl acetate in hexanes) followed trituration of the resulting oil with a 1:1 mixture of hexanes and diethyl ether (2 mL) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0184 g, 0.039 mmol, 7.7% over two steps), as a pale yellow powder. LC-MS (ESI) calculated for C23H21FN4O4S 468.13, found 469.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.54 (6H, m), 2.35 (1H, d, J=3.7 Hz), 2.46 (1H, s), 2.53 (1H, s), 3.26 (1H, d, J=9.5 Hz), 4.23 (1H, d, J=15.8 Hz), 4.94 (1H, d, J=15.0 Hz), 7.08-7.13 (3H, m), 7.24-7.28 (2H, m), 8.44 (1H, d, J=4.8 Hz), 8.67 (1H, s).

Workup

  1. stirringthe mixture was stirred at 50° C. for 16 h
  2. temperatureUpon cooling
  3. washwashed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL)
  4. dry with materialThe organic layer was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% to 100% ethyl acetate in hexanes)
  8. additionwith a 1:1 mixture of hexanes and diethyl ether (2 mL)

Sources & evidence

ORD record
ord-99ff94feb97c4a7fbdd8e0897f7ea260
Source dataset
uspto-grants-2015_10
Patent number
US09156832B2

Reaction notes

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