Triethylamine → HCID 135923075, compound

HRID 424273Notes

Reaction equation

HRID 424273 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.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.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

7

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 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 61, 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-2066ffff5fb54c3d92227410e7478412
Source dataset
uspto-grants-2012_01
Patent number
US08101800B2

Reaction notes

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