Triethylamine → (1R,2S,7R,8S)-5-(7-Bromo-1,1-dioxo-1,4-dihydro-1lambda6-pyrido[2,3-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

HRID 1751292Notes

Reaction equation

HRID 1751292 reaction equation
C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[Na].[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([CH2:34][C:35]([O-])=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1.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>[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:36])[N:12]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[C@@H:11]4[C@H:6]([C:4]=3[OH:3])[C@@H:7]3[CH2:21][C@H:10]4[CH2:9][CH2:8]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1

Participants

6

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 86638953Sodium (7-bromo-1,1-dioxo-1,4-dihydro-1lambda6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate

Product 1

HCID 136402482(1R,2S,7R,8S)-5-(7-Bromo-1,1-dioxo-1,4-dihydro-1lambda6-pyrido[2,3-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-oneYield 60.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 0.213 g, 0.73 mmol), sodium-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate (0.25 g, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.305 g, 0.803 mmol) were combined and dissolved in N,N-dimethylformamide (1.5 mL). The mixture was shaken vigorously for about 1 min until everything dissolved. The solution continued to stir for 1 h. Triethylamine (0.5 mL, 3.65 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to a volume of ˜5 mL. Water (˜20 mL) was added and the product precipitated. The solid was collected by vacuum filtration and purified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes) to afford the desired product, (0.24 g, 0.44 mmol, 60%) as a white, brittle foam. A portion of the product (0.07 g, 0.128 mmol) was recrystallized from n-propanol (0.5 mL) to afford the pure desired product, 5-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-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 (0.044 g, 0.081 mmol, 63%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.23 (2H, m), 1.38-1.60 (4H, m), 2.51 (1H, s), 2.63 (1H, s), 3.00 (1H, d, J=8.4 Hz), 3.55 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=14.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.5 Hz), 8.66 (1H, s), 8.82 (1H, s). LC-MS (ESI) calcd for C23H20BrFN4O4S 546.04, found 547.2 [M+H+].

Workup

  1. dissolutiondissolved
  2. stirringto stir for 1 h
  3. stirringthe mixture was stirred at 50° C. for 16 h
  4. concentrationThe mixture was concentrated in vacuo to a volume of ˜5 mL
  5. additionWater (˜20 mL) was added
  6. customthe product precipitated
  7. filtrationThe solid was collected by vacuum filtration
  8. custompurified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-a14de71a2f4b4493ac2218352315a62e
Source dataset
uspto-grants-2015_10
Patent number
US09156832B2

Reaction notes

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