Sarcosine → (1R,2S,7R,8S)-5-[7-(1,1-Dioxo-1lambda6-isothiazolidin-2-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[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 548327Notes

Reaction equation

HRID 548327 reaction equation
N(CC(O)=O)C.[S:7]1(=[O:13])(=[O:12])[CH2:11][CH2:10][CH2:9][NH:8]1.[F:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[C:29](=[O:30])[C:28]([C:31]3[NH:36][C:35]4[CH:37]=[CH:38][C:39](I)=[CH:40][C:34]=4[S:33](=[O:43])(=[O:42])[N:32]=3)=[C:27]([OH:44])[C@H:26]3[C@@H:21]2[C@H:22]2[CH2:45][C@@H:25]3[CH2:24][CH2:23]2)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[O:12]=[S:7]1(=[O:13])[CH2:11][CH2:10][CH2:9][N:8]1[C:39]1[CH:38]=[CH:37][C:35]2[NH:36][C:31]([C:28]3[C:29](=[O:30])[N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:47][CH:46]=4)[C@@H:21]4[C@H:26]([C:27]=3[OH:44])[C@@H:25]3[CH2:45][C@H:22]4[CH2:23][CH2:24]3)=[N:32][S:33](=[O:43])(=[O:42])[C:34]=2[CH:40]=1

Participants

6

Reactant 4

HCID 1088SarcosineHCID 62657Potassium Phosphate, TribasicHCID 6421571,3-PropanesultamHCID 136395898(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one

Product 1

HCID 136402459(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-1lambda6-isothiazolidin-2-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[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

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst

Conditions

Temperature
100 °C

Procedure

A reaction flask was charged with copper (I) iodide (8 mg, 0.042 mmol), sarcosine (N-methyl glycine) (9 mg, 0.1 mmol), isothiazolidine 1,1-dioxide (204 mg, 1.685 mmol), (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 100 mg, 0.168 mmol) and potassium phosphate (179 mg, 0.842 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (3 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 17 h, and then allowed to cool to 25° C. The mixture was diluted with ethyl acetate (30 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×20 mL) and saturated aqueous brine solution (40 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; I column: 100% dichloromethane, 2nd column: 5% hexanes in dichloromethane) to afford the desired product. The crude product was triturated with absolute ethanol (3×) and dried in vacuo at 60° C. to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[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 (70 mg, 0.119 mmol, 71%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.17-1.24 (2H, m), 1.40-1.61 (4H, m), 2.39-2.46 (2H, m), 2.51-2.54 (1H, m), 2.64-2.65 (1H, m), 3.03-3.05 (1H, m), 3.53-3.60 (3H, m), 3.83 (2H, t, J=6.3 Hz), 4.43 (1H, d, J=15.4 Hz), 4.97 (1H, d, J=15.6 Hz), 7.15 (2H, t, J=9.0 Hz), 7.32-7.35 (2H, m), 7.51-7.54 (2H, m), 7.62 (1H, d, J=8.5 Hz). LC-MS (ESI) calcd for C27H27FN4O6S2 586.14, found 587.4 [M+H+].

Workup

  1. customThe flask was degassed
  2. additionanhydrous N,N-dimethylformamide (3 mL) was added
  3. temperatureto cool to 25° C
  4. additionThe mixture was diluted with ethyl acetate (30 mL)
  5. washwashed with 1.0 M aqueous hydrochloric acid solution (2×20 mL) and saturated aqueous brine solution (40 mL)
  6. dry with materialThe organic layer was dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by flash column chromatography (Teledyne Isco RediSep column; I column: 100% dichloromethane, 2nd column: 5% hexanes in dichloromethane)

Sources & evidence

ORD record
ord-4287d55102f348688ae1f83886ddcd07
Source dataset
uspto-grants-2011_05
Patent number
US07939524B2

Reaction notes

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