Triethylamine → (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one

HRID 1516025Notes

Reaction equation

HRID 1516025 reaction equation
[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:14]2[S:13](=[O:16])(=[O:15])[N:12]=[C:11]([CH2:17][C:18]([OH:20])=O)[NH:10][C:9]=2[S:8][CH:7]=1.C([O:23][C:24]([C@H:26]1[C@@H:31]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C@H:30]2[CH2:41][C@@H:27]1[CH2:28][CH2:29]2)=O)C.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:32]2[C:18](=[O:20])[C:17]([C:11]3[NH:10][C:9]4[S:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:14]=4[S:13](=[O:15])(=[O:16])[N:12]=3)=[C:24]([OH:23])[C@H:26]3[C@@H:31]2[C@H:30]2[CH2:41][C@@H:27]3[CH2:28][CH2:29]2)=[CH:39][CH:38]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 58000269(7-Methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acidHCID 66658077(1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

Product 1

HCID 136395904(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-oneYield 67%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.38 g, 1.20 mmol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.42 g, 1.44 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g, 1.80 mmol). The reaction was stirred at 25° C. for 15 min before triethylamine (1 mL, 7.20 mmol) was added. The reaction was then stirred at 75° C. overnight. The reaction was cooled to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (5 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-50% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.44 g, 0.80 mmol, 67%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.55-2.56 (1H, m), 2.82-2.86 (2H, m), 3.45 (3H, s), 4.21 (1H, d, J=15.6 Hz), 4.79 (2H, s), 4.82 (2H, s), 5.15 (1H, d, J=15.2 Hz), 7.00-7.07 (3H, m), 7.20 (2H, dd, J=5.6, 8.8 Hz).

Workup

  1. additionwas added
  2. temperatureThe reaction was cooled to 25° C.
  3. customquenched with 1.0 M aqueous hydrochloric acid solution (5 mL)
  4. extractionThe resulting mixture was extracted with dichloromethane (3×10 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-e453c57b61aa474e8493b07f7f7e34ba
Source dataset
uspto-grants-2012_07
Patent number
US08222404B2

Reaction notes

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