Ethanol → HCID 135857093, compound

HRID 1172389Notes

Reaction equation

HRID 1172389 reaction equation
C(O[C:4]([C:6]1([CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH: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)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:35](=[O:36])[C:34]([C:29]3[NH:28][C:27]4[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=4[S:31](=[O:33])(=[O:32])[N:30]=3)=[C:4]([OH:5])[C:6]3([CH2:7][CH2:8]3)[CH2:9]2)=[CH:17][CH:16]=1

Participants

9

Reactant 6

HCID 702EthanolHCID 79724-MethylmorpholineHCID 2723922Sodium ethoxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 248585392H-1,2,4-Benzothiadiazine-3-acetic acid, 7-[(methylsulfonyl)amino]-, 1,1-dioxideHCID 59555492HCID 59555492, compound

Product 1

HCID 135857093HCID 135857093, compoundYield 39%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 1-[(4-fluoro-benzylamino)-methyl]-cyclopropanecarboxylic acid ethyl ester (72 mg, 0.29 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (105 mg, 0.32 mmol) in anhydrous N,N-dimethylformamide (4 mL) was treated sequentially with N-methylmorpholine (70 μL, 0.64 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol). The reaction mixture was stirred at 25° C. for 1 h, diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL), treated with a 21 wt % solution of sodium ethoxide in ethanol (0.5 mL, 1.37 mmol). The reaction was stirred and heated at 60° C. for 1.5 h, allowed to cool to 25° C., and quenched with a 0.5 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-HPLC {Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to give N-{3-[5-(4-fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro[2.5]oct-7-en-7-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (58 mg, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.97 (br s, 2H), 1.34 (br s, 2H), 3.06 (s, 3H), 3.41 (s, 2H), 4.65 (s, 2H), 7.17 (t, J=8.8 Hz, 2H), 7.36 (dd, J1=8.8 Hz, J2=5.4 Hz, 2H), 7.51 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.57-7.60 (m, 2H), 10.16 (s, 1H), 13.86 (br s, 1H). LC-MS (ESI) calculated for C22H21FN4O6S2: 520.1, found 521.3 [M+H+].

Workup

  1. extractionextracted with ethyl acetate (3×30 mL)
  2. washThe combined organic layers were washed with brine (20 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in ethanol (5 mL)
  7. stirringThe reaction was stirred
  8. temperatureheated at 60° C. for 1.5 h
  9. temperatureto cool to 25° C.
  10. customquenched with a 0.5 M aqueous hydrochloric acid solution (10 mL)
  11. extractionThe resulting mixture was extracted with ethyl acetate (3×30 mL)
  12. washthe combined organic layers were washed with brine (20 mL)
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customThe crude residue was purified by prep-HPLC {Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in 7 min

Sources & evidence

ORD record
ord-544862a3aefa465eb6d8410a2140f883
Source dataset
uspto-grants-2010_11
Patent number
US07834009B2

Reaction notes

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