Ethanol → N-[3-[1-(3,3-dimethylbutyl)-4-hydroxy-2-oxo-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-4H-1$l^{6},4-benzothiazin-7-yl]methanesulfonamide

HRID 2374384Notes

Reaction equation

HRID 2374384 reaction equation
[CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])C=C.[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[CH3:39][C:36]([CH3:37])([CH3:38])[CH2:35][CH2:34][N:33]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[CH:12]=2)=[C:26]([OH:27])[C:28]2=[CH:32][CH:31]=[CH:30][N:29]12

Participants

7

Reactant 4

HCID 702EthanolHCID 2723922Sodium ethoxideHCID 598535731-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl esterHCID 59853605(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-acetic acid

Product 1

HCID 54728266N-[3-[1-(3,3-dimethylbutyl)-4-hydroxy-2-oxo-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-4H-1$l^{6},4-benzothiazin-7-yl]methanesulfonamideYield 42.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

N,N-Dicyclohexylcarbodiimide (0.476 mL of a 1.0 M solution in dichloromethane, 0.476 mmol) was added to a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 8h, 0.190 g, 0.572 mmol) and 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 4c, 0.119 g, 0.475 mmol) in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h then was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (12 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.23 mL, 0.71 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. After cooling to 25° C., the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 40-100% ethyl acetate in hexanes) afforded a solid which was triturated with diethyl ether to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.101 g, 0.20 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.07 (9H, s), 1.65-1.72 (2H, m), 3.09 (3H, s), 4.25-4.29 (2H, m), 5.54 (2H, s), 6.43-6.45 (1H, m), 7.01-7.03 (1H, m), 7.08-7.09 (1H, m), 7.30 (1H, d, J=8.5 Hz), 7.39 (1H, bs), 7.61 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.73 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C22H26N4O6S2 506.13. found 507.27 [M+H+].

Workup

  1. filtrationthen was filtered
  2. concentrationThe filtrate was concentrated in vacuo
  3. dissolutionthe residue was dissolved in ethanol (12 mL) at 25° C
  4. temperaturethe reaction mixture was heated at 80° C. for 5 h
  5. temperatureAfter cooling to 25° C.
  6. customthe mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
  7. dry with materialThe organic layers were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 40-100% ethyl acetate in hexanes)
  11. customafforded a solid which
  12. customwas triturated with diethyl ether

Sources & evidence

ORD record
ord-1631489a53ca4f8580ac678b63e4bc4f
Source dataset
uspto-grants-2008_12
Patent number
US07462611B2

Reaction notes

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