Dimethylformamide → 1H-Purine-2,6-dione, 7-(2-(ethyl(2-hydroxyethyl)amino)ethyl)-3,7-dihydro-1,3-dimethyl-8-(phenylmethyl)-, hydrochloride (1:1)

HRID 1800858Notes

Reaction equation

HRID 1800858 reaction equation
[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH:38]([N:41](C(C)C)CC)(C)[CH3:39].[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52]([OH:54])=[O:53])=[CH:50][C:49]=1[S:57](=[O:60])(=[O:59])[NH2:58].C[N:62]([C:64]([O:68]N1N=NC2C=CC=NC1=2)=[N+:65]([CH3:67])C)[CH3:63].F[P-](F)(F)(F)(F)F.CN(C=[O:89])C>>[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52]([N:29]2[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]3[C:2]([F:1])=[C:7]([S:8][C:9]4[S:13][C:12]([NH:14][C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[N:11][CH:10]=4)[CH:6]=[CH:5][N:4]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:31][CH2:30]2)=[O:53])=[CH:50][C:49]=1[S:57](=[O:59])(=[O:60])[NH2:58].[CH3:39][CH2:38][N:41]([CH2:51][CH2:52][OH:54])[CH2:6][CH2:5][N:4]1[C:3]2[C:2]([N:62]([CH3:63])[C:64]([N:65]([CH3:67])[C:22]=2[N:24]=[C:25]1[CH2:26][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:68])=[O:89].[ClH:47]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 145684-Chloro-3-sulfamoylbenzoic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 250328563-Fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide

Product 2

HCID 685491H-Purine-2,6-dione, 7-(2-(ethyl(2-hydroxyethyl)amino)ethyl)-3,7-dihydro-1,3-dimethyl-8-(phenylmethyl)-, hydrochloride (1:1)HCID 59321434N-((1-(4-chloro-3-sulfamoylbenzoyl)-4-phenylpiperidin-4-yl)methyl)-3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamide

Procedure

50 mg of 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was mixed with 0.05 ml diisopropylethylamine and 1 ml DMF. 24 mg of 4-chloro-3-sulfamoylbenzoic acid and 40 mg HATU were added and the mixture stirred at room temperature overnight. LC/MS showed completed consumption of compound II. Volatiles were evaporated under a stream of nitrogen and the crude product re-dissolved in 2 ml 5% TFA/MeOH and purified by prep HPLC (C-18 reversed phase column, water/MeOH gradient, buffered with 0.1% TFA). Alternatively a water/acetonitrile gradient, buffered with 10 mM NH4OAc can be used. Product containing fractions were filtered through a cartridge filled with cation exchange resin, rinsed with methanol, eluted with 2 M solution of ammonia in methanol and evaporated. The residue was dissolved in methanol, 1.0 equiv. aq. 1.00 N HCl were added and the title compound was isolated as the mono-HCl salt by evaporation. LC/MS (M+H)+: 752. Ret. time: 2.12 min. (Condition J); analytical HPLC Ret. time: 13.29 min (Condition K).

Workup

  1. customconsumption of compound II
  2. customVolatiles were evaporated under a stream of nitrogen
  3. dissolutionthe crude product re-dissolved in 2 ml 5% TFA/MeOH
  4. custompurified by prep HPLC (C-18 reversed phase column, water/MeOH gradient, buffered with 0.1% TFA)
  5. additionProduct containing fractions
  6. filtrationwere filtered through a cartridge
  7. additionfilled with cation exchange resin
  8. washrinsed with methanol
  9. washeluted with 2 M solution of ammonia in methanol
  10. customevaporated
  11. dissolutionThe residue was dissolved in methanol
  12. addition1.0 equiv. aq. 1.00 N HCl were added

Sources & evidence

ORD record
ord-487bbd8da8c94c0cb05a4d68a2af43df
Source dataset
uspto-grants-2013_01
Patent number
US08343999B2

Reaction notes

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