Tetrahydrofuran → 4-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)-2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812436Notes

Reaction equation

HRID 1812436 reaction equation
[S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3][CH2:2]1.C1COCC1.[CH3:17][O:18][C:19]1[CH:60]=[CH:59][C:22]([CH2:23][N:24]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:25]2[N:30]=[C:29]([CH3:31])[N:28]=[C:27]([C:32]3[C:33]([NH:40][C:41]4[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=4)=[N:34][CH:35]=[C:36]([CH:39]=3)[CH:37]=O)[N:26]=2)=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:11]=[S:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][N:8]([CH2:37][C:36]3[CH:39]=[C:32]([C:27]4[N:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:24]([CH2:23][C:22]5[CH:59]=[CH:60][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[CH2:50][C:51]5[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=5)[N:26]=4)[C:33]([NH:40][C:41]4[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=4)=[N:34][CH:35]=3)[CH2:9][CH:4]2[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 5003444Sodium cyanoborohydrideHCID 59215775Hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxideHCID 715003625-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

Product 1

HCID 666116654-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)-2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 77%

Reagents, catalysts & solvents 1

HCID 76524Titanium tetraethoxideCatalyst

Conditions

Temperature
0 °C

Procedure

To a stirred mixture of hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (ref: WO2007028654, 0.180 g, 1.021 mmol) in THF (2.50 mL, 30.5 mmol) was added 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (preparation previously described, 0.3042 g, 0.511 mmol) and titanium (IV) ethoxide (0.529 mL, 2.55 mmol) and the mixture was heated at 70° C. overnight. The resulting mixture was cooled to 0° C. and excess sodium cyanoborohydride (0.160 g, 2.55 mmol) was added and the entire mixture was stirred at the same temperature for 1 h prior to being quenched with MeOH (1.0 mL). The mixture was concentrated and adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 70% ethyl acetate in DCM to obtain the desired product 4-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)-2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.297 g, 77%) as a yellow syrup. m/z (ESI, +ve ion) 756 (M+H)+.

Workup

  1. custompreparation
  2. customto being quenched with MeOH (1.0 mL)
  3. concentrationThe mixture was concentrated
  4. customchromatographed through a silica gel column (100% DCM to 70% ethyl acetate in DCM

Sources & evidence

ORD record
ord-3b84e9373c0841dba3fb5d29dc61763d
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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