Ammonium Chloride → 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine

HRID 1621880Notes

Reaction equation

HRID 1621880 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:56][C:57]1[CH:58]=[C:59]([NH2:65])[CH:60]=[N:61][C:62]=1[O:63][CH3:64].[NH4+].[Cl-]>C1COCC1>[F:56][C:57]1[CH:58]=[C:59]([NH:65][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)[CH:60]=[N:61][C:62]=1[O:63][CH3:64]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium Hexamethyldisilazide2×HCID 454803515-Fluoro-6-methoxypyridin-3-amine2×HCID 685155046-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine

Product 1

HCID 666003246-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamineYield 56.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) was added to a solution of 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.300 g, 0.47 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc. North Brunswick, N.J.) (0.101 g, 0.71 mmol) in THF (1.5 mL) at −10° C. More lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1.42 mL, 1.42 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.101 g, 0.71 mmol) were added and the reaction mixture was stirred for another hour. Saturated NH4Cl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.264 mmol, 55.9% yield) as a brown foam. m/z (ESI, +ve) 757.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.92 (br. s., 1H) 8.24 (dd, J=12.52, 2.15 Hz, 1H) 8.13 (d, J=1.57 Hz, 1H) 8.03 (d, J=2.15 Hz, 1H) 7.50 (br. s., 1H) 7.19 (d, J=6.46 Hz, 4H) 6.87 (d, J=8.61 Hz, 5H) 6.52 (br. s., 1H) 4.79 (br. s., 4H) 4.01 (s, 3H) 3.79 (s, 6H) 3.44 (br. s., 1H) 3.17 (br. s., 4H) 2.75 (s, 3H) 2.66 (s, 3H) 2.40-2.59 (m, 4H) 1.34 (br. s., 3H)

Workup

  1. extractionthe mixture was extracted with EtOAc (3×)
  2. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (40 g)
  6. washeluting with a gradient of 0% to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-0d6cd2a80c0b4eb9b0171dd833d97ff3
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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