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

HRID 1812292Notes

Reaction equation

HRID 1812292 reaction equation
F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][C@@H:37]2[CH3:46])[CH3:35])=[CH:4][N:3]=1.[F:47][C:48]1[CH:49]=[C:50]([NH2:56])[CH:51]=[N:52][C:53]=1[O:54][CH3:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1>[F:47][C:48]1[CH:49]=[C:50]([NH:56][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][C@@H:37]3[CH3:46])[CH3:35])=[CH:4][N:3]=2)[CH:51]=[N:52][C:53]=1[O:54][CH3:55]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium Hexamethyldisilazide2×HCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 685151326-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine

Product 1

HCID 685177176-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamineYield 32.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

A solution of 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.130 g, 0.200 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.043 g, 0.301 mmol) in THF (2.00 mL) at −10° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (0.60 mL, 0.60 mmol). After 30 minutes, more lithium bis(trimethylsilyl)amide, (1.0 M solution in THF) (0.60 mL, 0.60 mmol) was added and the reaction mixture stirred for another 30 minutes at −10° C. Saturated NH4Cl (aq.) was added and the mixture was extracted with CH2Cl2 (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 silica gel column (4 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-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.050 g, 0.065 mmol, 32.4% yield) as a brown oil. m/z (ESI, +ve) 771.2 (M+H)+.

Workup

  1. extractionthe mixture was extracted with CH2Cl2 (3×)
  2. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified by chromatography through a silica gel column (4 g)
  6. washeluting with a gradient of 0% to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-ae3a525cced24effbb293d62e5cf58fd
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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