Dichloromethane → 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812024Notes

Reaction equation

HRID 1812024 reaction equation
[CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)[N:10]=3)=[CH:17][C:18]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 66600044Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate

Product 1

HCID 665999414-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Procedure

A slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (8.77 g, 11.45 mmol) in DCM (25.00 mL, 389 mmol) was treated with TFA (15.00 mL, 195 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residual sticky material was taken up in DCM (100 mL) and carefully quenched with saturated NaHCO3(aq) until slightly basic. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a yellow solid. A portion of this solid (0.349 g, 0.524 mmol) was dissolved in DCM (5.00 mL, 78 mmol) and Et3N (0.365 mL, 2.62 mmol) at −15° C. The mixture was treated slowly with dimethylcarbamic chloride (0.169 g, 1.573 mmol) and stirred for 1 h before warming up to room temperature overnight. The reaction mixture was concentrated, the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (10 to 100% EtOAc in hexanes) to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide (0.3555 g, 92%) as a yellow solid (ESI, +ve ion) 736.7 (M+H)+.

Workup

  1. temperatureA slightly cooled
  2. concentrationThe mixture was concentrated
  3. customcarefully quenched with saturated NaHCO3(aq) until slightly basic
  4. extractionThe aqueous layer was extracted with DCM (2×100 mL)
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-37b2ca2c2b334198956f3d8c63c5d63e
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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