Ammonium Chloride → N-(5-cyano-4-((2-(trifluoromethoxy)ethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778015Notes

Reaction equation

HRID 1778015 reaction equation
[CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](OC2C=CC=CC=2)=[O:15])=[CH:6][C:5]=1[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH3:26].[NH2:31][C:32]1[CH:39]=[C:38]([NH:40][CH2:41][CH2:42][O:43][C:44]([F:47])([F:46])[F:45])[C:35]([C:36]#[N:37])=[CH:34][N:33]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[C:36]([C:35]1[C:38]([NH:40][CH2:41][CH2:42][O:43][C:44]([F:45])([F:47])[F:46])=[CH:39][C:32]([NH:31][C:14]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[C:4]([CH:3]([O:2][CH3:1])[O:29][CH3:30])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:15])=[N:33][CH:34]=1)#[N:37]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 1180364246-Amino-4-((2-(trifluoromethoxy)ethyl)amino)nicotinonitrile2×HCID 118036429Phenyl 7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate2×

Product 1

HCID 118037115N-(5-cyano-4-((2-(trifluoromethoxy)ethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of phenyl 7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 54A, 145 mg, 0.349 mmol) and 6-amino-4-((2-(trifluoromethoxy)ethyl)amino)nicotinonitrile (intermediate 102E, 103 mg, 0.419 mmol) in THF (6 ml) was slowly added 1M LHMDS in THF (0.699 ml, 0.699 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then left to warm to room temperature overnight. The reaction mixture was poured into saturated NH4Cl solution. The aqueous was extracted with DCM (×2). The combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in heptane, then eluting with 0-100% (DCM:MeOH+0.1% NH3 9:1) in DCM afforded the title compound. (UPLC-MS 3) Rt=1.07 min; MS m/z [M+H]+ 566.

Workup

  1. customat −78° C
  2. waitleft
  3. temperatureto warm to room temperature overnight
  4. extractionThe aqueous was extracted with DCM (×2)
  5. concentrationThe combined organic extracts were concentrated under reduced pressure
  6. customPurification of the crude product by chromatography on silica eluting with 0-100% EtOAc in heptane
  7. washeluting with 0-100% (DCM:MeOH+0.1% NH3 9:1) in DCM

Sources & evidence

ORD record
ord-594e8daac8dc411087cac74b0188427b
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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