Ammonium Chloride → 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1777883Notes

Reaction equation

HRID 1777883 reaction equation
[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 1180368416-Amino-4-(2-methoxyethoxy)nicotinonitrile2×HCID 131734775phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate2×

Product 1

HCID 1317347746-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 206 mg, 0.436 mmol) and 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 93 mg, 0.479 mmol) in THF (3 ml) at −78° C. was slowly added LHMDS (1 M in THF, 0.959 ml, 0.959 mmol). The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 50:50) followed by reverse phase chromatography (43 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as an off-white solid. (UPLC-MS 3) tR 1.59 min; ESI-MS 572.3 [M+H]+.

Workup

  1. customat −78° C.
  2. temperatureto warm to room temperature
  3. extractionextracted twice with DCM
  4. dry with materialThe organic phase was then dried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 50:50)

Sources & evidence

ORD record
ord-8a0dc3907e9147c1a1d40382952f02d5
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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