Ammonium Chloride → N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
Reaction equation
[Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23]C)OC)[N:16]([C:25]([O:27]C1C=CC=CC=1)=O)[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[C:39]([C:38]1[C:41]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:42][C:35]([NH:34][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:23])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:27])=[N:36][CH:37]=1)#[N:40]Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- -78 °C
Procedure
Phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 40 mg, 0.085 mmol) and 6-amino-4-((tetrahydro-2H-pyran-4-yl)oxy)nicotinonitrile (intermediate 45B, 22.3 mg, 0.102 mmol) were dissolved in THF (1 ml) under argon. The resulting solution was cooled to −78° C. and treated slowly with LHMDS (1 M in THF, 0.186 ml, 0.186 mmol). The reaction mixture was stirred at −78° C. for 45 min and then slowly warmed up to room temperature. The reaction mixture was poured into NH4Cl sat. aq. and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). The 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated and then dissolved in THF (1 ml) and water (1 ml) and treated with conc. HCl (0.14 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with DCM (3×). The org layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was treated with a small quantity of DCM and then the product was precipitated by addition of heptane. The solid was collected by centrifugation and dried under vacuum to obtain the title compound as a white solid.
Workup
- temperatureslowly warmed up to room temperature
- extractionextracted twice with DCM
- dry with materialThe organic phase was then dried over Na2SO4
- filtrationfiltered
- customevaporated
- customThe crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column)
- concentrationThe 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated
- dissolutiondissolved in THF (1 ml)
- additionwater (1 ml) and treated with conc. HCl (0.14 ml)
- stirringThe reaction mixture was stirred 16 h at room temperature
- customThe reaction mixture was quenched with sat. aq. NaHCO3
- extractionextracted with DCM (3×)
- dry with materialThe org layer was dried over Na2SO4
- filtrationfiltered
- concentrationconcentrated under vacuum
- additionThe crude material was treated with a small quantity of DCM
- customthe product was precipitated by addition of heptane
- customThe solid was collected by centrifugation
- customdried under vacuum
Sources & evidence
- ORD record
- ord-8d3842c526fe47f6a203dc98b58a446d
- Source dataset
- uspto-grants-2016_02
- Patent number
- US09266883B2
Reaction notes
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