Methylcyclohexane → racemic 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(quinuclidin-3-yloxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1777936Notes

Reaction equation

HRID 1777936 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1CCCCC1.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[N:35][C:36]=1[CH:37]([O:40][CH3:41])[O:38][CH3:39])[N:33]([C:42](OC1C=CC=CC=1)=[O:43])[CH2:32][CH2:31][CH2:30]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[NH2:51][C:52]1[CH:59]=[C:58]([O:60][CH:61]2[CH:66]3[CH2:67][CH2:68][N:63]([CH2:64][CH2:65]3)[CH2:62]2)[C:55]([C:56]#[N:57])=[CH:54][N:53]=1.[NH4+].[Cl-]>C1COCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[N:35][C:36]=1[CH:37]([O:38][CH3:39])[O:40][CH3:41])[N:33]([C:42]([NH:51][C:52]1[CH:59]=[C:58]([O:60][CH:61]3[CH:66]4[CH2:67][CH2:68][N:63]([CH2:64][CH2:65]4)[CH2:62]3)[C:55]([C:56]#[N:57])=[CH:54][N:53]=1)=[O:43])[CH2:32][CH2:31][CH2:30]2)([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19]

Participants

7

Reactant 5

HCID 7962MethylcyclohexaneHCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 118036915Racemic 6-amino-4-(quinuclidin-3-yloxy)nicotinonitrile2×HCID 131734775phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate2×

Product 1

HCID 131734786racemic 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(quinuclidin-3-yloxy)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

A solution of LHMDS in methylcyclohexane (0.9 M, 0.70 ml, 0.630 mmol) was added drop wise over 5 minutes to a mixture of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 135 mg, 0.287 mmol) and racemic 6-amino-4-(quinuclidin-3-yloxy)nicotinonitrile (intermediate 79, 70.0 mg, 287 mmol) in THF (2.9 ml) cooled at −78° C. The reaction mixture was stirred at −78° C. for a further 10 minutes then allowed to warm to 0° C. and aqueous NH4Cl (1 M) added. The mixture was extracted with DCM (3×), dried over Na2SO4 and evaporated. The residue was applied to a 4 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an off-white solid. (UPLC-MS 6) tR 1.27; ESI-MS 623.3 [M+H]+.

Workup

  1. temperatureto warm to 0° C.
  2. extractionThe mixture was extracted with DCM (3×)
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. custompurified by normal phase chromatography
  6. washeluting with a gradient from DCM to 10% MeOH in DCM
  7. additionProduct containing fractions
  8. customevaporated

Sources & evidence

ORD record
ord-9e76ff0e15ab450ebedf4deb9c3c646d
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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