Diisopropylethylamine → Tert-butyl 4-((3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate

HRID 1921975Notes

Reaction equation

HRID 1921975 reaction equation
N1(C([O-])=O)CCCCC1.Cl.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[C:14]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]([CH3:32])[CH3:31])[N:25]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.O=[C:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.C(OCC)(=O)C.C(O)(=O)C>[CH3:32][N:30]([CH3:31])[C:26]1[N:25]=[C:24]([C:14]2[CH:13]=[C:12]([NH:11][CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:29]=[CH:28][N:27]=1

Participants

10

Reactant 6

HCID 81531DiisopropylethylamineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate2×HCID 2724942TriacetoxyborohydrideHCID 5049666Sodium triacetoxyborohydrideHCID 21874245Piperidine carboxylateHCID 673061954-(4-amino-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine hydrochloride

Product 1

HCID 67305284Tert-butyl 4-((3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylateYield 73.4%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Procedure

Synthesis of tert-butyl 4-(3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate (142): To a slurry of 4-(4-amino-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (141) (203 mg) in 1,2-dichloroethane (12 ml) was added N,N-diisopropylethylamine (240 μl) and the mixture stirred at room temperature for 30 min until all of the material was in solution. Acetic acid (0.5 ml) was added followed by tert-butyl 4-oxopiperidine-1-carboxylate (165 mg) and sodium triacetoxyborohydride (219 mg). The mixture was stirred at room temperature for 24 hours. A further (100 mg) of both tert-butyl 4-oxopiperidine-1-carboxylate and triacetoxyborohydride was added and the mixture stirred for a further 8 hours. The mixture was poured into ethyl acetate (150 ml) washed with water (300 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow oil that was purified by silica gel chromatography eluting with 20-30% ethyl acetate in hexanes to yield tert-butyl 4-((3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate (142) as a yellow foam (215 mg). 1H NMR (CDCl3) 400 MHz δ 8.38 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.52 (m, 1H), 7.18 (dd, J=2.4 and 9.2 Hz 1H), 7.04 (m, 1H), 7.02 (d, J=5.6 Hz, 1H) 4.15-4.1 (m, 2H), 3.97 (s, 3H), 3.76 (m, 1H), 3.31 (s, 6H), 3.03 (m, 2H), 2.24 (m, 2H), 1.58-1.51 (m, 2H), 1.49 (s, 9H), LCMS m/e 478 (M+H)

Workup

  1. stirringThe mixture was stirred at room temperature for 24 hours
  2. stirringthe mixture stirred for a further 8 hours
  3. washwashed with water (300 ml)
  4. dry with materialthe organic layer dried over anhydrous magnesium sulfate
  5. customEvaporation to dryness
  6. customgave a yellow oil that
  7. customwas purified by silica gel chromatography
  8. washeluting with 20-30% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-ea3248623f15498cb565d5d71816f469
Source dataset
uspto-grants-2012_05
Patent number
US08173808B2

Reaction notes

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