Tri-o-tolylphosphine → (E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4'-piperidine]-1'-carboxylate

HRID 2175751Notes

Reaction equation

HRID 2175751 reaction equation
[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:16])[CH:14]=[CH2:15])[CH2:9][CH:8]=1.Br[C:18]1[CH:19]=[C:20]2[C:37](=[N:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:22]1([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[CH2:21]2.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:40]=[C:35]1[C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH2:21][C:20]2[C:37](=[N:38][CH:39]=[C:18](/[CH:15]=[CH:14]/[C:13](=[O:16])[N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)=[CH:8][CH2:9]3)[CH:19]=2)[NH:36]1

Participants

7

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 57742041Tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4'-piperidine]-1'-carboxylateHCID 896100261-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

Product 1

HCID 86296668(E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4'-piperidine]-1'-carboxylateYield 22.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 86641869DMF propionitrileSolvent

Conditions

Temperature
110 °C

Procedure

To a stirred solution of 1-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (Intermediate-4) (350 mg, 1.50 mmol) and tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (Intermediate-6) (500 mg, 1.20 mmol) in DMF/propionitrile (4 mL/16 mL) was added DIPEA (0.55 mL, 3.16 mmol) at 20-35° C. and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (28 mg, 0.12 mmol) and P(o-tolyl)3 (77 mg, 0.25 mmol) were added, again degassed with N2 for another 10 minutes and heated at 110° C. for 16 h. The reaction mixture was cooled to 20-35° C. and filtered through Celite®. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 3% MeOH/DCM as an eluent to get the desired compound as a light yellow solid (150 mg, 22%); 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=15.1 Hz, 1H), 7.28-7.16 (m, 1H), 5.68-5.64 (m, 1H), 4.24-4.21 (m, 1H), 4.08-4.03 (m, 1H), 3.75 (s, 2H), 3.64-3.61 (m, 1H), 3.57-3.52 (m, 3H), 3.27-3.21 (m, 2H), 2.94 (s, 2H), 2.18-2.13 (m, 2H), 1.80-1.68 (m, 2H), 1.39 (s, 9H), 1.40-1.31 (m, 2H); ES-MS: 548.2 (M−1)+.

Workup

  1. customthe mixture was degassed with N2 for 10 minutes
  2. customagain degassed with N2 for another 10 minutes
  3. temperatureThe reaction mixture was cooled to 20-35° C.
  4. filtrationfiltered through Celite®
  5. customThe filtrate was rotary evaporated under vacuum
  6. customto get residue which
  7. customwas purified by column chromatography
  8. additionmixture of 3% MeOH/DCM as an eluent

Sources & evidence

ORD record
ord-2a91ecd0933a412d8ec121bb4c07580c
Source dataset
uspto-grants-2015_06
Patent number
US09062075B2

Reaction notes

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