Tetrahydrofuran → Tert-butyl 3-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-ylcarbonyl)-6-methoxypyridin-2-yl)benzoate

HRID 2284356Notes

Reaction equation

HRID 2284356 reaction equation
[C:1]([O:5][C:6]([C:8]1[CH:13]=C[C:11](C2C=C(C=C(OC)N=2)C(O)=O)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([N:28]1[C:41]2[C:40](=[O:42])[CH2:39][C:33]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH2:32][C:31]=2[CH:30]=[N:29]1)([CH3:27])[CH3:26].C([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])C.[C:50](OCC)(=[O:52])C.[O:56]1[CH2:60][CH2:59][CH2:58]C1>>[CH:25]([N:28]1[C:41]2[C:40](=[O:42])[CH2:39][C:33]3([CH2:34][CH2:35][N:36]([C:60]([C:59]4[CH:47]=[C:46]([O:52][CH3:50])[N:45]=[C:48]([C:49]5[CH:13]=[C:8]([CH:9]=[CH:10][CH:11]=5)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:58]=4)=[O:56])[CH2:37][CH2:38]3)[CH2:32][C:31]=2[CH:30]=[N:29]1)([CH3:27])[CH3:26]

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 573370671-Isopropyl-1,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)-oneHCID 668354892-(4-(tert-Butoxycarbonyl)phenyl)-6-methoxypyridine-4-carboxylic acid

Product 1

HCID 86690988Tert-butyl 3-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-ylcarbonyl)-6-methoxypyridin-2-yl)benzoate

Procedure

A solution of 2-(4-(tert-butoxycarbonyl)phenyl)-6-methoxyisonicotinic acid (500 mg, 1.52 mmol) and 1,1-carbonyldiimidazole (271 mg, 1.67 mmol) in tetrahydrofuran (30 mL) was stirred at reflux for 1 hr. After cooling to room temperature 1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (539 mg, 1.68 mmol) and triethylamine (0.32 mL, 2.28 mmol) were added sequentially and the resulting slurry was heated at reflux temperature for 1 hr. After cooling, the reaction mixture was diluted into ethyl acetate, washed with 1N aqueous hydrochloric acid, saturated aqueous sodium chloride, dried over sodium sulfate to afford tert-butyl 3-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)-6-methoxypyridin-2-yl)benzoate (850 mg) as a white foam. This material was taken onto the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (t, J=1.66 Hz, 1H), 8.20 (dt, J=8.05, 1.44 Hz, 1H), 8.01 (dt, J=7.80, 1.37 Hz, 1H), 7.50 (t, J=7.80 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=0.98 Hz, 1H), 6.64 (d, 1H), 5.35 (spt, J=6.44 Hz, 1H), 4.04 (s, 3H), 3.71-3.84 (m, 2H), 3.36-3.42 (m, 2H), 2.79 (d, J=2.34 Hz, 2H), 2.58 (s, 2H), 1.66-1.72 (m, 2H), 1.61 (s, 9H), 1.56 (s, 2H), 1.40-1.48 (m, 6H); m/z (M+1)=559.2.

Workup

  1. temperatureat reflux for 1 hr
  2. additionwere added sequentially
  3. temperaturethe resulting slurry was heated
  4. temperatureat reflux temperature for 1 hr
  5. temperatureAfter cooling
  6. washwashed with 1N aqueous hydrochloric acid, saturated aqueous sodium chloride
  7. dry with materialdried over sodium sulfate

Sources & evidence

ORD record
ord-63bb2e73ff80435b84b228ddc02bd7f8
Source dataset
uspto-grants-2015_09
Patent number
US09145416B2

Reaction notes

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