Acetyl chloride → 5-Methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid

HRID 1913463Notes

Reaction equation

HRID 1913463 reaction equation
[C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.C(Cl)(=O)C.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([N:36]1[CH2:39][C:38]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:37]1)[CH2:31][CH2:30]2.C(N(CC)CC)C>>[CH3:14][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1](=[O:3])[N:42]2[CH2:43][CH2:44][C:38]3([CH2:37][N:36]([CH:32]4[C:33]5[C:29](=[CH:28][C:27]([C:22]6[N:21]=[CH:26][CH:25]=[CH:24][N:23]=6)=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)[CH2:39]3)[CH2:40][CH2:41]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]

Participants

5

Reactant 4

HCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 125931292-(Carboxymethyl)-5-methylbenzoic acidHCID 674066292-[(1S)-5-Pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride

Product 1

HCID 674059185-Methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acidYield 69%

Conditions

Temperature
130 °C

Procedure

To 2-(carboxymethyl)-5-methylbenzoic acid (100 mg, 0.52 mmol, prepared according to the procedure described in Tetrahedron, 1975, 31(20), 2607-2619) in a microwave reaction vessel was added acetyl chloride (0.5 mL). The tube was sealed and irradiated (Biotage Inc., microwave) while stirring at 130° C. for 20 minutes. The reaction was cooled to room temperature and the excess acetyl chloride was removed in vacuo. Dichloromethane was added to azeotrope the excess acetyl chloride and the crude anhydride was dried under vacuum. The crude anhydride was dissolved in acetonitrile (2 mL) and 2-[(1S)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 220 mg, 0.52 mmol) was added followed by triethylamine (0.16 mL, 2.06 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the desired product was purified using reverse phase chromatography (Biotage SNAP (15 g), water/CH3CN=95/5% to 50/50%) to afford (176 mg, 69%) 5-methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid. MS (ES+) 497.6 (M+H)+. 1H NMR (CDCl3) δ 1.54-1.58 (m, 2H), 1.60-1.64 (m, 2H), 2.15-2.38 (m, 5H), 2.78-3.02 (m, 2H), 3.04-3.24 (m, 1H), 3.26-3.52 (m, 6H), 3.62-3.66 (m, 2H), 4.41-4.45 (m, 1H), 7.06-7.27 (m, 3H), 7.34-7.57 (m, 1H), 7.68 (s, 1H), 8.31 (s, 2H), 8.73-8.79 (m, 2H).

Workup

  1. customin a microwave reaction vessel
  2. customThe tube was sealed
  3. customirradiated (Biotage Inc., microwave)
  4. temperatureThe reaction was cooled to room temperature
  5. customthe excess acetyl chloride was removed in vacuo
  6. additionDichloromethane was added
  7. dry with materialthe crude anhydride was dried under vacuum
  8. dissolutionThe crude anhydride was dissolved in acetonitrile (2 mL)
  9. stirringThe reaction was stirred at room temperature overnight
  10. concentrationThe reaction was concentrated
  11. customthe desired product was purified

Sources & evidence

ORD record
ord-8766aa5382df4322ba8448f39c747a5f
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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