Piperidine → HCID 67044256, compound

HRID 1964484Notes

Reaction equation

HRID 1964484 reaction equation
[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)(Cl)=O.N1CCCCC1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[F:38])[N:34]([CH2:39][C@H:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[C:33]([C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:32]2.C(N(CC)CC)C>CN(C=O)C.ClCCl>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][C:37]=4[F:38])[N:34]([CH2:39][C@H:40]4[CH2:44][O:43][C:42]([CH3:45])([CH3:46])[O:41]4)[C:33]([C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:32]5)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1

Participants

8

Reactant 5

HCID 8082PiperidineHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 442061031-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acidHCID 58201811HCID 58201811, compound

Product 1

HCID 67044256HCID 67044256, compoundYield 96%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (187 mg, 0.8 mmol) and thionyl chloride (0.13 mL, 1.8 mmol). After 30 minutes a clear solution had formed. A small amount was mixed piperidine to test that the acid chloride had been formed. The solution was concentrated on the rotovap and then toluene (1 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (2 mL) and added to a mixture of (S)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (200 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (4 mL). The reaction was stirred at room temperature for 45 minutes. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (320 mg, 96%). ESI-MS m/z calc. 560.6, found 561.5 (M+1)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.51-4.46 (m, 1H), 4.41-4.32 (m, 2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 2H), 1.48-1.45 (m, 2H), 1.40 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm.

Workup

  1. customAfter 30 minutes a clear solution had formed
  2. customhad been formed
  3. concentrationThe solution was concentrated on the rotovap
  4. additiontoluene (1 mL) was added
  5. concentrationthe mixture was concentrated again
  6. dissolutionThe acid chloride was then dissolved in dichloromethane (2 mL)
  7. washThe reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-eff7435deb724637b5649e4209fdcbb2
Source dataset
uspto-grants-2013_04
Patent number
US08415387B2

Reaction notes

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