Formaldehyde → Olopatadine impurity 146

HRID 1650225Notes

Reaction equation

HRID 1650225 reaction equation
C([Li])CCC.Br[C:7]1[CH:27]=[CH:26][C:10]2[O:11][CH2:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3/[C:15](=[CH:16]/[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])/[C:9]=2[CH:8]=1.C=[O:29].[O:30]1[CH2:34]CCC1>CCCCCC>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17]/[CH:16]=[C:15]1\[C:9]2[CH:8]=[C:7]([C:34]([OH:30])=[O:29])[CH:27]=[CH:26][C:10]=2[O:11][CH2:12][C:13]2[CH:25]=[CH:24][CH:23]=[CH:22][C:14]\1=2

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 8028TetrahydrofuranHCID 67782130(Z)-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamineHCID 178418339Butyllithium

Product 1

HCID 11485192Olopatadine impurity 146

Reagents, catalysts & solvents 1

HCID 8058HexaneSolvent

Conditions

Temperature
-70 °C

Procedure

A solution of n-butyl lithium in hexane (1.6M, 3.5 mL) was added dropwise to a solution of 1.8 g. pure (Z)-3-(2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine in 100 mL of dry tetrahydrofuran at -70° C. under a nitrogen atmosphere. After the yellowish-orange solution was stirred at -70° C. for 10 minutes, gaseous carbon dioxide was bubbled through the reaction medium to give a pale yellow solution. The solution was allowed to warm gradually to room temperature and was then concentrated under reduced pressure. The foamy residue was dissolved in water, and the mixture was neutralized with 1N hydrochloric acid and then extracted with chloroform. Concentration of the chloroform and recrystallization of the residue from water gave 0.5 g. pure Z-2-carboxylic acid, m.p. 121°-123° C. pmr (CDCl3) δ: 7.87 (d, J≤1 Hz, 1H, H1), 7.81 (dd, J=7.8, 2.2 Hz, 1H, H3), 7.25-7.28 (m, 4H, aromatic), 6.82 (degenerate d, J=8.8 Hz, 1H, H4), 6.45 (br s, 1H, CO2H), 5.50 (m, 1H, CH=), 5.20 (br, s, 2H, CH2O), 2.92 (m, 4H, NCH2CH2), 2.66 (s, 6H, NMe2).

Workup

  1. customat -70° C.
  2. customgaseous carbon dioxide was bubbled through the reaction medium
  3. customto give a pale yellow solution
  4. temperatureto warm gradually to room temperature
  5. concentrationwas then concentrated under reduced pressure
  6. dissolutionThe foamy residue was dissolved in water
  7. extractionextracted with chloroform
  8. customConcentration of the chloroform and recrystallization of the residue from water
  9. customgave 0.5 g

Sources & evidence

ORD record
ord-8c3332b168de43579562e8f2103c979a
Source dataset
uspto-grants-1990_05
Patent number
US04923892

Reaction notes

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