4-Methoxybenzylamine → HCID 178471990, compound

HRID 1486919Notes

Reaction equation

HRID 1486919 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[CH2:21]([O:23][C:24](=[O:30])[CH:25]=[CH:26][N:27]([CH3:29])C)[CH3:22].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36](CN)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([C:25](=[CH:26][NH:27][CH2:29][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[C:24]([O:23][CH2:21][CH3:22])=[O:30])=[O:8]

Participants

6

Reactant 4

HCID 754524-MethoxybenzylamineHCID 81531DiisopropylethylamineHCID 121015Ethyl 3-(N,N-dimethylamino)acrylateHCID 219426655-Bromo-2-fluorobenzoyl chloride

Product 1

HCID 178471990HCID 178471990, compoundYield 109.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
25 °C

Procedure

On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 g active, 17.71 mol) was charged to the vessel as a solution in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm. Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was added portion wise over 30 minutes maintaining a batch temperature <40° C. An exotherm from 21-24° C. was noted over the 30 minute addition with a further slow rise to 38° C. over 1 h. The reaction was stirred at 20-30° C. for 16.5 h, 4-Methoxybenzylamine (2439 g, 17.78 mol) was added portionwise over 30 mins maintaining a batch temperature <40° C. An exotherm of 25-30° C. was observed over the addition with cooling provided by a reduced jacket temperature of 15° C. The reaction was stirred for 4 h at 20-30° C. after which HPLC indicated 93.2% of desired material. The batch was split for workup with each half of the mixture diluted with DCM (28.6 L) and washed with water (3×7.8 L). The organics were dried over MgSO4 (˜550 g) and filtered, washing with DCM (4 L). The combined organics were then concentrated to give 8444 g of die desired material as an oil (8434 g, 106% yield, 94.7% parity by HPLC). Analytical data was consistent with that obtained from previous batches.

Workup

  1. temperaturemaintaining a batch temperature <40° C
  2. additionAn exotherm from 21-24° C. was noted over the 30 minute addition with a further slow rise to 38° C. over 1 h
  3. temperaturemaintaining a batch temperature <40° C
  4. additionAn exotherm of 25-30° C. was observed over the addition
  5. temperaturewith cooling
  6. customprovided by a reduced jacket temperature of 15° C
  7. stirringThe reaction was stirred for 4 h at 20-30° C. after which HPLC
  8. customThe batch was split for workup with each half of the mixture
  9. additiondiluted with DCM (28.6 L)
  10. washwashed with water (3×7.8 L)
  11. dry with materialThe organics were dried over MgSO4 (˜550 g)
  12. filtrationfiltered
  13. washwashing with DCM (4 L)
  14. concentrationThe combined organics were then concentrated

Sources & evidence

ORD record
ord-8d4a479c0402474291a700796b396939
Source dataset
uspto-grants-2016_08
Patent number
US09428503B2

Reaction notes

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