Thionyl Chloride → Ethyl 6-bromo-4-chloroquinoline-3-carboxylate

HRID 1486917Notes

Reaction equation

HRID 1486917 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[CH:7]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=O.S(Cl)([Cl:29])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]2[Cl:29]

Participants

4

Reactant 2

HCID 24386Thionyl ChlorideHCID 94674283Ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate

Product 1

HCID 2764138Ethyl 6-bromo-4-chloroquinoline-3-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

On a larger scale, ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (5765 g, 13.85 mol) was charged to the vessel with thionyl chloride (28.8 L). An exotherm from 20-26° C. was observed. DMF (4.4 mL) was added with no observed exotherm and the batch heated to 75° C. and stirred for 17 h. HPLC showed 1.3% starting material remained with 98.0% product. The reaction was concentrated in vacuo and the residue azeotroped with toluene (25 L). The resulting solid was then slurried in heptane (18.5 L) for 2.5 h, filtered and washed with heptane (3×4 L). The solid was dried under vacuum at 35° C. to give 4077 g of the desired material (93% crude yield) which contained ˜5% of ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate in addition to ˜4% hydrolysis product by HPLC (90% pure). The crude material (4077 g) was returned to the vessel and reprocessed with thionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to 75° C. for 40 h. The thionyl chloride was removed in vacuo and the residue azeotroped with toluene (10 L). The residue was slurried in heptane (18 L) for ˜16 h at 20° C. The solid was collected by filtration, one portion being filtered under nitrogen and washed with heptane (3 L) to yield 2196 g of desired material (90% NMR assay, 99% by HPLC). The remainder of the batch was filtered under air and washed with heptane (3 L) to yield 1905 g of the desired material (88% NMR assay, 99% by HPLC). The yellow solids were combined for further processing (4101 g, 3653 g active, 83% yield, 99% by HPLC).

Workup

  1. additionin addition
  2. customto ˜4% hydrolysis product by HPLC (90% pure)
  3. customThe thionyl chloride was removed in vacuo
  4. customthe residue azeotroped with toluene (10 L)
  5. filtrationThe solid was collected by filtration, one portion
  6. filtrationbeing filtered under nitrogen
  7. washwashed with heptane (3 L)

Sources & evidence

ORD record
ord-f719ff0f508846fd96429abeff168892
Source dataset
uspto-grants-2016_08
Patent number
US09428503B2

Reaction notes

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