Phenol → HCID 66556492, compound

HRID 1771107Notes

Reaction equation

HRID 1771107 reaction equation
[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OCC)=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:26]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27].C1(O)C=CC=CC=1>C(OC(O)C)C>[C:26]([NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=1)([CH3:29])([CH3:28])[CH3:27]

Participants

5

Reactant 3

HCID 996PhenolHCID 40274N-(1,1-Dimethylethyl)-1,3-propanediamineHCID 89690202HCID 89690202, compound

Product 1

HCID 66556492HCID 66556492, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 101298981-EthoxyethanolSolvent

Procedure

The first step involves the selective iodination of position 3 of the quinolone nucleus with iodine in the presence of n-butylamine in DMF to give 7-chloro-3-iodoquinolin-4-ol (B) according to the procedure of Hart (Hart, J Med Chem 49, 1101-1112 (2006) incorporated by reference herein), in approximately 59% yield. Without further purification, this material is converted cleanly to the corresponding 4,7-dichloro-3-iodoquinoline (C) in approximately 99% yield according to the procedure of Andersag (Andersag, Chem Ber 81, 499-507, (1948), incorporated by reference herein). The iodoquinoline is then treated in THF with potassium ethoxide in the presence of a catalytic amount of 18-crown-6 ether to give pure 7-chloro-4-ethoxy-3-iodoquinoline (D) in approximately 90% yield as shown, for example, by GC-MS and NMR. In the next step, Suzuki coupling conditions (Mphahlele, J Chem Res 2008, 437-440 (2008) incorporated by reference herein) may be used to react 4-(trifluoromethoxy)-phenyl)boronic acid with the iodoquinoline intermediate (D) in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and 2M potassium carbonate in DMF. The reaction is allowed to proceed at 85° C. to give 7-chloro-4-ethoxy-3-(4-(trifluoromethoxy)phenyl)quinoline (E) in approximately 63% yield as white crystalline material after flash chromatography. Finally, the desired compound (Compound 1) is obtained by reacting the 4-ethoxy quinoline derivative (E) with N-tert-butyl propane 1,3 diamine in the presence of phenol according to the procedure of Andersag supra, in a Carius tube using 2 ethoxyethanol as a solvent at 180° C. for 4 days. The crude product is further purified by flash chromatography followed by crystallization in ethyl acetate to give Compound 1 as transparent white rectangular plates in approximately 59% yield.

Workup

  1. customat 180° C.
  2. customfor 4 days
  3. customThe crude product is further purified by flash chromatography
  4. customfollowed by crystallization in ethyl acetate

Sources & evidence

ORD record
ord-7e5126d96f424b6c9fa45ab52bc93392
Source dataset
uspto-grants-2016_02
Patent number
US09249103B2

Reaction notes

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