Chlorotrimethylsilane → 1-(4-Amino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one

HRID 963376Notes

Reaction equation

HRID 963376 reaction equation
[Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].CON(C)[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[CH:14][C:13]=1[O:20][CH3:21].Cl[Si](C)(C)C.BrCC(Cl)CC>C1COCC1.Cl.O.C(OCC)(=O)C>[NH2:19][C:15]1[C:16]([Cl:18])=[CH:17][C:12]([C:11](=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][Cl:7])=[C:13]([O:20][CH3:21])[CH:14]=1

Participants

10

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 813641-Bromo-4-chlorobutaneHCID 5462224Magnesium2×HCID 136639211-Bromo-2-chlorobutaneHCID 190818494-Amino-5-chloro-N,2-dimethoxy-N-methylbenzamide

Product 1

HCID 190819081-(4-Amino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-oneYield 81.1%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

Magnesium (236 g, 9.71 mol) was suspended in 3.5 L of THF under nitrogen and 1-bromo-4-chlorobutane (1.11 L, 8.68M, 9.63 mol) was added at a rate such that the temperature of the mixture remained below 25° C. A solution of N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (400 g, 1.64 mol), prepared as in Example 2, under nitrogen in 4 L of THF was cooled to -20° C. and 410 mL of chlorotrimethylsilane was added. The mixture was allowed to warm to between -12 and 30° C. and then 2.5 L of the solution containing the magnesium and 1-bromo-2-chlorobutane was added over approximately 20 minutes. The mixture was cooled to 50° C. and then diluted with 420 mL of concentrated hydrochloric acid in 5 L of water. The mixture was heated to 32° C., stirred for 15 minutes and then diluted with approximately 2 L of ethyl acetate. The organic layer was separated and washed sequentially with 2 L of water and 2 L of 1:1 water/saturated sodium chloride solution and saturated sodium chloride solution. All aqueous layers were combined and extracted with ethyl acetate. All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was combined with hot hexane and allowed to stand at room temperature for approximately 12 hours giving a precipitate. The precipitate was isolated by filtration and washed with hexane. Drying in a vacuum oven at between 50 and 55° C. under a nitrogen gas bleed gave 1-(4-amino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one (365 g, 1.33 mol).

Workup

  1. customremained below 25° C
  2. temperatureto warm to between -12 and 30° C.
  3. additionwas added over approximately 20 minutes
  4. temperatureThe mixture was heated to 32° C.
  5. customThe organic layer was separated
  6. washwashed sequentially with 2 L of water and 2 L of 1:1 water/saturated sodium chloride solution and saturated sodium chloride solution
  7. extractionextracted with ethyl acetate
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. waitto stand at room temperature for approximately 12 hours
  12. customgiving a precipitate
  13. customThe precipitate was isolated by filtration
  14. washwashed with hexane
  15. customDrying in a vacuum oven at between 50 and 55° C. under a nitrogen gas

Sources & evidence

ORD record
ord-e3b91f35fe4d4b2d8052433071053bbf
Source dataset
uspto-grants-1998_06
Patent number
US05763458

Reaction notes

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