Tris(hydroxymethyl)aminomethane → 2-Chloro-6-fluoro-N-[3-(piperidin-4-yloxy)-phenyl]-benzamide hydrochloride

HRID 1822023Notes

Reaction equation

HRID 1822023 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCOCC1.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>CO.O1CCOCC1>[ClH:28].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=1)=[O:32]

Participants

7

Reactant 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 8083MorpholineHCID 27365472-Chloro-6-fluorobenzoyl chlorideHCID 57803194790667-68-4

Product 1

HCID 690710202-Chloro-6-fluoro-N-[3-(piperidin-4-yloxy)-phenyl]-benzamide hydrochloride

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
106 °C

Procedure

Combine 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 100 mg, 0.342 mmol), dioxane (2 mL) and polymer bound morpholine resin (205 mg, 0.513 mmol) and add 2-chloro-6-fluoro-benzoyl chloride (0.048 mL, 0.376 mmol), shake (in a J-KEM® block) and heat at 106° C. After 2 hr., dilute with methanol (5 mL) and add tris-amine resin (100 mg), shake in a rotary evaporator overnight, filter, concentrate and use directly in the next step. Combine methanol (5 mL) and acetyl chloride (2.5 mL) and stir at 0° C. After 1 hr., add a solution of 4-[3-(2-chloro-6-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester in methanol (2 mL) and stir at room temperature. After 30 min., concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 mL), wash with NaHCO3 (sat. aq., 10 mL), dry the organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give 100 mg (84%, 2 steps) of the titled compound as the free base. Following a method similar to Example 2 gives the title compound as the hydrochloride salt (130 mg, off-white solid). Mp: 139-42° C.; mass spectrum (free base, ion spray): m/z=311.2 (M+1); 1H NMR (free base, CDCl3): 8.19 (bs, N—H), 7.41 (t, J=2.1 Hz, 1H), 7.35-7.29 (m, 1H), 7.26-7.20 (m, 2H), 7.07-7.02 (m, 2H), 6.70 (dd, J=2.3 Hz, 8.4 Hz, 1H), 4.43-4.36 (m, 1H), 3.11-3.04 (m, 2H), 2.74-2.67 (m, 2H), 2.50 (bs, N—H), 2.04-1.95 (m, 2H), 1.72-1.62 (m, 2H).

Workup

  1. customin a rotary evaporator overnight
  2. filtrationfilter
  3. concentrationconcentrate
  4. waitAfter 1 hr
  5. addition, add a solution of 4-[3-(2-chloro-6-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester in methanol (2 mL)
  6. stirringstir at room temperature
  7. waitAfter 30 min.
  8. concentrationconcentrate under reduced pressure
  9. dissolutiondissolve the residue in ethyl acetate (10 mL)
  10. washwash with NaHCO3 (sat. aq., 10 mL)
  11. dry with materialdry the organic layers over magnesium sulfate
  12. filtrationfilter
  13. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-241846ceda4b45da99bb7a8d2682c9f6
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

Loading…