Hydrochloric Acid → INCB-9471 dihydrochloride

HRID 2244919Notes

Reaction equation

HRID 2244919 reaction equation
[CH2:1]([O:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2].[ClH:38].[CH3:39][C:40]1[C:45]([C:46]([OH:48])=O)=[C:44]([CH3:49])[N:43]=[CH:42][N:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[ClH:38].[ClH:38].[CH2:1]([O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=2)[C@H:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26]([C:46]([C:45]3[C:40]([CH3:39])=[N:41][CH:42]=[N:43][C:44]=3[CH3:49])=[O:48])[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 149222224,6-Dimethylpyrimidine-5-carboxylic acidHCID 68742358HCID 68742358, compound

Product 1

HCID 68745743INCB-9471 dihydrochlorideYield 80.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

t-Butyl 4-{(3S)-4-[2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (48.4 g, 0.0921 mol) was treated with a 4.0 M solution of hydrogen chloride in 1,4-dioxane (230 mL) at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was further dried under high vacuum. The formed amine hydrochloride was mixed with 4,6-dimethyl-pyrimidine-5-carboxylic acid (16.80 g, 0.110 mol) in methylene chloride (100 mL), and then 1-hydroxybenzotriazole (16.80 g, 0.1243 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25.00 g, 0.1304 mol) and triethylamine (65.0 mL, 0.466 mol) were added. The resulting reaction mixture was stirred at room temperature overnight before it was diluted with methylene chloride and washed with aqueous sodium hydroxide (1 M) and brine. The organic layer was collected and dried over magnesium sulfate. After removal of the solvent, the residue was dissolved in methylene chloride (50 mL) and the solution was passed through a silica plug with ethyl acetate containing 1% triethylamine. The solution was concentrated and the residue was dissolved in 900mL of isopropyl acetate. To the above solution, 185 mL of 1.0 N HCl in isopropyl acetate was slowly added. The mixture slowly turned cloudy, and was stirred overnight. The formed white solid was collected, washed with 40 mL of isopropyl acetate. The cake was air-dried to give 47.0 g (80.7%) of product. MS (EI) 560.3 (M+1).

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. customthe residue was further dried under high vacuum
  3. customThe resulting reaction mixture
  4. washwashed with aqueous sodium hydroxide (1 M) and brine
  5. customThe organic layer was collected
  6. dry with materialdried over magnesium sulfate
  7. customAfter removal of the solvent
  8. dissolutionthe residue was dissolved in methylene chloride (50 mL)
  9. concentrationThe solution was concentrated
  10. dissolutionthe residue was dissolved in 900mL of isopropyl acetate
  11. additionTo the above solution, 185 mL of 1.0 N HCl in isopropyl acetate was slowly added
  12. stirringwas stirred overnight
  13. customThe formed white solid was collected
  14. washwashed with 40 mL of isopropyl acetate
  15. customThe cake was air-dried

Sources & evidence

ORD record
ord-69ca289b890e423a8a66b001213ab5ce
Source dataset
uspto-grants-2010_03
Patent number
US07678798B2

Reaction notes

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