Triethylamine → Apixaban

HRID 860836Notes

Reaction equation

HRID 860836 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=O)=[N:10]2)=[CH:5][CH:4]=1.C([N:37](CC)CC)C.ClC(OCC(C)C)=O.[OH-].[NH4+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([NH2:37])=[O:34])=[N:10]2)=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 14923Ammonium HydroxideHCID 62365Isobutyl chloroformateHCID 222404401-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxylic acid

Product 1

HCID 10182969ApixabanYield 70%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

Method A. A suspension of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (61, 1.5 g, 3.3 mmol) in EtOAc (20 mL) was treated with triethylamine (TEA, 433 mg, 0.60 mL, 4.3 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was treated dropwise with iso-butyl chloroformate (587 mg, 0.55 mL, 4.3 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for an additional 30 min. When TLC and HPLC showed the mixed anhydride formation reaction was complete, the reaction mixture was poured into a cold (0–5° C.) ammonium hydroxide solution (NH4OH, 28% aqueous solution, 25 mL) with good stirring. The resulting mixture was stirred at room temperature for an additional 4 h. The solids were collected by filtration, washed with a mixture of methanol and water (1:1 v/v, 2×20 mL), and dried in vacuo at 40–45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (62, 1.06 g, 1.52 g theoretical, 70%) as off-white crystals. For 62, CIMS m/z 460 (M++H, C25H25N5O4).

Workup

  1. customthe resulting reaction mixture
  2. customThe resulting reaction mixture
  3. stirringThe resulting mixture was stirred at room temperature for an additional 4 h
  4. filtrationThe solids were collected by filtration
  5. washwashed with a mixture of methanol and water (1:1 v/v, 2×20 mL)
  6. customdried in vacuo at 40–45° C. for 12 h

Sources & evidence

ORD record
ord-6e90d07231b34a2897a08ebc6a348be0
Source dataset
uspto-grants-2006_12
Patent number
US07153960B2

Reaction notes

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