Hydrochloric Acid → Apalutamide Acid Impurity

HRID 515830Notes

Reaction equation

HRID 515830 reaction equation
[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[C:20]([F:29])[CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:29])[CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 866834891332388-83-62×

Product 1

HCID 86683488Apalutamide Acid ImpurityYield 95.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Compound 3, 1 g, 2.03 mmol) and NaOH (3M, 10 mL) in MeOH (10 mL) was stirred at room temperature for 18 h. Aqueous HCl (2M) was added to the reaction mixture until the pH=2 and the aqueous layer was extracted with DCM (5×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 900 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.13 (t, 1H), 7.51 (dd, 1H), 7.43 (dd, 1H), 2.69-2.49 (m, 4H), 2.03-1.93 (m, 1H), 1.63-1.57 (m, 1H).

Workup

  1. extractionthe aqueous layer was extracted with DCM (5×)
  2. dry with materialdried over sodium sulfate
  3. customevaporated to dryness

Sources & evidence

ORD record
ord-a5a44d63fa5e471da47f781e565a1017
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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