Citric Acid → HCID 59252794, compound

HRID 563442Notes

Reaction equation

HRID 563442 reaction equation
[C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C@H:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]([CH3:30])([CH3:29])[C:21]([NH:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[N:11]1)#N.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:40].[OH2:50]>>[S:25]1[CH:26]=[N:27][N:28]=[C:24]1[NH:23][C:21](=[O:22])[C:20]([CH3:30])([CH3:29])[C@H:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[C:1]([OH:40])=[O:50])[N:11]=[CH:12]2)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1

Participants

4

Reactant 3

HCID 311Citric AcidHCID 962WaterHCID 59252865HCID 59252865, compound

Product 1

HCID 59252794HCID 59252794, compound

Conditions

Temperature
90 °C

Procedure

A suspension of (3S)-3-(1-(2-cyano-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide (35 mg, 0.072 mmol) and Na2O2 (77 mg, 1.1 mmol) in water (7 mL) was stirred under nitrogen at 70° C. for 30 min and at 90° C. for 1 day. The mixture was acidified with 10% aqueous citric acid solution to pH=2 and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were concentrated in vacuo. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoic acid; Example 157 (24 mg, 0.047 mmol, 64% yield) as a yellow solid. MS found: (M+H)+=516. 1H-NMR (500 MHz, METHANOL-d3) δ ppm 8.95 (s, 1H) 8.16 (s, 1H) 7.89 (s, 1H) 7.72 (dd, J=8.80, 3.02 Hz, 1H) 7.60 (dd, J=8.66, 4.81 Hz, 1H) 7.49 (td, J=8.25, 3.02 Hz, 1H) 7.39-7.43 (m, 3H) 7.15-7.27 (m, 4H) 4.82 (s, 1H) 1.46 (s, 3H) 1.44 (s, 3H).

Workup

  1. extractionextracted with ethyl acetate (3×5 mL)
  2. concentrationThe combined ethyl acetate extracts were concentrated in vacuo
  3. customPurification
  4. customphase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA)

Sources & evidence

ORD record
ord-25aa75ba7e9648fc95c63065b96e3271
Source dataset
uspto-grants-2011_11
Patent number
US08067447B2

Reaction notes

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