HCID 90112953, compound → HCID 90110496, compound

HRID 521723Notes

Reaction equation

HRID 521723 reaction equation
[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:15][CH:14]3[C:10]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([N:11]([C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[S:17])[O:12][CH2:13]3)[CH2:9]2)=[N:6][CH:7]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:15][CH:14]([CH2:13][OH:12])[C:10]([NH:11][C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:17])([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:9]2)=[N:6][CH:7]=1

Participants

4

Reactant 1

HCID 90112953HCID 90112953, compound

Product 1

HCID 90110496HCID 90110496, compoundYield 26.3%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 176Acetic AcidSolvent

Procedure

A mixture of N-[5-(5-fluoropyrimidin-2-yl)-6a-(3-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-1-carbothioyl]benzamide (550 mg, 1.22 mmol) and powdered zinc (798.33 mg, 12.21 mmol) in acetic acid (5 mL) is sonicated for 2 hours at room temperature. The mixture is extracted with ethyl acetate (100 mL) and a saturated aqueous sodium bicarbonate solution (30 mL). The aqueous phase is re-extracted three times with dichloromethane (100 mL). The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the intermediate N-[[1-(5-fluoropyrimidin-2-yl)-4-(hydroxymethyl)-3-(3-pyridyl)pyrrolidin-3-yl]carbamothioyl]benzamide (145 mg). This is dissolved in dichloromethane (6 mL) and is cooled to 0° C. 1-Chloro-N,N,2-trimethylpropenylamine (0.05 g, 374.19 μmol) is then added and the mixture stirred at 0° C. for 1 hour. A saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (100 mL) are added. The phases are separated and the organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title product (110 mg, 17%). ES/MS (m/e): 435 (M+1).

Workup

  1. customis sonicated for 2 hours at room temperature
  2. extractionThe mixture is extracted with ethyl acetate (100 mL)
  3. extractionThe aqueous phase is re-extracted three times with dichloromethane (100 mL)
  4. dry with materialThe combined organic extracts are dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a residue
  8. customThe residue is purified by silica gel chromatography

Sources & evidence

ORD record
ord-d2f11a178f964958b1ca06dac5f9f964
Source dataset
uspto-grants-2016_05
Patent number
US09328124B2

Reaction notes

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