Hydrochloric Acid → HCID 24983246, compound

HRID 1676240Notes

Reaction equation

HRID 1676240 reaction equation
[CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:2].C1(C)C=CC=CC=1.C(O)C.Cl.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[S:49])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:26]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 12454157Phenylacetyl isothiocyanateHCID 21863594Toluene ethanolHCID 67346706HCID 67346706, compound

Product 1

HCID 24983246HCID 24983246, compoundYield 31.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred solution of 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (369 mg, 1.00 mmol) in 1:1 toluene/ethanol (5 mL) was added a solution of 4N HCl (0.375 mL, 1.50 mmol) in dioxane. Then 2-phenylethanoyl isothiocyanate (886 mg, 5.00 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (1 mL) all at once. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated. The residue was triturated with EtOAc (5 mL), and the resulting suspension was stirred for 1 hour to break up large chunks. The yellow suspension was filtered. The yellow solid was partitioned between EtOAc (15 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a Biotage Horizon system using a reverse phase C18 column (M25 size). The following gradient was utilized [solvent A=water, solvent B=CH3CN]: 15-30% B (100 mL), 30-70% B (300 mL), 70-95% B (100 mL), 95-100% B (100 mL), collecting in 96×9 mL tubes. Residual water/CH3CN was azeotroped with absolute EtOH (3×20 mL). The product was obtained as a white powder (170 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 12.51 (br s, 1H), 8.59 (br s, 1H), 8.51 (d, J=6 Hz, 1H), 7.94 (m, 1H), 7.59 (s, 1H), 7.41 (m, 4H), 7.32 (m 2H), 7.26 (m, 1H, overlaps chloroform), 6.54 (d, J=6 Hz, 1H), 3.76 (s, 2H), 3.74 (s, 2H), 2.67 (q, J=7 Hz, 4H), 1.15 (t, J=7 Hz, 6H). LRMS (APCI neg) m/e 545 (M−1). HPLC: 100% purity (220 nm).

Workup

  1. concentrationthe reaction mixture was concentrated
  2. customThe residue was triturated with EtOAc (5 mL)
  3. stirringthe resulting suspension was stirred for 1 hour
  4. filtrationThe yellow suspension was filtered
  5. customThe yellow solid was partitioned between EtOAc (15 mL)
  6. customThe phases were separated
  7. extractionthe aqueous phase was re-extracted with EtOAc (2×15 mL)
  8. washThe combined organic phases were washed with brine (20 mL)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude was purified on a Biotage Horizon system
  13. custom15-30% B (100 mL), 30-70% B (300 mL), 70-95% B (100 mL), 95-100% B (100 mL), collecting in 96×9 mL tubes
  14. customResidual water/CH3CN was azeotroped with absolute EtOH (3×20 mL)

Sources & evidence

ORD record
ord-f73d9d7986d2420b86b6de842ea54dce
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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