Hydrochloric Acid → (S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl dihydrogen phosphate

HRID 596047Notes

Reaction equation

HRID 596047 reaction equation
[P:1]([O:44]C(C)(C)C)([O:39]C(C)(C)C)([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2].Cl.O1CCOCC1>CO>[P:1]([OH:39])([OH:44])([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 118046009(S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate

Product 1

HCID 118045635(S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl dihydrogen phosphateYield 76.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of (S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (315 mg, 0.392 mmol) was added HCl 4M in dioxane (5 mL, 20.00 mmol) and methanol (Volume: 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour followed by LCMS. The solvent was concentrated off. The crude material was basified and dissolved with 3M NaOH solution with minimal MeOH added. The material was purified by 12 gram Grace Reveleris C18 reverse phase column eluted with 0-15% ACN/water over 18 minutes at a flow rate of 15 ml/minute, without buffers. The desired fractions were collected, acidified with 1 M HCl to pH of 1 and extracted with ethyl acetate (5×). The combined organic layer (800 ml) was washed with minimal water (3×25 ml) to remove salts. The solvent was concentrated off, dissolved in 1:1 ACN/water and lyophilized to give 207 mg of the desired product as HCL salt. (72% yield). LCMS (m/z): 693.2 (MH+), 0.64 min. 1H NMR (<cd3od>) d: 7.87 (s, 1H), 7.81-7.86 (m, 1H), 7.65-7.72 (m, 2H), 7.61 (dd, J=11.7, 1.6 Hz, 1H), 7.46 (ddd, J=8.0, 2.3, 1.4 Hz, 1H), 7.26 (dt, J=9.5, 1.9 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.29-4.49 (m, 1H), 4.18-4.29 (m, 2H), 3.64 (tdd, J=11.6, 8.6, 4.9 Hz, 1H), 2.76-2.92 (m, 1H), 2.27 (ddd, J=8.8, 5.9, 2.5 Hz, 1H), 2.01-2.13 (m, 1H), 1.76-1.94 (m, 2H), 1.58-1.71 (m, 1H), 1.39-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.16 (br. s., 1P).

Workup

  1. concentrationThe solvent was concentrated off
  2. dissolutiondissolved with 3M NaOH solution with minimal MeOH
  3. additionadded
  4. customThe material was purified by 12 gram Grace Reveleris
  5. washeluted with 0-15% ACN/water over 18 minutes at a flow rate of 15 ml/minute, without buffers
  6. customThe desired fractions were collected
  7. extractionextracted with ethyl acetate (5×)
  8. washThe combined organic layer (800 ml) was washed with minimal water (3×25 ml)
  9. customto remove salts
  10. concentrationThe solvent was concentrated off
  11. dissolutiondissolved in 1:1 ACN/water

Sources & evidence

ORD record
ord-662811055e0f4c8797bc887834e55a3f
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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