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

HRID 596044Notes

Reaction equation

HRID 596044 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 118046178(S)-2-(4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate

Product 1

HCID 118046414(S)-2-(4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl dihydrogen phosphateYield 100.7%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

(S)-2-(4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (4600 mg, 5.72 mmol) was fully dissolved in MeOH (Volume: 70 mL). Then HCl 4M in Dioxane (14.29 mL, 57.2 mmol) was added and stirred at room temperature for 3 hours, followed by LCMS. The solvent was concentrated mostly off. Then MeOH (Volume: 70 mL) was added and the solvent was concentrated off to residue, additional MeOH (Volume: 70 mL) was added and the residue concentrated to constant mass. The product was dissolved in 90 ml of 1:1 ACN/water and lyophilized to give 3.99 grams of the desired product as HCl salt. (94% yield). LCMS (m/z): 692.9 (MH+), 0.63 min. 1H NMR (<cd3od>) d: 7.84-7.93 (m, 1H), 7.75 (s, 1H), 7.60-7.71 (m, 3H), 7.45-7.51 (m, 1H), 7.26 (dt, J=9.7, 1.6 Hz, 1H), 5.40 (t, J=5.9 Hz, 1H), 4.31-4.50 (m, 1H), 4.22-4.30 (m, 2H), 3.64 (tdd, J=11.7, 8.6, 5.1 Hz, 1H), 2.82-2.98 (m, 1H), 2.32 (ddt, J=11.7, 5.8, 2.8 Hz, 1H), 2.01-2.15 (m, 1H), 1.89-1.97 (m, 1H), 1.75-1.89 (m, 1H), 1.58-1.72 (m, 1H), 1.42-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.00 (s, 1P).

Workup

  1. concentrationThe solvent was concentrated mostly off
  2. additionThen MeOH (Volume: 70 mL) was added
  3. concentrationthe solvent was concentrated off to residue, additional MeOH (Volume: 70 mL)
  4. additionwas added
  5. concentrationthe residue concentrated to constant mass
  6. dissolutionThe product was dissolved in 90 ml of 1:1 ACN/water

Sources & evidence

ORD record
ord-9f4e798d24cd465a862974207149a3c9
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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