Ammonium Hydroxide → HCID 178465312, compound

HRID 2274369Notes

Reaction equation

HRID 2274369 reaction equation
[P:1]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])([O:8][C:9]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:32]([F:33])=[C:31]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:21]3[NH:22][C:23]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:24][C:20]=3[CH:19]=2)=[CH:14][N:13]=1)([CH3:11])[CH3:10])([O:3]CCC#[N:7])=[O:2].[OH-].[NH4+]>CO>[P:1]([O-:3])([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])([O:8][C:9]([C:12]1[N:13]=[CH:14][C:15]([C:18]2[C:32]([F:33])=[C:31]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:21]3[NH:22][C:23]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:24][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)([CH3:10])[CH3:11])=[O:2].[NH4+:7]

Participants

4

Reactant 2

HCID 14923Ammonium Hydroxide2×HCID 178465311HCID 178465311, compound

Product 1

HCID 178465312HCID 178465312, compoundYield 63.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of 2-cyanoethyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-((R)-tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl phosphate (30) (734 mg, 1.106 mmol) in MeOH (20 mL) at 23° C. was added ammonium hydroxide (430 μL, 11.04 mmol). After stirring for 16 hours, more ammonium hydroxide (1 mL) was added. After a further 4 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (7 mL) and purified via preparative HPLC, 7 injections Using a Waters XBridge C18 5 μm OBD column (19×100 mm) eluting with a 10-90% aqueous MeCN with 0.1% NH4OH buffer, gradient over 15 min at 20 mL/min flow rate. Product fractions were pooled, frozen and lyophilized to give ammonium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl 2-(2-methoxyethoxy)ethyl phosphate (X) (443 mg, 0.7010 mmol, 63.38%) as a white solid. ESMS (M+1)=611.5; 1H NMR (300.0 MHz, CD3OD) δ 8.86 (d, J=1.0 Hz, 2H), 7.30 (d, J=6.3 Hz, 1H), 5.24 (t, J=7.6 Hz, 1H), 4.23 (dd, J=7.0, 14.8, 1H), 4.13-4.05 (m, 2H), 3.94 (dd, J=7.2, 15.0 Hz, 1H), 3.72-3.64 (m, 4H), 3.56-3.51 (m, 2H), 3.35 (s, 3H), 3.34-3.28 (m, 2H), 2.52-2.42 (m, 1H), 2.12-2.00 (m, 2H), 1.90 (d, J=1.6 Hz, 6H), 1.89-1.74 (m, 1H) and 1.22 (t, J=7.2 Hz, 3H) ppm. Elemental Analysis Calculated for C26H39FN7O8P (corrected for 4.73% w/w water, as determined by the Karl-Fischer oven method): C, 47.41; H, 6.49; N, 14.88; F, 2.89; P, 4.71. Found: C, 47.71; H, 6.27; N, 14.08; F, 2.93; P, 5.15.

Workup

  1. waitAfter a further 4 hours
  2. concentrationthe reaction mixture was concentrated in vacuo
  3. dissolutionThe residue was dissolved in MeOH (7 mL)
  4. custompurified via preparative HPLC, 7 injections
  5. wash5 μm OBD column (19×100 mm) eluting with a 10-90% aqueous MeCN with 0.1% NH4OH buffer, gradient over 15 min at 20 mL/min flow rate
  6. temperaturefrozen

Sources & evidence

ORD record
ord-30f0220ddfd24d5488ddbe3b94a3d395
Source dataset
uspto-grants-2015_09
Patent number
US09125922B2

Reaction notes

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