Ethyl Acetate → N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-(oxetan-2-ylmethoxy)pyrazine-2-carboxamide

HRID 1754874Notes

Reaction equation

HRID 1754874 reaction equation
CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C@:32]23[CH2:40][O:39][CH2:38][C@@:37]2([F:41])[CH2:36][S:35][C:34]([NH2:42])=[N:33]3)[CH:31]=1.[O:44]1[CH2:47][CH2:46][CH:45]1[CH2:48][O:49][C:50]1[N:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1>ClCCl>[NH2:42][C:34]1[S:35][CH2:36][C@:37]2([F:41])[CH2:38][O:39][CH2:40][C@:32]2([C:30]2[CH:31]=[C:26]([NH:25][C:56]([C:53]3[CH:52]=[N:51][C:50]([O:49][CH2:48][CH:45]4[CH2:46][CH2:47][O:44]4)=[CH:55][N:54]=3)=[O:57])[CH:27]=[CH:28][C:29]=2[F:43])[N:33]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 111923Propylphosphonic anhydrideHCID 1177383715-(Oxetan-2-ylmethoxy)pyrazine-2-carboxylic acidHCID 117738545(4aR,7aS)-7 a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Product 1

HCID 117738838N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-(oxetan-2-ylmethoxy)pyrazine-2-carboxamideYield 29.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-Propanephosphonic acid cyclic anhydride 50 wt % solution in ethyl acetate (8.90 μL, 1.50 mmol) is added to a microwave vial containing a mixture of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine (81.2 mg, 0.285 mmol), 5-(oxetan-2-ylmethoxy)pyrazine-2-carboxylic acid (140 mg, 0.300 mmol) and anhydrous dichloromethane (10 mL). The vial is sealed and the mixture stirred at room temperature overnight. The mixture is then partitioned between water and dichloromethane and the layers separated through a Phase Separating cartridge. Organics are combined and the solvent evaporated under reduced pressure. The resulting oil is dissolved in methanol, filtered, and purified by preparative-HPLC (Phenomenex Gemini 10 μm 50*150 mm C-18) (CH3CN and water with 10 mM ammonium bicarbonate, 10% to 100% CH3CN over 10 minutes at 120 ml/min) (1 injection). Fractions bearing product are concentrated to dryness overnight in a centrifugal evaporator to give the title compound as a white solid (40 mg, 28%). ES/MS (m/e): 478.2 (M+1).

Workup

  1. additioncontaining
  2. customThe vial is sealed
  3. customThe mixture is then partitioned between water and dichloromethane
  4. customthe layers separated through a Phase
  5. customSeparating cartridge
  6. customthe solvent evaporated under reduced pressure
  7. dissolutionThe resulting oil is dissolved in methanol
  8. filtrationfiltered
  9. custompurified by preparative-HPLC (Phenomenex Gemini 10 μm 50*150 mm C-18) (CH3CN and water with 10 mM ammonium bicarbonate, 10% to 100% CH3CN over 10 minutes at 120 ml/min) (1 injection)
  10. concentrationare concentrated to dryness overnight in a centrifugal evaporator

Sources & evidence

ORD record
ord-1b4ca7b3f0494261ab12ea9331fbc528
Source dataset
uspto-grants-2015_10
Patent number
US09169271B2

Reaction notes

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