Ammonia → HCID 71542227, compound

HRID 931653Notes

Reaction equation

HRID 931653 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C4C=CC=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.N>C1COCC1.CO>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:41][C:39]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=2)=[O:40])=[CH:11][CH:10]=3)[N:16]=1

Participants

6

Reactant 3

HCID 222Ammonia2×HCID 21828942HCID 21828942, compoundHCID 89473230HCID 89473230, compound2×

Product 1

HCID 71542227HCID 71542227, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

The title compound was synthesized analogous to step 1 (Method D) described in example 34, but using (S)—N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide (88 mg, 0.153 mmol, Intermediate 24B) and 5-methoxypyrazine-2-carboxamide (28.1 mg, 0.183 mmol). The residue from step 1 was dissolved in THF (1 mL) and treated with ammonia (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) at 50° C. After 12 hours another portion of ammonia, (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) was added and the reaction mixture was allowed to stir for additional 5 hours The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 10 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-methoxypyrazine-2-10 carboxamide were obtained as an off-white solid. MS m/z=497.1 [M]+. Calculated for C21H17BrN6O4: 497.30. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1H) 1.94-2.04 (m, 1H) 4.08 (s, 3H) 4.11-4.18 (m, 1H) 4.20-4.30 (m, 1H) 7.31 (d, J=9.21 Hz, 1H) 7.69-7.77 (m, 2H) 7.94 (d, J=2.34 Hz, 1H) 8.18 (d, J=1.32 Hz, 1H) 8.32 (d, J=2.48 Hz, 1H) 9.04 (d, J=1.32 Hz, 1H) 9.55 (s, 1H).

Workup

  1. customwas removed under reduced pressure
  2. customthe residue was purified by preparative reversed-phase
  3. customover 20 min
  4. concentrationThe combined fractions were concentrated
  5. dissolutionThe residue was dissolved in MeOH
  6. washThe product was eluted with a 2M solution of NH3 in MeOH

Sources & evidence

ORD record
ord-19c8198eb6ad4ba399094f540dcad75c
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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