Methyl chloroformate → (+/-)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate

HRID 921734Notes

Reaction equation

HRID 921734 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>CO>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]3[N:22]=2)=[CH:4][C:5]([C:18]#[N:19])=[CH:6][C:7]=1[N:8]1[CH2:17][CH2:16][C@@H:15]2[C@H:10]([O:11][CH2:12][CH2:13][N:14]2[C:44]([O:45][CH3:46])=[O:47])[CH2:9]1

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 81531DiisopropylethylamineHCID 86708616(+/-)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 86708618(+/-)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol, was taken up in MeOH (1 mL) and DIPEA 20 μL was added. The reaction was stirred at 5° C. (ice bath) and methyl carbonochloridate (1.617 μl, 0.021 mmol) was added; the reaction stirred at 25° C. 1 hr. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (7.8 mg).

Workup

  1. additionwas added
  2. custom1 hr
  3. customThe solvents removed
  4. customthe crude material was purified via preparative LC/MS with the following conditions
  5. customa 5-minute hold
  6. additionFractions containing the desired product
  7. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-b9be5dbe32c7458aad1e6d8294b4b4a4
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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