Sodium Bicarbonate → 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine

HRID 1631790Notes

Reaction equation

HRID 1631790 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[N:26](C(OC(C)(C)C)=O)[CH:25]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[C:24]([C:2]2[N:11]=[CH:10][C:9]3[NH:8][CH2:7][CH:6]4[CH2:12][O:13][CH2:14][CH2:15][N:5]4[C:4]=3[N:3]=2)=[CH:25]1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 53217196tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 86670087HCID 86670087, compound

Product 1

HCID 601967592-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridineYield 15%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (114 mg, 0.331 mmol) and PdCl2(dppf) (8.07 mg, 0.011 mmol) were partially dissolved in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). The resulting brown suspension was stirred overnight at 100° C. By the following day, the coupling reaction was complete and the BOC group had also been removed. The reaction mixture was subsequently diluted with ethyl acetate and washed with brine (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was first purified by LC/MS using a gradient of 0-30% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The product and the starting material co-eluted, yielding no pure fractions. The fractions which contained product were concentrated and lyophilized to give a yellow solid, which was re-purified via LC/MS using a 15-40% gradient of CH3CN in H2O with 10 mmol NH4HCO3. The pure fractions were combined and lyophilized to give the title compound as a white solid (10 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 2.89-3.08 (m, 2H), 3.12-3.26 (m, 1H), 3.39-3.52 (m, 2H), 3.52-3.67 (m, 1H), 3.83-4.14 (m, 2H), 4.45-4.63 (m, 1H), 5.60-5.80 (m, 1H), 7.04-7.23 (m, 1H), 7.53-7.68 (m, 1H), 7.91-8.03 (m, 1H), 8.13-8.30 (m, 1H), 8.59-8.78 (m, 1H), 11.70-11.88 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C16H16N6O, 309.14. found 309.3.

Workup

  1. customBy the following day, the coupling reaction
  2. customthe BOC group had also been removed
  3. additionThe reaction mixture was subsequently diluted with ethyl acetate
  4. washwashed with brine (3×10 mL)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe product was first purified by LC/MS
  9. customThe product and the starting material co-eluted, yielding no pure fractions
  10. concentrationwere concentrated
  11. customto give a yellow solid, which
  12. customwas re-purified via LC/MS

Sources & evidence

ORD record
ord-7d8eb2e844904cec9ec2f2612f9a387c
Source dataset
uspto-grants-2014_07
Patent number
US08791107B2

Reaction notes

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