Sodium Hydroxide → (S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate

HRID 2177635Notes

Reaction equation

HRID 2177635 reaction equation
[CH3:1][C@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:16]([C:19]1[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[N+:17]=[N-:18].N1CCCC1.C([O-])(O)=O.[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:25][C:22]1[CH:21]=[N:20][C:19]([N:16]2[C:6]3[CH2:7][C@H:2]([CH3:1])[N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:5]=3[N:18]=[N:17]2)=[N:24][CH:23]=1

Participants

9

Reactant 6

HCID 14798Sodium HydroxideHCID 31268PyrrolidineHCID 70297m-Chloroperbenzoic acidHCID 516892Sodium BicarbonateHCID 11401606tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylateHCID 904092602-Azido-5-fluoropyrimidine

Product 1

HCID 90408514(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (2.76 g, 12.9 mmol) in toluene (100 mL) at 100° C. was added 2-azido-5-fluoropyrimidine (2.34 g, 16.8 mmol) as a solution in toluene (15 mL) followed by pyrrolidine (1.06 mL, 12.9 mmol). After stirring for 3 h at rt, the reaction was cooled to 0° C. and CH2Cl2 (100 mL) was added followed by NaHCO3 (2.17 g, 25.9 mmol) and mCPBA (4.47 g, 25.9 mmol). The reaction was allowed to warm to rt over 30 min followed by the addition of 1N NaOH (100 mL). The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a 9:1 mixture of regioisomers (9:1=(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate: (S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-4-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate (2.85 g, 66%). The minor regioisomer was separated by SFC (Chiralpak IC 5 μm 250*21 mm, mobile phase 70% CO2, 30% iPrOH) to provide the product as a white solid. MS (ESI) mass calcd. C15H19FN6O2, 334.16. m/z found, 335.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.73 (s, 2H), 5.16 (d, J=16.1 Hz, 1H), 4.96 (br s, 1H), 4.25 (d, J=16.4 Hz, 1H), 3.38-3.28 (m, 1H), 3.19-3.10 (m, 1H), 1.50 (s, 9H), 1.16 (d, J=7.0 Hz, 3H).

Workup

  1. temperaturethe reaction was cooled to 0° C.
  2. temperatureto warm to rt over 30 min
  3. customThe organic layer was separated
  4. extractionthe water layer was extracted with CH2Cl2 two times
  5. dry with materialThe combined organic layers were dried over anhydrous MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-34c49e99c2f94217ada4aa5daab0f149
Source dataset
uspto-grants-2015_06
Patent number
US09066946B2

Reaction notes

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