Diisopropylethylamine → tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

HRID 516125

Reaction equation

HRID 516125 reaction equation
[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](Cl)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>CS(C)=O.CC(O)C>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 68077633tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamateHCID 86654739tert-Butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Product 1

HCID 86654748tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylateYield 86%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.42 g, 4.43 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (1.15 g, 5.52 mmol), diisopropylethylamine (3.87 mL, 22.16 mmol) in DMSO (10 mL) and 2-propanol (40 mL) were heated to 100° C. in an oil bath for 20 h. The solution was then concentrated and the resulting oil was dissolved in water (50 mL) and heated in an oil bath to 50° C. for 1 h then allowed to cool to RT. The solution was subsequently heated to 50° C. for 15 min, allowed to cool to RT, again heated to 50° C. for 15 min, and allowed to cool to RT. The resulting precipitate was filtered and rinsed with water to give the title compound as a pale pinkish-white solid (1.90 g, 86%, 4:1 mixture with regioisomer) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9 H), 1.50 (s, 3 H), 1.59-1.61 (m, 1 H), 1.97-1.99 (m, 1 H), 1.97-1.99 (m, 1 H), 3.46-3.49 (m, 2 H), 3.80-3.83 (m, 3 H), 4.31-4.33 (m, 1 H), 4.73 (s, 1 H), 6.59 (d, J=7.30 Hz, 1 H), 7.43 (d, J=7.30 Hz, 1 H). [M+H] calc'd for C22H30ClFN4O6, 501; found, 501.

Workup

  1. concentrationThe solution was then concentrated
  2. dissolutionthe resulting oil was dissolved in water (50 mL)
  3. temperatureheated in an oil bath to 50° C. for 1 h
  4. temperatureto cool to RT
  5. temperatureThe solution was subsequently heated to 50° C. for 15 min
  6. temperatureto cool to RT
  7. temperatureagain heated to 50° C. for 15 min
  8. temperatureto cool to RT
  9. filtrationThe resulting precipitate was filtered
  10. washrinsed with water

Sources & evidence

ORD record
ord-d2414520c6134d26abea1f6492991bde
Source dataset
uspto-grants-2015_08
Patent number
US09108970B2

Linked notes

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