Tetrahydrofuran → 8-Chloro-9-cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine

HRID 875963Notes

Reaction equation

HRID 875963 reaction equation
[Cl:1][C:2]1[C:7](F)=[C:6]([C:9]2[C:10]([NH:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[N:16]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:6]=2[CH:5]=[CH:4][N:3]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 516892Sodium BicarbonateHCID 2733832Lithium HexamethyldisilazideHCID 58299996HCID 58299996, compound

Product 1

HCID 582995878-Chloro-9-cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amineYield 55.2%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

Compound 193 (3.10 g, 10.1 mmol) was combined with 30 mL of anhydrous 1,4-dioxane. To this was added LiHMDS 1M in THF (30.2 mL, 30.2 mmol) and the solution was heated to 85° C. for 5 hours. The solution was cooled to room temperature and then diluted with ice/sat. NaHCO3. The product was extracted with 15% 2-propanol/DCM and the organics were dried over MgSO4 before being concentrated under vacuum. The residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/DCM to 6% methanol/DCM. Trituration with acetone and ethyl acetate left a light brown solid. Repurification of the supernatants provided additional material. The solids were combined to give compound 194 (1.60 g, 55.2%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (1 H, s), 8.14 (1 H, d, J=4.9 Hz), 7.98 (1 H, d, J=4.9 Hz), 7.07 (2 H, br. s.), 5.90 (1 H, quin, J=8.7 Hz), 2.44-2.49 (2 H, m), 2.04-2.13 (2 H, m), 1.95-2.03 (2 H, m), 1.63-1.73 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 288.1.

Workup

  1. temperatureThe solution was cooled to room temperature
  2. additiondiluted with ice/
  3. extractionThe product was extracted with 15% 2-propanol/DCM
  4. dry with materialthe organics were dried over MgSO4
  5. concentrationbefore being concentrated under vacuum
  6. customThe residue obtained
  7. customwas purified on CombiFlash column (dry loaded)
  8. washeluting with a gradient of 2% methanol/DCM to 6% methanol/DCM
  9. waitTrituration with acetone and ethyl acetate left a light brown solid
  10. customRepurification of the supernatants
  11. customprovided additional material

Sources & evidence

ORD record
ord-e7bc0a6f22a342bc8d72ec4953a57407
Source dataset
uspto-grants-2015_03
Patent number
US08980903B2

Reaction notes

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