Dichloromethane → HCID 118598618, compound

HRID 1050386Notes

Reaction equation

HRID 1050386 reaction equation
Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=C(F)C=3)([CH3:26])[NH:23][C:24](=[O:25])[C:3]=12.[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>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].O>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][N:14]=3)[C:5](=[O:21])[N:4]3[C:22]4([CH2:26][CH2:30][CH2:31][CH2:32][CH2:27]4)[NH:23][C:24](=[O:25])[C:3]=23)[CH2:38][CH2:39]1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 118598561HCID 118598561, compound

Product 1

HCID 118598618HCID 118598618, compound

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A vial was charged with 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 0.50 g, 1.44 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2, 0.36 g, 1.73 mmol) in 1,4-dioxane (10 mL). Sodium carbonate (0.46 g, 4.33 mmol) was added followed by water (1.44 mL) and purged the mixture with argon for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.11 g, 0.144 mmol) was then added and purging was continued for 5 more min. The reaction was sealed and heated at 110° C. for 16 h. After completion of reaction by TLC and LCMS. Water (100 mL) was added and extracted with 10% methanol in dichloromethane (3×150 mL). The organics were washed with brine (1×100 mL). The organics were then separated and dried (sodium sulfate) before concentration to dryness. The crude was then purified by flash column chromatography eluting with 2-3% methanol in dichloromethane. The desired fractions were concentrated to dryness under vacuum to afford 8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3) as an off white solid. Yield: 0.35 g, 61%; MS (ESI) m/z 394 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H), 8.61 (s, 1H), 8.43 (d, J=6.08 Hz, 1H), 7.44 (d, J=5.72 Hz, 1H), 5.75 (s, 1H), 4.18 (s, 2H), 3.79 (s, 2H), 3.05 (m, 2H), 2.45 (m, 2H), 1.84 (m, 6H), 1.56 (s, 2H).

Workup

  1. additionwas then added
  2. custompurging
  3. customThe reaction was sealed
  4. customAfter completion of reaction by TLC and LCMS
  5. extractionextracted with 10% methanol in dichloromethane (3×150 mL)
  6. washThe organics were washed with brine (1×100 mL)
  7. customThe organics were then separated
  8. dry with materialdried (sodium sulfate)
  9. concentrationbefore concentration to dryness
  10. customThe crude was then purified by flash column chromatography
  11. washeluting with 2-3% methanol in dichloromethane
  12. concentrationThe desired fractions were concentrated to dryness under vacuum

Sources & evidence

ORD record
ord-6ddc681d40254984aa9b9231d31e77bd
Source dataset
uspto-grants-2016_07
Patent number
US09382248B2

Reaction notes

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