Hydrochloric Acid → (1-(6-((9-cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)-amino)-3-pyridinyl)-4-piperidinyl)methanol

HRID 876002Notes

Reaction equation

HRID 876002 reaction equation
[Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[C:31]5[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:30]=5[N:29]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:28]=3)=[N:20][CH:21]=2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.CO.C(O)C.C(OCC)C>[CH:37]1([N:29]2[C:27]3[N:28]=[C:23]([NH:22][C:19]4[N:20]=[CH:21][C:16]([N:13]5[CH2:12][CH2:11][CH:10]([CH2:9][OH:8])[CH2:15][CH2:14]5)=[CH:17][CH:18]=4)[N:24]=[CH:25][C:26]=3[C:31]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:30]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2724141Tetrabutylammonium FluorideHCID 58300053N-(5-(4-(((tert-Butyl(dimethyl)silyl)oxy)methyl)-1-piperidinyl)-2-pyridinyl)-9-cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine

Product 1

HCID 58299866(1-(6-((9-cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)-amino)-3-pyridinyl)-4-piperidinyl)methanolYield 27.5%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Compound 282 (118 mg, 205 μmol) was dissolved in dry THF (3 mL). Tetrabutylammonium fluoride, 1.0M in THF (0.75 mL, 750 μmol) was added and the reaction was stirred at room temperature for 80 minutes. The resulting solution was added to aqueous K2CO3 (10%, 30 mL) and extracted with dichloromethane+10% methanol (2×30 mL). The combined organics were dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution ethyl acetate+2.5% TEA/0-5% methanol) afforded a yellow solid. This residue was taken up in methanol (1.5 mL) and HCl in ethanol (1.0M, 0.5 mL) was added. Diethyl ether (20 mL) was added to precipitate the product as a yellow solid, which was filtered and dried in vacuo to give compound 283 as a yellow solid (26 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1 H) 9.27-9.37 (m, 1 H) 8.11 (d, J=9.05 Hz, 1 H) 7.99-8.06 (m, 4 H) 7.48 (dd, J=9.17, 2.81 Hz, 1H) 5.46 (quin, J=9.11 Hz, 1 H) 4.50 (t, J=5.26 Hz, 2 H) 3.70 (d, J=11.98 Hz, 2 H) 2.61-2.71 (m, 2 H) 2.35 (d, J=12.72 Hz, 2 H) 2.10 (br. s., 2 H) 1.95-2.06 (m, 2 H) 1.77 (t, 4 H) 1.45-1.59 (m, 1 H) 1.28 (qd, J=12.23, 3.67 Hz, 2 H) ppm.

Workup

  1. extractionextracted with dichloromethane+10% methanol (2×30 mL)
  2. dry with materialThe combined organics were dried (MgSO4)
  3. customevaporated
  4. customto give an orange oil
  5. washSilica gel chromatography (gradient elution ethyl acetate+2.5% TEA/0-5% methanol)
  6. customafforded a yellow solid
  7. customto precipitate the product as a yellow solid, which
  8. filtrationwas filtered
  9. customdried in vacuo

Sources & evidence

ORD record
ord-702cd6aac11546999d2f6faa557f1e80
Source dataset
uspto-grants-2015_03
Patent number
US08980903B2

Reaction notes

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