Acetic Acid → 3-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-ol

HRID 1923324Notes

Reaction equation

HRID 1923324 reaction equation
[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][N:20]([CH:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 121599Tetrahydro-4H-pyran-4-one2×HCID 5049666Sodium triacetoxyborohydride2×HCID 596060743-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]azetidine-3-ol

Product 1

HCID 596056283-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-ol

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-azetidin-3-ol (490 mg, 1.13 mmol), tetrahydropyran-4-one (158 mg, 1.58 mmol), AcOH (130 μL, 2.25 mmol) and 4 Å powdered molecular sieves (640 mg) in DCE (15 mL) was allowed to stir for 5 min before the addition of sodium triacetoxyborohydride (478 mg, 2.25 mmol) portion wise over 5 min. The resulting mixture was allowed to stir for 4 h at r.t before the addition of further tetrahydropyran-4-one (158 mg, 1.58 mmol) and sodium triacetoxyborohydride (478 mg, 2.25 mmol). The mixture was stirred for 2 h then diluted with DCM and washed with 1M NaOH. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, 2M NH3/MeOH:DCM, 0-15%) then (C18, MeOH:H2O, 7.5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 720 as a white foam (309 mg, 53%). LCMS (method I): RT 2.40 min, [M+H]+ 519.3. 1H NMR (MeOD, 400 MHz): δ 8.01-8.00 (1 H, m), 7.66-7.61 (1 H, m), 7.28-7.27 (2 H, m), 4.38 (4 H, s), 4.24 (2 H, d, J=8.76 Hz), 3.97-3.94 (2 H, m), 3.85 (7 H, s), 3.56 (2 H, d, J=8.75 Hz), 3.31-3.31 (5 H, m), 2.54-2.52 (1 H, m), 1.83-1.73 (2 H, m), 1.38 (5 H, t, J=7.49 Hz)

Workup

  1. washwashed with 1M NaOH
  2. customThe organic phase was dried (phase separator)
  3. concentrationconcentrated in vacuo
  4. customThe resulting oil was purified by column chromatography (Si—PCC, 2M NH3/MeOH:DCM, 0-15%)
  5. washwas washed with DCM and MeOH
  6. washthe product eluted with 2M NH3/MeOH affording 720 as a white foam (309 mg, 53%)
  7. customRT 2.40 min, [M+H]+ 519.3

Sources & evidence

ORD record
ord-75fa6ff491f94eeab87b0b51c3a6129b
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

Loading…