2-Hydroxyisobutyric acid → 1-(3-((5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-one

HRID 1946177Notes

Reaction equation

HRID 1946177 reaction equation
[NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[S:7][C:8]3[N:9]=[C:10]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]4[CH2:30][CH3:31])[N:11]=[C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:13]=3[N:14]=2)[CH2:2]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:13]3[N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:4]4)[S:7][C:8]=3[N:9]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]

Participants

6

Reactant 4

HCID 116712-Hydroxyisobutyric acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 596054122-Azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine

Product 1

HCID 596058511-(3-((5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-oneYield 35.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (209 mg, 0.48 mmol), 2-hydroxyisobutyric acid (56 mg, 0.54 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (94 μL, 0.54 mmol) in DCM (5 mL) was allowed to stir at r.t. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-2%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 814 as a white solid (89 mg, 35%). LCMS (method I): RT 3.39 min, [M+H]+ 522.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.28 (2 H, m), 4.62-4.12 (7 H, m), 4.05-3.92 (1 H, m), 3.88 (4 H, t, J=4.76 Hz), 3.45 (1 H, s), 3.43-3.38 (2 H, m), 3.33 (2 H, q, J=7.47 Hz), 3.27-3.21 (1 H, m), 1.43-1.42 (9 H, m)

Workup

  1. washwas washed with MeOH
  2. washthe product eluted with 2M NH3/MeOH
  3. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-2%)

Sources & evidence

ORD record
ord-c646e0e085d24eeea7b6269b78c4e0f1
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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