Lithium Hydroxide → 2-hydroxy-2-methyl-1-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)propan-1-one

HRID 1946195

Reaktionsgleichung

Reaktionsgleichung von HRID 1946195
[CH3:1][C:2]([O:37]C(=O)C)([CH3:36])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:37][C:2]([CH3:36])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4]

Komponenten

5

Edukt 2

HCID 3939Lithium Hydroxide2×HCID 59606028Acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester

Produkt 1

HCID 596052092-hydroxy-2-methyl-1-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)propan-1-oneAusbeute 77 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (125 mg, 0.23 mmol) and LiOH (114 μL, 0.46 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (343 μL, 1.37 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue 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, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 855 as a white solid (88 mg, 77%). LCMS (method I): RT 2.88 min, [M+H]+ 505.3. 1H NMR (DMSO, 400 MHz): δ 8.09-8.08 (1 H, m), 7.64-7.61 (1 H, m), 7.28-7.27 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.94 Hz), 4.26 (4 H, brd s), 4.17 (1 H, dd, J=10.24, 5.60 Hz), 4.03 (1 H, t, J=8.97 Hz), 3.77 (4 H, t, J=4.64 Hz), 3.74 (3 H, s), 3.67 (1 H, dd, J=9.96, 5.41 Hz), 3.21-3.20 (3 H, m), 2.85 (3 H, s), 1.28-1.21 (6 H, m)

Aufarbeitung

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. washwas washed with MeOH
  3. washthe product eluted with 2M NH3/MeOH
  4. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%)
  5. dissolutionthen dissolved in a mixture of MeCN and H2O
  6. customto freeze-dry

Quellen und Nachweise

ORD-Eintrag
ord-68cf199eadd94b2585d7fcf5f13287bb
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08394796B2

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