Hydrochloric Acid → (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)-3-((S)-1-hydroxypropan-2-yloxy)propanamide

HRID 1098038Notes

Reaction equation

HRID 1098038 reaction equation
Cl.[Si]([O:9][CH2:10][C@@H:11]([O:13][CH2:14][C@H:15]([O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=3)[N:34]=[CH:35][C:28]=12)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[O:17])[CH3:12])(C(C)(C)C)(C)C>C1COCC1>[Cl:42][C:41]1[C:36]([N:33]2[C:29]3=[N:30][CH:31]=[N:32][C:27]([O:26][C@@H:15]([CH2:14][O:13][C@@H:11]([CH3:12])[CH2:10][OH:9])[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)=[O:17])=[C:28]3[CH:35]=[N:34]2)=[N:37][CH:38]=[CH:39][CH:40]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 57504540(2S)-3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide

Product 1

HCID 57504420(2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)-3-((S)-1-hydroxypropan-2-yloxy)propanamideYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

HCl (4M in Dioxane) (0.530 mL, 2.12 mmol) was added to (2S)-3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate AO3) (638 mg, 1.06 mmol) in THF (5 mL) at room temperature. The resulting solution was stirred for 20 minutes. The reaction mixture was evaporated and the residue partitioned between EtOAc (25 mL) and sat NaHCO3 (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent to afford the product (397 mg, 77%). 1H NMR (400 MHz, CDCl3) δ1.16 (d, 3H), 2.73 (s, 1H), 3.51-3.68 (m, 2H), 3.69-3.78 (m, 1H), 4.12-4.28 (m, 2H), 6.06 (t, 1H), 7.42-7.50 (m, 2H), 7.99-8.03 (m, 1H), 8.13 (d, 1H), 8.21-8.26 (m, 1H), 8.47 (s, 1H), 8.60-8.65 (m, 2H), 9.09 (s, 1H); m/z (ESI+) (M+H)+=488.42; HPLC tR=1.75 min

Workup

  1. customThe reaction mixture was evaporated
  2. customthe residue partitioned between EtOAc (25 mL)
  3. dry with materialThe organic layer was dried (MgSO4)
  4. customevaporated
  5. customThe crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column
  6. washeluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent

Sources & evidence

ORD record
ord-5fff1b2295244f28ac0e20c1c8e9e22e
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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