Ethyl Acetate → Ticagrelor

HRID 2404977Notes

Reaction equation

HRID 2404977 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@H:26]4[C@@H:30]5[O:31]C(C)(C)[O:33][C@@H:29]5[C@@H:28]([O:36][CH2:37][CH2:38][OH:39])[CH2:27]4)[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@@H:26]4[CH2:27][C@H:28]([O:36][CH2:37][CH2:38][OH:39])[C@@H:29]([OH:33])[C@H:30]4[OH:31])[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

6

Reactant 3

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 672892902-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-1,2,3-triazolo(4,5-d)pyrimidin-3-yl)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol

Product 1

HCID 9871419TicagrelorYield 48%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 887MethanolSolvent

Procedure

A solution of 2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (450 mg, 0.80 mmol, 1.00 equiv.) in methanol (4 mL) and 12N hydrochloric acid (1.5 mL) was stirred at ambient temperature for about 3 hours. The pH value of the solution was adjusted to 8-9 by adding potassium carbonate. Following standard extractive workup with ethyl acetate (3×20 mL), the resulting crude residue was purified by silica gel column chromatography (dichloromethane/methanol (50:1)) to give a semi-crude product (200 mg; yield=48%). The semi-crude product, which contained about 5% of other diastereoisomers, was then further purified by chiral-prep HPLC (column: Chiralpak IA2×25 cm, 5 umChiral-P(IA)004IA00CJ-MB003) to afford the title compound (100 mg). [α]D24.1-43.2° (c, 0.2 g/100 mL in MeOH). LC-MS: m/z=523.0 (MH)+, Retention time: 1.58 minute. 1H NMR (300 MHz, CD3OD) δ: 7.08-7.23 (m, 3H), 5.13 (q, 1H), 4.75-4.79 (m, 1H), 4.17-4.20 (m, 1H), 3.91-3.95 (m, 1H), 3.63-3.73 (m, 4H), 3.06-3.26 (m, 2H), 2.90-3.00 (m, 1H), 2.70-2.80 (m, 1H), 2.05-2.29 (m, 2H), 1.60-1.88 (m, 2H), 1.38-1.59 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).

Workup

  1. customthe resulting crude residue was purified by silica gel column chromatography (dichloromethane/methanol (50:1))
  2. customto give a semi-crude product (200 mg; yield=48%)
  3. customwas then further purified by chiral-prep HPLC (column: Chiralpak IA2×25 cm, 5 umChiral-P(IA)004IA00CJ-MB003)

Sources & evidence

ORD record
ord-85b1dd3c38fa40979b3b8f51ca34c133
Source dataset
uspto-grants-2014_08
Patent number
US08802850B2

Reaction notes

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