Pyridine → HCID 89853813, compound

HRID 338169Notes

Reaction equation

HRID 338169 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10](NC(=O)C2C=CC=CC=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[N:33]1[CH:38]=CC=CC=1.[ClH:39].CO[NH2:42]>C(O)C>[ClH:39].[NH2:42][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:18]=[CH:19][C:20]([F:23])=[CH:21][N:22]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:38]#[N:33])[N:9]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 521874O-Methylhydroxylamine hydrochlorideHCID 89832315HCID 89832315, compound

Product 1

HCID 89853813HCID 89853813, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of racemic N-[7a-(3-bromophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (180 mg, 393 μmol) in ethanol (8.0 mL) is added sequentially pyridine (0.5 mL, 6.2 mmol) and O-methylhydroxylamine hydrochloride (350 mg, 4.19 mmol). The mixture is heated at 60° C. for 16 hours, cooled to ambient temperature, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with a gradient of 0 to 10% of dichloromethane/2 M ammonia in methanol to give the free base form of the title compound as a colorless oil. The racemic material is separated chirally by SFC (Column: Chiralpak AS-H, 5μ; eluent: 35% isopropyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the free base of the title compound, (Rt=0.92 minutes). EI/MS (m/e): 355 (M+H). This isomer is dissolved in dichloromethane (1 mL) and hydrogen chloride gas is bubbled through this solution for approximately 10 seconds. The solution is then concentrated to give the title compound as a white solid (55 mg, 36%, >99% ee).

Workup

  1. temperaturecooled to ambient temperature
  2. concentrationconcentrated to dryness
  3. customThe residue is purified by silica gel flash chromatography
  4. washeluting with a gradient of 0 to 10% of dichloromethane/2 M ammonia in methanol

Sources & evidence

ORD record
ord-d688bf6550434db6acacafc366600fbe
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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