Hydrochloric Acid → (2R,4R)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

HRID 1963553Notes

Reaction equation

HRID 1963553 reaction equation
C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730463trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate

Product 1

HCID 66732693(2R,4R)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 45%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 3.13 mmol) (from example 101, step 1) was dissolved in methanol (10 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.000 mL) was added dropwise and continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.192 mL, 3.13 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15 mL, 90.00 mmol) and the mixture continued to stir at 80° C. for 55 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to a yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (468 mg, 45%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.46-1.77 (m, 2H), 1.80-2.13 (m, 2H), 2.28-3.23 (m, 4H), 3.38-3.80 (m, 3H), 4.04-4.34 (m, 1H), 4.50-4.80 (m, 1H), 5.65 (s, 1H), 6.99-7.12 (m, 2H), 7.12-7.30 (m, 2H). MS m/z 335 (M+H)+

Workup

  1. additionwas added dropwise
  2. stirringThe resulting solution was stirred at −40° C. for 2 h
  3. stirringto stir at 80° C. for 55 min
  4. customThe solvent was evaporated
  5. additionMTBE/water added
  6. customThe phases were separated
  7. dry with materialthe organic phase dried over Na2SO4
  8. customevaporated to a yellow foam
  9. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min

Sources & evidence

ORD record
ord-34b091b3d849449b99a7da29c8c0d1a5
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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