Hydrochloric Acid → HCID 68501980, compound

HRID 1963654Notes

Reaction equation

HRID 1963654 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:36]O.Cl>CO.O.C(Cl)Cl>[C:30]([C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:22][NH:36][C:17](=[O:19])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:33])([CH3:32])[CH3:31]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730503HCID 131730503, compound

Product 1

HCID 68501980HCID 68501980, compoundYield 72%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.03 g, 4.42 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.177 g, 4.42 mmol) dissolved in water (1.600 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.271 mL, 4.42 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (20 mL, 120.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-50% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.358 g, 72%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.22-1.33 (m, 18H), 1.80-2.10 (m, 4H), 2.59-2.67 (m, 1H), 2.71-2.78 (m, 1H), 2.92-2.98 (m, 1H), 3.07-3.15 (m, 1H), 3.55 (s, 3H), 3.97 (dd, 1H), 4.18-4.27 (m, 1H), 5.68 (s, 1H), 6.92 (d, 2H), 7.22 (s, 1H). MS m/z 429 (M+H)+

Workup

  1. additionwas added during 10 min
  2. stirringThe resulting solution was stirred at −40° C. for 3.5 h
  3. stirringto stir at 80° C. for 20 min
  4. customThe phases were separated
  5. customevaporated
  6. customto yield a yellow semi-solid
  7. customThe compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
  8. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-6fb31361d1db4d2f8b542e0ac6708570
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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