Comprehensive Fentanyl Synthesis Protocol

Materials:
- N-phenethyl-4-piperidone (NPP), 25g
- 4-ANPP (4-anilino-N-phenethylpiperidine), 20g
- Aniline (phenylamine), 15g
- Propionyl chloride, 12mL
- Sodium borohydride (NaBH4), 8g
- Dichloromethane (DCM), 200mL
- Tetrahydrofuran (THF), 150mL
- Triethylamine, 20mL
- Hydrochloric acid solution, 100mL

Equipment:
- Three-neck round-bottom flask
- Reflux condenser
- Ice bath
- Separatory funnel
- Rotary evaporator
- Fume hood with proper ventilation
- PPE including nitrile gloves and respirator

Procedure:

1. Reductive Amination to form 4-ANPP:
   a. Dissolve 25g of N-phenethyl-4-piperidone (NPP) in 100mL THF
   b. Add 15g aniline (phenylamine) dropwise
   c. Cool to 0-5 degrees Celsius in ice bath
   d. Add sodium borohydride (NaBH4) portionwise over 30 minutes
   e. Stir at room temperature (20-25°C) for 4 hours
   f. Monitor reaction progress

2. N-Acylation with Propionyl Chloride:
   a. Dissolve 4-ANPP in 100mL dichloromethane (DCM)
   b. Cool to 0 degrees Celsius
   c. Add triethylamine as base
   d. Add propionyl chloride dropwise for propionylation
   e. Allow to warm to room temperature
   f. Heat to 60-80 degrees Celsius under reflux for 2 hours
   g. Maintain at 1 atmosphere pressure

3. Workup and Extraction:
   a. Perform liquid-liquid extraction using separatory funnel
   b. Wash organic layer with water
   c. Dry over anhydrous sodium sulfate
   d. Remove solvent under reduced pressure

4. Purification:
   a. Perform column chromatography
   b. Recrystallization from ethanol

5. Salt Formation:
   a. Dissolve freebase in DCM
   b. Bubble HCl gas to form hydrochloride salt
   c. Filter and dry crystals

6. Analysis:
   a. Determine yield and purity by HPLC
   b. Confirm structure by GC-MS

Safety Notes:
- Extremely potent compound - microgram quantities are lethal
- All work must be done in fume hood
- Wear appropriate PPE at all times
- Potency requires extreme caution with dosage

Expected yield: 85-90%
