G.Patton
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Introduction
The method have developed for the manufacture of amphetamine, that avoids the use of bases, avoids the use of toxic and dangerous reagents, requires mild reaction conditions, produces essentially no by-products or impurities in the final products thereby eliminating the need for separate purification steps, is short, does not use controlled substances, is very robust and is Suited to large-scale manufacture. This method also takes advantage of the innate stereochemistry of the starting materials, thereby eliminating the need for resolution steps.
Equipment and glassware:
Equipment and glassware:
- Three necked round bottom flask 150 mL;
- pH indicator papers;
- Beakers (100 mL x2, 1 L, 250 mL x2);
- Laboratory scale (1-100 g is suitable);
- Ice/water bath;
- Glass rod and spatula;
- Laboratory grade thermometer;
- Buchner flask and funnel;
- Hirsch funnel;
- Filter paper;
- TLC plate;
- Celite;
- Drip funnel;
- Hydrogen gas (H2) source;
- Balloon;
Reagents:
- (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone 6.00 g (33.9 mmol);
- Palladium on-carbon (50% water wet) 10% 0.34 g;
- SDA-3A (a solvent constituting 95% Ethanol and 5% Methanol) 60 mL;
- Sulphuric acid (H2SO4 (aq)) 25% ~7 mL;
- Isopropyl alcohol IPA (or ether);
Procedures
1. A mixture of 6.00 g (33.9 mmol) (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone, 0.34 g 10% palladium on-carbon (50% water wet), and 60 mL SDA-3A (a solvent constituting 95% Ethanol and 5% Methanol) is stirred in a three necked 150 mL round bottom flask under a hydrogen filled balloon at ambient temperature (approximately 20°C) until no more oxazolidinone was detected by TLC, ~4h.
2. The reaction mixture is then filtered through a pad of Celite on a Hirsch funnel to remove the catalyst.
3. Whereupon a total of 7 mL 25% H2SO4 (aq) was added dropwise to the filtrate over 3 min to a neutral pH.
4. After cooling in an ice/water bath for 15 min, the mixture is filtered to collect the dextroamphetamine sulfate using cold dry IPA (or ether) as a flask and cake rinse.
5. After drying, a total of 5.79 g of dextroamphetamine sulfate is obtained, 93% yield. This material is assayed at 100% by HPLC.
2. The reaction mixture is then filtered through a pad of Celite on a Hirsch funnel to remove the catalyst.
3. Whereupon a total of 7 mL 25% H2SO4 (aq) was added dropwise to the filtrate over 3 min to a neutral pH.
4. After cooling in an ice/water bath for 15 min, the mixture is filtered to collect the dextroamphetamine sulfate using cold dry IPA (or ether) as a flask and cake rinse.
5. After drying, a total of 5.79 g of dextroamphetamine sulfate is obtained, 93% yield. This material is assayed at 100% by HPLC.
Source
United States (12) Patent Application Publication US 2010.01251.46A1