Amfetamin

Speed, pulver, tjack, vitt, uppåt, affe, don - kärt barn har många namn. Amfetamin, C6H5CH2CH(NH2)CH3, är ett syntetiskt centralstimulerande preparat. Historiskt har amfetamin använts relativt länge, t ex inom de medicinska och militära områdena. Amfetamin är en av de vanligaste illegala drogerna i Sverige och inom t ex kriminalvården är centralstimulantia ett allvarligt problem. Tullen gör också stora beslag och tecken finns på en ökad smuggling. CAN beräknar att antalet tunga missbrukare är ca 30.000 personer och av dem använder ungefär en tredjedel amfetamin som dominerande drog. Statistik visar nu att dödsfallen, i form av t ex cirkulations-, hjärt- och kärlsjukdomar ökar. Man räknar också med att ca 90 % av de brukare som injicerar har någon form av hepatit.

Det finns ännu ingen evidensbaserad behandling mot amfetaminberoende, varken medicinsk eller psykosocial. Nu pågår dock intressanta studier när det gäller läkemedelsbehandling av människor som brukar och är beroende av amfetamin. Flera olika typer av läkemedel prövas nu runt om i världen för att motverka drogsug och återfall hos denna grupp av brukare.

Kemi för Amfetamin

CAS-nr: 300-62-9 Summaformel: C9H13N Molekylmassa: 135,21 g/mol IUPAC: 1-fenyl-isopropylamin Trivialnamn: amfetamin, fenylisopropylamin, tjack, speed

MSDS för amfetamin i fribas/grundform respektive amfetaminsulfat

Amfetamin Smältpunkt (°C): - 300+ Kokpunkt (°C): 200-203 - Övrigt: svagt gul olja med typisk aminlukt. Löslig i de flesta opolära organiska lösningsmedel, såsom Et2O, petroleumeter, diklormetan. Även lösligt i enkla alkoholer (MeOH, EtOH, IPA etc.). Densitet: 0913 g/cm³. den vanligaste förekommande formen av amfetamin. En (1) del amfetaminsulfat löser sig i 8,8 delar vatten, 515 delar 95% EtOH. En lösning med koncentrationen 1 g/10 ml har pH=5-6. Administrering: fribasen intas enklast genom att inhalera dess ångor under upphettning. VARNING! Risken för tillvänjning vid inhalering av amfetaminångor är mycket stor. peroralt, sublingualt, nasalt, eller intravenöst. Subkutan och intramuskulär injektion är möjligt, men amfetamin är vävnadsirriterande. VARNING! Risken för tillvänjning vid intravenöst intag är mycket stor.

Tillverkning av amfetamin

Fenylalanin-metoden

Schematisk syntesbeskrivning

  * Reduction of the carboxylic acid with LiBH4/TMSCl
  * BOC protection of the amino group
  * Conversion of the alcohol to the iodide
  * Reduction of the iodide with N-Selectride (sodium tri-sec-butylborohydride)
  * BOC deprotection with TriFluoroAcetic acid 

This is what they call a enantiomerically pure reduction of amino acids. It means that if you start with D-phenylalanine, that you get the good stuff; dexedrine. You will need a well equipped lab, do not try this in your kitchen: the reactions are carried out in flame-dried flasks under a dry nitrogen atmosphere. I think that the reaction where they substitute the alcohol for the iodide, is the Mitsunobu reaction, but it seems that they have used imidazole instead of diethyl azodicarboxylate (DEAD) to activate the triphenylphosphine toward nucleophilic attack by the alcohol. Procedure

Step 1: D-Phenylalaninol

To a cold solution of LiBH4 (1.32g, 60.54 mmol) in THF (30 ml, freshly distilled from LiAlH4) wass added trimethylsilyl chloride (15.36 ml, 121.07 mmol). The ice/water bath was removed and the mixture was allowed to stir at room temperature for 15 min. The mixture was recooled to 0°C and D-phenylalanine (5g, 30.27 mmol) was added. The ice/water bath was removed, and the reaction mixture was stirred overnight. The mixture was again cooled to 0°C and MeOH (45 ml) was added dropwise, followed by 2.5 M aqueous NaOH (25 ml). This mixture was evaporated in vacuo, and the residue extracted 5x with chloroform. The combined extracts were dried (Na2SO4), filtered, and evaporated in vacuo to leave 4.55 g (99%) of the product as a white crystalline solid, mp 88-90°C.

Step 2: N-t-Boc-D-phenylalaninol

To a stirred, chilled (0°C) solution of D-phenylalaninol (5 g, 33.1 mmol) in 85 ml of chloroform was added solid di-tert-butyl dicarbonate (7.22g, 33.1 mmol). The solution was stirred at 0°C for 30 min and then stirred at room temperature overnight. The solution was washed with 20% phosphoric acid, a saturated NaHCO3 solution, and a saturated NaCl solution, then dried (Na2CO3) and evaporated to dryness under reduced pressure. The resulting solid was recrystallized from a hot hexane/ethyl acetate mixture to afford 7.48g (95%) of the product as white fibrous crystals, mp 96°C.

Step 3: tert-Butyl (1R)-1-Benzyl-2-iodoethyl Carbamate

To a stirred, chilled (0°C) suspension of 2.92 g of polymer-supported triphenylphosphine (8.75 mmol) in dry DCM (35 ml) was added 2.22 g of iodine (8.75 mmol), followed by 0.65 g of imidazole (9.55 mmol). The mixture was allowed to warm to ambient temperature, and after 30 min a solution of 1.26 g (3.98 mmol) of N-t-Boc-D-phenylalaninol in DCM (15 ml) was added dropwise. The mixture was then heated at reflux for 2 hours. The cooled mixture was then filtered and the solution waswashed with dilute aqueous Na2S2O3 and water, dried (Na2SO4), and evaporated to a white crystalline solid. Passing the residue through a short silica gel column (3:2, EtOAc:hexane) yielded the pure product which was recrystallized from hot hexane to obtain 1.09 g of product (88 %) as white crystals, mp 121-122°C. Step 4: tert-Butyl (1S)-1-Methyl-2-phenylethyl carbamate

A solution of 1.00g (2.77 mmol) of the iodo compound in anhydrous THF (20 ml) was stirred at -15°C as 3.04 ml (3.04 mmol) of a 1.0 M solution of N-Selectride (in THF) was added dropwise via syringe. The mixture was allowed to warm to 5°C over 1.5h. Reaction progress was monitored by TLC (4:1 hexane:EtOAc). The solution was cooled to 0°C, and the reaction was quenched by the slow addition of 1.3 ml of water. This was followed by the dropwise addition of a solution made by combining 15 ml of H2O, 1.0 g of K2CO3, and 2.6 ml of 30% H2O2. The reaction mixture was stirred at ambient temperature for 1h. The THF was evaporated under reduced pressure, and the product was extracted from the residue with 3 portions of DCM. The organic extracts were dried (Na2SO4) and the solvent evaporated to yield a white solid. Passing this material through a short silica column (4:1 hexane:EtOAc) yields the product (0.61g, 94%) as a white crystalline solid.

Step 5: (1S)-1-Methyl-2-phenylethylamine HCl (Dexedrine, d-amphetamine)

To a stirred, cooled (0°C) solution of tert-Butyl (1S)-1-Methyl-2-phenylethyl Carbamate (2.59 g, 11.0 mmol) in DCM (20 ml) was added trifluoroacetic acid (5 ml). The solution was stirred at ambient temperature for 18 h. The volatile components were reduced under reduced pressure, and the residure was treated with water (10 ml), chloroform (15 ml) and a 50% NaOH solution (2 ml). The mixture was shaken, and the layers were separated. The aquous layer was extracted five times with chloroform and the combined organic extracts were dried over Na2SO4 and filtered. To this was added 6 ml of a 1.0 M HCl solution (in Et2O) and the solvents were removed to yield a yellow solid. This was recrystallized in hot hexane/acetone to yield the product as white, needle-shaped crystals, 1.34 g (91%), [alpha]25D = 9.21 (c 9.56, MeOH).

Referenser

[1] Journal of Organic Chemistry 65(16), 5037 (2000) Tillverkning av Amfetamin, Efedrin-metoden

Går ut på att extrahera amfetamin ur Efedrin, mycket enklare än ovanstående Syntes

Framställs vanligen, i liten skala genom kondensation av bensaldehyd med nitroetan, vilket bildar 1-fenyl-2-nitropropen som i sin tur kan reduceras till aminen medelst exempelvis litiumaluminiumhydrid, Pd/C eller anna form av katalytisk hydrogenering.

Toxicitet

LD50-värdet för amfetaminsulfat i möss respektive råtta är 24,2 mg/kg och 55 mg/kg, peroralt. Referenser: M. R. Warren, H. W. Werner, J. Pharmacol. Exp. Ther. 85, 119 (1945)

Förekomst

Förekommer som regel som amfetaminsulfat. Detta till trots att de flesta psykoaktiva aminer erhålles i form av hydrokloridsaltet. Anledningen är att amfetaminhydroklorid är synnerligen hygroskopiskt, och är följaktligen inte praktiskt att handskas med om en pulverformig substans är att föredra.

Farmakologi

Amfetamin är typexemplet på en dopaminerg stimulant. Referenser: Handb. Exp. Pharmacol. 45, 3-304 (1977) Handb. Exp. Pshychopharmacol. 11, 1-98 (1978) O. J. Kalant, The Amphetamines: Toxicity and Addiction (Thomas, Springfield, 1966) 151 pp.

Terapeutiska anvädningsområden

Amfetamin används som behandling vid ADHD och DAMP, då det ökar koncentrationsförmåga och stabilitet genom att öka den inhibitoriska dopaminerga transmissionen i frontala kortex.

Dosering

Minsta aktiv dos: 2-5 mg Liten dos: 20 mg Stark dos: - Överdos: 400-500 mg+

Slang för amfetamin

• Bums
• Tjack
• Speed
• Affe
• Snabba skor
• Mösch
• Muschna
• Arbetarknark
• Bucktjack
• Malvax
• Sportpulver
• Sportis
• Snabbkaffe