pHarmacist (Hive Bee)
12-22-02 14:29
No 391707
      PCP ---> meta-nitro-PCP ---> meta-amino-PCP  Bookmark   

This is done in similar fashion fashion as:

Post 391588 (pHarmacist: "4-nitroamphetamine/4-nitromethamphetamine", General Discourse)

Synthesis of meta-Nitrophencyclidine

To an ice cooled solution of phencyclidine hydrochloride (5 g, 1.8.times.10@-2 mol) in concentrated sulfuric acid (9 ml) was added dropwise, and with stirring, fuming nitric acid (2 ml). The reaction mixture was stirred in an ice-water bath for 1 hour and then poured onto crushed ice/water. The mixture was made basic with 10N sodium hydroxide (50 ml) to pH 12 and extracted with diethyl ether (2.times.100 ml). The combined organic layers were washed with water (2.times.100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was treated with methyl alcohol (20 ml) and heated on a hot water bath (80 DEG C.) until solute dissolved. The flask was covered with aluminum foil (product is light sensitive) and the solution was allowed to stir at room temperature overnight when a yellow solid precipitated. The solid was collected by filtration and dried under vacuum to afford 3.0 g (58%) of m-nitrophencyclidine as fine yellow crystals which were protected from light: mp 81 DEG -82 DEG C.


Synthesis of meta-Aminophencyclidine

To a stirring solution of m-nitrophencyclidine (3.0 g, 10.4.times.10@-3 mol) in methyl alcohol (150 ml) was added, under a flow of argon, 10% palladium-carbon (0.5 g) followed by ammonium formate (4.0 g, 6.3.times.10@-2 mol). The reaction mixture was stirred at room temperature for 2 hours after which time the catalyst was removed by filtration and the solvent was evaporated under vacuum. The residue was treated with 1N potassium hydroxide solution (30 ml) and extracted with diethyl ether (2.times.50 ml). The combined organic extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in hexane (20 ml) and the solution was stirred at room temperature overnight when a white solid precipitated. The solid was collected by filtration and dried under vacuum to afford 1.4 g (52%) of m-aminophencyclidine: mp 121 DEG-122 DEG C.

Reference: Patent US5331109

Dedicated to: Bwiti wink

See also:
../rhodium/chemistry /pcp/sar.html
Scroll down to: 1. Substituents at the 3-postition of the phenyl ring at the above link.

But what is also interesting is the introduction of amino group that can readily be replaced by other functional groups thus giving rise to other designer drugs based on PCP. :)

/pHarmacist


"Turn on, Tune in and Drop Out"
 
 
 
 
    pHarmacist
(Hive Bee)
12-22-02 16:04
No 391724
      Just for fun!  Bookmark   

Speaking about PCP-like compounds, here is new process for preparing norbenzomorphan -the central intermediate- in the preparation of pharmaceutically useful benzomorphan derivatives. Note that this is chemically compleately unrelated to PCP.

1st Reaction step

Ethyl 3-amino-4(3-methoxyphenyl) -2-dimethylbutanoate (4) [R2 =m-CH3 O]

229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10 DEG C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2 N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl) -2-dimethyl-butanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil.

2nd Reaction step

Ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (5) [R2 =m-CH3 O]

382.2 g (1.4 mol) of ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) and 195.4 ml (1.8 mol) of ethyl acrylate are dissolved in 570 ml of absolute ethanol and refluxed for 7 d. The mixture is then evaporated down completely in vacuo. The ethyl 3-(2-ethoxycarbonylethylamino-4-(3-methoxyphenyl)-dimethylbutanoate (5) is isolated in a yield of 469.2 g (89.2% of theory) as a reddish-brown oil.

3rd Reaction step

5-Carboethoxy-3,3-dimethyl-2-(3-methoxyphenyl)methyl-4-piperidone (6) [R2 =m-CH3 O]

469.2 g (1.3 mol) of ethyl 3-(2-ethoxycarbonylethyl)-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (5) [R2 =m-CH3 O] are dissolved in 7.8 liters of toluene and first about 100 ml of a solvent/water mixture are distilled off. The residue is allowed to cool to about 70 DEG C., mixed with 158.3 g (1.4 mol) of potassium tert.-butoxide and heated to 105 DEG C. for 40 minutes, whilst the ethanol formed is distilled off. It is then cooled to 5 C and mixed with 1.2 liters of ice water and 280 ml of conc. hydrochloric acid. 1.2 liters of ether and 220 ml of conc. ammonia solution are added, the organic phase is separated off and the aqueous phase is extracted twice more with 600 ml of diethylether. The combined organic phases are washed twice with 600 ml of water, dried over sodium sulphate and evaporated down in vacuo. The 5-carbethoxy-3,3-dimethyl-2-(3-methoxyphenyl)-methyl-4-piperidone (6) is isolated in a yield of 390.1 g (95.1% of theory) as a reddish-brown oil.

4th Reaction step

2-(3-Methoxyphenyl)methyl-3,3-dimethyl-4-piperidone-hydrochloride (7) [R2 =m-CH3 O]

390.1 g (1.22 mol) of 5-carboethoxy-3,3-dimethyl-2-(3-methoxyphenyl)methyl-4-piperidone (6) [R2 =m-CH3 O] are dissolved in a mixture of 204.8 g (5.1 mol) of sodium hydroxide, 680 ml of ethanol and 680 ml of water and refluxed for 20 minutes. The solvent is eliminated in vacuo, the residue is taken up in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid. The 2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-piperidone-hydrochloride (7) is isolated in a yield of 311.9 g (90.1% of theory) in the form of white crystals, m.p. 224-225 DEG C.

5th Reaction step

Enantiomer separation of the piperidone (+)-2-(3-Methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium hydrogen tartrate (8) [R2 =m-CH3 O]

28.7 g (101 mmol) of 2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-piperidone-hydrochloride (7) are dissolved in 57 ml of water. The aqueous phase is extracted three times with 35 ml of dichloromethane. The combined organic phases are washed with 25 ml of water, then dried with sodium sulphate and the solvent is removed in vacuo. The residue is dried at 80 DEG C. in vacuo until a constant weight is achieved (24.7 g). Then the residue is dissolved warm in 200 ml of ethanol with 15 g (100 mmol) of D-(-)-tartaric acid and 50 ml of isopropanol and a small amount of seed crystals are added with stirring. The mixture is left to crystallise for 24 hours at ambient temperature and suction filtered to remove the crystals (15 g, m.p. 142 DEG C.; [.alpha.]D@25 =+31.7 DEG (c=1 in MeOH)). The mother liquor is evaporated to dryness in vacuo, combined with 150 ml of a mixture of ethanol and isopropanol (80:20) and refluxed for 20 hours. Then the solution is again mixed with a small amount of seed crystals and left to stand for 6 days. It is then suction filtered again (6.65 g,m.p. 142 DEG C.; [.alpha.]D@25 =+32.2 DEG (C=1 in methanol)) and the mother liquor is refluxed for a further 20 hours and then evaporated to dryness. The residue is taken up in 100 ml of water, 10 ml of 2 N hydrochloric acid are added and the mixture is extracted three times with 25 ml of diethylether. The ethereal phase is discarded (nonbasic impurities) and the aqueous phase is made alkaline with conc. ammonia solution and extracted three times more with 30 ml of diethylether. The combined ethereal phases are dried over magnesium sulphate and evaporated down in vacuo (10.35 g residue). The residue together with 6.28 g (42 mmol) of D-(+)-tartaric acid is dissolved warm in 104 ml of a mixture of ethanol and isopropanol (80:20). Seed crystals are added and the mixture is left to crystallise for 1 d at ambient temperature. The crystals are suction filtered (5.8 g, m.p. 142 DEG C., [.alpha.]D@25 =+31.6 DEG (C=1 in methanol)). The mother liquor is evaporated down and the residue (11.5 g) is dissolved in 72 ml of a mixture of ethanol and isopropanol (80:20) and refluxed for 20 hours. Then seed crystals are added and the mixture is allowed to stand for 6 days at ambient temperature. The crystals precipitated are suction filtered (2.66 g,m.p. 140 DEG C.; [.alpha.]D@25 =+31.8 DEG (C=1 in methanol) and combined with the previous fractions. In this way (+)-2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium hydrogen tartrate (8) is obtained in a total yield of 30.11 g (75% of theory). .quadrature.

6th Reaction step

(+)-2-(3-Methoxyphenyl)methyl-3,3-dimethyl-4-methylene-piperidine hydrochloride (9)

24.0 g (60.3 mmol) of (+)-2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium hydrogen tartrate (8) are dissolved in 50 ml of water and combined with 15 ml of conc. ammonia solution and 50 ml of dichloromethane. The phases are separated, the aqueous phase is extracted twice with 25 ml of dichloromethane and the combined organic phase is dried over magnesium sulphate. Then the solvent is removed in vacuo and the residue is taken up in 30 ml of absolute tetrahydrofuran.

25.7 g (720 mmol) of methyltriphenylphosphonium bromide are suspended in 205 ml of absolute tetrahydrofuran and combined under nitrogen with 8.1 g (720 mmol) of potassium tert.-butoxide at ambient temperature. The mixture is stirred for 30 minutes at 40 DEG C., cooled down to ambient temperature once more and within 10 minutes combined with the above prepared solution of the piperidone in 30 ml of tetrahydrofuran. The resulting mixture is left to react for 1 hour at ambient temperature, cooled to 10 DEG C. and then mixed with 66 ml of water within 15 minutes. The tetrahydrofuran is then eliminated in vacuo and the residue is mixed with 46 ml of dichloromethane and 30 ml of ice water. The phases are separated, the aqueous phase is extracted twice more with 15 ml of dichloromethane and the combined organic extracts are extracted once more with 40 ml of water. Then the mixture is dried over magnesium sulphate, the solvent is eliminated in vacuo, the residue is dissolved in 85 ml of isopropanol and 5.7 ml of conc. hydrochloric acid are added whilst cooling with ice. After 1 hour the mixture is suction filtered (8.5 g), the mother liquor is mixed with 150 ml of diethylether for recrystallisation and after 1 hour it is suction filtered again (5.2 g). The mother liquor is evaporated down in vacuo, the residue is taken up in 30 ml of isopropanol once more and mixed with 200 ml of diethylether. After 3 hours' crystallisation at ambient temperature it is suction filtered (2.1 g) and subsequently all the crystallisation fractions are dried at 60 DEG C. All three fractions proved to be identical according to thin layer chromatography (dichloromethane:methanol:conc. ammonia=95:5:0.1).

In this way the (+)-2-(3-methoxyphenyl)-methyl-3,3-dimethyl-4-methylene-piperidine (9) is isolated in the form of its hydrochloride in a yield of 15.8 g (93.2% of theory), m.p. 199-200 DEG ; [.alpha.]D@25 =+59.9 DEG (C=1 in methanol).

7th Reaction step

(+)-N-Formyl-2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-methylene-piperidine (10) [R2 =3-CH3 O)]

12.7 g (45 mmol) of (+)-2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-methylene-piperidine-hydrochl oride (9) are dissolved in 50 ml of water and combined with 8 ml of conc. ammonia. The mixture is extracted three times with 20 ml of dichloromethane, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue is taken up in 15 ml of toluene and evaporated down once more, taken up again in 75 ml of toluene and refluxed for 4 hours with 23.1 g (22 g mmol) of n-butylformate. The mixture is then evaporated down in vacuo, after which 12.2 g (99.5% of theory) of (+)-N-formyl-2-(3-methoxyphenyl)methyl-3,3-dimethyl-4-methylene piperidine (10) are left in the form of an oil [.alpha.]D@25 =+52.0 DEG (C=1 in methanol).

8th Reaction step

(-)-2-Formyl-3'-methoxy-5,9,9-trimethyl-6,7-benzomorphan (11) [R2 =3'-CH3 O]

16 g (120 mmol) of aluminium chloride are placed in 140 ml of dichloromethane at a temperature of -10 DEG C. and 10.9 g (40 mmol) of (+)-N-formyl-2-(3-methoxyphenyl)-methyl-3,3-dimethyl-4-methylene piperidine--dissolved in 35 ml of dichloromethane--are added dropwise so slowly that the temperature does not rise above -5 DEG (about 45 min.). Then the mixture is left to react for 30 minutes at 0 DEG C., poured onto 100 g of ice and stirred vigorously. The organic phase is separated off, the aqueous phase is extracted twice more with 30 ml of dichloromethane, the combined organic extracts are dried and the solvent is eliminated in vacuo.

In this way the (-)-2-formyl-3--methoxy-5,9,9-trimethyl-6,7-benzomorphan (11) is obtained in a yield of 10.9 g (99.6% of theory in the form of an oil; [.alpha.]D@25 =-198.4 DEG (C=1 in methanol)).

9th Reaction step

(-)-3'-Methoxy-5,9,9-trimethyl-6,7-benzomorphan (12) [R2 =3'-CH3 O]

9.57 g (35 mmol) of (-)-2-formyl-3'-methoxy-5,9,9-trimethyl-6,7-benzomorphan (11) are dissolved in 75 ml of n-propanol and refluxed with 25 ml of conc. hydrochloric acid and 14.3 ml of water for 14 hours. The mixture is then evaporated down in vacuo, the residue is taken up in 50 ml of ice water and extracted three times with 20 ml of ethyl acetate (discarded). The aqueous phase is combined with 55 ml of conc. ammonia and extracted three times with 25 ml of dichloromethane. The combined organic extracts are dried over magnesium sulphate and evaporated down in vacuo. In this way the (-)-3'-methoxy-5,9,9-trimethyl-6,7-benzomorphan (11) is isolated in a yield of 7.9 g (92.0% of theory) as an oil; [.alpha.]D@25 =-66.0 DEG (C=1 in methanol).

10th Reaction step

(-)-3'-Hydroxy-5,9,9-trimethyl-6,7-benzomorphan-hydrobromide (13) [R1 =3'-OH]

10 g (41 mmol) of (-)-3'-methoxy-5,9,9-trimethyl-6,7-benzomorphan (12) are refluxed for 2 hours with 22.5 ml of water and 77.5 ml of 62% hydrobromic acid. Then the mixture is evaporated down in vacuo and the residue is recrystallised from about 80 ml of acetone, after which 11.8 g (92.8% of theory) of (-)-3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan-hydrobromide (13) are obtained in the form of crystals, m.p.>290 DEG C.; [.alpha.]D@25 =-55.8 DEG (C=1 in methanol).

Ref: Patent US5945535

See also:
../rhodium/chemistry /pcp/pcp_struc.html#Figure2

...The best known compound with appreciable affinity for the sigma receptor is the benzomorphan Pentazocine (Talwin, figure 2). This drug is a mixed agonist/antagonist at opiate receptors and generally has lower abuse potential in opiate (ab)users than pure agonists such as morphine. However, this drug is more desired than other opiates by certain users. When it is injected intravenously, especially in combination with an antihistamine (so-called "T's and Blues"), it may produce a euphoric rush that is said to be unique and overwhelmingly pleasurable...

../rhodium/chemistry /pcp/research_refs.html

It looks like this family has abuse potential :)



"Turn on, Tune in and Drop Out"
 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
12-22-02 19:15
No 391772
      Nice contribution! Continue to be naughty!  Bookmark   

Nice contribution! Continue to be naughty!smile With all the potential hydroxyl-PCA's and other analogs, it's AMAZING that PCP-analogues aren't competing with the sale of nasty-ass, impure, sloppy, black tar heroin and other pain-killers like oxys that contain so many fillers which jam-up your syringe before you get a chance to slam the fucking muck! Thanks for the dedication!cool Btw, at some point, a hopelessly addicted bear in my dreams will be cooking-up a legal? analogue, using a mixture of diethylamine/benzylamine and posting the synth. Peace!cool

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