Rhodium (Chief Bee)
07-30-02 17:18
No 339141
      Revolutionary novel subst. amphetamine synthesis!     

Now, I will present the two of the most information-rich articles regarding novel synthetic methods for the preparation of substituted amphetamines I have ever seen, and they even appear consecutively in the same journal - namely Bull. Soc. Chim. Fr. 130, 450-458 (1993) and Bull. Soc. Chim. Fr. 130, 459-466 (1993). You might already have guessed what the catch is - both articles are written in french.

One of the great things about the Hive is that together, we can accomplish much more than on our own - for example, I do not have the time or energy to translate these articles myself, one of the reasons why, is that I don't speak french. This is scientific literature, and therefore it is relatively easy to guess your way through it, so please let us all translate a small part each.

The articles can be found at the URL's below, and I have scanned them in a high enough resolution for them to be OCR'able, if anybody would want to do it that way:

../rhodium/pdf /archive/fenfluramine1.pdf
../rhodium/pdf /archive/fenfluramine2.pdf


Contents:

Article 1

* Bromobenzene + Mg + CuBr + propylene oxide -> Phenyl-2-Propanol (90%)
The oxirane may be chiral, making the product alcohol chiral too
* Phenyl-2-Propanol + MsCl/TfCl/TsCl + base -> Alcohol sulfonyl ester (80-90%)
* Sulfonyl ester + Alkylamine -> N-alkyl amphetamine (40-60%)
Reaction conditions: Polar aprotic solvent, or alcohol/autoclave
* Phenyl-2-Propanol + Thionyl Chloride -> Phenyl-2-Chloropropane (91%)
* Phenyl-2-Chloropropane + sodium azide -> Phenyl-2-Azidopropane (78%)
* Sulfonyl ester + sodium azide -> Phenyl-2-Azidopropane (78%)
* Phenyl-2-Azidopropane + Pd/H2 -> Amphetamine (67%)
* Phenyl-2-Azidopropane + Triethyl phosphite + HBr -> Amphetamine
* Phenyl-2-Azidopropane + Triethyl phosphite + Dialkylsulfate + HBr -> N-alkyl-Amphetamine (83%)

Article 2

* Bromobenzene + Mg + Allyl chloride -> Allylbenzene (81%)
* Allylbenzene + Base -> Propenylbenzene (94%)
* Propenylbenzene + MCPBA -> Epoxide (78%)
* Epoxide + alkylamine -> Alkylamino alcohol (97%)
* Alkylamino Alcohol + Triethyl Phosphite -> Aziridine (75%)
* Aziridine + Pd/H2 -> N-alkyl Amphetamine (91%)
All of the above epoxide/amino alcohol/aziridine/amphetamine steps seems to be stereoselective!
 
 
 
 
    alchemy_bee
(Philosopher, Stoned)
07-30-02 22:34
No 339252
      Wfew... I took some french but none that means ...     

Wfew... I took some french but none that means anything to me anymore alas... Im interested to know how they formed the epoxide in 78% and how it compares with electrolytic oxidation.

A nut for a jar of tuna.
-The drive by palindromer
 
 
 
 
    hypo
(Official Hive Approximator)
07-31-02 01:19
No 339302
      /me speaks french...     

hi, rhodium

i speak french. and i already have (accidentally!) translated the first one laugh
i just need to go through it and remove the worst frenchisms.

they are primarly interested in the synthesis of an enantiomeric pure product.
they suppose that some things only work because the ring is deactivated with
CF3 (so don't be sure that everything can be done with our favourite amphetamines)

i agree that you can guess most parts of technical texts, but if you don't speak
the language, it is possible (or even likely) that you miss small but important details!

so don't do the first one, unless you want to duplicate work, bees!

official gene trash
 
 
 
 
    hypo
(Official Hive Approximator)
07-31-02 03:08
No 339342
      translation - title too long to fit :)
(Rated as: excellent)
    

ok, ok, the CF3 group seems only to be important for the enantiomeric conservation
in one step. i was blahblahing out of my ass again... tongue

Bull. Soc. Chim Fr. (1993) 130, 450-458
(c) Elsevier, Paris

Synthesis of (S)-fenfluramine from (R) or (S) 1-[3-(trifluoromethyl)phenyl]propan-2-ol




Introduction

  Fenfluramine 1 is the active ingredient of a obesity drug acting on the digestion of carbohydrates, the activity being restricted mainly to the S enantiomer [1, 2], which can be obtained by separation of the diastereoisomers [3] or by preferential crystallisation of derivates, which were identified of being conglomerates [4]. Only two syntheses of optical active fenfluramine have been described until now: one by stereoselective reduction of the imine derived from the ketone 2 and (R) or (S)-alpha-phenylethylamine [5], the other starting from (S)-alanine [6]. Two recent publications [7, 8] about the synthesis of (S)-fenfluramine via the intermediate alcohol (S)-3 (scheme 1) made us publish our previous results [9]. Through yeast reduction of the ketone 2, the authors obtain the alcohol (S)-3, the configuration of which they inverse in three steps. The alcohol (R)-3, via the intermediate tosylate (R)-4a and further the azide (S)-5 leads to the amine (S)-6 after reduction and finally to the (S)-fenfluramine (S)-1 after reductive amination in presence of acetaldehyde:



  The (S)-fenfluramine is such obtained in 7 steps starting from the alcohol (S)-3 or in 4 steps from the alcohol (R)-3

  In this article we present a new way of preparing the two enantiomers of the alcohol 3, a new two step synthesis of (S)-fenfluramine starting from the alcohol (R)-3, a one step synthesis of (S)-fenfluramine starting from the azide (S)-5, which doesn't pass over the intermediate primary amine (S)-6 and finally a much faster process (3 steps) of preparing (S)-fenfluramine starting from the alcohol (S)-3

Results and discussion

Synthesis of 1-[3-(trifluoromethyl)phenyl]propan-2-ol (R)-3

  The racemic alcohol is seldom mentioned. It's one of the metabolites of fenfluramine in the human body, secreted in urine [10]. It can also be obtained by metabolic transformations of an oxime by different kinds of microorganisms [11]. It was used as an intermediate for the synthesis of a family of anorexics [12] and a family of antispasmodic and psychotherapeutic agents [13]. It was obtained by the reaction of methyloxirane 7 with the magnesium compound 8, with a yield of 50%. This same reaction was described earlier as being little regioselective [14], a fact we observed too [9].

  The only synthesis of the optically active alcohol 3 is the reduction of the ketone 2 with yeast as described above. One abtains the S enantiomer, the R enantiomer is obtained by inversion.

  On our part we used the condensation of the commercial [15] methyloxirane (R)-7, of which many syntheses are known [16], with the magnesium compound 8 and cuprous chloride [17, 18].



  The yield is about 90% and the reaction very selective (purity GC: 93%). The optical purity of the methyloxirane 7 was determined by 1H-NMR in presence of the europium complex Eu(hfc)3 [19]. The optical purity of the alcohol (R)-3 was obtained by 1H-NMR and HPLC over silica of the Mosher derivate [20]. The comparison of these values show that the chiral centre is preserved. This procedure has the advantage of allowing us the preparation of the alcohol (S)-3 with the same reaction, because the methyloxirane (S)-7 is also commercially available and multiple syntheses are known [21].

Two step synthesis of the fenfluramine (S)-1 starting from the alcohol (R)-3

  With the goal of obtaining the simplest procedure we have studied at first the transformation of the alcohol (R)-3 into fenfluramine (S)-1 in two steps via the intermediate of the easily obtained sulfonates (R)-4:



  The substitution of the mesitylate (R)-4b and the tosylate (R)-4a with ethylamine was realised with medium yields always between 40 and 50% in spite of the large number of conditions tested: solvents (DMSO, DMF, ethanol, ethylamine), different dilutions (in proportions from 1 to 5) and temparatures from 50 to 160C (with different times of contact). With the triflate (R)-4c the yield of the substitution is 60% but under non comparable conditions (-20C in acetonitrile) because of its higher reactivity. In all cases the non aminated, and thus easily separated, byproducts are mainly the alkenes 9, 10Z and 10E (10E >> 10Z > 9).



  The enantiomeric purity of the amine (S)-1 is analysed by HPLC chromatography through silica of the camphanylated derivate [22] and compared to the previously analysed alcohol (R)-3: we have thus shown that the optical centre is conserved during the nucleophilic substitution. One had indeed to fear that due to the participation of the aromatic ring as neighbour group there could be partial or complete racemisation with an phenonium ion as intermediate. With the results obtained, which match with the literature [23-26], one can suppose that the trifluoromethyl group in meta position is sufficiently deactivating the aromatic ring in order to prevent participation in the substitution. We probably have thus in our case a pure nucleophilic SN2 substitution in competition with an elimination reaction. We believe that this elimination reaction is due to the simultaneous nucleophilic and basic properties of the ethylamine.

  Although the yields are medium, this method has the advantage of being relatively fast because it permits to prepare fenfluramine (S)-1 starting from the alcohol (R)-2 in two steps instead of four [7, 8]. As far as we know it was never mentioned in literature.

Synthesis of fenfluramine (S)-1 from 2-azido-1-[3-(trifluoromethyl)phenyl]propane (S)-5

  The substitution of the mesylate (R)-4b by sodium azide (scheme 4), an only slightly basic nucleophile compared to ethylamine, forms no elimination side products. One obtains the optically pure azide (S)-5 with a yield of 95%.

  The enantiomeric purity couldn't be directly analysed on the azide (S)-5. Only for analytical purposes did we reduce it into the amine (S)-6. Among the numerous methods for the reductions of azides to amines mentioned in the literature [27] we chose the catalytic hydrogenation with 5% Pd on calcium carbonate at standard temperature and pressure [27f]. The HPLC analysis through silica column of the champhanyl derivate [22] of the amine (S)-6 such obtained shows that the enantiomeric centre was totally inverted during the substitution when compared to the enantiomeric purity of the alcohol (R)-3.



The reductive amination of the amine 6 in presence of acetaldehyde is known for a long time [28]. It was used recently in the works listed in the introduction [7, 8]. On our part, we propose another synthetic route for fenfluramine (S)-1 starting from the azide (S)-5 which does not go via the primary amine (S)-6 (schema 5).



  The reaction of Staudinger, reacting a stoichiometric quantity of triethylphosphite on the azide (S)-5 in THF at room temperature [29], gives quantitative yields of the phosphorimide 11 in 48 hours. It's total conversion into the phosphoramide 13, by reacting with ethyl iodide [30] could not be realised [9]. We always obtained different mixtures of the phosphoramides 12 and 13 (referential compounds prepared from the amines 6 and 1). We also noted that the phosphorimide 11 can't be isolated. When the solvent is evaporated, a partly transformation into the phosphoramide 12 takes place. This transformation is completed in less then 2h by simple heating to 100C under argon after evaporation of the solvent. Because the phosphorimides are strongly basic compounds, we believe that an intramolecular arrangement of the phosphorimide, pictured in schema 6, takes place.



  Having the phosphoramide 12, we investigated the alkylation into the phosphoramide 13 in DMF at room temperature [31, 32]: one deprotonates with sodium hydride then alkylates with diethyl sulfate. After treatment with hydrogen bromide [33], one obtains fenfluramine 1 with a yield of 85% and a purity of 97% (GC).

  With the goal of simplifying the reaction scheme by avoiding the isolation of the intermediates we have again studied the transformation 5 -> 11 -> 12 in DMF (schema 7). First, we noted that the reaction of Staudinger can be directly realised in this solvent. Thereafter we pinned down the transformation of the phosphorimide 11 into the phosphoramide 12 by reaction with water [34]. One then proceeds as described above. The transformation is thus performed without isolation of a single intermediate with a yield of 83%.



  HPLC analysis on silica column of the camphanyl derivate of the amine (S)-1 [22] shows that the optical centre is conserved during the whole transformation.

Synthesis via the intermediate 2-chloro-1-[3-(trifluoromethyl)phenyl]propane 14

  The yeast reduction of the ketone 2 gives the alcohol (S)-3, of which the authors have inverted the configuration to get the pharmacological active S enantiomer of fenfluramine [7, 8]. Independent research, using the epoxidation method of Sharpless [9, 35] lead us too to the alcohol (S)-3 which we tried to convert into fenfluramine (S)-1 using a different method. The reaction scheme we kept uses the chloride 14 and proceeds via two inversions of the optical centre (scheme 8). Not owning enough alcohol (S)-3 during the studies, we tested the principle starting with the alcohol (R)-3, produced earlier, and studied the transformation into the azide (R)-5 (scheme 8), the latter being able to lead to (R)-fenfluramine using different methods, like the one outlined above:



  It is well known that the action of thionylchloride on an optically active alcohol gives the corresponding chlorine derivate, with inversion of the configuration in presence of bases and with retention of the configuration in the other case. We have performed the reaction with a catalytical amount of pyridine. One thus obtains the chloride (S)-14 with 91% yield and a purity of 91% (GC): it contains 9% of the elimination products 9, 10Z and 10E which are not separable by chromatography on silica.

  The direct substitution of the chloride 14 with ethylamine with similar conditions to those used for the mesylate (R)-4b (EtNH2, DMSO, 110C, 5h30 or EtNH2 (solvent and reactant), 140C, 5h), gives mainly the elimination products. The yield of fenfluramine is below 10%.

  By action of sodium azide in DMSO, on the other hand, one obtains the azide (R)-5 with a yield of 78%, the elimination products formed here or in the last step can be removed by chromatography on silica. HPLC analysis on silica of the camphanyl derivate of the amine (R)-6 [22] obtained by catalytic reduction of the azide (R)-5 has confirmed the double inversion without racemisation after comparison with the starting alcohol (R)-3. Then the fenfluramine (R)-1 is prepared without racemisation with a 83% yield starting from the azide (R)-5 like detailed above.

  This procedure with two inversions allows to transform the alcohol 3 in the azide 5 with the same configuration in two steps with a global yield (non optimised) of 70% and without racemisation. It's thus preferred over the recently published one [7, 8], which needs 5 steps for a lower global yield (55%) and in addition features an epimerisation of 10% [8]. It's a promising way to fenfluramine (S)-1 starting from the alcohol (S)-3.

Conclusion

  We described a new method allowing the preparation of the (R) or (S)-1-[3-(trifluoromethyl)phenyl]-propan-2-ols 3 starting from optical active methyloxiranes and showed the importance of both enantiomers of this alcohol for the synthesis of (S)-fenfluramine 1.
  Starting with the enantiomer (R)-3 we have described on on hand the new 2 step synthesis of (S)-fenfluramine using the reaction of ethylamine on the sulfonate derivate from this alcohol and on the other hand a new synthesis of (S)-fenfluramine via the azide (S)-5, made in two steps from this alcohol (R)-3

  Further we have proposed a method for the preparation of (S)-fenfluramine starting with the alcohol (S)-3 in three steps including a double inversion via the chloride derivate (R)-14

  All reactions were realised without racemisation. They could be applied to other analogous structures.

Experimental Part

General notes

  The 1H NMR spectra where recorded on a Perkin Elmer R12 (60MHz) or a Bruker AW 80 (80MHz), the 13C spectra on a Varian CFT 20 (20MHz). The chemical shifts are expressed in ppm. Unless otherwise stated, the solvent is deutero-chloroform and the internal reference TMS.

  Concerning the 13C spectra: the used spectrometer did not allow proton and fluorine decoupled spectra at the same time. The carbon of the CF3 group (q, 1JCF=271.1 Hz) and the carbon on alpha of the CF3 group (q, 2JCF = 32.3 Hz) are barely or not at all visible. On the other hand, the two carbons in beta of the CF3 group are very characteristic (q,3JCF = 3.9 Hz).

  The IR spectra were recorded on a Perkin Elmer 377. The optical rotation was measured using a Perkin Elmer 241 polarimeter. The microanalyses were performed by the microanalysis service of the INSA in Rouen.

  The gas chromatographs were performed on a Girdel series 30 chromatograph with a flame ionisation detector. We used a column: 30% SE 30 + 1% triethanolamine on chromosorb W AW 80-100 mesh (0.75m) (maximum usage temperature: 150C)

  The liquid chromatographs were realised either with a Chromatem 800 HPLC apparatus of Touzart and Matignon consisting of two Chromatem 380 pumps and a Shimadzu SPD-2A variable wavelength detector, or with a Beckman HPLC apparatus consisting of a Beckman 110B pump and a Beckman 160 fixed wavelength detector (254 nm). We used a Lichrosorb Si60 (5um) Merck (25 cm x 4.6 mm) column with the following eluants:
  - Hexane-THF 99.5:0.5 (2 ml/min) for the Mosher derivate of the alcohol 3
  - Hexane-isopropanol 98:2 (1 ml/min) for the camphanyl derivate of the amine 1
  - Hexane-isopropanol 90:10 (1 ml/min) for the camphanyl derivate of the amine 6

  The composition of the mixtures was measured with an Shimadzu C-R1B integrator.

  The TLCs were realised on Merck Kieselgel 254GF plates of 0.25mm thickness. They were developed by UV (254nm) or an ethanolic vanilline solution.

  The silica used for purification is a new Merck Kieselgel 60 230-400 mesh. It was used as is.

  The anhydrous THF and ether were distilled over sodium and benzophenone right before use. The DCM and the chloroform were distilled and filtered over basic alumina. The DMSO and the DMF were dried over potash, distilled over barium oxide and finally stored over molecular sieves 3A. The acetonitrile was dried and distilled over calcium hydride. None of the presented reactions has been optimised.

Reference products

 - 1-Methyl-2-[3-(trifluoromethyl)phenyl]ethylamine 6

This product was supplied by the Oril society.
bp = 87-88C/14mmHg
IR(film): 3280 and 3380 cm-1
1H NMR: 1.10(d, J=6.4 Hz, 3H); 1.25(s, 2H swappable with D2O); 2.50-2.75(m, 2H); 2.80-3.45(m, 1H); 7.35-7.55(m, 4H)
13C NMR: 22.6(q); 45.5(t); 47.5(d); 122.2(d); 125.1(d); 128.0(d); 131.9(d); 140.1(s)
R enantiomer: HPLC analysis of the camphanyl derivate: 94.5%
Optical rotation at 23C (c=7.93, absolute ethanol):
 lambda(nm):  589   578   546   436   365
 alpha:     -19.2 -20.1 -23.1 -42.0 -72.4
Literature [3]: [alpha]25/D = -21.5 (c=8, ethanol).

 - N-ethyl-1-methyl-2-[3-(trifluoromethyl)phenyl]-ethylamine 1

This product was supplied by the Oril society.
bp = 97-98C/14mm Hg
1H NMR: 0.90-1.25 (m, 7H, 1H swappable with D2O); 2.40-3.20 (m, 5H); 7.40-7.60 (m,4H)
13C NMR: 14.6(q); 19.3(q); 40.6(t); 42.7(t); 53.7(d); 122.2(d); 125.2(d); 128.0(d); 132.0(d); 140.4(s)
S enantiomer: HPLC analysis of the camphanyl derivate: 100%
Optical rotation at 24C (c=8.18, absolute ethanol):
 lambda(nm):  589   578   546   436   365
 alpha:      +8.8  +9.1 +10.3 +17.0 +25.9
Literature [3]: [alpha]25/D = +9.6 (c=8, ethanol)

 - [1-methyl-2-(3-[trifluoromethyl]phenyl)ethyl]-diethylphosphoramidate 12

  To a solution of the amine 6 (2,05g; 10.1 mmol) in DCM (20 ml) is added triethylamine (1.12g; 1.1 eq.) and three minutes later diethylphosphorochloridate (1.53ml; 1.05 eq.) (the reaction heats up). The reaction is stirred for 24h at room temperature. 1N Sodium hydroxide (25 ml) is added, and the phases separated after shaking. The aqueous phase is reextracted with DCM (20 ml). The combined organic phases are washed with 1N HCl (25 ml) and water (10 ml) and dried over magnesium sulfate. After evaporation, the raw product is filtered through 5g silica (eluant: 150 ml ether). One such obtains the phophsoramide 12 (3.0g; yield 88%)
IR (film): 3230 cm-1 (N-H) and 1235 cm-1 (P=O).
NMR 1H: 1.05-1.50 (m, 9H); 2.60-4.40 (m, 8H); 7.40-7.60 (m, 4H)
NMR 13C: 15.2 (q, JCP = 7.2 Hz); 22.1 (q); 44.0 (t, JCP = 6.8 Hz); 48.7 (d); 61.0 (t, JCP = 9.4 Hz); 122.1 (d); 125.4 (d); 127.9 (d); 132.4 (d); 139.8 (s)
Anal: C14H21F3NO3P; Computed %: C 49.56; H 6.31; N 4.13; Found %: C 49.5; H 6.2; N 4.0

 - Ethyl-[1-methyl-2-(3-[trifluoromethyl]phenyl)ethyl]-diethylphosphoramide 13

  It was prepared in the same way as the phosphoramide 12, starting with the amine 1 (yield: 91%)
IR (film): 1260 cm-1 (P=O)
NMR 1H: 0.95-1.50 (m, 12H); 2.50-4.40 (m, 9H); 7.40-7.55 (m, 4H)
NMR 13C: 15.4 (q, JCP = 7.4 Hz); 15.7 (q); 19.1 (q); 37.8 (t, JCP = 4.2 Hz); 41.7 (t); 54.0 (d, JCP = 5.0 Hz); 61.1 (t, JCP = 8.0 Hz); 122.3 (d); 125.4 (d); 128.0 (d); 132.2 (d); 140.2 (s)
Anal: C16H25F3NO3P; Computed %: C 52.31; H 6.86; N 3.81; Found %: C 52.2; H 6.8; N 3.6

  - Methyloxirane (R)-7

  We used commercial product sold by Fluka. The enantiomeric purity was evaluated to be 82% (+/-5%) using 80Mhz 1H NMR: To 0.5 ml CDCl3 containing 3% TMS is added 23 mg epoxide (R)-7 and 103 mg europium (III) tris(heptafluoropropylhydroxymethylene camphorate) (Eu(hfc)3). The signal of one of the protons of the methylene is thus split in two: 3.15 (d, 3H); 5.60-5.80 (m, 1H); 6.14 (t, 0.09H); 6.34 (t, 0.91H); 6.75-6.90 (m, 1H); i.e. a 82% enantiomeric purity.

  - 1-[3-(Trifluoromethyl)phenyl]propan-2-ol (R)-3

  To fine magnesium turnings (2.16 g, 88.9 mmol) in ether (20 ml) is added a iodine crystal and few ml of a solution of 1-bromo-3-(trifluoromethyl)benzene (20 g; 88.9 mmol) in ether (30 ml). The flask is kept in a hot water bath until the reaction starts. Stirring is started and the rest of the solution is added during 2h30 maintaining the temperature between 34-36C. After the addition, the vial is rinsed with some ether (5 ml) and the stirring maintained for further 30 min at room temperature before dosing [36] (titer = 1.37N)


  To cupric bromide (0.34 g; 2.4 mmol; 0.15 eq; 99.999% Aldrich Gold Label) in ether (20 ml) at -30C is added during 20 min the solution of the magnesium compound 8 in ether (25.7 ml; 35.3 mm, 1.5 eq.) prepared above and the reaction stirred for 5 min at -30C. One then adds during 5 min using a syringe the methyloxirane (R)-7 (1.65 ml; 1.0 eq; 82% ep). One then lets the temperature rise to 0C and maintains for 3 hours at 0C, then pours on a mixture of ice (50 g) and hydrochloric acid 3N (50 ml). The phases are separated and the aqueous phase is reextracted with ether (2 x 100 ml). The combined organic phases  are dried over magnesium sulfate, filtered and the solvent evaporated. The product is distilled (bp = 102-103C/13-14 mm Hg), then chromatographed over silica (eluant: PE-ether 100:9 to 0:100) giving the alcohol (R)-3 (4.34 g; 90% yield; 93% GC)
IR (film): 3380 cm-1 (O-H, big).
1H NMR: 1.13 (d, J = 6.0 Hz, 3H); 2.40 (1H exchangeable with D2O); 2.75 (d, J = 6.0 Hz, 2H); 4.00 (sextuplet, J = 6.0 Hz, 1H); 7.35-7.55 (m, 4H).
13C NMR: 22.5 (q); 45.0 (t); 68.2 (d); 122.8 (d); 125.8 (d); 128.5 (d); 132.6 (d); 139.6 (s).
[alpha]25/D = -22.6 (c = 2.59; CHCl3)
HPLC analysis of the Mosher derivate: R/S = 80%

2 step synthesis of fenfluramine

 - 2-[Methylsulfonyloxy)-1-[3-(trifluoromethyl)-phenylpropane (R)-4b

  To the alcohol (R)-3 (1.19g; 5.8 mmol; 80% ep) in pyridine (6 ml) at 0C is added drop by drop in 2 minutes mesyl chloride (0.74g; 1.1 eq). The reaction is stirred for 22h30 at room temperature, the pyridine evaporated and the residue taken up in DCM (30 ml). The solution is washed with 1N hydrochloric acid (15 ml), a saturated sodium hydrogen carbonate solution (15ml) and water (15ml), dried over magnesium sulfate, filtered and the solvent evaporated. The product (1.48 g) is chromatographed over 18g silica (eluant: PE-ether 100:0 to 75:25) giving the mesylate (R)-4b (1.37 g; 83% yield) containing about 5% alcohol (R)-3 (1H NMR).
1H NMR: 1.40 (d, J = 6.5 Hz, 3H); 2.62 (s, 3H); 2.96 (d, J = 6.5 Hz, 2H); 4.77 (sextuplet, J = 6.5 Hz, 1H); 7.45-7.70 (m, 4H).
13C NMR: 20.7(q); 37.5 (q); 42.1 (t); 79.9 (d); 123.5 (d); 126.0 (d); 128.8 (d); 132.8 (d); 137.4 (s).
[alpha]24/D = -14.3 (c = 1.21; MeOH).

 - 2-(Trifluoromethylsulfonyloxy)-1-[3-(trifluoro-methy)phenyl]propane (R)-4c

  To trifluoromethanesulfonic anhydride (0.35 ml; 1.05 eq) in DCM (2 ml) at 0C is added drop by drop the alcohol (R)-3 (0.41 g; 2.0 mmol; 80% ep) and pyridine (175 mg; 1.1 eq) in DCM (1 ml) over the course of 5 min. The reaction is stirred for 2h at 0C. Water (5 ml) is rapidly added, then DCM (10 ml). The phases are separated and the organic phase washed with 1N hydrochloric acid (10 ml), saturated sodium hydrogencarbonate solution (10 ml) and water (10 ml), dried over magnesium sulfate, filtered and the solvent evaporated. One gets the triflate (R)-4c (0.63 g; 92% yield). This product is unstable and thus used right away.
1H NMR: 1.55 (d, J = 6.5 Hz, 3H); 3.12 (d, J = 6.5 Hz, 2H); 5.28 (sextuplet, J = 6.5 Hz, 1H); 7.40-7.65 (m, 4H).
13C NMR: 20.5 (q); 42.4 (t); 88.6 (d); 124.2 (d); 126.2 (d); 129.2 (d); 133.0 (d); 135.9 (s); C of the CF3SO3 group not detected.

 - Substitution of the mesylate by ethylamine: typical procedure in DMSO

  To the mesylate (R)-4b (364 mg; 1.29 mmol; prepared starting from the alcohol (R)-3 with 80% ep) in DMSO (1 ml) at 22C in an autoclave is added anhydrous ethylamine (0.4 ml; about 4 eq.). One heats to 100-105C during 3 h, then lets cool. 3N Hydrochloric acid (3 ml) is added and the reaction extracted with ether (2 x 10 ml). The combined organic phases are washed with water (5 ml), dried over magnesium sulfate, filtered and the solvent evaporated. One such obtains the fraction of the "non animated byproducts" which is analysed by GC (identification by comparison to the reference products in our possession). One extracts in the same manner the aqueous phase basified with 10N sodium hydroxide (1 ml). One thus obtains the amine (S)-1 (121 mg; 41% yield; 90% pure on GC).
[alpha]24/D = +6.9 (c = 7.07; absolute ethanol)
HPLC analysis of the camphanylated derivate: S/R = 91/9 (ep: 82%)

 - Typical procedure in ethylamine

  In an autoclave, the mesylate (R)-4b (386 mg; 1.37 ml; prepared from the alcohol (R)-3 with 80% ep) in anhydrous ethylamine (2 ml) is heated to to 90C for 16 h. One cools, opens the autoclave and lets the ethylamine evaporate under the fume hood. The residue is taken up in 5N sodium hydroxide (5 ml), shaken and extracted with ether (3 x 10 ml). The combined organic phases are extracted with 3N hydrochloric acid (2 x 3 ml), filtered and evaporated. One such obtains the byproducts. The combined aqueous hydrochloric acid phases are made basic with 10N sodium hydroxide (2.5 ml) and extracted with ether (3 x 10 ml). The combined organic phases are washed with water (5 ml) and dried over magnesium sulfate. After evaporation, one obtains the amine (S)-1 (152 mg; 48% yield; >99% GC)

[alpha]24/D = +7.8 (c = 7.90; absolute ethanol) (ep: 89%).
HPLC analysis of the camphanylated derivate: S/R = 92/8 (ep: 84%).

 - Substitution of the triflate by ethylamine

  To the triflate (R)-4c (0.63 g; 1.87 mmol; prepared from the alcohol (R)-3 with 80% ep) in acetonitrile (8 ml) at -20C is added during 3 min anhydrous ethylamine (0.5 ml, about 4 eq.) in acetonitrile (2 ml) preferably cooled. One maintains for 4 h at -20C than lets the temperature climb to room temperature. The solvent is evaporated, the residue taken up in 5N sodium hydroxide (6ml) and vigorously shaken. One extracts with ether (2 x 20 ml). The combined organic phases are extracted with 3N hydrochloric acid (5 ml), washed with water (10 ml), dried over magnesium sulfate, filtered and evaporated. These byproducts are analysed with GC. The combined aqueous hydrochloric acid phases are made basic with 10N sodium hydroxide (4 ml) and extracted with ether (2 x 20ml). The combined organic phases are washed with water (10 ml), dried over magnesium sulfate, filtered and evaporated. One thus obtains the amine (S)-1 (0.26 g; 60% yield; > 99% GC)

[alpha]24/D = +7.5 (c = 7.86; absolute ethanol) (ep: 85%).
HPLC analysis of the camphanylated derivate: S/R = 88/12 (ep: 76%).

  Remark: While doing experiments with racemic compounds, we omitted the treatment with 5N sodium hydroxide and obtained a white solid which has been characterised as being the trifluoromethanesulfonate of the amine (yield: 15 to 40%, depending on the experiment)
mp = 112C (Kfler).
IR (nujol): 3160 cm-1 (N-H)
1H NMR (acetone-d6): 1.32-1.70 (m, 6H); 2.85-4.10 (m, 7H); 7.60-7.85 (m, 4H).
13C NMR (acetone-d6): 11.0 (q); 14.9 (q); 38.8 (t); 41.0 (t); 55.7 (d); 124.1 (d); 126.2 (d); 129.8 (d); 133.7 (d); 138.2 (s).
Anal: C13H17F6NO3S; Computed % C 41.95; H 4.49; N 3.67; Found % C 42.1; H 4.7; N 3.8

Synthesis of the azide 5

 - 2-chloro-1-[3-(trifluoromethyl)phenyl]propane (S)-14

  To the alcohol (R)-3 (684 mg; 3.1 mmol; 80% ep) in chloroform (1.5 ml) is added thionyl chloride (0.4g; 1.1 eq) and a drop pyridine. The mixture is refluxed with heavy stirring for 7 h 30. The low boiling products are evaporated and the residue taken up in DCM (10 ml). One washes with water (5 ml), saturated sodium bicarbonate solution (5 ml) and water (5 ml), dries over magnesium sulfate and evaporates the solvent. The thus obtained product is filtered through  5g silica (eluant: petroleum ether) to give the chloride (S)-14 (682 mg; raw yield = 91%; 91% GC (9% elimination products)).
1H NMR: 1.50 (d, J = 6.7 Hz, 3H); 3.05 (d, J = 6.7 Hz, 2H); 4.20 (sextuplet, J = 6.7 Hz, 1H); 7.35 - 7.65 (m, 4H).
13C MNR: 24.5 (q); 46.1 (t); 57.7 (d); 123.5 (d); 125.9 (d); 128.7 (d); 132.8 (d); 138.9 (s)
[alpha]23/D = +19.0 (c = 2.16; CHCl3).

 - 2-Azido-1-[3-(trifluoromethyl)phenyl]propane 5 : Azide (R)-5 from the chloride (S)-14

  To the chlorine (S)-14 (0.66 g; 3.0 mmol; prepared from the alcohol (R)-3 with 80% ep) in DMSO (4 ml) is added sodium azide (0.38 g; 2eq). One heats to 75C for 8 h. One lets return to room temperature, adds 0.1N hydrochloric acid (10 ml) and extracts with ether (3 x 10 ml). The combined organic phases are washed with water (5 ml) and dried over magnesium sulfate. After evaporation of the solvent, the raw product (3.73 g) is chromatographed on 8 g silica (eluant: pentane) to give the azide (R)-5 (0.53 g; 78% yield; 95% GC (contains 3% of the chloride (S)-14))
[alpha]23/D = -42.8 (c = 1.16; CH2Cl3).

  In order to determine the enantiomeric purity, a part of the product has been reduced to the amine in the following way: to the azide (R)-5 (258 mg; 1.13 mmol) in THF (5 ml), one adds 5% palladium on calcium carbonate (26 mg; 10% per weight). Under heavy stirring, a temperature of 21C and a standard pressure of hydrogen are maintained for 18h. The catalyst is filtered off and rinsed with THF (10 ml) and the solvent evaporated. The raw product (189 mg) is distilled (bp = 90-95C/15 mm Hg) to give the colourless amine (R)-6 (155 mg; 67% yield; 95% GC).
[alpha]23/D = -16.6 (c = 7.59; absolute ethanol)
HPLC analysis of the camphanylated derivate: R/S = 91/9 (ep: 82%).

 - Azide (S)-5 from the mesylate (R)-4b

  To the mesylate (R)-4b (0.39g; 17 mmol; prepared from the alcohol (R)-3 with 80% ep) in DMSO (2ml) is added sodium azide (135 mg; 1.5 eq). The mixture is heated for 30 min at 70C, then cooled. One adds 0.1N hydrochloric acid (5 ml) and extracts with ether (2 x 10 ml). The combined organic phases are washed with water (5 ml), dried over magnesium sulfate, filtered and the solvent evaporated. The raw product (309 mg) is filtered through 5 g silica (eluant: petroleum ether) to give the azide (S)-5 (248 mg; 78% yield; 99% GC)
IR (film): 2100 cm-1 (N3)
1H NMR: 1.27 (d, J = 6.7 Hz, 3H); 2.80 (d, J = 6.7 Hz, 2H); 3.74 (sextuplet, 1H); 7.40-7.65 (m, 4H).
13C NMR: 18.9 (q); 42.2 (t); 58.5 (d); 123.5 (d); 125.9 (d); 128.8 (d); 132.6 (d); 138.6 (s).
Optical rotations at 24C (c = 1.14; CH2Cl2):

 lambda (nm):    589    578    546    436     365
 [alpha] =    +45.8  +48.1  +55.0  +97.7  +163.4

HPLC analysis of the camphanylated derivate of the amine (S)-6 (obtained by catalytic reduction): S/R = 90/10 (ep: 80%)

  Remark: Trials with bigger amounts (> 5g) of the racemic products gave yields greater or equal to 95%

Synthesis of fenfluramine 1 starting from the azide 5
 - Characterisation of [1-methyl-2-(3-[trifluoromethyl]phenyl)ethyl]triethylphosphorimidate 11

  To the azide 5 (207 mg; 0.903 mmol) in THF-d8 (1 ml), is added ethyl phosphite (0.19 ml; 1.0 eq). After 40 h at 26-29C the spectra are recorded (after adding a drop of TMS):
1H NMR: 0.95-1.25 (m, 12H); 2.30-30.. (m, 2H); 3.00-4.50 (m, 7H); 7.30-7.60 (m, 4H).
13C NMR: 22.8; 23.2; 33.5; 55.2; 56.1; 57.7; 69.4; 69.8; 129.3; 133.9; 135.4; 140.7; 150.8.

  When the reaction is done in the same manner in ether or THF, but the solvent evaporated, the 1H NMR and the 13C NMR (in CDCl3) show that a mixture of the products 11 and 12 of indeterminable composition is obtained.

 - Pinning down the ethylation of the phosphoramide 12: typical procedure

  To the racemic phosphoramide 12  (331 mg; 0.976 mmol) in DMF (2.5 ml) at 24C is added at once sodium hydride (86%; 94 mg; about 3.5 eq). After stirring for 1 h 30, diethyl sulfate (0.26 ml; 2 eq) is added at once (exothermic reaction). The reaction is stirred at 24C over night. One slowly adds water (5 ml) and extracts the aqueous phase with ether (2 x 20 ml). The combined organic phases are washed with water (10 ml) dried over magnesium sulfate, filtered, concentrated to 5 ml and slowly gassed with hydrobromic acid for 10 min. After standing over night at room temperature, the solvent is evaporated and the residue taken up in 5N sodium hydroxide (5 ml). One extracts with ether (2 x 15 ml). The organic phases are washed with water, dried over magnesium sulfate, filtered and the solvent evaporated. One obtains the amine 1 (192 mg; 85 % yield; 97% GC (amine 6 < 1%)).

 - Transformation of the azide 5 into the amine 1 through the intermediate of the phosphoramides 12 and 13

* Case of the azide (R)-5 (prepared from the alcohol (R)-3 at 80% ep, via the chloride (S)-14)

  To the azide (R)-5 (254 mg; 1.11 mmol) in DMF (1 ml) at room temperature is added ethyl phosphite (0.25 ml; 1.1 eq) and the mixture heated to 40C. After 2 h 30, water (30 ul; 1.5 eq) is added and the stirring continued at 40C during 21 h 30. One weights the sodium hydride (86%; 134 mg; 4eq), rapidly adds about a half and after 15 minutes the second half. One maintains 2 h 30 at room temperature. One then adds diethyl sulfate (0.29 ml, 2 eq) (exothermic reaction) and stirs at room temperature over night. Carefully water (5 ml) is added and the workup done like in the previous example. One obtains the amine (R)-1 (213 mg; 83$ yield; 97% GC (amine (R)-6: 1.5%)).
[alpha]23/D = -7.4 (c = 7.97; absolute ethanol) (ep: 84%).
HPLC analysis of the camphanylated derivate: R/S = 92.5/7.5 (ep: 85%).

* Case of the azide (S)-5 (prepared from the alcohol (R)-3 at 92% ep, via the mesylate (R)-4b)

  Using the same procedure, starting with 273 mg of the azide (S)-5 we obtained 229 mg of the amine (S)-1 (yield = 83%). After distillation (yield = 47%), on obtains: GC purity = 86% (amine (S)-6: 11%).
[alpha]23/D = +8.2 (c = 7.84; absolute ethanol).
HPLC analysis of the camphanylated derivate: S/R = 97/3 (ep: 94%)







official gene trash
 
 
 
 
    hypo
(Official Hive Approximator)
07-31-02 03:34
No 339349
      misssing pix..     

sorry for missing pix:

"The web site you are trying to access has exceeded its allocated data transfer." tonguetonguetongue

(btw: the software sure gets sluggish with long posts!)

official gene trash
 
 
 
 
    Cyrax
(Hive Bee)
07-31-02 05:39
No 339366
      Elimination is a BITCH     

The substitution of the mesitylate (R)-4b and the tosylate (R)-4a with ethylamine was realised with medium yields always between 40 and 50% in spite of the large number of conditions tested: solvents (DMSO, DMF, ethanol, ethylamine), different dilutions (in proportions from 1 to 5) and temparatures from 50 to 160C (with different times of contact). With the triflate (R)-4c the yield of the substitution is 60% but under non comparable conditions (-20C in acetonitrile) because of its higher reactivity. In all cases the non aminated, and thus easily separated, byproducts are mainly the alkenes 9, 10Z and 10E (10E >> 10Z > 9).

It is too bad that this reaction does not proceed more cleanly.  But what about post Post 102978 (Ritter: "Re: MDMA via Tosyl Chloride Intermediate?", Chemistry Discourse)  (Read also the other posts from the thread). They do the reaction on a primary sulphonate, and it works just fine.  OK, I guess that there will be more alkene formed here, because the alkene is in conjugation with the aromatic ring (and hence thermodynamically more stable).  But still, it is an easy procedure.

It could be interesting to discuss this reaction with respect to
../rhodium/chemistry /mdma.tosylate.html

Siegfried did the SN2 with MeNH2 in MeOH (with a little THF for solubility reasons), and after 5 days stirring at room temperature, the got 50 - 60 % of MDMA.

This is completely in harmony with the findings of that article.  The mediocre yield is due to the elimination.  I don't think that the aquous MeNH2 procedure of Ritter will give better results.  I guess it is just a question of thermodynamics: elemination is somewhat favoured by the formation of the conjugated propenylbenzene frown.

For synthetic reasons, I think it would be better practice to oxidize the P2Pol to P2P, form an imine with MeNH2 & reduce it.
 
 
 
 
    hest
(Hive Addict)
07-31-02 10:14
No 339429
      Off topic ???
(Rated as: excellent)
    

From Tet.Lett. 1996 3099-3100
and JOC 1999 7184-7201


Iff wee want's to work with Grignard why not use the aziridin route, two steps and wee are home (the hydrolyse can eaven bee done in the stomac :-)
 
 
 
 
    alchemy_bee
(Philosopher, Stoned)
07-31-02 12:45
No 339481
      hypo: Excellent work!!!     

hypo: Excellent work!!!



A nut for a jar of tuna.
-The drive by palindromer
 
 
 
 
    Rhodium
(Chief Bee)
07-31-02 15:19
No 339510
      Hest: Do you propose a better deprotection of the ...     

Hest: Do you propose a better deprotection of the tosylamphetamine than birch reduction?
 
 
 
 
    Beaker
(Stranger)
07-31-02 22:38
No 339667
      Enantioselective Ampetamine Synthesis     

I wonder what the ee is when P2P's are reduced with CBS catalyst/BH3? I don't recall seeing a published example for that kind of substrate, so maybe the enantioselectivity is shit. If that gave good results, that would be so much better than a grignard/chiral oxirane route.
 
 
 
 
    hest
(Hive Addict)
08-01-02 10:43
No 339838
      deprotecting     

Na in amonia
Na in amonia and THF
Na in diglyme and naphtalene
HBr in AcOH (easy one)
48% HBr and phenol TL1983 2935 (also easy)
No pertsonal eksp. all from the litt.
 
 
 
 
    Rhodium
(Chief Bee)
08-01-02 11:13
No 339848
      Sulfonamide cleavage
(Rated as: good read)
    

Thanks Hest! The TL article points to JACS 74, 2006 (1952), where an excellent method is to be found - 5g benzenesulfonanilide, 10g phenol and 75ml HBr are refluxed for 20 min, and after workup, around 90% of amine is recovered.
 
 
 
 
    hypo
(Official Hive Approximator)
08-23-02 08:44
No 348137
      Bull. Soc. Chim. Fr. (1993) 130, 459-466
(Rated as: excellent)
    

interesting stuff here!


On the key precursor epoxides, aminoalcohols and aziridines in the asymmetric synthesis of (S)-fenfluramine




Introduction

During our studies on the asymmetric synthesis of (S)-fenfluramine 1 [1], we investigated the following scheme, using classical reactions and simple intermediates: alkenes, epoxides, aminoalcohols and aziridines:



The asymmetric center can for example be introduced using the alkene 2E using enantioselective epoxidation. This method is subject of lots of research and the yields are constantly improved [2]. The such obtained epoxide 3trans is then subjected to the action of a carefully selected nucleophile in order to give the enantiomerical pure aminoalcohol 4E. Hydrogenolysis of the hydroxyl in benzylic position will give (S)-fenfluramine 1. The aminoalcohol 4E and the aziridine 5trans could also be obtained starting with the alkene 2E using enantioselective hydroxyamination [3, 4] or enantioselective aziridination. This latter method, studied by multiple teams in the last years [5, 6] deserves being considered, because encouraging results have been obtained recently [7]. Another alternative would be the regiospecific reduction of the epoxide 3trans to the alcohol (R)-6, of which we have shown before that it can be used as precursor for (S)-fenfluramine in multiple processes.

We studied some of these possibilities starting with the alkenes 2E, 2Z and 7. Before embarking upon the asymmetric epoxidation, hydroxyamination and aziridination of these alkenes, we realised the synthesis of all compounds of the racemic series (schema 2). The results of these preliminary studies, which allowed us to characterise the different intermediates and to study the limits of each reaction, are presented in this paper. Then we studied the synthesis of (S)-fenfluramine 1 via the intermediate aminoalcohol (S)-9.

Results and discussion

Starting with the isomeric alkenes 2E, 2Z and 7 we have investigated three parallel reaction paths (schema 2).

We have pictured the optical active products, only which are of interest for the asymmetric synthesis of (S)-fenfluramine, but all the presented reactions were realised using racemic products, with the exception of the transformation 9 -> 12 -> 1.



Preparation of the epoxides and the aminoalcohols

The alkene 7 is obtained by condensation of 3-(trifluoromethyl)phenyl magnesium bromide with allyl chloride in refluxing ether, then isomerised by the action of sodium hydroxide in refluxing n-butanol into a mixture of the alkenes 2Z and 2E (2E/2Z : about 85/15), which are separated by distillation. The epoxides 3trans, 3cis and 8 were obtained by reacting 3-chloroperoxybenzoic acid (mCPBA) with the corresponding alkene and purification by distillation.

According to the literature [9] it seems rather difficult to obtain uniform ring opening of the epoxides favouring the aminoalcohols 4 and 10. In a first attempt we reacted the epoxides with ethylamine in ethanol during two days at 70C, hoping to obtain and characterise the different aminoalcohols 4, 9, 10 and 11.

Starting with the epoxide 8 we have isolate the alcohol 9, pure according to GC, with a yield of 97% without purification. The regioisomer aminoalcohol 10 could not be detected.

The epoxide 3trans gives the aminoalcohols erythro 4E and 11E (4E/11E: 24/76) with 82% yield. The epoxide 3cis gives the epoxides threo 4T and 11T (4T/11T: 93/7) with 86% yield. This result was obtained by extrapolation because the sample used contained 8% of the epoxide 3trans. The products were separated by chromatography on silica. The configurations could be revealed using the 1H NMR coupling constants between the protons attached to the carbons attached to the heteroatoms and by comparison to the aminoalcohols with related structure [10].



The results show an inverse regioselectivity for the epoxides 3trans (4E/11E: 24/76) and 3cis (4T/11T: 93/7). Using the epoxide 3cis, one obtains better regioselectivity and further it gives the preferred product 4T. Ring opening in alpha position to the aromatic group predominates only in the case of the isomer 3trans where the conjugation of the aromatic group with the neighbouring carbon, carrying the oxygen, is possible.



Try at the hydrogenolysis of the benzylic hydroxyl function of the aminoalcohols 4

According to the literature [11], hydrogenation of an alcohol group in benzylic position is easy and is performed in mild conditions (5% Pd/C in alcohol at room temperature and standard pressure). However beta-aminated benzylic alcohols are much harder to hydrogenolyse: the yield is acceptable when the reaction is performed in acidic medium [12-14].

Our experiments, using a mixture of the aminoalcohols 4E + 4T + 11E + 11T and different conditions were not successful: when using mild conditions (ethanol-60C-24h without activator), the reactants were isolated unchanged, and using harder conditions (acetic acid or water-100-110C-1 to 16 h-in presence of concentrated hydrochloric and sulfuric acid), gives general degradation. The expected products, the amine 1 and the alcohol 6 could only be detected in trace amounts. We believe that the trifluoromethyl group renders the cutting in benzylic position difficult by deactivating the aromatic ring.

The regioselective opening of the epoxides on one hand and the difficulties of the hydrogenolysis of the aminoalcohols 4 and 11 on the other hand made us study a new strategy, going via the aziridines 5 and 12. One notes that the 2 aminoalcohols 4E and 11E give the same aziridine 5trans, likewise the aminoalcohols 4Z and 11Z giving the aziridine 5cis. A given epoxide is transformed into the aziridine with opposite configuration (see scheme 2).

Preparation of the aziridines

One finds in the literature multiple methods giving aziridines starting from aminoalcohols [15-19]. They all use phosphorus compounds, with the exception of the method by Wenker [19] which uses concentrated sulfuric acid in very hard conditions. Using phosphorus compounds, the transformation is realised in one step in mild conditions. One can use dibromo-triphenylphosphine in presence of triethylamine [15], triphenylphosphine in presence of triethylamine and carbon tetrachloride [16], tretraiodophoshporus [17] and (diethoxy triphenyl)phosphorane [18]. In two cases [15, 18], the conservation of the chiral centres by Walden inversion has clearly been established.

The method we retained used the simplest and most easily accessed reagents: triphenylphosphine, triethylamine and carbon tetrachloride [16]. Starting with the aminoalcohols 4, 11 and 9 we thus obtained the aziridines 5cis, 5trans and 12, which have never been described before. The yields after purification by distillation are between 70 and 75%.

For the preparation of the aziridine 12 we have also carried out multiple experiments with triethyl phosphite. The yield is a bit less (60%). This variation of the original method [16] has never been described as far as we know.

Going via these aziridines has the following advantages: it is unnecessary to separate the aminoalcohols 4 and 11, and the useless aminoalcohol 11 is such recycled in the reaction without any additional work. It is also a quick method for the valorisation of the aminoalcohol 9. Further, it is no longer necessary to bother with the regioselectivity of the nucleophilic attack on the epoxide, which allows the usage of the simplest method for the preparation of the aminoalcohols: ethylamine in ethanol.

Reduction of the aziridines

It remained to work out the transformation of the aziridines 5 and 12 into fenfluramine 1. The aziridines 5 can lead to the amines 1 and 13, the aziridine 12 to the amines 1 and 14 [20] (scheme 3).



In order to realise the ring opening of the aziridines 5 and 12 into fenfluramine 1, we used catalytic hydrogenation [11], peculiar to open the ring at the less substituted side, in the case of the aziridine 12, and benzylic hydrogenolysis in the case of the aziridines 5. The experiments were performed in ethanol at standard temperature and pressure (table I).



We noted that in all three cases the reaction is perfectly regioselective, the amines 13 and 14 could not be detected. The only observed side reaction is the formation of the diethylamine 15, especially when using palladium on calcium carbonate. We believe that, on contact with the catalyst, the ethanol is dehydrogenated into acetaldehyde [21] which gives the diethylamine by amination of the amine 1 formed during the reduction. Provided that the regioselectivity is preserved, the replacement of ethanol by another solvent should allow to obtain the pure amine 1.

Usage of palladium on carbon minimises the formation of diethylamine 15 in the case of the aziridines 5trans and 12. On the other hand, the aziridine 5cis is less reactive and needs a reaction time of 3 days instead of one. Therefore the byproduct is present in non deniable amounts.

Reduction of the epoxides

The epoxide 3 can lead to the alcohols 6 and 16 and the epoxide to the alcohols 6 and 17.



Only the alcohol 6 is a potential precursor of the fenfluramine 1.

Given the satisfying results obtained using the aziridines, we realised the same type of study (table II).

The alcohol 16 was never detected. In the case of the epoxide 8, the alcohol 17, formed when using palladium on carbon, disappears when replacing the latter by palladium on calcium carbonate.

Among the byproducts one finds the deoxygenated product 18, when using palladium on carbon and the ketone 19, formed by dehydrogenation of the alcohol 6 on contact with the catalyst [21], particularly when using palladium on calcium carbonate.



Thus, like in the case of the aziridines, we were able to obtain a regioselective ring opening of the epoxides 3 and 8 by hydrogenolysis of the bond in benzylic position using palladium on carbon in the case of the epoxide 3 and by hydrogenation of the ring on the less substituted side by palladium on calcium carbonate in the case of the epoxide 8.

Asymmetric synthesis of the (S)-fenfluramine

From a stereochemical viewpoint, one could contemplate to access the many proposed precursors of the amine 1 (epoxide, aminoalcohol or aziridine) by totally different reactions than those we have described. Thus the validity of our reaction scheme for the asymmetric synthesis of (S)-fenfluramine has been shown starting with the aminoalcohol (S)-9. The latter was prepared using the epoxyalcohol (1R,2R)-20, which in turn was obtained by asymmetric epoxidation of the corresponding allyl alcohol according to the method of Sharpless and transformed into fenfluramine via the intermediate aziridine (R)-12 (schema) using the technique described above.



The comparison of the enantiomeric excesses of the epoxyalcohol 20 and the fenfluramine (S)-1 shows that there is no racemisation during the different reactions, notably during the cyclisation into aziridine. The detailed results of these transformations will be published later [22].

Conclusion

Regarding synthesis, we have prepared and characterised a number of intermediates: racemic epoxides, aminoalcohols and aziridines, and shown possible synthetic pathways to fenfluramine 1 using simple methods starting with the alkenes 2Z, 2E and 7.

Regarding stereochemistry, we have shown the validity of our reaction scheme to prepare (S)-fenfluramine starting with the aminoalcohol (S)-9. The enantioselective epoxidation, hydroxyamination and aziridination reactions can now be approached.

From a general point of view, given the large applicability of the presented reactions, the regiospecificity of the hydrogenation reactions and the hydrogenolysis, we believe that this work gives new perspectives for the synthesis of 2-(alkylamino)-1-arylpropanes and 1-arylpropane-2-ols which are potential precursors.

Experimental part

General indications

The 1H NMR spectra were recorded on an Perkin Elmer R 12 (60 Mhz) or a Bruker AW 80 (80 MHz), the 13C NMR spectra on a Varian CFT 20 (20 MHz). The chemical shifts are expressed in ppm. Unless otherwise noted, the solvent is deuterochloroform and the internal reference is TMS.

Concerning the 13C NMR spectra: the used spectrometer did not allow the recording of fluorine and proton decoupled spectra at the same time. The carbon of the CF3 group (q, 2JCF=271.7 Hz) and the carbon on alpha to the CF3 group (q, 2JCF=32.3 Hz) are only hardly or not at all visible. They were never indicated. On the other hand, the 2 carbons beta to the CF3 group are very characteristic (q, 3JCF=3.9 Hz).

The IR spectra were recorded using a Perkin Elmer 377. The melting points were measured using a melting point microscope Reichert Jung. The microanalyses were performed by the common microanalysis service of the INSA of Rouen.

The gas chromatographs were realised with a Girdel series 30 chromatograph with a flame ionisation detector. The used columns are:
Column A: 30% SE 30 + 1% triethanolamine on chromosorb W AW 80-100 mesh (0.75 m) (maximum usage temperature: 150C)
Column B: 2.5% SE 30 + 2.5% XE 60 on chromosorb W AW 80-100 mesh (1.50 m)
Column C: 5% carbowax 20M on chromosorb W AW 100-120 mesh (1.40 m)
Unless otherwise noted, column A was used.

The percentages of the components were measured using a Shimadzu C-R1B integrator.

The TLCs were realised on silica plates Merk Kieselgel 254GF with 0.25mm thickness. They were developed using UV (254 nm) or an ethanolic vanilline solution.

The silica used for purification is a Merck Kieselgel 60 230-400 mesh. It was used as is.

The anhydrous ether was distilled over sodium and benzophenone right before use. The dichloromethane was distilled and filtered over basic aluminium. The acetonitrile was dried and distilled over calcium hydride. The RPE anhydrous ethanol (Carlo Erba) was used as is.

None of the described reactions was optimised.

Preparation of the alkenes

- 3-[3-(Trifluoromethyl)phenyl]propene 7

The magnesium compound is prepared liked previously described [8] using 3-(trifluoromethyl)bromobenzene (50.2 g; 223 mmol) and fine magnesium turnings (5.55 g; 228 mmol). After 30 min at room temperature, the reaction is newly refluxed. Allyl chloride (17.6 g; 230 mmol) in ether (30 ml) is then added over 45 min. The reaction is refluxed for 2h then cooled and poured on ice (65g). The flask is rinsed with water (20 ml). The phases are separated and the aqueous phase extracted with ether (45 ml). The combined organic phases are dried over magnesium sulfate, filtered and evaporated. After distillation (bp = 54-54C/13-14 mm Hg), the alkene 7 (33.8 g; 81% yield) is obtained.
IR(film): 1745 cm-1 (C=C)
1H NMR: 3.45 (d, J=10.0 Hz, 2H); 4.85-5.25 (m, 2H); 5.60-6.30 (m, 1H); 7.20-7.50 (m, 4H).
13C NMR: 39.8 (t); 116.5 (t); 122.9 (d); 125.2 (d); 128.7 (d); 131.9 (d); 136.3 (d); 141.0 (s).
Anal: C10H9F3; Calc % C 64.51; H 4.87; Found % C 64.5; H 4.5

 - 1-[3-(trifluoromethyl)phenyl]propene 2 cis and 2 trans

Sodium hydroxide (392 mg 9.8 mmol) is added to 3-[3-(trifluoromethyl)phenyl]propene (33.1 g; 178 mmol) in n-butanol (33 ml). The reaction is refluxed for 7h, cooled and tranfered into a separatory funnel. It is washed with 3N hydrochloric acid (4 ml), water (2 x 3.5 ml), and distilled: first the n-butanol then the products (bp = 66-70C/13-14 mm Hg). A mixture of both isomers is obtained (31.1g; 94% yield; cis/trans = 13/87 according to GC).

In order to separate both isomers, we have distilled 21g of the mixture at 15 mmHg through a Nester Faust spinning band column and obtained 3 main fractions:

63C <= bp <= 65C: 1.85g (yield = 9%) GC: 89% 2cis
65C < bp < 73C: 3.90 g (yield = 19%) GC: cis/trans = 24/76
bp = 73C: 14.5g (yield = 71%) GC: 98.4% 2trans

Alkene 2cis (1st fraction): bp = 63-65C/15 mm Hg. GC purity = 89% (8% 2trans and 3% impurities) (column B)
IR (film): 1650 cm-1 (C=C)
1H NMR: 1.85 (dd, J=0.9 and 6.7 Hz, 3H); 5.60-6.60 (m, 2H); 7.40-7.60 (m, 4H).
1C NMR: 14.1 (q); 123.0 (d); 125.4 (d); 128.5 (d); 131.9 (d); 138.3 (s).

Alkene 2trans (3rd fraction): bp = 73C/15 mm Hg. GC purity = 98.4% (1.6% 2cis and impurities < 0.1%) (column B)
IR (film): 1660 cm-1 (C=C)
1H NMR: 185 (d, J = 4.8 Hz, 3H); 5.70-6.40 (m, 2H); 7.25-7.60 (m, 4H).
13C NMR: 18.1 (q); 122.4 (d); 123.1 (d); 127.6 (d); 128.7 (d); 138.7 (s).

Preparation of the epoxides

 - 2-[3-(Trifluoromethyl)benzyl]oxirane 8

Meta-chloroperoxybenzoic acid (80%; 5.8g; 27.0 mmol) is added over 5 min to dichloromethane (25 ml) at 20C in small aliquots. The reaction is stirred for 5h30 at 20C. Dichloromethane (20 ml) is added and the reaction is washed successively with 10% aqueous sulfite solution (10 ml), saturated sodium bicarbonate solution and water (10 ml). The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is taken up in petroleum ether (25 ml) and left standing at room temperature over night. Then the precipitate is removed by filtration, the solvent evaporated and the residue distilled (bp = 65-95C / 13-14 mmHg). The epoxide 8 (2.12 g; 78% yield) is thus obtained.
1H NMR: 2.40-3.30 (m, 5H); 7.45-7.70 (m, 4H).
13C NMR: 38.2 (t); 46.4 (t); 51.7 (d); 123.3 (d); 125.5 (d); 128.7 (d); 132.3(d); 138.0 (s).

 - 2-methyl-3-[3-(trifluoromethyl)phenyl]oxirane 3 (cis and trans)

The epoxides 3cis and 3trans were prepared like previously described, starting with the alkenes 2cis and 2trans.

Epoxide 3cis (85% yield; 89% GC (9% 3trans and 2% impurities) (column B)). Bp = 84-86C/13 mm Hg.
1H NMR: 1.05 (d, J=5.6 Hz, 3H); 3.40 (qd, J=4.3 and 5.6 Hz, 1H); 4.10 (d, J=4.3 Hz, 1H); 7.45-7.70 (m, 4H).
13C NMR: 12.0 (q); 54.9 (d); 56.6 (d); 123.2 (d); 124.1 (d); 128.3 (d); 129.8 (d); 136.7 (s).

Epoxide 3trans (71% yield; 98% GC). bp = 70-90C/13-14 mm Hg.
1H NMR: 1.42(d, J=51 Hz, 3H); 3.00(qd, J=2.3 and 5.1 Hz, 1H); 3.58 (d, J=2.3 Hz, 1H); 7.40-7.65 (m, 4H).
13C NMR: 17.4 (q); 58.5 (d); 59.1 (d); 122.1 (d); 124.5 (d); 128.7 (d); 138.9 (s).

Preparation of the amino alcohols

 - 3-Ethylamine-1-[3-(trifluoromethyl)phenyl]propan-2-ol 9

Anhydrous ethylamine (5 ml; 76.6 mmol) is added at once to the epoxide 8 (2.11 g; 10.5 mmol) in absolute ethanol (50 ml). The reaction is heated to 70C during 47h. After evaporation of the solvent and the excess ethylamine, one obtains the aminoalcohol 9 (2.52g; yield 97%; GC >99%). mp = 43-45C (microscope).
1H NMR: 1.00 (t, J=7.3 Hz, 3H); 2.20-2.80 (m, 6H); 3.37 (s, 2H interchangeable with D2O); 3.60-4.05 (m, 1H); 7.35-7.60 (m, 4H).
13C NMR: 14.4 (q); 41.4 (t); 43.4 (t); 54.5 (t); 69.7 (d); 122.7 (d); 125.8(d); 128.3 (d); 132.6 (d); 139.7(s)
Anal: C12H16F3NO; calc % C 58.29; H 6.52; N 5.66; Found % C 58.7; H 6.4; N 5.5

 - 1-Ethylamino-1-[3-(trifluoromethyl)phenyl)propan-2-ol 11 and 2-ethylamino-1-[3-(trifluoromethyl)phenyl]propan-1-ol 4

* With erythro configuration 4E and 11E
Reacting the epoxide 3trans with the same conditions as the epoxide 8 gives a mixture of the two aminoalcohols 4E and 11E with erythro structure. After two fruitless distillations under vacuum (bp = 90-100C/0.3-0.4 mm Hg), we were able to separate the mixture using chromatography over silica (eluant: ether then acetone) giving 11E (yield = 62%) and 4E (yield = 20%) (global yield = 82%).

Aminoalcohol 4E (eluant: ether). mp = 65-67C (microscope).
1H NMR: 0.80 (d, J=6.7 Hz, 3H); 1.05 (t, J=7.3 Hz, 3H); 2.50-3.00 (m, 3H); 3.22 (s, 2H exchangeable with D2O); 4.80 (d, J=3.6 Hz, 1H); 7.40-7.75 (m, 4H).
13C NMR: 13.7 (q); 15.1 (q); 41.2 (t); 58.1 (d); 72.4 (d); 122.7 (d); 123.5 (d); 128.2 (d); 129.3 (d); 143.1 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 57.9; H 6.3; N 5.6

Aminoalcohol 11E (eluant: ether then acetone): very thick oil.
1H NMR: 0.90-1.30 (m, 6H); 2.40 (s, 2H exchangeable with D2O); 2.55 (q, J=6.7 Hz, 2H); 3.68 (d, J=4.0 Hz, 1H); 4.02 (qd, J=4.0 and 6.7 Hz, 1H); 7.45-7.70 (m, 4H).
13C NMR: 15.1 (q); 18.4 (q); 41.7 (t); 67.7 (d); 68.8 (d); 124.0 (d); 124.8 (d); 128.5 (d); 131.5 (d); 140.9 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 58.1; H 6.5; N 5.9.

* With threo configuration 4T and 11T
We operated in the same manner starting with 1.20g epoxide 3cis (containing 8% epoxide 3trans) and obtained a mixture of the aminoalcohols 4T and 11T (containing some erythro aminoalcohols), which we were able to separate by chromatography (global yield = 86%).

11: Yield = 11% (about 50% erythro and 50% threo),
4: Yield = 75% (threo, only 2-3% erythro).

Aminoalcohol 4T: mp = 54-56C (microscope)
1H NMR: 0.80-1.25 (m, 6H); 2.30-3.20 (m, 5H whereof 2H exchangeable with D2O); 4.20 (d, J=8.3 Hz, 1H); 7.40-7.70 (m, 4H)
13C NMR: 15.1 (q); 15.8 (q); 41.2 (t); 59.5 (d); 76.8 (d); 123.7 (d); 124.3 (d); 128.5 (d); 130.5 (d); 144.1 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 58.4; H 6.7; N 5.8

Aminoalcohol 11T: very thick oil.
1H NMR: 0.85-1.20 (m, 6H); 2.44 (q, J=6.8 Hz, 2H); 3.85 (s, 2H exchangeable with D2O); 3.33 (d, J=8.7 Hz, 1H); 3.40-4.10 (m, 1H); 7.40-7.60 (m, 4H).
13C NMR: 15.0 (q); 19.6 (q); 41.5 (t); 70.0 (d); 70.3 (d); 124.2 (d + d); 128.8 (d); 130.9 (d); 142.2 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 57.9; H 6.5; N 5.5.

Preparation of the aziridines

 - 1-Ethyl-2-[3-(trifluoromethyl)benzyl]aziridine 12

* Method using triphenylphosphine

Triethylamine (491 mg; 1 eq), tetrachloromethane (747 mg; 1 eq) and triphenylphosphine (1.46 g; 1.15 eq) are added to the aminoalcohol 9 (1.2 g; 4.85 mmol) in acetonitrile (5 ml). The reaction is heated to 42C for 3h30. The precipitate is filtered off and washed with acetonitrile (5 ml). The solvent is evaporated and the residue taken up 4 times in petroleum ether (10 ml). The organic phases are combined and the solvent evaporated. The residue is distilled (bp = 70-75C/0.5 mm Hg) giving the aziridine 12 (817 mg; 73% yield; GC >99%)

1H NMR: 1.00 (t, J=6.7 Hz, 3H); 1.20-1.80 (m, 3H); 1.95-2.55 (m, 2H); 2.75 (d, J=5.3 Hz, 2H); 7.40-7.70 (m, 4H).
13C NMR: 14.0 (q); 33.2 (t); 38.9 (t); 39.9 (d); 54.9 (t); 122.8 (d); 125.1 (d); 128.5 (d); 131.9 (d); 140.5 (s).

* Method using triethyl phosphite

Triethylamine (208 mg; 1 eq), tetrachloromethane (316 mg; 1 eq) and triethylphosphite (0.49 ml; 1.15 eq) are added to the aminoalcohol 9 (508 mg; 2.05 mmol) in acetonitrile (2 ml). The reaction is heated to 45C for 5h20. After cooling, first 1N hydrochloric acid (10 ml) then ether (20 ml) are added. The phases are separated and the aqueous phase is washed with ether (2 x 20 ml).  It is basified with 10N sodium hydroxide (2 ml) and reextracted with ether (2 x 20ml). The two etherical phases are combined,  washed with water, dried over magnesium sulfate, filtered and evaporated. The aziridine 12 (341 mg; 73% yield; GC about 80%) is thus obtained.

 - 1-Ethyl-2-methyl-3-[3-(trifluoromethyl)phenyl]aziridine 5

We proceeded in the same way as for the aziridine with the triphenylphosphine route.

Aziridine 5trans: Reacting the aminoalcohol 11E (1.27 g; 5.12 mmol) for 6h at 40C gives after distillation (bp = 105-107C/14-15 mm Hg) the aziridine 5trans (882 mg, 75% yield; GC 98%).
1H NMR (CCl4): 1.18 (t, J = 7.3 Hz, 3H); 1.40 (d, J = 7.0 Hz, 3H); 1.80-2.10 (m, 2H); 2.30-2.80 (m, 2H); 7.30-7.50 (m, 4H)
13C NMR (CCl4): 11.6 (q); 15.9 (q); 44.3 (d); 46.7 (d); 47.9 (t); 123.7 (d + d); 129.0 (d); 130.0 (d); 143.6 (s).
Anal: C12H14F3N; Calc % C 62.87; H 6.16; N 6.11; Found % C 62.5; H 6.0; N 6.1.

Aziridine 5cis: Reacting the aminoalcohol 4T (489 mg; 1.98 mmol) for 3h at 45C gives after distillation (bp = 93-96C/15 mm Hg) the aziridine 5cis (317 mg; 70% yield; GC 95%).
1H NMR: 0.88 (d, J=5.6 Hz, 3H); 1.18 (t, J=7.2 Hz, 3H); 1.77 (quintuplet, J=6.0 Hz, 1H); 2.10-2.95 (m, 3H); 7.40-7.60 (m, 4H).
13C NMR: 12.8 (q); 14.0 (q); 41.5 (d); 45.5 (d); 55.0 (t); 123.2 (d); 124.5 (d); 128.2 (d); 131.2 (d); 139.3(s).

Reduction of the aziridines: typical procedure

Palladium on carbon 5% (35 mg; 10% per weight) is added to the aziridine 12 (332 mg; 1.45 mmol) in ethanol (5 ml). The reaction is stirred for 16 h at 19C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The amine 1 is thus obtained (305 mg; 91% yield; 95% GC).

Catalytic reduction of the epoxides

 - Reference alcohols 16 and 17

* 3-[3-(trifluoromethyl)phenyl]propan-1-ol 17

Palladium on carbon 5% (46 mg; 10% per weight) is added to 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (452 mg) [22] in ethanol (10 ml). The reaction is vigorously stirred for 26 h at 20C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The raw product (342 mg) is chromatographied over 6 g silica (eluant: petroleum ether-ether 100:0 to 75:25) to give the alcohol 17 (263 mg; 57% yield; 98% GC).
IR(film): 3340 cm-1 (intense O-H)
1H NMR: 1.60-2.15 (m, 3H whereof 1H exchangeable with D2O); 2.60-2.95 (m, 2H); 3.60 (t, J=6.0 Hz, 2 H); 7.30-7.50 (m, 4H).
13C NMR: 31.7 (t); 33.6 (t); 61.5 (t); 122.6 (d); 124.8 (d); 128.6 (d); 131.7 (d); 142.6 (s).
Anal: C10H11F3O: Calc % C 58.82; H 5.43; Found % C 58.5; H 5.4.

* 1-[3-(Trifluoromethyl)phenyl]propan-1-ol 16

Platinum oxide (4 mg; 1% per weight) is added to 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (407 mg; 2.01 mmol) [22] in ethanol (5 ml). The reaction is vigorously stirred for 24 h at 20C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (5 ml) and the solvent evaporated. The raw product (390 mg) is chromatographied over 6 g silica (eluant: petroleum ether-ether 100:0 to 95:5) to give the alcohol 16 (333 mg; 81% yield; 95% GC).
IR(film): 3360 cm-1 (intense O-H).
1H NMR: 0.88 (t, J=7.5 Hz, 3H); 1.50-20.00 (m, 2H); 2.20 (s, 1H exchangeable with D2O); 4.62 (t, J=6.7 Hz, 1H); 7.50-7.75 (m, 4H).
13C NMR: 9.4 (q); 31.6 (t); 75.1 (d); 122.6 (d); 124.0 (d); 128.6 (d); 129.2 (d); 145.5 (s).

 - Catalytical reduction of the epoxides

The reaction time and the quantity of catalyst were not optimised.
Typical procedure: Palladium on carbon 10% (102 mg; 39% per weight) is added to the epoxide 3 (260 mg; 1.28 mmol; trans/cis=83/17) in ethanol (5 ml). The reaction is vigorously stirred for 28h30 at 22C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The alcohol 6 (205 mg; 78% yield; 96% GC (column C)) is such obtained.




couch terrorist
 
 
 
 
    Lego
(Hive Bee)
07-30-03 04:15
No 450698
      Stereospecific synthesis of amphetamines
(Rated as: excellent)
    


Tet. Asy., 2003, 14, 2119-2125
(http://angelfire.lycos.com/scifi2/lego/journals/26.pdf)
DOI:10.1016/S0957-4166(03)00438-5
The DOI is not working although it is listed in the paper and on the homepage.


Abstract: AbstractRegioselective addition of aryl lithium to commercially available (S)-(+)-propylene oxide  provides the corresponding (S)-aryl-2-propanol. The (R)-amphetamine is obtained by conversion of the alcohol to the tosylate followed by azide displacement and hydrogenation. Mitsunobu conversion of the alcohol to the (R)-bromide followed by azide displacement and hydrogenation affords the (S)-amphetamine.

[...]

Experimental

4-Bromo-2,5-dimethoxytoluene 6b
To a solution of 2,5-dimethoxytoluene (100 g, 0.657 mol) and NaOAc (56.6 g, 0.690 mol) in HOAc (400 mL) in a 1000 mL three necked, round bottomed flask equipped with N2 inlet, magnetic stirrer, and addition funnel was added Br2 (110 g, 0.688 mol), dropwise. The solution changed from clear to yellow and eventually to dark orange. After stirring for 20 min the reaction was quenched with a solution of saturated NaHSO3 and the mixture was extracted with CHCl3 (3500 mL). The combined organic extract was dried over Na2SO4 and concentrated to a yellow solid. Recrystallization from hot EtOAc/hexane gave 6b as a white crystalline solid; mp 90C (lit.3 91C)


(2',5'-Dimethoxy-4'-methylphenyl)-2-propanol 9b
To a solution of 4-bromo-2,5-dimethoxytoluene 6b (20 g, 0.087 mol) in dry THF (700 mL) in a 1000 mL round bottomed flask equipped with N2 inlet at ?72C was added a solution of 2.0 M n-BuLi in pentane (43 mL, 0.086 mol). After stirring for 10 min, propylene oxide 8 (2.51 g, 0.043 mol) was added. Stirring was continued for 10 min and BF3Et2O (9.22 g, 0.065 mol) was added. The reaction was allowed to stir for 15 min. It was then quenched with satd NH4Cl and extracted with Et2O (3250 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness leaving a residual oil. Treatment with MeOH resulted in a white ppt. The ppt was separated by filtration and discarded, and the MeOH filtrate was evaporated to dryness leaving brown crystals. Purification by column chromatography (SiO2; hexane:EtOAc 5:1) afforded 9b (7.67 g, 84%) as white powdery crystals: mp 8081C (lit.9 80.581.5C)


(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl tosylate 10b
A mixture of 9b (1 g, 0.005 mol), p-toluenesulfonyl chloride (1 g, 0.005 mol), and pyridine (20 mL) was prepared while stirring a 1000 mL round-bottomed flask, in an ice bath. The mixture was transferred to the freezer and after 48 h crystals had formed. The reaction mixture was poured over ice, forming a white solid which was filtered, washed with hexanes and water, and dried under vacuum to give 10b (1.56 g, 90%): mp 99100C


(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl azide 11b
After stirring overnight in a round bottomed flask, a mixture of 10b (1 g, 0.003 mol) and NaN3 (0.75 g, 0.012 mol) in DMF (20 mL) was taken up in water and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to give 11b (640 mg, 95%) as a light brown oil.


2,5-Dimethoxy-4-methylamphetamine hydrochloride 5b
To a solution of 11b (640 mg, 2.7 mmol) in MeOH (20 mL) in a Parr flask was added 10% Pd/C catalyst (60 mg) and the mixture was rocked under 40 psi H2 for 12 h. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The residual solid was taken up in Et2O and HCl gas was allowed to bubble through. No solids formed. The Et2O was evaporated and the residual solid was taken up in a minimal amount of MeOH; Et2O was added dropwise. The crystals that formed overnight were filtered, washed with Et2O, and dried to yield 5b (400 mg, 60%): mp 188190C (lit.12 184185C)


(S)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propanol (S)-9b
A solution of 6b (33 g, 0.143 mol) in freshly distilled THF (1000 mL) in a 2000 mL round bottomed flask was cooled to ?72C. To the chilled, stirring solution was added a solution of 2.0 M n-BuLi (71 mL, 0.142 mol) dropwise. After 10 min, S-(?)-proplyene oxide (S)-8 (5 mL, 0.072 mol) was added, followed by BF3Et2O (13.6 mL, 0.107 mol). After stirring for 15 min the reaction was quenched with saturated NH4Cl and extracted with Et2O (3400 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness. The residue was taken up in MeOH, causing a white precipitate to form. The ppt was separated by filtration and discarded, and the MeOH was evaporated to dryness. The residual solid was recrystallized from hot EtOAc/hexanes several times. Evaporation of the combined mother liquors afforded a brown oil which, when eluted through a silica column (hexanes:EtOAc 4:1), afforded additional (S)-9b, which was combined with the previously recrystallized batches. A further recrystallization from hot EtOAc/hexanes yielded pure (S)-9b (13.00 g, 74%): mp 90-92C,


5.7. (S)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl tosylate (S)-10b
A mixture of (S)-9b (9.88 g, 0.048 mol), p-toluenesulfonyl chloride (10.8 g, 0.057 mol), and pyridine (200 mL) was prepared while stirring in a 1000 mL round bottomed flask, in an ice bath. The mixture was transferred to the freezer and after 48 h crystals had formed. These crystals were removed by filtration and washed with hexanes. The volatiles were evaporated from the combined filtrate and washings and the residual liquid was poured over ice. Since no solid was formed, the mixture was extracted with CHCl3. After drying over Na2SO4 and evaporation of the solvent, the residue was triturated with hexanes to afford a white solid which was filtered, washed with hexane and water, and dried under vacuum to give (S)-10b (13.2 g, 77%): mp 7778C



(R)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl azide (R)-11b
After stirring overnight, a mixture of (S)-10b (12 g, 0.035 mol) and NaN3 (8.96 g, 0.138 mol) in DMF (200 mL), in a round-bottomed flask, was treated with H2O and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to give (R)-11b (7.4 g, 91%) as a light brown oil.


(R)-(-)-2,5-Dimethoxy-4-methylamphetamine hydrochloride (R)-5b
To a solution of (R)-11b (7.3 g, 0.032 mol) in MeOH (200 mL), in a Parr flask, was added 10% Pd/C catalyst (600 mg) and the mixture was rocked under 40 psi H2 for 12 h. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The residual solid was then taken up in CHCl3 and extracted with 1 M HCl. The combined extract was basified with NaOH and extracted with CHCl3. After drying over Na2SO4, the solvent was evaporated and the residual solid was taken up in Et2O. Treatment with HCl gas followed by evaporation of the solvent resulted in a solid hydrochloride salt. The solid was taken up in a minimal amount of MeOH and Et2O was added dropwise. Crystals formed overnight, which were  filtered, washed with Et2O, and dried under vacuum to yield (R)-5b (5.3 g, 70%): mp 198200C (lit.1 204205C)


S-(-)-2,5-Dimethoxy-4-methylamphetamine (S)-5b
To a solution of (S)-(2',5'-dimethoxy-4'-methylphenyl)-2-propanol (S)-9b (0.4 g, 0.002 mol) in dry THF (5 mL) was added triphenylphosphine (1 g, 0.004 mol) and CBr4 (1.26 g, 0.004 mol). After stirring overnight the solids were removed by filtration and the filtrate was evaporated to dryness. The residual oil was taken up in DMF, sodium azide (0.5 g, 0.008 mol) was added and stirring was continued overnight. The reaction was quenched with H2O and the mixture was extracted with CHCl3. The organic extract was dried and evaporated to dryness. The residue was dissolved in EtOH, treated with 10% Pd/C and shaken under 40 psi of H2 overnight. The catalyst was removed by filtration and the solvent was evaporated to near dryness. The residue was taken up in H2O and the pH was adjusted to 7. After washing with Et2O the pH was adjusted to 11 and the solution was extracted with CHCl3. The organic extract was dried over Na2SO4 and evaporated to dryness.
GC analysis showed the product to be (S)-5b of 97% optical purity.


(S)-2,5-Dimethoxyphenyl-2-propanol (S)-9c
To a solution of 1-bromo-2,5-dimethoxybenzene 6c (43.41 g, 0.200 mol) in dry THF (700 mL) in a 1000 mL three necked round bottom flask equipped with an N2 inlet and cooled to ?72C was added a solution of 2.0 M n-BuLi in pentane (100 mL, 0.200 mol). After stirring for 10 min, (S)-propylene oxide (S)-8 (6.00 g, 0.103 mol) was added. Stirring was continued for 10 min and BF3Et2O (21.29 g, 0.15 mol) was added. After  stirring for 15 min the solution was quenched with saturated NH4Cl and extracted with Et2O (3250 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness leaving an oil with a precipitated solid. The solid was filtered off, washed with MeOH and discarded. The oil was again evaporated, dried in vacuo and purified by column chromatography (SiO2; hexane:EtOAc 5:1). The fractions that contained the product were evaporated and recrystallized from EtOAc/hexane yielding (S)-9c (13.60 g, 67% yield) as clear colorless needle crystals. The chiral purity of the product was determined to be 100% by GC analysis of a diastereomeric mixture obtained by derivatizing with menthyl chloroformate (MCF). The compound had mp 5657C


(S)-2,5-Dimethoxyphenyl-2-propyl tosylate (S)-10c
To a solution of (S)-2,5-dimethoxyphenyl-2-propanol (S)-9c (10.19 g, 0.052 mol) in pyridine (70 mL) in a 1000 mL round bottomed flask was added p-toluenesulfonyl chloride (11.88 g, 0.062 mol) while stirring in an ice bath. The flask was then transferred to the freezer and left for three days. The flask was full of crystals, which were collected by filtration. The pyridine solution was washed with a cold biphase of aqueous 3% NaOH and CHCl3. The CHCl3 layer was drawn off and washed with cold aqueous 2% HCl. The CHCl3 layer was dried over MgSO4 and evaporated to an oil. The oil was then recrystallized from EtOAc and hexane yielding (S)-10c (10.38 g, 57% yield) as white crystals.


(R)-2,5-Dimethoxyphenyl-2-propyl azide (R)-11c
To a solution of (S)-2,5-dimethoxyphenyl-2-propyl tosylate (S)-10c (10.17 g, 0.029 mol) in DMF (80 mL) was added sodium azide (7.55 g, 0.116 mol) and the solution was stirred for 5 days. TLC indicated complete conversion. The mixture was taken up in water and extracted with Et2O (3300 mL). The Et2O layers were combined and washed with H2O to remove excess DMF. The aqueous layer was backextracted with Et2O (200 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to give (R)-11c (6.19 g, 96% yield) as a clear light yellow colored oil.


[/b](R)-2,5-Dimethoxyamphetamine (R)-5c
To a solution of (R)-2,5-dimethoxyphenyl-2-propylazide [b](R)-11c
(6.19 g, 0.028 mol) in MeOH (200 mL) was added 10% Pd/C (0.65 g) and the slurry was hydrogenated at 4045 psi overnight. The catalyst was removed by filtration through celite and the MeOH was evaporated to leave (R)-5c (5.42 g, 100% yield) as a clear light yellow colored oil.
GC analysis indicated 98% enantiomerically pure (R)-5c.


(R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d
To a solution of (R)-2,5-dimethoxyamphetamine (R)-5c (5.42 g, 0.028 mol) in EtOH (100 mL) was added I2 (14.10 g, 0.066 mol) and Ag2SO4 (17.32 g, 0.066 mol) and the reaction mixture was allowed to stir overnight. The precipitated yellow solid was collected by filtration and the EtOH evaporated. The solid residue was dissolved in CHCl3 and washed with aqueous 5% NaOH (250 mL). The aqueous layer was extracted with CHCl3 (2300 mL) and the organic layers were combined and washed with H2O. The organic layer was then dried over Na2SO4, filtered, and evaporated down to a purplish brown solid (8.45 g). Column chromatography (SiO2, 8% EtOH/CHCl3) gave (R)-5d (4.31 g, 48% yield) as an off white solid.


(R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d hydrochloride
Treatment of a CHCl3 solution of (R)-5d (6.29 g, 0.020 mol) with HCl/MeOH, followed by evaporation of the solvent gave a solid that was recrystallized using MeOH/Et2O. The white crystals were collected and washed with Et2O giving R-5d hydrochloride
(5.50 g, 0.015 mol, 79% yield): TLC single spot using UV visualization Rf 0.72 (chloroform:methanol:ammonium hydroxide (80:18:2)), mp 222223C (lit.6 218219C)

The candle that burns twice as bright burns half as long
 
 
 
 
    Rhodium
(Chief Bee)
07-30-03 11:28
No 450731
      Wow, what an article!     

Wow, what an article! Super-excellent, Mr. Lego!
 
 
 
 
    hellman
07-30-03 20:42
      fuk!
(Rated as: whining)
    
 
 
 
    Chimimanie
07-31-03 04:36
      Hey!
(Rated as: off-topic)
    
 
 
 
    hellman
07-31-03 18:56
      Your kidding yourself, I don't think anybody...
(Rated as: off-topic)
    
 
 
 
    GC_MS
07-31-03 22:29
      Your kidding yourself, I don't think anybody...
(Rated as: off-topic)
    
 
 
 
    hellman
08-03-03 18:49
      point
(Rated as: incomprehensible)
    
 
 
 
    java
08-28-03 11:32
      RE: Hellman and your comments....
(Rated as: off-topic)
    
 
 
 
    hellman
10-03-03 19:26
      Hey Java, I would like to respond to your...
(Rated as: off-topic)
    
 
 
 
    hypo
10-04-03 03:08
      sorry,
(Rated as: off-topic)
    
 
 
 
    pHarmacist
10-04-03 03:41
      your missing the point, A box within a box,...
(Rated as: off-topic)
    
 
 
 
    lugh
(Moderator)
10-04-03 04:19
No 462524
      Exercising Logic     


Logically rather than moderating my posts, the whole thread should be removed,.




Your off topic posts are still visible if you click the post title, which you would know if you'd really read the FAQ tongue This thread was started on the topic of a novel route to substituted amphetamines, not the travails of an OTC chemist, so it won't bee closed on your demand laugh As far as your problems in vacuum distillation, the Europeans who created the science of organic chemistry, and their Greek and Arabic predecessors didn't know about borosilicate glass, or of companies that would provide such equipment, they made it themselves cool There's considerable information available here and on Rhodium's page on scientific glassblowing, perhaps you should spend more time studying what's available here, instead of trying to run the place wink


Chemistry is our Covalent Bond
 
 
 
 
    hellman
10-07-03 21:27
      Mr Pharmacist, That's a wonderful generic...
(Rated as: Shut up, this is the wrong forum for this type of discussion!)