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...
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-olIntroduction 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 160°C (with different times of contact). With the triflate (R)-4c the yield of the substitution is 60% but under non comparable conditions (-20°C 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 100°C 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
. 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
, 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, 110°C, 5h30 or EtNH2 (solvent and reactant), 140°C, 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 PartGeneral 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: 150°C)
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 6This product was supplied by the Oril society.
bp = 87-88°C/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 23°C (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 1This product was supplied by the Oril society.
bp = 97-98°C/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 24°C (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
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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 34-36°C. 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 -30°C 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 -30°C. 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 0°C and maintains for 3 hours at 0°C, 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 = 102-103°C/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 0°C 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 0°C 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 0°C. 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 22°C in an autoclave is added anhydrous ethylamine (0.4 ml; about 4 eq.). One heats to 100-105°C 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 90°C 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 -20°C 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 -20°C 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 = 112°C (Köfler).
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).
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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 75°C 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 21°C 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 = 90-95°C/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%).
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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 70°C, 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 24°C (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 26-29°C 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.
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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 24°C 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 24°C 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%)).
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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 40°C. After 2 h 30, water (30 ul; 1.5 eq) is added and the stirring continued at 40°C 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%).
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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%)
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