Introduction
Fluoxetine are top-selling pharmaceuticals used for the treatment of major depressive disorder (MDD) and other conditions. Fluoxetine (also known as Prozac, Adofen and Sarafem; N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine) belongs to the selective serotonin reuptake inhibitor (SSRI) class of anti-depressants class. Due to the success and importance of these drugs, several groups have been interested in their preparation. It is interesting to note that Fluoxetine, despite being a chiral compound, is marketed as the racemic HCl-salt. However, studies have revealed evidence of differing pharmacological and pharmacokinetic properties depending on the enantiomer of Fluoxetine. This evidence suggests that the (S)-enantiomer of Fluoxetine is more active in the inhibition of serotonin than the (R)-enantiomer. Additionally, one of the major metabolites of Fluoxetine, norfluoxetine (demethylated Fluoxetine), is significantly more active as an inhibitor. Here in, we report an efficient, catalytic, asymmetric synthesis of fluoxetine with key steps that involve: (1) an in situ imine formation, (2) a copper-catalysed asymmetric β-borylation protocol that requires a specific bulky amine to block the imine functionality and prevent 1,2 addition versus 1,4 addition of the Cu-Bpin system, (3) a sequential transimination reaction, (4) a reduction of CvN bond and (5) a C–B oxidation protocol. Interestingly, since the asymmetry is induced in the second step by using a cheap chiral ligand (R/S)-dimethyl-BINAP [(R/S)-DM-BINAP)], another key point is the prevalence of the asymmetric induction along the following synthetic steps towards the target product.
Here is represented an efficient, catalytic, asymmetric route to (R)-Fluoxetine (45% overall yield) through the asymmetric copper-mediated β-borylation of α, β-unsaturated imines. Although this strategy involves six steps, the first five steps are conducted following a one-pot strategy, which greatly simplifies the instrumental part. Importantly, the asymmetric induction provided by CuCl, modified with a cheap chiral ligand (R/S)-DM-BINAP L1/L2, is high and is constant along the following transformation towards the targeted pharmaceuticals.
Here is represented an efficient, catalytic, asymmetric route to (R)-Fluoxetine (45% overall yield) through the asymmetric copper-mediated β-borylation of α, β-unsaturated imines. Although this strategy involves six steps, the first five steps are conducted following a one-pot strategy, which greatly simplifies the instrumental part. Importantly, the asymmetric induction provided by CuCl, modified with a cheap chiral ligand (R/S)-DM-BINAP L1/L2, is high and is constant along the following transformation towards the targeted pharmaceuticals.
Equipment and glassware:
- In 50 or 100 mL pear shaped round bottom flask;
- Schlenk-tube 100 mL;
- Nitrogen balloon (5 L is enough);
- Laboratory scale (0.01 — 100 g is suitable);
- Flash chromatography kit (optional);
- Pasteur pipette's;
- Water-jet aspirator;
- Buchner flask and funnel (or small Schott filter);
- Conventional funnel;
- Drip funnel 50 mL;
- Rotary evaporator (optional);
- Reflux condenser (small);
- Separatory funnel, 500 ml;
- Beakers 100 ml x2; 50 ml x4; 10 ml x2;
- Spatula.
Reagents:
- Cinnamaldehyde (1) 0.63 mL, 5.00 mmol;
- Benzhydrylamine 0.86 mL, 5.00 mmol;
- THF (40 mL);
- Molecular sieve 3 Å-MS 5.0 g;
- [to get racemic Fluoxetine] CuCl (12.0 mg, 0.12 mmol), PPh3 (62.9 mg, 0.24 mmol);
- [to get (R)-Fluoxetine] (R)-DM-BINAP (88.2 mg, 0.12 mmol), NaOt-Bu (34.6 mg, 0.36 mmol) and B2pin2 (1.12 g, 4.4 mmol);
- Methanol (MeOH) 8.4 mL;
- Methylamine (MeNH2) 8 mL, 16.0 mmol, 2 M THF solution;
- Sodium borohydride (NaBH4) 0.46 g, 12.0 mmol;
- Sodium hydroxide (NaOH) 2.4 mL, w/v 20%;
- Hydrogen peroxide (H2O2) 1.1 mL, w/v 35%;
- Dimethylacetamide (DMA) 2.8 mL;
- Sodium hydride (NaH) 100 mg, 2.2 mmol, 60% in mineral oil;
- 4-Chlorobenzotrifluoride 354 μL, 2.4 mmol;
- EtOAc;
- Sodium chloride;
- Magnesium sulfate MgSO4;
- DCM and Et3N (optional).
Boiling Point: 395.1±42.0 at 760 mm Hg;
Melting Point: 158.4-158.9 °C;
Molecular Weight: 309.33 g/mol;
Density: 1.2±0.1 g/ml (20 °C);
CAS Number: 54910-89-3.
Procedure
Synthesis of 3-(methylamino)-1-phenylpropan-1-ol (9a)
1. Benzhydrylamine (0.86 mL, 5.00 mmol) and cinnamaldehyde (1) (0.63 mL, 5.00 mmol) was added to a stirring solution of THF (20 mL) and oven-dried 3 Å-MS (5.0 g) (Molecular sieve) for 6 h, to form the α, β-unsaturated imine (2) in situ in 50 or 100 ml pear shaped round bottom flask.
1. Benzhydrylamine (0.86 mL, 5.00 mmol) and cinnamaldehyde (1) (0.63 mL, 5.00 mmol) was added to a stirring solution of THF (20 mL) and oven-dried 3 Å-MS (5.0 g) (Molecular sieve) for 6 h, to form the α, β-unsaturated imine (2) in situ in 50 or 100 ml pear shaped round bottom flask.
2. After 6 h, an aliquot of the solution containing the in situ-formed imine (2) (16.0 mL, 4.00 mmol) was transferred to a Schlenk-tube (under argon or nitrogen) containing [to get racemic Fluoxetine] CuCl (12.0 mg, 0.12 mmol), PPh3 (62.9 mg, 0.24 mmol) or [to get (R)-Fluoxetine] (R)-DM-BINAP (88.2 mg, 0.12 mmol), NaOt-Bu (34.6 mg, 0.36 mmol) and B2pin2 (1.12 g, 4.4 mmol). After 5 min, MeOH (400 μL, 10.0 mmol) was added to the solution and the reaction was stirred overnight.
3. Methylamine (8 mL, 16.0 mmol, 2 M THF solution) was added under argon (or nitrogen) and the resulting solution was stirred for 1.5 h.
4. NaBH4 (0.46 g, 12.0 mmol) was added, followed by the drop-wise addition of MeOH (8.0 mL). The mixture was stirred for 3 h, followed by the removal of solvent under reduced pressure.
5. THF (20 mL) was added to the resulting residue, followed by NaOH (2.4 mL, w/v 20%) and H2O2 (1.1 mL, w/v 35%), and the solution was heated to reflux for 1 h.
After cooling, the resulting solution was partitioned between EtOAc and brine. The aqueous layer was extracted further with EtOAc (3×). The organic phase was separated and dried over anhydrous MgSO4. After filtration, the organic phase was removed under reduced pressure to yield a crude product.
Purification by silica gel chromatography (DCM → DCM–MeOH–NEt3, 5 : 1 : 1%) gave the pure product as an off colorless oil, which formed an off colorless solid on standing [356 mg, 54% when using PPh3 and 402 mg, 61% when using (R)-DM-BINAP].
Synthesis of Fluoxetine, N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine (1)
6. 3-(Methylamino)-1-phenyl-propan-1-ol (6) (330 mg, 2.00 mmol) was dissolved in dry dimethylacetamide (2.8 mL) and transferred to an oven-dried Schlenk-tube and purged with argon (or nitrogen). NaH (100 mg, 2.2 mmol, 60% in mineral oil) was transferred directly to the solution and heated (70 °C) under argon or nitrogen for 30–40 min, or until hydrogen evolution had ceased. 4-Chlorobenzotrifluoride (354 μL, 2.4 mmol) was added under argon or nitrogen, and the resulting solution was heated (100 °C) for 3 h.
Purification by silica gel chromatography (DCM → DCM–MeOH–NEt3, 5 : 1 : 1%) gave the pure product as an off colorless oil, which formed an off colorless solid on standing [356 mg, 54% when using PPh3 and 402 mg, 61% when using (R)-DM-BINAP].
Synthesis of Fluoxetine, N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine (1)
6. 3-(Methylamino)-1-phenyl-propan-1-ol (6) (330 mg, 2.00 mmol) was dissolved in dry dimethylacetamide (2.8 mL) and transferred to an oven-dried Schlenk-tube and purged with argon (or nitrogen). NaH (100 mg, 2.2 mmol, 60% in mineral oil) was transferred directly to the solution and heated (70 °C) under argon or nitrogen for 30–40 min, or until hydrogen evolution had ceased. 4-Chlorobenzotrifluoride (354 μL, 2.4 mmol) was added under argon or nitrogen, and the resulting solution was heated (100 °C) for 3 h.
On cooling, the solution was partitioned between toluene and H2O and washed (3× H2O). The organic phase was separated and dried over anhydrous MgSO4. After filtration, the organic phase was removed under reduced pressure to yield a crude product. Purification by silica gel chromatography (DCM → DCM–MeOH–NEt3, 5 : 1 : 1 %) gave the pure product as a yellow oil (7), (458 mg, 74 %).
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