Patent Application
20070270487
The present invention is described in more detail by the following examples, which do not limit the scope of the present invention.
Lithium diisopropylamide (LDA, 52 L, 1.8 M, 93.6 mol) in a solution of Tetrahydrofuran (THF)/Heptane and ethylbenzene was charged to a reactor under a nitrogen atmosphere, and THF (52 L) was then added. The temperature was adjusted to an inner temperature (the temperature of the reaction solution) of −48° C. 4-Fluorophenylacetonitrile (13.0 kg, 96.2 mol) in a THF-solution (25 L) was charged during 1 h and 50 min to the solution comprising LDA, while the temperature of the reaction mixture was kept below −30° C. The temperature was increased to −6° C. over 1 h, during that time the yellow slurry transformed into a dark purple solution. THF (5 L) followed by tert-butylbromoacetate (20.25 kg, 104 mol) and finally THF (25 L) was charged to a second reactor. The temperature was lowered to an inner temperature of −48° C. The dark purple solution above was charged to the tert-butyl-bromoacetate-solution over 7.5 h, while the inner temperature was kept below −34° C. The inner temperature was adjusted to −5° C. and the reaction mixture was quenched by adding a solution of ammonium chloride (12.7 kg) and water (55 L) over 15 min. Methyl tert-butyl ether (MTBE 43 L) was charged and the obtained mixture was stirred for 5 min. After phase separation, the aqueous phase was discarded. Brine (7.6 kg sodium chloride in 25 L of water) was charged to the remaining organic phase and the mixture was stirred for 5 min. The aqueous phase was discarded and the remaining solution was concentrated by distillation at reduced pressure to a volume of 150 L. Isooctane (43 L) was charged and the distillation was continued until the resulting volume was 60 L at which point crystallization started. MTBE (25 L) was charged and the jacket temperature was set to 0° C. After 2 h the batch was filtered (inner temperature 2° C.) and washed with isooctane (2×20 L). After drying 16.8 Kg (72%) of the title compound was obtained.
1H NMR (DMSO-d6) δ 7.51 (app d, J=8 Hz, 1 H), 7.50 (app d, J=8 Hz, 1 H), 7.24 (app t, J=8 Hz, 2H), 4.50 (app dd, J1=6 Hz, J2=8 Hz, 1 H), 3.02 (app dd, J1=8 Hz, J2=16 Hz, 1 H), 2.86 (app dd, J1=6 Hz, J2=16 Hz, 1 H), 1.36 (s, 9 H); 13C NMR (DMSO-d6) δ 168.4, 161.7 (d, JC,F=244 Hz), 131.3 (d, JC,F=3 Hz), 129.8 (d, JC,F=9 Hz), 120.6, 115.7 (d, JC,F=22 Hz), 81.0, 39.1, 31.4, 27.6.
The compound (formula (III-1) obtained from Example 1 (16.7 kg, 67.0 mol) was charged under nitrogen atmosphere to a reactor and THF (50 L) was then added. The temperature was adjusted to an inner temperature of 65° C. Borane-dimethylsulfide complex (16.6 L, 166 mol) in a THF solution (5 L) was charged to the reaction mixture over a period of 43 minutes. The mixture was then refluxed for 2 hours. The reaction mixture was cooled to 10° C. Water (75 L) and hydrochloric acid (25.5 L) was charged to a second vessel and the reaction solution above was charged to this aqueous phase accompanied by gas evolution (H2 is formed). When the addition was complete (after 1.5 h), the jacket temperature was increased to 105° C. and the solvents were distilled off until the temperature of the reaction mixture reached 85° C. The reaction mixture was refluxed for 12.5 h and then cooled to 24° C. Aqueous sodium hydroxide (50% solution, 32.4 kg) was charged followed by toluene (55 L) and THF (18 L). After phase separation, the aqueous phase was extracted with a mixture of toluene (30 L) and THF (13 L). The organic phases were combined and approximately 65 L of solvent mixture was removed by distillation under reduced pressure. Toluene (40 L) and THF (5 L) was charged to the organic phase and the resulting mixture was clear filtered and returned to the reactor. The solvents were distilled off at reduced pressure until 50 L remained. Toluene (20 L) was charged and the distillation was continued until approximately 35 L remained. The inner temperature was lowered from 59° C. to 12° C. over 1 h and seeding crystals (0.2g) were added, which started the crystallization. Heptane (12 L) was charged and the slurry was cooled down to 6° C. over 2 h. The slurry was filtered and the solid was washed with heptane (2×10 L) and dried. 6.13 kg (50%) of the title compound was obtained.
1H NMR (DMSO-d6) δ 7.21 (app d, J=8 Hz, 1 H), 7.19 (app d, J=8 Hz, 1 H), 7.10 (app t, J=8 Hz, 2H), 3.13-3.35 (m, 2 H), 2.59-2.81 (m, 2 H), 1.77-1.94 (m, 2 H), 1.50-1.68 (m, 2 H); 13C NMR (CDCl3) δ 161.7 (d, JC,F=244 Hz), 139.9 (d, JC,F=3 Hz), 129.0 (d, JC,F=8 Hz), 115.6 (d, JC,F=21 Hz), 61.1, 48.2, 46.7, 38.6.
(R)—O-Acetylmandelic acid (18.79 kg, 96.76 mol) was charged to a reactor followed by to water (845 g) and ethyl acetate (EtOAc, 100 L). The solution was stirred at an inner temperature of 17-20° C. for 0.5 h. The clear solution was collected in a drum and the reactor was rinsed with EtOAc (20 L). The rinsing solution was then combined with the above clear (R)—O-acetylmandelic acid solution. 4-Amino-3-(4-fluoro-phenyl)-butan-1-ol (20.64 kg, 112.65 mol) was charged to a reactor followed by absolute ethanol (99.7% w/w, 19 L) and EtOAc (43 L). Stirring was started and the inner temperature was raised to 59° C. The (R)—O-acetylmandelic acid solution was charged to the solution of 4-Amino-3-(4-fluoro-phenyl)-butan-1-ol over 24 min. The dark yellow solution thus obtained started to crystallize at an inner temperature of 53° C. about 5 min after complete addition of (R)—O-acetylmandelic acid. The inner temperature was kept at 52-53° C. for 20 min, and the slurry was then cooled down to 25° C. over 1 h and 20 min. The white slurry was filtered and the solid was washed with EtOAc (2×37.5 L) to give, after drying on the filter, 15.33 kg of needle like white crystals having an optical purity of 83% enantiomeric excess (ee). The ee corrected yield is 66%.
The obtained product (15.33 kg, 40.62 mol) was charged to a reactor followed by absolute 99.5% ethanol (27.5 L) and EtOAc (22.5 L). Stirring was started and the mixture was heated to an inner temperature of 70° C. EtOAc (105 L) was charged to the mixture over 44 min. The inner temperature was kept between 67-70° C. during the addition. The crystallization started 8 min after the last addition of EtOAc (inner temperature 69° C.). The slurry was cooled to an inner temperature of 25° C. over 1 h and 50 min and then filtered. The obtained solid was washed with EtOAc (2×37.5 L) and dried giving 11.65 kg (82% ee corrected yield) of needle-like white crystals having an optical purity of 98% ee according to chiral HPLC.
1H NMR (DMSO-d6) δ 7.41 (app dd, J1=7 Hz, J2=1 Hz, 2 H), 7.16-7.34 (m, 5 H), 7.12 (app t, J=9 Hz, 2H), 5.53 (app s, 1 H), 3.08-3.33 (m, 2 H), 2.92-3.08 (m, 2 H), 2.78-2.92 (m, 1 H), 2.04 (s, 3 H), 1.77-1.94 (m, 1 H), 1.50-1.69 (m, 1 H); 13C NMR (DMSO-d6) δ 170.6, 169.7, 168.4, 161.1 (d, JC,F=242 Hz), 138.3, 137.7 (d, JC,F=3 Hz), 129.7 (d, JC,F=8 Hz), 127.9, 127.4, 127.3, 115.2 (d, JC,F=21 Hz), 77.2, 58.2, 44.0, 38.7, 36.3, 21.1. [α]D (c 1.0 in methanol, 25° C.) −60.4°.
((S)-(−)-4-Amino-3-(4-fluoro-phenyl)-butan-1-ol, (11.61 kg, 30.76 mol) was charged to a stirred solution of aqueous sodium hydroxide (11.30 kg of 50% sodium hydroxide in water, 141.3 mol, diluted to approximately 70 L) at 16° C. inner temperature under nitrogen atmosphere. THF (7.5 L) and toluene (74 L) was charged resulting in a clear two-phase system. The solution was cooled to −1° C. and ethyl chloroformate (3.60 kg, 33.2 mol) in a mixture of THF (1.1 L) and toluene (10 L) was charged to the mixture over 18 min. During the addition the inner temperature rose to 9° C. The reaction mixture was heated to 18° C. over 1 h and 48 min at which point HPLC indicated that the reaction was complete. Toluene (17.5 L) was charged and good mixing was achieved followed by phase separation. The resulting two phases were separated and the aqueous phase was discarded. The organic phase was washed with water (3×8 L) and concentrated to approximately 50 L by distillation at reduced pressure. Toluene (25 L) was charged and the distillation was continued until approximately 30 L of the solvents had been distilled off. Toluene (25 L) was charged and the distillation continued until approximately 40 L remained in. The toluene solution containing the desired product was taken straight into the next Step.
Lithium aluminium hydride (2.11 kg, 55.6 mol) was charged to a reactor containing THF (50 L) at an inner temperature of 20° C. under a nitrogen atmosphere, while stirring. The mixture was heated to an inner temperature of 51° C. and 4 (S)-N-[2-(4-Fluorophenyl)-4-hydroxy-butyl]-carbamic acid ethyl ester in toluene (total volume 43 L) from the previous Step was charged to the lithium aluminium hydride slurry in THF over 2 h. The temperature was kept between 51-68° C. during the addition. The charging vessel was rinsed with toluene (5 L) and the batch was held at 56-58° C. for 2 h after the last addition of 4 (S)-N-[2-(4-Fluorophenyl)-4-hydroxy-butyl]-carbamic acid ethyl ester. The reaction mixture was cooled to an inner temperature of 2 IC and a solution of aqueous sodium bicarbonate (26 L) was charged over 44 min (inner temperature 15° C. and jacket temperature −25° C. at the end of the quench) after which the jacket was adjusted to 20° C. and the batch was left for 15 h. The slurry in the reactor was filtered and the resulting solid was washed with toluene (30 L) in four portions. The filtrate was returned to the reactor (cleaned from aluminium salts) and washed with water (2×10 L) and then clear filtered. The clear filtered solution was returned to the reactor and concentrated to approximately 15 L by distillation under reduced pressure. The distillation was stopped and isooctane (30 L) was charged to the slurry. The slurry was cooled from an inner temperature of 32° C. to 20° C. over 40 min, then filtered and the isolated solid was washed with isooctane (30 L) in four portions. The solid was dried and this resulted in 4.54 kg (75% over two Steps) of the pure title compound.
1H NMR (DMSO-d6) δ 7.22 (app d, J=8 Hz, 1 H), 7.20 (app d, J=8 Hz, 1 H), 7.08 (app t, J=8 Hz, 2H), 3.11-3.34 (m, 2 H), 3.72-3.88 (m, 1 H), 3.52-3.66 (m, 2 H), 2.21 (s, 3 H), 1.73-1.91 (m, 1 H), 1.48-1.68 (m, 1 H); 13C NMR δ 160.6 (d, JC,F=241 Hz), 140.7 (d, JC,F=3 Hz), 129.3 (d, JC,F=8 Hz), 114.8 (d, JC,F=21 Hz), 58.9, 57.8, 41.3, 37.4, 36.1. [α]D (c 1.0 in methanol, 25° C.) +8.8°.
3,5-Dibromobenzoic acid (6.002 kg, 21.44 mol) was mixed with toluene (41.8 kg) and the mixture was stirred under nitrogen. Triethylamine (0.110 kg, 1.09 mol) was added and the temperature was increased to 75° C. jacket temperature. Thionyl chloride (5.172 kg, 43.47 mol) was added continuously over 1 h using a dose pump, which was rinsed with toluene (1.2 kg) after completion of the addition. The reaction mixture was stirred at 73° C. jacket temperature for 12 h and then the temperature was decreased to an inner temperature of 30° C. before sampling. HPLC analysis indicated complete conversion to the acid chloride and the mixture was then evaporated to dryness. The isolated 3,5-dibromobenzoyl chloride was dissolved in toluene (11.44 kg) and the formed solution was evaporated to dryness again at a jacket temperature of 40° C.
Sodium hydroxide (3.49 kg of a 49% aqueous solution, 42.8 mol) was mixed with water (24.0 kg) in a reactor. A nitrogen atmosphere was established and (S)-(+)-3-(4-Fluorophenyl)-4-methylamino-butan-1-ol (4.01 kg, 20.3 mol) was added. The resulting mixture was agitated at a jacket temperature of 18° C. The isolated 3,5-dibromobenzoyl chloride from above was dissolved in toluene (30.7 kg) using a jacket temperature of 29° C. and the resulting solution was added to the slurry of (S)-(+)-3-(4-Fluorophenyl)-4-methylamino-butan-1-ol in aqueous sodium hydroxide over 2 h at an inner temperature of between 22° C. and 27° C., to give a yellowish emulsion. After complete addition the addition vessel was rinsed with toluene (8.00 kg) and this solvent was added to the reaction mixture, which was then agitated at a jacket temperature of 20° C. for another 30 min. HPLC analysis of the organic layer indicated complete conversion (>99%) and the aqueous phase was separated off. Water (11.2 kg) was added and the resulting two-phase system was agitated for about 10 min. The aqueous phase was separated off and the organic layer was washed in the same way as described above using a second portion of water (12.1 kg). The organic layer was evaporated to dryness using a jacket temperature of 40° C. giving 10.9 kg of title compound having a chromatographic purity of 98.9% and an assay of 90.8% according to proton-NMR (assay-corrected yield 106%). The main volatile impurities were toluene 5.9% w/w and water 0.2% w/w. The optical purity according to HPLC was 99% ee.
1H NMR (spectrum complicated by restricted rotation around the amide bond, DMSO-d6) δ 7.89 and 7.84 (two singlets appearing as a doublet with J=22 Hz, 1 H), 7.29-7.40 (m, 1 H), 7.20 (app s, 1 H), 6.98-7.24 (m, 3 H), 6.94 (app s, 1 H), 4.37-4.47 (m, 1 H), 3.53-3.77 (m, 1 H), 3.00-3.46 (m, 4 H), 2.65 and 2.96 (methyl group on nitrogen appears as two separate singlets, totally 3 H), 1.54-1.89 (m, 1 H), 13C NMR δ (spectrum complicated by restricted rotation around at least the amide bond, DMSO-d6) 167.2 and 167.0 (carbonyl carbon), 161.0 (d, JC,F=243 Hz), 140.5, 140.0, 138.4,137.8, 134.0, 133.8, 129.85, 129.79, 129.73, 129.67, 128.1 (d, JC,F=8 Hz), 122.5, 122.2, 115.1, 115.0, 114.8, 58.42, 58.35, 51.9, 39.8, 37.4, 36.2, 35.2, 33.0; [α]D (c 1.0 in methanol, 25° C.) −11.4°.
Under a nitrogen atmosphere 39.9 g (148 mmol) of 3-bromo-5-(trifluoromethyl)benzoic acid, 400 mL of toluene, and 1.1 mL of triethylamine (7.9 mmol) were charged to a 1L flask. The mixture was stirred to obtain a solution and warmed to 75° C. 27.2 g (229 mmol) of thionyl chloride was added over 20 minutes resulting in a pale yellow solution. After complete addition the temperature was increased to 100° C. After 1 hour the mixture was sampled and conversion found to be complete. Excess thionyl chloride and some solvent (total 145 mL) were distilled off at 30° C. using a water aspirator. Fresh solvent (160 mL) was added, and again partially removed by distillation. The resulting acid chloride solution (3-bromo-5-(trifluoromethyl)benzoyl chloride, 320 mL) was transferred to a dropping funnel. The reaction flask was filled with 28.3 g of (3S)-3-(4-fluorophenyl)-4-(methylamino)butan-1-ol (143.5 mmol), 145 mL of water and 12.5 g of sodium hydroxide (313 mmol) with some cooling. Starting at 20° C. the solution of acid chloride, 3-bromo-5-(trifluoromethyl)benzoyl chloride, was added at such a rate (˜20 mins) that the temperature was kept below 30° C. The reaction was continued for 30 minutes, then checked for conversion and worked up. The phases were separated. The toluene solution was washed once at 55° C. with 100 mL of water. The turbid organic phase was dried by azeotropic distillation under reduced pressure. In addition some solvent was removed. The final obtained amount of solution was 125.5 g. This was split in two equal parts. One part was used directly for the next reaction. The second part was used to isolate the pure product. 62.8 g of solution was concentrated to 32.5 g of a brown liquid. This was then chromatographed over 450 g of silica, and eluted with dichloromethane with some methanol as modifier (gradually increase from 1% to 3%). Several fractions with in total 25.9 g (57.8 mmol) of product, 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-hydroxybutyl]-N-methyl-5-(trifluoromethyl)benzamide, as a yellowish viscous oil with a purity of 96.5% or better (by GC-MS) were collected. This corresponds to a yield of 80.5%.
1H NMR (spectrum complicated by restricted rotation around the amide bond, chloroform-d) δ 7.75 (apparent singlet, 1 H), 6.73-7.51 (m, 6 H), 2.83-3.92 (m, 5 H), 3.08 and 2.67 (methyl group on nitrogen appears as two separate singlets, totally 3 H), 1.42-2.06 (m, 3 H), 13C NMR δ (spectrum complicated by restricted rotation around at least the amide bond, chloroform-d) 168.8 and 168.5 (carbonyl carbon), 161.9 (d, JC,F=246 Hz), 139.0, 138.6, 137.4, 136.2, 133.2, 133.1, 132.6 (apparent quartet, JC,F=34 Hz), 129.5, 129.4, 129.3, 126.8, 124.1, 122.9, 122.7, 122.3, 121.3, 118.6, 116.0, 115.7, 115.5, 59.9, 59.6, 57.8, 53.5, 53.1, 39.8, 39.6, 38.3, 36.5, 35.5, 33.5; MS 450 and 448 (M+1, Br isotope pattern); [α]D (c 1.0 in methanol, 20° C.) −5.6°.
This application claims the priority benefit of U.S. Provisional Application No. 60/908,253, filed Mar. 27, 2007 and U.S. Provisional Application No. 60/801,555, filed May 18, 2006.
| Number | Date | Country | |
|---|---|---|---|
| 60801555 | May 2006 | US | |
| 60908253 | Mar 2007 | US |
