Structure of 133487-66-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 133487-66-8 |
Formula : | C10H8F4O2 |
M.W : | 236.16 |
SMILES Code : | O=CC1=CC=CC(OCC(F)(F)C(F)F)=C1 |
MDL No. : | MFCD27943794 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Synthesis of the Compound of Formula IThe detailed synthesis of N-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamine as the monohydrochloride salt is provided in Scheme V. Procedure:The tartrate salt of 2-(6-Fluoro-1H-indol-3-yl)-ethylamine (49.3 g) was stirred in a mixture of toluene (270 ml), THF (100 ml), 2M NaOH (200 ml) and 15% NaCl (65 ml). The phases were separated. The organic phase was washed with 5% NaCl (200 ml). The organic phase was concentrated under reduced pressure to dryness and the residue dissolved in isopropanol (400 ml).3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (39 g) and isopropanol (200 ml) were charged to the reaction mixture. The reaction mixture was heated at 60 C. for 2.5 hours and then cooled to about 55 C. To the hot reaction mixture was charged a suspension of NaBH4 (7.4 g) in isopropanol (100+50 ml). The reaction mixture was heated at 55 C. for 2.5 hours and then cooled to about 15-20 C. 2M HCl (80 ml) was added drop-wise over a period of about 30 minutes. 2M HCl (140 ml) was added over a period of 15 minutes. The mixture was stirred vigorously for 15 minutes. The mixture was concentrated to half volume followed by addition of 6M NaOH (83 ml) to pH14. Toluene (400 ml) was added. The phases were separated and the organic phase was washed with 2M NaOH (200 ml), 3% NH4Cl (200 ml) and water (200 ml), respectively. The organic phase was filtered and concentrated to dryness. The residue was dissolved in toluene (550 ml) and acetonitrile (50 ml). 6M HCl (33 ml) was added drop-wise. The resulting suspension was stirred for 2-4 hours and then filtered. The filter-cake was washed with toluene/acetonitrile (9:1, 2×75 ml) and 0.1M HCl (2×75 ml), respectively. The crude HCl salt of the compound of Formula I was dried under vacuum at about 45 C. for about 16 hours.Final purification of HCl salt of the compound of Formula I HCl was performed by first dissolving the isolated HCl salt in acetone (300 ml). The solution was filtered and concentrated to a volume of about 90-120 ml. Filtered 0.1M HCl (1900 ml) was added drop-wise over 30 minutes. The resulting suspension was stirred at 20-25 C. for 16 hours and then filtered. The filter-cake was washed with filtered 0.1M HCl (200 ml) and filtered water (150 ml), respectively. The purified HCl salt was dried at 40 C. under vacuum for about 16 hours and isolated as a white solid. Yield: 80%. Purity by HPLC (280 nm): >99.5%. MS m/z: 399 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Compound (V) (49.3 g, 0.150 mol) was stirred in a mixture of toluene (270 mE), THF (100 mE), aq. NaOH (200 mE, 2 M) and aq. NaCl (65 mE, 15% w/w). The phases were separated. The organic phase was washed with aq. NaCl (200 mE, 5% w/w). The organic phase was concentrated under reduced pressure to dryness and the residue dissolved in isopropanol (400 mE). Compound (IX) (39.0 g, 0.165 mol) and isopropanol (200 mE) were charged to the reaction mixture. The reaction mixture was heated at 60 C. for 2.5 h and then cooled to about 55 C. To the hot reaction mixture was charged a suspension of NaI3H4 (7.4 g, 0.196 mol) in isopropanol (100 and 50 mE). The reaction mixture was heated at 55 C. for 2.5 hand then cooled to about 15-20 C. Aq. HC1 (80 mE, 2 M) was added dropwise over a period of about 30 mi Aq. HC1 (140 mE, 2 M) was added over a period of 15 mm. The mixture was stirred vigorously for 15 mm. The mixture was concentrated to half volume followed by addition of aq. NaOH (83 mE, 6 M) to pH14. Toluene (400 mE) was added. The phases were separated and the organic phase was washed with aq. NaOH (200 mE, 2 M), aq. NH4C1 (200 mE, 3% w/w) and water (200 mE), respectively. The organic phase was filtered and concentrated to dryness. The residue was dissolved in toluene (550 mE) and acetonitrile (50 mE). Aq. HC1 (33 mE, 6 M) was added drop-wise. The resulting suspension was stirred for 2-4 hours and then filtered. The filter-cake was washed with toluene: acetonitrile mixture (9:1, 2x75 mE) and aq. HC1 (2x75 mE, 0.1 M), respectively. The crude HC1 salt of Compound (I) was dried under vacuum at about 45 C. for about 16 h. Final purification of the HC1 salt of Compound (I) was performed by first dissolving the isolated salt in acetone (300 mE). The solution was filtered and concentrated to a volume of about 90-120 mE. Filtered aq. HC1 (1900 mE, 0.1 M) was added dropwise over 30 mm. The resulting suspension was stirred at 20-25 C. for 16 h and then filtered. The filtercake was washed with filtered HC1 (200 mE, 0.1 M) and filtered water (150 mE), respectively. The purified HC1 salt of Compound (I) (52.2 g, 80%) was dried at 40 C. under vacuum for about 16 h and isolated as a white solid with>99.5% UV purity in HPEC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A mixture of Compound (III) (11.0 g, 62 mmol)and Compound (IV) (14.4 g, 59 mmol) was heated intoluene (120 mL) and isopropanol (96 mL) at 75 C. for 3 h. The mixture was allowed to cool to room temperature, and 3% Pt/C (type Noblyst P8080 from Evonik, 61.2% w/w water, 3.06 g, 0.183 mmol) was added. The mixture was hydrogenated at 70-75 C. and 5 bar for 6 h. The reaction mixture was cooled, filtered and the filtrate was evaporated to dryness to yield crude Compound (I) (25.7 g). The crude Compound (I) (24.7 g used, 1 g kept for analysis) was dissolved in toluene (205 mL) at it and the organic layer was washed twice with a 2% sodium hydroxide solution (79 mL), followed by washing with a mixture of 3% solution of ammonium chloride (74 mL) and water (74 mL). A solution of diluted hydrochloric acid (prepared from 6.4 mL 37% w/w aq. HC1 and 21.3 mL water) was added over a period of 10 mi Acetonitrile (20 mL) was added and the mixture was heated to 50 C. Upon cooling to 30 C. Compound (I) as HC1-salt (1:1) precipitated, and it was isolated by filtration at it, and washed with a mixture of toluene/acetonitrile, dilute HC1 and watet The wet product was dried at 65 C. under vacuum overnight providing dry Compound (I) as HC1 salt (1:1) (20.4 g, 47 mmol, 83% yield corrected forg sample taken), with 99.1% UV purity in HPLC analysis. |
Tags: 133487-66-8 synthesis path| 133487-66-8 SDS| 133487-66-8 COA| 133487-66-8 purity| 133487-66-8 application| 133487-66-8 NMR| 133487-66-8 COA| 133487-66-8 structure
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