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Chemical Structure| 70627-20-2 Chemical Structure| 70627-20-2

Structure of 70627-20-2

Chemical Structure| 70627-20-2

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Product Details of [ 70627-20-2 ]

CAS No. :70627-20-2
Formula : C14H11FO2
M.W : 230.23
SMILES Code : O=CC1=CC=C(OCC2=CC=CC=C2F)C=C1
English Name :4-((2-Fluorobenzyl)oxy)benzaldehyde
MDL No. :MFCD01590568
InChI Key :HSFLULIGUCYNMW-UHFFFAOYSA-N
Pubchem ID :702717

Safety of [ 70627-20-2 ]

Application In Synthesis of [ 70627-20-2 ]

* 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.

  • Downstream synthetic route of [ 70627-20-2 ]

[ 70627-20-2 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 70627-20-2 ]
  • [ 33208-99-0 ]
  • [ 133865-88-0 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: (S)-alaninamide hydrochloride With triethylamine In methanol at 20℃; Stage #2: 4-((2-fluorobenzyl)oxy)benzaldehyde In methanol at 25℃; for 3.33333h; Stage #3: With sodium hydroxide; sodium tetrahydroborate In methanol; water at 8℃; for 4h; 2.c Anhydrous triethylamine (19.8 kg, 0.20 kmol) is added at room temperature, under stirring, to a mixture of methanol (275 L) and L- alaninamide hydrochloride (24.4 kg, 0.20 kmol).4-(2-fluorobenzyloxy)benzaldehyde (40.0 kg, 0.17 kmol), prepared in Example 1.6, is added in about 20 min to the above mixture and the reaction mixture is stirred for 3 hours at 25 °C whereupon the temperature is lowered to 8°C (mixture A).In a second reactor, methanol (50 1) and sodium hydroxide 30% in water (3.2 kg) are mixed at 0-5 °C. Sodium borohydride powder (6.6 kg, 0.17 kmol) is added to the above mixture, in portions, at 0 - 5 °C. The mixture is stirred for 2 hours at 0-5 °C under nitrogen (mixture B). The mixture B is added, under stirring and under nitrogen, in about 4 hours to the above reaction mixture A, keeping the temperature at 8 °C. The reaction mixture is concentrated under vacuum to a 70 1 residual volume. Toluene (170 kg) and water (280 kg) are added, under stirring and under nitrogen, to the residue and the mixture is heated up to 60-65 °C. The organic phase is separated and added with water (70 kg) and the two phases mixture is stirred at 60-65 °C.The organic phase is separated and cooled gradually to 20 °C. The mixture is centrifuged and the solid is washed with toluene to provide, after drying at reduced pressure, the product of the title (48.4 Kg, 0.16 kmol), yield: 92%.The HPLC purity of the product is 99.87 (area %, see Example 25A) and the content of C,O-dialkylated (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide is less than 0.005 % by weight (see Example 25B); m.p. 109.5 °C (capillary).The enantiomeric composition of ralfinamide determined with a chiral HPLC column consists of 100% of S-enantiomer (area %, see Example 26A).
85% Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; (S)-alaninamide hydrochloride With triethylamine In methanol at 20 - 25℃; for 1h; Stage #2: With hydrogen In methanol at 20 - 35℃; for 5h; 2 EXAMPLE 2Preparation of (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide, Ib) of high purity degree (one pot reaction)An autoclave is loaded with 4-(2-fluorobenzyloxy)benzaldehyde (2.0 kg, 8.69 mol) prepared according to Example 1, and then a solution prepared apart of L-alaninamide hydrochloride (1.2 kg, 9.63 mol) and triethylamine (0.97 kg, 9.63 mol) in methanol (9.5 kg) is added thereto. The mixture is stirred at 20-25 0C for about 1 hour and then, after seeding it with a few grams of (S)-2-[4-(2-fluorobenzyloxy)benzylideneamino] propanamide, the stirring is continued for additional 15 minutes. To the stirred heterogeneous mixture, methanol (1.6 kg) and wet (50% H2O) Pt/ C 5% (Engelhard cod.Escat 22, Engelhard S.r.l., Rome, Italy) (0.28 kg) are then added at 20-25 0C.The air is purged from the autoclave with nitrogen and then hydrogen is introduced at 5.0 bar and the pressure is maintained at this value during the hydrogenation course. After 5 hours at 30-35 0C the reaction mixture is cooled to 15 0C and, after addition of methanol (4.8 kg) and heating to 40-45 0C the suspension is filtered and the solid is washed with methanol (1.6 kg).The solvent is eliminated under reduced pressure at about 30 0C and the residue is additioned of water (5 L) at 20-25 0C on cooling and under stirring, as the water addition is an exothermic process. The heterogeneous mixture is further cooled to 15-20 0C, kept at this temperature for 1 hour and then filtered. The collected solid is washed with cool water (4 L) and dried under reduced pressure to give 2.23 kg (85.0% yield) of ralfinamide with a HPLC purity of 98.8 (area%) determined according to the method of Example 17A and a C,O-dialkylated (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide content of 0.01% by weight determined by HPLC, according to the method of Example 17B.
70% Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; (S)-alaninamide hydrochloride With triethylamine In methanol at 20 - 25℃; for 1h; Stage #2: With hydrogen In methanol at 20 - 35℃; for 5h; 2.1 2.1 Preparation of (S)-2-[4-(2-fluorobenzyloxy)benzylamino] propanamide (Ib) of high purity degree by using a palladium catalystA mixture of 5 g of 4-(2-fluorobenzyloxy)benzaldehyde, prepared according to the Ex. 1 and the corresponding amount L-alaninamide hydrochloride and triethylamine is hydrogenated according to the same procedure of Example 2, but using wet (50% H2O) Pd /C 10% instead of wet (50% H2O) Pt/ C 5% to obtain (S)-2-[4-(2-fluorobenzyloxy) benzylamino] propanamide (Ib) in a 70% yield.
58.8% With sodium cyanoborohydride 23.2.a; 23.2.b (S)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide (Ib) is prepared following the procedure of Example 22.2. a) by using 4- (2- fluorobenzyloxy)benzaldehyde (10 mmol, prepared as in Example 23.1a) instead of 4-(3-fluorobenzyloxy)benzaldehyde. (S)-2[4-(2-Fluorobenzyloxy)benzalamino]propanamide is obtained in 67.3% yield as a white solid. The product has a HPLC purity of 86.7 (area %, see Example 25A) and a content of (S)-2-[3-(2-fLuorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide (lib) of 0.22% by weight determined by HPLC (see Example 25B).; S)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide (Ib) is prepared according to Example 22.2. b) by using 4-(2-fluorobenzyloxy)benzaldehyde(10 mmol, prepared according to Example 23.1.b) instead of 4-(3- fluorobenzyloxy)benzaldehyde .(S)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide is obtained as a white solid in 58.8 % yield. The product has a HPLC purity 83.8 (area %, see Example 25A) and a content of (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide (lib) of 0.15% by weight determined by HPLC (see Example 25B).
With 3 A molecular sieve; sodium cyanoborohydride 1.) MeOH, RT, 15 min, 2.) MeOH, RT, 3 h; Yield given. Multistep reaction;
Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; (S)-alaninamide hydrochloride With triethylamine In methanol at 25℃; for 3h; Stage #2: With sodium tetrahydroborate In methanol at 8℃; for 3.5h; 2.a A reactor is loaded under stirring with methanol ( 25 L ) and L- alaninamide hydrochloride ( 2.0 kg ) and the mixture is stirred at 23°C for 15 min (pH value 3.8); then, triethylamine (1.65 kg ) and 4-(2- fluorobenzyloxy)benzaldehyde ( 3.32 kg ), prepared according to Example 1.1, are added to the previously prepared solution adjusting the pH value to 8.3. The mixture is stirred at 25°C for 3 hours (pH 8 of the heterogeneous mixture) and cooled under stirring to 8 °C. Sodium borohydride (0.53 kg) is added, subdivided in twenty small portions in 3 hrs to the mixture under stirring, which is maintained for additional 30 min. The reaction mixture is concentrated under vacuum at 40°C until a residue (5.2 L) is obtained. Toluene (13.9 kg) and water (23.0 L) are added to the reaction mixture with stirring under nitrogen atmosphere. The mixture is heated up to 60 °C and kept at this temperature under stirring for 30 min. After separation of the phases, the organic phase is washed with water (6.4 L) at 60°C and the water is discharged. The organic phase is cooled to 18°C in two hours and kept under these conditions for 1 hour. The heterogeneous mixture is filtered and the solid is washed with toluene ( 3 x 1.0 L ) and dried at about 40°C under vacuum to yield 3.96 Kg of the (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide, Ib) with a HPLC purity of 99.4 (area%) determined according to the method of Example 25A and a C,O-dialkylated (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide content less than 0.005% by weight determined by HPLC, according to the method of Example 25B.
Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; (S)-alaninamide hydrochloride With triethylamine In methanol at 25℃; for 3h; Stage #2: With potassium hydroxide; sodium tetrahydroborate In methanol; water at 8℃; for 1h; 2.b The reaction is carried out under the same conditions described above with the exception that the sodium borohydride is previously dissolved in a mixture of methanol (about 5.8 g of methanol for each gram of sodium borohydride) and 30% sodium hydroxide (about 0.5 g of 30% sodium hydroxide for each gram of sodium borohydride) and then dropped in about 30 min. into the Schiff base blend keeping the temperature at 8°C.The obtained product has a HPLC purity degree of 99.5% determined according to Example 25A and a content of C,O-dialkylated impurity less than 0.005% by weight determined by HPLC according to Example 25B.

  • 2
  • [ 70627-20-2 ]
  • [ 71810-97-4 ]
  • [ 878379-14-7 ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; D-alaninamide hydrochloride With triethylamine at 40℃; for 4h; Molecular sieve; Stage #2: With sodium tetrahydroborate at 10 - 20℃; for 6.25h; 1 Example 1 (R) -2- [4- (2-fluorobenzyloxy)benzylamino]propanamide To 50 ml of dry methanol with bubbling in (R) alaninamide hydrochloride (1.37 g, 11 mmol) , 4-(2- fluorobenzyloxy)benzaldehyde (2.3 g 10 mmol), triethylamine (1,12 g, 11 mmol) and Ig of 3-A molecular sieves were added and the mixture was stirred for 4 h at 40 0C. The temperature was then lowered to 10 0C and sodium borohydryde (0.19 g, 5 mmol) was added in 15'. The reaction mixture was stirred for βh at room temperature, then it was filtered and evaporated to dryness under vacuo. The residue was taken up with water and toluene at 60 0C, and the organic phase was washed twice with warm water and dried at the same temperature with anhydrous sodium sulphate. The solution was filtered, and gradually cooled at 10 0C. The precipitate was filtered, washed with a small amount of cooled toluene and dried under vacuum to give 2,69 g (89.0% yield) of white crystals.
30.3% Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; D-alaninamide hydrochloride With triethylamine In methanol at 20 - 40℃; for 4h; Stage #2: With sodium tetrahydroborate In methanol at 10 - 20℃; for 6.25h; 23.3.a; 23.3.a1 In a 250 mL glass reactor, dry methanol 109 mL), containing 0.01% water, (pH of the mixture = 7.30 ) D-alanimamide hydrochloride ( 3 g; 24 mmol ) (Nova Biochem A36136821) (pH of the mixture = 3.98), , triethylamine (2.43 g; 24 mmol), 4-(2-fluorobenzyloxy)benzaldehyde (5.06 g, 22 mmol) (pH of the mixture = 8.60), prepared as described in Example (23.1a) with GC purity 94.21 (area %, see example 24A) and a content of 3- (2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.39% by weigth determined by G. C; see Example 24B, and 3A° molecular sieves (2.19 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40°C and stirred at this temperature for 4 h. The reaction temperature is then lowered to 10°C (pH of the mixture 8.24) and sodium borohydride (0.42g, 11 mmol) is added portion wise in 15 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at room temperature. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (80 mL) and toluene (70 mL) at 60°C, the organic phase is separated and added with water (80 mL). The two phases mixture is warmed up to 60°C under stirring. The organic phase is separated and added with water (80 mL). The two phases mixture is warmed up to 60°C under stirring. The organic phase is dried at 60°C over anhydrous sodium sulphate. The aqueous phases are combined together (solution A, about 240 mL). The toluenic mixture is filtered, and the solution is gradually cooled to 10°C. The mixture is kept under stirring and under nitrogen at 10°C for 3 hours. The mixture is filtered and the solid is washed with cold (10°C) toluene (10 mL), dried under vacuum at room temperature to provide 2.13 g (7.1 mmol; 32% yield) of (R)-2-[4-(2-fluorobenzyloxy)benzylamino] propanamide (I'b) as white crystals.The product has 98.00 (area %, see Example 25A) HPLC purity and a content of (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)- benzylamino]propanamide (Il'b) of 0.15% by weight determined by HPLC(see Example 25B).Enantiomeric ratio R: S = 99.6: 0.4 as determined with a chiral HPLC column (area %, see Example 26B).The toluenic mother liquor and the toluenic washing are combined together and the solution is concentrated, under vacuum, in a rotary evaporator to provide a yellow residue (1.97 g).The residue is dissolved in methanol (30 mL) and the known species present in solution are determined quantitatively vs. external standard byHPLC (see Example 25A): (i?)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) (0.81 g; 2.7 mmol) ;4-(2-fluorobenzyloxy)benzaldehyde (0.16 g; 0.7 mmol);4-(2-fluorobenzyloxy)benzyl alcohol (0.53 g: 2.2 mmol) and others non quantified impurities. (I'b) HPLC purity is 28.65% (area %, see Example 25A)Aqueous solution A is evaporated in a rotary evaporator, under vacuum, to residue. The residue is suspended in methanol (30 mL), filtered, the solvent evaporated under vacuum to residue (4.5 g). The residue is dissolved in methanol (30 mL) and the known species present in solution are determined quantively vs. external standard by HPLC (see Example 25A):(i?)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) (0.69 g; 2.3 mmol) ;4-(2-fluorobenzyloxy)benzaldehyde (0.07 g; 0.3 mmol);4-(2-fluorobenzyloxy)benzylalcohol (0.06 g: 0.2 mmol) and others non quantified impurities.(I'b) HPLC purity is 53.87% (area %, see Example 25A).As per above, the overall quantity of (I'b) produced is 3.63 g; 12.1 mmol;55% yield. The mass balance accounts for about 90 % of the charged 4-(2- fluorobenzyloxy)benzaldehyde .; The preparation described above has been repeated on a larger scale as follows: al) In a 50 L glass reactor, dry methanol 21.43 L, containing 0.01% water, D-alaninamide hydrochloride (589.9 g; 4.72 mol), triethylamine (477.8 g; 4.72 mol) 4-(2-fluorobenzyloxy)benzaldheyde (1000 g, 4.33 mol) prepared as described in Example 23.1a) with GC purity 93.20 (area %, see Example 24A) and a content of 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.43% by weigth determined by GC (see Example 24B), and 3A° molecular sieves (430.62 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40°C and stirred at this temperature for 4 hours. The reaction temperature is then lowered to 10°C and sodium borohydride (82.58g, 2.16 mol) is added portion wise in 30 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at 20+/-2 °C. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (16 L) and toluene (14 L) at 60°C, the organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60°C +/- 2 under stirring. The organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60°C+/- 2 under stirring. The organic phase is dried by azeotropic distillation at about 60°C under vacuum. The aqueous phases are combined together (solution A, about 50 L). The toluenic solution is gradually cooled to 10°C. The mixture is kept under stirring and under nitrogen at 10°C +/- 2 for 4 hours. The mixture is filtered and the cake is washed with cold (10°C) toluene (2 L), dried under vacuum at room temperature to provide 393.3 g (1.31 mol; 30.3% yield) of (R)-2-[4-(2-fluorobenzyloxy)benzylamino] propanamide (I'b) as white solid. The product has 97.70 (area %, see Example 25A) HPLC purity and a content of (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)- benzylamino]propanamide (Il'b) of 0.16% by weight determined by HPLC (see Example 25B).Enantiomeric ratio R: S = 99.5: 0.5 (area %, see Example 26B) as determined with a chiral HPLC column.
Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; D-alaninamide hydrochloride With triethylamine In methanol at 25℃; for 3h; Stage #2: With sodium tetrahydroborate In methanol at 8℃; for 3.5h; 5.a R)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide (I'b) A reactor is loaded under stirring with methanol (28 L) and D-alaninamide hydrochloride (2.1 kg) and the mixture is stirred at 23°C for 15 min; then, triethylamine (1.65 kg) and 4-(2-fluorobenzyloxy)benzaldehyde (3.30 kg), prepared according to Example 1.1, are added to the previously prepared solution. The mixture is stirred at 25°C for 3 hours and cooled under stirring to 8 °C. Sodium borohydride (0.50 kg) is added in small portion in 3 hours under stirring and the mixture is stirred for additional 30 min. The reaction mixture is concentrated under vacuum at 40°C until a residue (5.0 L) and then toluene (14 kg) and water (25.0 L) are added to the reaction mixture under stirring under nitrogen. The mixture is heated up to 60 °C and kept at this temperature under stirring for 30 min. After separation of the phases, the organic phase is washed with water (7.0 L) at 60°C and the water is discharged. The organic phase is cooled to 18°C in two hours and kept under these conditions for 1 hour. The heterogeneous mixture is filtered and the solid is washed with toluene ( 3 x 1.2 L ) and dried at about 40°C under vacuum to provide 3.90 Kg of (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) with a HPLC purity of 99.9 (area%) determined according to the method of Example 25A and a C,O-dialkylated (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)- benzylamino]propanamide content less than 0.005% by weight determined by HPLC, according to the method of Example 25B.
  • 3
  • [ 70627-20-2 ]
  • [ 71810-97-4 ]
  • [ 1161738-33-5 ]
YieldReaction ConditionsOperation in experiment
91% With triethylamine In methanol at 20℃; for 1h; 7.a (R)-2-[4-(2-Fluorobenzyloxy)benzylideneamino]propanamide (Ill'b) To a suspension of 4-(2-fluorobenzyloxy)benzaldehyde (60.0 g, 0.26 mol), prepared as in the Example 1.1 and D-alaninamide hydrochloride (35.7 g, 0.29 mol) in methanol (280 mL), triethylamine (29.1 g, 0.29 mol) is added at room temperature with stirring under nitrogen atmosphere. Stirring is maintained for one additional hour.The solution is then seeded with a few mg of (R) -2- [4- (2- fluorobenzyloxy)benzylideneamino]propanamide, the temperature is lowered to 5- 10 °C and the stirring continued for 2 hours. The solid is collected by filtration and washed with methanol at 0 °C.After drying it at reduced pressure, the title compound is obtained in 91% yield with m. p. 121 °C (capillary).1H-NMR: (CDCl3, 300 MHz, 298K) δ (ppm, with respect to TMS): 1.46 (3H, d, J= 7.0 Hz, CH3); 3.91 (IH, q, J= 7.0 Hz, CH-CO); 5, 17 (2H, s, O-CH2);7,02 (2H, d, J=8,9 Hz aromatic H ortho to O-CH2 ); 7.09 (IH, ddd, JH F=9,78 Hz Jorto= 8,55 Hz Jmeta= 1 ,23 Hz aromatic H ortho to F); 7, 15 (IH, dt,Jorto= 7,35 Hz Jmeta= 1 ,23 Hz aromatic H para to F); 7,27-7,40 (IH, m, aromatic H para to CH2); 7,48 (IH, dt, JOrto= JH F= 7,35 Hz Jmeta= 1 ,53 Hz aromatic H ortho to CH2); 7,71 (2H, d, J=8,9 Hz aromatic H ortho to CH=N);8, 17 (IH, s, C=N)13C-NMR: (CDCl3, 75.4 MHz, 298K) δ (ppm): 21.4 (CH3); 63.8 (OCH2); 68.4 (H2NCOCH); 1 15.0 (d, Jc F= 22.4 Hz, aromatic CH), 1 15.5 (d, Jc F= 20.7 Hz, aromatic CH); 123.7 (d, Jc F= 14.4 Hz, quaternary aromatic C); 124.5 (bd, aromatic CH ); 129.0 (quaternary aromatic C); 129.8 (bd, aromatic CH); 130.1 (bd, 2 aromatic CH); 160.5 (d, Jc F= 246.4 Hz, quaternary aromatic C); 161.1 (aromatic C-O); 161.1 (C=N); 176.9 (CONH2)
  • 4
  • [ 70627-20-2 ]
  • [ 80222-96-4 ]
  • [ 878379-14-7 ]
  • [ 133865-88-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-((2-fluorobenzyl)oxy)benzaldehyde; 2-aminopropanamide hydrochloride With triethylamine In methanol at 25℃; for 12h; Stage #2: With sodium hydroxide; sodium tetrahydroborate In methanol; water at 10℃; for 1h; 7A.a Methanol (54 mL) and (R,S)alaninamide hydrochloride (10.09 g, 82 mmol) are charged into a 250 mL glass reactor and anhydrous triethylamine (11.36 mL, 96 mmol) is added drop wise at 25° C.4-(2-fluorobenzyloxy)benzaldehyde (15.99 g, 69 mmol) prepared in Example1.6 is added in about 10 min and the mixture is stirred for 12 hours at 25°C (mixture A).In a second reactor (50 mL), methanol (20 mL) and sodium hydroxide 30% in water (1.3 g) are mixed under stirring and the temperature is lowered to0.6 °C. Sodium borohydride powder (2.61 g, 69 mmol) is added, in portions, to the solution at 1 °C. The mixture is stirred for 2 hours at 1°C under nitrogen (mixture B) .Mixture B is added, under stirring and under nitrogen, in about 30 min to the above mixture A, keeping the temperature at 10 °C.The reaction mixture is stirred for 30 min at 10° C and concentrated under vacuum to a 20 mL residual volume. Toluene (70 mL) and water (120 mL) are added, under stirring and under nitrogen, to the residue and the mixture is heated up to 60-65 °C. The organic phase is separated and added with water (20 mL) and the mixture stirred at 60-65 °C.The organic phase is separated and cooled gradually to about 7 °C and kept under these conditions for 3 hours.The mixture is filtered and the solid is washed with toluene (3x5 mL) to provide, after drying at reduced pressure, (R,S) 2-[4-(2- fluorobenzyloxy)benzylamino]propanamide (13.59 g); 65.2% yield.The HPLC purity of the product is 97.73% (area %, see Example 25A) and the content of C,O-dialkylated (R,S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide is 0.020 % by weight (see Example 25B).(R,S)ralfinamide thus obtained is shown to be a mixture of enantiomersS:R=52.3:47.7 (area %, see Example 26A) by a chiral HPLC column.
  • 5
  • [ 7324-05-2 ]
  • [ 70627-20-2 ]
  • [ 878379-14-7 ]
  • [ 133865-88-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: L-alanine amide; 4-((2-fluorobenzyl)oxy)benzaldehyde In methanol at 20℃; for 20h; Stage #2: With sodium tetrahydroborate In methanol at 6 - 10℃; for 12h; 4.a In a round bottom flask 21.1 g of L-alaninamide is dissolved in 320 g (about 405 mL) of methanol.After 15 min. at 20°C, 48.8 g of 4-(2-fluorobenzyloxy)benzaldehyde, prepared according to Example 1.1 , is added and the mixture is stirred at room temperature for 20 hours. The mixture is cooled to 8 +/- 2°C and 8 g of solid NaBH4 are added portion wise to the mixture keeping the temperature at 8 +/- 2 °C.The reaction mixture is stirred for at least 12 hours then concentrated to a minimum volume.Toluene (248 mL) and water (355 mL) are added and the biphasic mixture is stirred at 70°C and then the organic layer is separated.The organic solution is washed with water (70 mL) at 70°C then cooled at room temperature obtaining a suspension which is filtered and washed with toluene.The solid is dried at 40°C under vacuum, yielding 47.7 g (74.4% yield) of the title product, as white powder.The HPLC purity of the obtained product is 95.85 (area %, see Example25A) and a content of C,O-dialkylated (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide less than 0.005% by weight(see Example 25B). The R/ S enantiomeric ratio of ralfinamide determined with a chiral HPLC column is 52.5/47.5 (area %, see Example 26A).A further control of the iminoalkylation reaction course shows that the racemization occurs during this step.
  • 6
  • [ 70627-20-2 ]
  • [ 202825-45-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triethylamine / methanol / 1 h / 20 - 25 °C 1.2: 5 h / 20 - 35 °C / 3750.38 Torr 2.1: isopropyl alcohol / 3.25 - 3.5 h / 15 - 55 °C
  • 7
  • [ 70627-20-2 ]
  • [ 10557-21-8 ]
  • [ 3037881-62-9 ]
YieldReaction ConditionsOperation in experiment
15.63% With ammonium acetate In methanol at 20℃; for 16h; 2.2 Step 2 To a stirred solution of 4-((2-fluorobenzyl)oxy)benzaldehyde (0.150 g, 0.65 mmol, 1.0 eq) in methanol (2.5 mL) was added 1-(4-chlorophenyl) propane-1,2-dione (0.118 g, 0.65 mmol, 1.0 eq) and ammonium acetate (0.250 g, 3.2 mmol, 5.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete conversion of starting material, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer was dehydrated with Na2SO4, concentrated under reduced pressure to get the crude product, which was purified by Prep HPLC using 0.1% TFA in water/acetonitrile, followed by lyophilized the product fraction to give 2-(4-(benzyloxy)phenyl)-5-(4-chlorophenyl)-4-methyl-1H-imidazole as a white amorphous solid (0.040 g, 15.63 % yield).m/z=393[M+H]+,1H NMR (400 MHz, DMSO d6) 12.32 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 7.60 (d, J=6.0 Hz, 1H), 7.46 (d, J=6.0 Hz, 3H), 7.30 - 7.27 (m, 2H), 7.14 (d, J=8.8 Hz, 2H), 5.20 (s, 2H), 2.47 (s, 3H).
 

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