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A solution of L-alanine amide hydrochloride 84. 41 g (0.68 mol) was added to the reaction flask,Triethylamine 171 · 42 g (l. 69 mol)Methanol 1300ml, room temperature stirring 30min,Then add 4- (3-fluorobenzyloxy) benzaldehyde 130. llg (0. 56 mol) and stirred at room temperature for 2 h.Then add KBH4 182. 71g (3. 39mol) and stir well overnight.After completion of the reaction, the reaction solution was concentrated to dryness,Add 1300ml water room temperature stirring 1h, pumping filter,40 ° C in vacuo for 4 h to give a white solid (S) -2- [4- (3-fluorobenzyloxy)Benzylamino] propanamide 163. 92 g, yield: 96.0percent. HPLC purity: 99.04percent.
94.8%
With hydrogen In methanol at 35℃; for 1 h;
b) (S)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (Ia)An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene- amino] propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50percent H2O) Pt/C 5percent (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35 0C for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40 0C, until two clear phases are obtained. These two phases are separated and the aqueous layer is <n="36"/>extracted with 50 mL of ethyl acetate at 40 0C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20 0C. The solid formed is collected by filtration, washed with n-hetpane (15 mL) and dried under reduced pressure to give 15.2 g (94.8percent yield) of safinamide with a HPLC purity of 99.8 (area percent, see Example 17A)and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)- benzylamino]propanamide lower than 0.005percent by weight measured by HPLC (see Example 17B).
89.2%
With sodium tetrahydroborate In methanol at 2 - 5℃; for 2.33333 h;
A mixture of (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide (III a) (150 g), prepared as described in Example 16a), and methanol (900 mL) is cooled under stirring to 2-5°C. Sodium borohydride (19.0 g) is added in small portions in 2 hours to the previously prepared cold mixture keeping the temperature below 5°C. The mixture is then stirred for additional 20 min at 5°C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to give 135 g (89.2percent yield) of (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (Ia) with a HPLC purity of 98.8 (areapercent determined according to the method of Example 25A and a C,O-dialkylated (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propanamide content of 0.005percent by weight determined by HPLC, according to the method of Example 25B.
87.7%
With palladium 10% on activated carbon; hydrogen In methanol at 35℃; for 5 h;
(15.4 g, 110 mmol) of (S) -2-aminopropionic acid methyl ester hydrochloride,(22.0 g (100 mmol) of 4- (3-fluorobenzyloxy) benzaldehyde (SFXA01) and 11.2 g (111.5 mmol) of triethylamine were added to 200 ml of anhydrous methanol,Adding 20.0g molecular sieve, stirring at room temperature for 1.2h, filtering, adding 10percent Pd / C2.4, adding hydrogen,The reaction was carried out at 35 ° C for 5 h, filtered, and the filter cake was washed with methanol (20 ml x 3)The filtrate and the washings were combined and the solvent was distilled off under reduced pressure. The residue was recrystallized from toluene,To a solution of 26.5 g (87.7percent) of white solid (S) -2- [4- (3-fluorobenzyloxy) benzylamino] propionamide (SFXA02), mp 114.7 ~115.5 ° C
Reference：
[1] Patent: CN106565520, 2017, A, . Location in patent: Paragraph 0016
[2] Patent: WO2007/147491, 2007, A1, . Location in patent: Page/Page column 34-35
[3] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 69
[4] Patent: CN106220525, 2016, A, . Location in patent: Paragraph 0015; 0016; 0019
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[ 66742-57-2 ]
[ 33208-99-0 ]
[ 133865-89-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With triethylamine In methanol at 30℃; for 0.166667 h; Stage #2: at 20℃; for 3.5 h; Stage #3: With sodium tetrahydroborate In methanol at 5℃; for 2 h;
In a 2 1 four necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, L-alaninamide hydrochloride (124.6 g, 0.49 mol) and methanol (840 mL) are charged and stirred for 15 min at 20 °C. Triethylamine (49.5 g, 0.49 mol) is added at such a rate that the temperature remains below 30 °C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (100 g) , prepared in Es. 10 b), is added portion wise in about 30 min. After stirring for 3 hours at 20 °C, the mixture is cooled to 5 °C and solid NaBIHU (16.4 g, 0.44 mol) is added in ten portion with caution over a period of 1.5 hours. After the end of the addition, the mixture is stirred for 30 min at 5 °C. The mixture is concentrated at reduced pressure to a volume of 100- 150 mL. To the residue, toluene (550 mL) and water (750 mL) are added and the temperature raised to 75 °C. After stirring for 30 min phases are separated and the organic phase is washed with water (140 mL). After phase separation, the organic phase is cooled to 68 °C, seeded and stirred at this temperature for 1 hour. The mixture is cooled to 20 °C in about 2 hours and stirred at this temperature for 2 hours. The solid is isolated by filtration, washed with toluene (2x40 mL) and dried under vacuum to yield 1 18 g of white solid; 90percent yield.The HPLC purity of the obtained product is 99.95 (area percent, see Example 25A) and the content of C,O-dialkylated (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propanamide is 0.008percent by weight (see Example 25B).The enantiomeric purity of safinamide determined with a chiral HPLC column is 100percent (area percent, see Example 27A).1H-NMR (D2O) (Bruker A V300) δ (ppm, with respect to H2O at 4.7 ppm): <n="63"/>1.43 (3H, d, J = 7 Hz, CH3); 2.66 (3H, s, CH3SO3H); 3.87 (IH, q, J = 7 Hz, H-2); 3.97 (2H, bs, CH2NR); 4.89 (2H, s, CH2OR); 6.88 and 7.23 (4H, AA'XX' aromatic p-disubstituted system,; 6.90 il .11 (4H, aromatic H)13C-NMR (D2O) (Bruker AV300) δ ppm: 15.68 (CH3); 38.27 (CH3SO3H); 48.99 (CH2NR); 54.81 (CH); 69.00 (OCH2); 1 14.15 (d, Jc F = 21 Hz, aromatic CH); 1 14.76 (d, Jc F = 20 Hz, aromatic CH); 1 15.38 (aromatic CH); 123.06 (d, Jc F = 24 Hz, aromatic CH); 123.24; 130.29 (d, Jc F = 6 Hz, aromatic CH); 131.54 (aromatic CH); 138.76 (d, JC F = 7 Hz, aromatic CH); 158.52; 162.89 (d, Jc F = 245 Hz, C-F); 171.92 (CO)
90%
Stage #1: With triethylamine In methanol at 20 - 25℃; for 1 h; Stage #2: With hydrogen In methanol at 20 - 35℃; for 5 h;
EXAMPLE 6 <n="32"/>Preparation of fS)-2-f4-(3-fluorobenzyloxy)benzylamino1propanamide (safinamide, Ia) of high purity degree (one pot reaction)An autoclave is loaded with, 4-(3-fluorobenzyloxy) benzaldehyde (2.0 kg, 8.69 mol) prepared as in Example 4, 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 (7.1 kg) is added thereto.The mixture is stirred at 20-25 0C for 1 hour and, after seeding with few grams of (S)-2-[4-(-3-fluorobenzyloxy)benzylideneamino]propanamide, stirring is continued for additional 15 minutes. To the stirred heterogeneous mixture, methanol (1.8 kg) and, wet (50percent H2O) Pt/C 5percent (Engelhard cod. Escat 22 )(0.3 kg) are then added, at 20-250C. The air is purged from the autoclave with nitrogen and then hydrogen is introduced at 5.0 bars. After 5 hours at 30-350C, the mixture is cooled to 15 0C, methanol (4.8 kg) is added and the mixture is heated to 40-45 0C; finally the solid is filtered out and washed with methanol (1.6 kg).The solvent is eliminated under reduced pressure approximately at 30 0C and then a mixture of ethyl acetate (23.0 kg) and water (18.0 kg) is added to the residue. After stirring for 15 minutes, the aqueous phase is separated and extracted with ethyl acetate (7.0 kg). The collected organic phases are concentrated until a residue of approximately 6.0 kg is obtained. To this residue n-heptane (10.8 kg) is added and the mixture is stirred at 20 0C for about 2 hours. The solid is then collected by filtration and washed with n-heptane. After drying the solid under reduced pressure, 2.41 kg (91.8percent yield) of the title compound are obtained with a HPLC purity of 98.4 (area percent, see Example 17A), and a content of C,O-dibenzylated (S)-2-[3-(3-fluorobenzyl)- 4-(3-fluorobenzyloxy)-ben2ylamino]propanamide) of 0.005percent by weight (see Example 17B). 6.2 Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino] propanamide (Ia) of high purity degree by hydroge nation at 1 barA mixture of (S)-2-[4-(2-fluorobenzyloxy)benzaldehyde, L-alaninamide hydrochloride and triethylamine is hydrogenated according to the same procedure of Example 6, but at 1 bar/ H2 instead of 5 bar/ H2. The yield of (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide is 90percent with a HPLC purity of 98.7 (area percent, see Example 17A) and a content of (S)- 2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzylamino]propanamide of0.005percent by weight determined by HPLC (see Example 17B ).
88.5%
Stage #1: With triethylamine In methanol at 30℃; for 0.166667 h; Stage #2: at 30℃; for 3.5 h; Stage #3: With sodium hydroxide; sodium tetrahydroborate In methanol; water at 5℃; for 2 h;
As an alternative procedure, the reduction is carried out by using a methanolic solution of NaBH4, instead of solid NaBH4. A methanolic solution of NaBH4 is prepared by adding under stirring and under nitrogen at 0 - 5 °C NaBH4 (16.4 g) to a mixture of methanol (12OmL) and NaOH 30percent aqueous solution (5.8mL).In a 2 L four necked round bottomed flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, L- alaninamide hydrochloride (124.6 g, 0.49 mol) and methanol (720 mL) are charged and stirred for 15 min at 20 °C. Triethylamine (49.5 g, 0.49 mol) is added at such a rate that the temperature remains below 30 °C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy) benzaldehyde (100 g), prepared in Example 1Ob)), is added portion wise in about 30 min. After stirring for 3 hours at 20 °C, the mixture is cooled to 5 °C and the previously prepared solution of NaBH4 is cautiously added through a dropping funnel over a period of 1.5 hours. After the end of the addition, the mixture is stirred for 30 min at 5 °C. The mixture is concentrated at reduced pressure to a volume of 100- 150 mL. To the residue, toluene (550 mL) and water (750 mL) are added and the temperature raised to 75 °C. After stirring for 30 min phases are separated and the organic phase is washed with water (140 mL). After phase separation, the organic phase is cooled to 68 °C, seeded and stirred at this temperature for 1 hour. The mixture is cooled to 20 °C in about 2 hours <n="64"/>and stirred at this temperature for 2 hours. The solid is isolated by filtration, washed with toluene (2x40 mL), dried at 40°C under vacuum: 116 g of white solid, 88.5percent yield.The HPLC purity of the product is 100.0 percent (area percent, see Example 25A) and the content of C,O-dialkylated (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propanamide is 0.009percent by weight (see Example 25B).The enantiomeric purity of safinamide determined with a chiral HPLC column is 100percent (area percent, see Example 27A).
72%
Stage #1: With triethylamine In methanol at 20 - 25℃; for 1 h; Stage #2: With hydrogen In methanol at 20 - 35℃; for 5 h;
6.1 Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino] propanamide (Ia) of high purity degree by using a Pd catalyst (S)-2-[4-(2-Fluorobenzyloxy)benzaldehyde (5g) in the presence of the corresponding amounts of L-alaninamide hydrochloride and triethylamine <n="33"/>is hydrogenated according to the same procedure of Example 6, by using wet (50percent H2O) Pd/C 10percent, instead of wet (50percent H2O) Pt/C 5percent, to produce Ia in a 72percent yield.
Stage #1: at 20 - 25℃; for 1 h; Stage #2: With hydrogen In methanol at 20 - 35℃; for 5 h;
6.3 Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino] propanamide (Ia) of high purity degree (one pot reaction) by using L- alaninamide base(S)-2-[4-(3-fluorobenzyloxy]benzaldehyde (1Og) is reacted according to the same procedure of Example 6, but using L-alaninamide base, instead of its hydrochloride and triethylamine. The yield of (S)-2-[4-(3- fluorobenzyloxy)benzylamino] propanamide is 92percent with a HPLC purity of 99.7 (area percent, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4- (3-fluorobenzyloxy)benzylamino]propanamide lower than 0.005percent by weight determined by HPLC (see Example 17B).
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