4-(Phenylmethyl) hydrogen L-aspartate

Crystalline

L-aspartic acid beta-benzyl ester is an aspartic acid derivative.

In a 500mL beaker by adding 100mL of anhydrous ether, and then slowly add 20mL concentrated sulfuric acid, while the side of the edge of the stirring, such as coldBut to room temperature, Add 150mL benzyl alcohol, stir well, The ether was removed under reduced pressure and then 26 g of aspartic acid was added in 5 batchesTo the reaction flask. Room temperature stir the reaction 24h, Then add 300 mL of 95percent ethanol and drop 80 mL with a dropping funnelPyridine, edge dripping vigorously stirring, and then frozen through the refrigerator overnight, filter to get solid, solid 80 ethanol stirring dissolved, heatFiltered, the filtrate was frozen for 8 h, filtered and lyophilized to obtain pure β-aspartic acid benzyl ester (90percent yield).EXAMPLE 3 L-Aspartic acid (1b) (50 g, 0.38 mol), benzyl alcohol (125 g, 1.16 mol), a mixture of concentrated sulfuric acid (40.5 g) and water (10 g) were mixed in a water bath at 70 °C for 0.5 h to give a clear solution, which was stirred for s further 2 h. The resulting solution was evaporated in vacuo to an oily product, which was added to a cold solution containing sodium hydrogen carbonate (70 g) and water (250 mL) at 0 °C. The obtained cooled solution was mixed with ether (150 mL) to give a precipitate, which was filtered and washed with cold water to give another precipitate (88 g). This was recrystallized twice with water to give 34 g (41 percent). m.p. 218-219 °C (lit.23) 222 °C).70 percent aq. HClO4 (13, 5 g; 0, 134 mol) was dropped into a suspension of L-aspartic acid 4-(phenylmethyl) ester 4 (commercially available) (25 g; 0, 112 mol) in SuOAc (515 mL; 3, 822 mol) stirred at room temperature. After 18 h at room temperature the obtained clear solution was diluted with H2O (470 mL) and the phases were separated; the aqueous phase was extracted with EtOAc (2 x 235 mL). The organic phases were collected and washed with 5 percent aq. NaHCO3 (2 x 250 mL) and water (2 x 200 mL). The new aqueous phases were collected and extracted with EtOAc (3 x 100 mL). All organic phases were collected, dried over Na2SO4 and evaporated to obtain 5 (24, 12 g) as a colourless oil. Yield 77percent. MS: 280.2 (M+H), 302, 2 (M+Na). Elemental Analysis (for C15H21NO4): CaIc. C 64, 50; H 7, 58; N 5, 01. Found C 64, 40; H 7, 60; N 5, 17.A 70percent aqueous solution of HClO4 (0.930 mL; 10.75 mmol) was slowly added to a suspension of aspartic acid 4-phenylmethyl ester 15 (2.0 g; 8.95 mmol) in t-butyl acetate (50 mL). The mixture was then stirred for 36 h at room temperature. The reaction mixture was diluted with H2O (40 mL) and after separation the aqueous phase was extracted with EtOAc (3*15 mL). The combined organic phases were washed with 10percent aq Na2CO3 (50 mL) and H2O (50 mL), then dried (Na2SO4). The solvent was evaporated under reduced pressure to give 16 (1.4 g; 56percent) as a colorless oil. Rf=0.52 (EtOAc); HPLC Rt=14.4 min, 97percent (area percent); 1H NMR (CDCl3, 300 MHz, 298 K): delta 7.42-7.23 (5H, m, Ph), 5.12 (2H, br s, CH2Ph), 3.73 (1H, dd, J1=7.0 Hz, J2=4.9 Hz, CH-N), 2.81 (1H, dd, J1=16.5 Hz, J2=4.9 Hz, CH2), 2.73 (1H, dd, J1=16.8 Hz, J2=7.0 Hz, CH2), 2.68 (2H, br s, NH2), 1.40 (9H, s, tBu); 13C NMR (CDCl3, 75.6 MHz, 298 K): delta 173.1 (C), 171.2 (C), 135.7 (C), 128.6 (CH), 128.4 (2*CH), 81.7 (C), 66.6 (CH2), 51.8 (CH), 39.0 (CH2), 28.0 (CH3); [alpha]D20 +16.0 (c 0.57, CHCl3) (lit. 56 +10.9, c 0.57, CHCl3); numax (KBr): 3350, 2974, 2942, 1728, 1736, 1667, 1368, 1360, 1250, 1151, 750, 736, 697; ESI/MS m/z calcd for: [C15H21NO4+H]+: 280.15; found: 280.05.In a 500mL beaker by adding 100mL of anhydrous ether, and then slowly add 20mL concentrated sulfuric acid, while the side of the edge of the stirring, such as coldBut to room temperature, Add 150mL benzyl alcohol, stir well, The ether was removed under reduced pressure and then 26 g of aspartic acid was added in 5 batchesTo the reaction flask. Room temperature stir the reaction 24h, Then add 300 mL of 95% ethanol and drop 80 mL with a dropping funnelPyridine, edge dripping vigorously stirring, and then frozen through the refrigerator overnight, filter to get solid, solid 80 ethanol stirring dissolved, heatFiltered, the filtrate was frozen for 8 h, filtered and lyophilized to obtain pure beta-aspartic acid benzyl ester (90% yield).EXAMPLE 3 Preparation of beta-benzyl L-aspartate 100 g (0.75 mol, 1 eq.) of L-aspartic acid and 162 g (1.5 mol, 2 eq.) of benzyl alcohol are introduced into a fitted-out 1 litre reactor and the mixture is stirred. 86.4 g (0.9 mol, 1.2 eq.) of methanesulphonic acid are subsequently introduced gradually while allowing the temperature to rise.The temperature is brought by heating to 60 C., stirring of the mixture is continued for 12 hours and then the mixture is cooled to 40 C. 200 ml of water are subsequently added, then 300 ml of ethanol are added and subsequently 95 ml of 22 B aqueous ammonia are added, so as to precipitate the ester at a PH of 6.5-7. The mixture is subsequently heated to 60 C. and is stirred at this temperature for 2 hours to improve the crystalline form of the product. It is cooled to a temperature of 5 C.-10 C. The crystalline precipitate is filtered off and washed twice with 100 ml of ethanol and 3 times with 100 ml of water. A wet product is collected and is dried under vacuum. 108 g (64% yield) of beta-benzyl L-aspartate are thus obtained, the characteristics of which are as follows: Appearance: white powder. Melting point: 212 C. [alpha]D20: +27.6 (read at 1% in HCl 1N).L-Aspartic acid (1b) (50 g, 0.38 mol), benzyl alcohol (125 g, 1.16 mol), a mixture of concentrated sulfuric acid (40.5 g) and water (10 g) were mixed in a water bath at 70 C for 0.5 h to give a clear solution, which was stirred for s further 2 h. The resulting solution was evaporated in vacuo to an oily product, which was added to a cold solution containing sodium hydrogen carbonate (70 g) and water (250 mL) at 0 C. The obtained cooled solution was mixed with ether (150 mL) to give a precipitate, which was filtered and washed with cold water to give another precipitate (88 g). This was recrystallized twice with water to give 34 g (41 %). m.p. 218-219 C (lit.23) 222 C).A solution of 167 ml benzyl alcohol, 167 ml diethyl ether and 16.7 ml conc. H2SO4 prepared at room temperaturewas evaporated without heating, by removing diethyl ether. To this solution at room temperature under vigorous stirring22.2 g (166.8 mmol) H-Asp-OH was added in small portions. The resulting suspension was stirred vigorously at 20Cuntil a completely homogeneous clear solution was obtained which was allowed to stand at room temperature for 2 days.Then 335 ml ethyl alcohol and 85 ml pyridine were added under vigorous stirring. The reaction mixture was stirred at20C for 1 h. A gradual formation of a white finely dispersed precipitate took place. The solution containing the precipitatewas allowed to stand at 0C for 1 day. Then the precipitate was filtered off and washed with water. The resulting crystallinemass was recrystallized from 335 ml water supplemented with 335 ml pyridine. The recrystallization was performed froma hot solution (80-85C) by allowing it to cool to room temperature and to stand for 1 day. The resulting crystals werefiltered off, washed with acetone and dried to yield 10.5 g (28%) of the product as white crystals. Rf 0.28 (E), Rf 0.15 (I);m.p. 214-215C. 1H NMR (DMSO-d6 - CF3COOD): 2.95 and 2.99 (2H, 2d, CH2 Asp), 4.24 (1H, m, CH Asp), 5.14 (2H, s, -CH2C6H5), 7.35 (5H, m, -CH2C6H5), 8.42 (av. s, NH2 amide, OH).Take 500 m L single mouth bottle, Add 100 mL of anhydrous ether, Then add 10 mL of H2SO4 (98%), While adding edge mixing, After cooling to room temperature, Add 100 mL of benzyl alcohol (1 mol, 1.04 g / mL, 108.06 g / mol)Stir well and spin off the ether.A total of 13.3 g (0.1 mol, 133.04 g / mol) of L-aspartic acid was added in multiple portions.After stirring for 24 h at room temperature, 200 mL of 95% ethanol was added, and then 50 mL of pyridine was added dropwise with vigorous stirring.Then placed in the refrigerator frozen overnight, suction filtration, the filter cake was washed with ultrapure water several times, and then washed twice with anhydrous ether.Drained, placed in 500 mL flask, add 300 ~ 400 mL of water, 70 heating and stirring to dissolve, water can be added to 400 ~ 500 mL, all dissolved within 1.5 h, the solution becomes clear.Heat filtration, the filtrate refrigerated overnight. Filtered and recrystallized to obtain pure aspartic acid benzyl ester.L-Aspartic acid (1.33 g, 10 mmol) and benzyl alcohol (1.08 g, 10 mmol) were disolved in 60% sulfuric acid (1.65 g) and heated at 70 C for 45 min. Clear gel gained by vacuum concentration at 70 C was neutralized using sodium bicarbonate and the white sample thus obtained was dried over a period of 16 h. The sample (0.60 g)was mixed with salicylaldehyde (0.24 g, 2 mmol) in methanol and the mixture was heated at 40 for 3 h. Copper(II) acetate monohydrate (0.20 g, 1 mmol) was added, the mixture was stirred for an additional 3 h, and a green sample was then obtained by concentration. Complex 3 was recrystallized from MeOH.Synthesis of benzyl beta-aspartate is first synthesized. A 500 mL single-mouth eggplant-shaped flask was taken, and 100 mL of anhydrous diethyl ether, 12 mL of H2SO4 (98%) and 120 mL of benzyl alcohol (1.2 mol, 1.04 g/mL, 108.06 g/mol) were successively added, and the mixture was stirred and evaporated to remove diethyl ether. A total of 16 g (0.12 mol, 133.04 g/mol) of L-aspartic acid was added in three portions with stirring. After stirring for 12 h at room temperature, it was diluted with 240 mL of 95% ethanol, and then 60 mL of pyridine was added dropwise to precipitate a white precipitate. After freezing in a refrigerator overnight, the solid was withdrawn and washed with pure water. The obtained crude product was recrystallized twice with pure water at 80 C to give purified benzyl aspartate.(1) Prepare a single-mouth bottle (500m L), add 100mL of anhydrous ether, Add 10 mL of H2SO4 (98%) slowly and stir vigorously while adding dropwise.After cooling to room temperature, 100 mL of benzyl alcohol was added, and after stirring well, the ether was distilled off by a rotary evaporator;(2) Then add 13.3 g of L-aspartic acid to the reaction flask in three portions;Stir the reaction evenly at room temperature for 24 h.Then add 200 mL of 95% ethanol, and add 50 mL of pyridine dropwise with a dropping funnel, and vigorously stir while dropping;Then, it was frozen overnight in a refrigerator, and the solid after the reaction was stirred and dissolved at 80 C.Heat filtration, the filtrate was refrigerated overnight, and the solution was recrystallized twice as described above.After lyophilization, pure beta-benzyl-L-aspartate is obtained.The reaction process is as follows:

Used in biochemical reagents and pharmaceutical intermediates.

Molecular Weight:223.22
XLogP3:-2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:223.08445790
Monoisotopic Mass:223.08445790
Topological Polar Surface Area:89.6
Heavy Atom Count:16
Complexity:248
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes